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15.16: Physical Evidence - Biology

15.16: Physical Evidence - Biology


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Fossils

Fossils provide solid evidence that organisms from the past are not the same as those found today, and fossils show a progression of evolution. For example, scientists have recovered highly detailed records showing the evolution of humans and horses (Figure 1b).

Anatomy and Embryology

Another type of evidence for evolution is the presence of structures in organisms that share the same basic form. For example, the bones in the appendages of a human, dog, bird, and whale all share the same overall construction (Figure 2) resulting from their origin in the appendages of a common ancestor. Over time, evolution led to changes in the shapes and sizes of these bones in different species, but they have maintained the same overall layout. Scientists call these synonymous parts homologous structures.

Some structures exist in organisms that have no apparent function at all, and appear to be residual parts from a past common ancestor. These unused structures without function are called vestigial structures. Some examples of vestigial structures are wings on flightless birds, leaves on some cacti, and hind leg bones in whales.

Visit this interactive site to guess which bones structures are homologous and which are analogous, and see examples of evolutionary adaptations to illustrate these concepts.

Another evidence of evolution is the convergence of form in organisms that share similar environments. For example, species of unrelated animals, such as the arctic fox and ptarmigan, living in the arctic region have been selected for seasonal white phenotypes during winter to blend with the snow and ice (Figure 3). These similarities occur not because of common ancestry, but because of similar selection pressures—the benefits of not being seen by predators.

Embryology, the study of the development of the anatomy of an organism to its adult form, also provides evidence of relatedness between now widely divergent groups of organisms. Mutational tweaking in the embryo can have such magnified consequences in the adult that embryo formation tends to be conserved. As a result, structures that are absent in some groups often appear in their embryonic forms and disappear by the time the adult or juvenile form is reached. For example, all vertebrate embryos, including humans, exhibit gill slits and tails at some point in their early development. These disappear in the adults of terrestrial groups but are maintained in adult forms of aquatic groups such as fish and some amphibians. Great ape embryos, including humans, have a tail structure during their development that is lost by the time of birth.

Learning Objectives

Since Darwin developed his ideas on descent with modification and the pressures of natural selection, a variety of evidence has been gathered supporting the theory of evolution. Fossil evidence shows the changes in lineages over millions of years, such as in hominids and horses. Studying anatomy allows scientists to identify homologous structures across diverse groups of related organisms, such as leg bones. Vestigial structures also offer clues to common ancestors. Using embryology, scientists can identify common ancestors through structures present only during development and not in the adult form.


Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.


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Preoperative Testing Before Noncardiac Surgery: Guidelines and Recommendations

This version of the article contains supplemental content.

Article Sections

Preoperative testing (e.g., chest radiography, electrocardiography, laboratory testing, urinalysis) is often performed before surgical procedures. These investigations can be helpful to stratify risk, direct anesthetic choices, and guide postoperative management, but often are obtained because of protocol rather than medical necessity. The decision to order preoperative tests should be guided by the patient's clinical history, comorbidities, and physical examination findings. Patients with signs or symptoms of active cardiovascular disease should be evaluated with appropriate testing, regardless of their preoperative status. Electrocardiography is recommended for patients undergoing high-risk surgery and those undergoing intermediate-risk surgery who have additional risk factors. Patients undergoing low-risk surgery do not require electrocardiography. Chest radiography is reasonable for patients at risk of postoperative pulmonary complications if the results would change perioperative management. Preoperative urinalysis is recommended for patients undergoing invasive urologic procedures and those undergoing implantation of foreign material. Electrolyte and creatinine testing should be performed in patients with underlying chronic disease and those taking medications that predispose them to electrolyte abnormalities or renal failure. Random glucose testing should be performed in patients at high risk of undiagnosed diabetes mellitus. In patients with diagnosed diabetes, A1C testing is recommended only if the result would change perioperative management. A complete blood count is indicated for patients with diseases that increase the risk of anemia or patients in whom significant perioperative blood loss is anticipated. Coagulation studies are reserved for patients with a history of bleeding or medical conditions that predispose them to bleeding, and for those taking anticoagulants. Patients in their usual state of health who are undergoing cataract surgery do not require preoperative testing.

The goal of preoperative evaluation is to identify and optimize conditions that increase perioperative morbidity and mortality. Historically, testing before noncardiac surgery involved a battery of standard tests applied to all patients (e.g., chest radiography, electrocardiography [ECG], laboratory testing, urinalysis). However, these tests often do not change perioperative management, may lead to follow-up testing with results that are often normal, and can unnecessarily delay surgery, all of which increase the cost of care. An extensive systematic review concluded that there was no evidence to support routine preoperative testing.1

More recent practice guidelines continue to recommend testing in select patients guided by a perioperative risk assessment based on pertinent clinical history and examination findings, although this recommendation is based primarily on expert opinion or low-level evidence.2 – 9 Many of the recommendations include wording such as 𠇌onsider testing if ” or “testing may be reasonable.” Recommendations are not always user-friendly. For example, the National Institute for Clinical Excellence guideline, which may be the most scientifically rigorous of the group, includes 36 tables organized via a flowchart that physicians may reference to make a decision for or against testing.8 Although the guideline is scholarly, its cumbersome nature renders it ineffective in a busy clinical setting.

Primary care physicians are in an ideal position to take an active role in the multidisciplinary, system-based approach to defining preoperative testing standards for their own institutions to provide high-quality, cost-effective health care. This article compares and contrasts key guidelines and the evidence they cite, and makes recommendations for the primary care physician evaluating the preoperative patient. Detailed charts outlining the individual guideline recommendations are available as an online appendix .

SORT: KEY RECOMMENDATIONS FOR PRACTICE

The decision to perform preoperative testing should be based on the history and physical examination findings, perioperative risk assessment, and clinical judgment.


References

Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). A comprehensive review of cancer.

Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).

Vong, S. & Kalluri, R. The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis. Genes Cancer 2, 1139–1145 (2011).

Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013). A good review of the tumour microenvironment.

Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3, 422–433 (2003).

Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

Pietras, K. & Ostman, A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324–1331 (2010).

Bhowmick, N. A. et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).

Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014). A review about CAFs and their likely heterogeneity.

Marsh, T., Pietras, K. & McAllister, S. S. Fibroblasts as architects of cancer pathogenesis. Biochim. Biophys. Acta 1832, 1070–1078 (2013).

Ostman, A. & Augsten, M. Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr. Opin. Genet. Dev. 19, 67–73 (2009).

Tampe, B. & Zeisberg, M. Contribution of genetics and epigenetics to progression of kidney fibrosis. Nephrol. Dial. Transpl. 29 (Suppl. 4), iv72–iv79 (2013).

Zeisberg, E. M. & Zeisberg, M. The role of promoter hypermethylation in fibroblast activation and fibrogenesis. J. Pathol. 229, 264–273 (2013).

Micallef, L. et al. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair 5, S5 (2012).

Ronnov-Jessen, L. & Petersen, O. W. Induction of α-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).

Paunescu, V. et al. Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J. Cell. Mol. Med. 15, 635–646 (2011). A comprehensive comparative analysis of MSCs and CAFs.

Sappino, A. P., Skalli, O., Jackson, B., Schurch, W. & Gabbiani, G. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int. J. Cancer 41, 707–712 (1988).

Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).

LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

Zeisberg, M., Strutz, F. & Muller, G. A. Role of fibroblast activation in inducing interstitial fibrosis. J. Nephrol. 13 (Suppl. 3), S111–S120 (2000).

Desmouliere, A., Darby, I. A. & Gabbiani, G. Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Lab. Invest. 83, 1689–1707 (2003).

Lajiness, J. D. & Conway, S. J. The dynamic role of cardiac fibroblasts in development and disease. J. Cardiovasc. Transl Res. 5, 739–748 (2012).

Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

Monaco, J. L. & Lawrence, W. T. Acute wound healing an overview. Clin. Plast. Surg. 30, 1–12 (2003).

Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

Bliss, L. A. et al. Use of postmortem human dura mater and scalp for deriving human fibroblast cultures. PLoS One 7, e45282 (2012).

Virchow, R. Die Cellularpathologie in lhrer Begruendung auf Physiologische und Pathologische Gewebelehre (ed. Hirschwald, A.) (Berlin, 1858).

Duvall, M. Atlas d'Embryologie. (ed. Masson, G.) (Paris, 1879).

Tarin, D. & Croft, C. B. Ultrastructural features of wound healing in mouse skin. J. Anat. 105, 189–190 (1969).

Gabbiani, G., Ryan, G. B. & Majne, G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27, 549–550 (1971).

Darby, I. A., Laverdet, B., Bonte, F. & Desmouliere, A. Fibroblasts and myofibroblasts in wound healing. Clin. Cosmet. Investigat. Dermatol. 7, 301–311 (2014).

Castor, C. W., Wilson, S. M., Heiss, P. R. & Seidman, J. C. Activation of lung connective tissue cells in vitro. Am. Rev. Respir. Dis. 120, 101–106 (1979).

Muller, G. A. & Rodemann, H. P. Characterization of human renal fibroblasts in health and disease: I. Immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am. J. Kidney Dis. 17, 680–683 (1991).

Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).

Parsonage, G. et al. A stromal address code defined by fibroblasts. Trends Immunol. 26, 150–156 (2005).

Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007). A study showing that MSC-derived CCL5 enhances breast cancer metastasis.

Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011). A study indicating that MSC-derived CAFs promote inflammation-induced gastric cancer progression and are characterized by global DNA hypomethylation and elevated expression of IL-6, WNT5A and bone morphogenetic protein 4 (BMP4).

Xu, J. et al. Contribution of bone marrow-derived fibrocytes to liver fibrosis. Hepatobiliary Surg. Nutr. 4, 34–47 (2015).

Raab, S., Klingenstein, M., Liebau, S. & Linta, L. A. Comparative view on human somatic cell sources for iPSC generation. Stem Cells Int. 2014, 768391 (2014).

Lorenz, K. et al. Multilineage differentiation potential of human dermal skin-derived fibroblasts. Exp. Dermatol. 17, 925–932 (2008).

Miyake, T. & Kalluri, R. Cardiac biology: cell plasticity helps hearts to repair. Nature 514, 575–576 (2014).

Ubil, E. et al. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature 514, 585–590 (2014).

Sriram, G., Bigliardi, P. L. & Bigliardi-Qi, M. Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. Eur. J. Cell Biol. 94, 483–512 (2015).

Driskell, R. R. & Watt, F. M. Understanding fibroblast heterogeneity in the skin. Trends Cell Biol. 25, 92–99 (2015).

Rodemann, H. P. & Muller, G. A. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am. J. Kidney Dis. 17, 684–686 (1991).

Simian, M. et al. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development 128, 3117–3131 (2001).

Wiseman, B. S. & Werb, Z. Stromal effects on mammary gland development and breast cancer. Science 296, 1046–1049 (2002).

Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).

Dulauroy, S., Di Carlo, S. E., Langa, F., Eberl, G. & Peduto, L. Lineage tracing and genetic ablation of ADAM12 + perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18, 1262–1270 (2012).

Hamburg-Shields, E., DiNuoscio, G. J., Mullin, N. K., Lafyatis, R. & Atit, R. P. Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes. J. Pathol. 235, 686–697 (2015).

Rock, J. R. et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl Acad. Sci. USA 108, E1475–E1483 (2011).

De Wever, O., Van Bockstal, M., Mareel, M., Hendrix, A. & Bracke, M. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin. Cancer Biol. 25, 33–46 (2014).

Dumont, N. et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15, 249–262 (2013).

Ryan, G. B. et al. Myofibroblasts in an avascular fibrous tissue. Lab. Invest. 29, 197–206 (1973).

Ryan, G. B. et al. Myofibroblasts in human granulation tissue. Hum. Pathol. 5, 55–67 (1974).

Tsukada, T., McNutt, M. A., Ross, R. & Gown, A. M. HHF35, a muscle actin-specific monoclonal antibody. II. Reactivity in normal, reactive, and neoplastic human tissues. Am. J. Pathol. 127, 389–402 (1987).

Schor, S. L., Schor, A. M., Grey, A. M. & Rushton, G. Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells. J. Cell Sci. 90, 391–399 (1988).

Durning, P., Schor, S. L. & Sellwood, R. A. Fibroblasts from patients with breast cancer show abnormal migratory behaviour in vitro. Lancet 2, 890–892 (1984).

Elenbaas, B. & Weinberg, R. A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp. Cell Res. 264, 169–184 (2001).

Lohr, M. et al. Transforming growth factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).

Aoyagi, Y. et al. Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br. J. Cancer 91, 1316–1326 (2004).

Ishii, G., Ochiai, A. & Neri, S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv. Drug Delivery Rev. 99, 186–196 (2015).

Bronzert, D. A. et al. Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc. Natl Acad. Sci. USA 84, 5763–5767 (1987).

Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

Dvorak, H. F., Form, D. M., Manseau, E. J. & Smith, B. D. Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J. Natl Cancer Inst. 73, 1195–1205 (1984).

Folkman, J. & Kalluri, R. Cancer without disease. Nature 427, 787 (2004). A concept piece proposing the cancer-restraining actions of desmoplasia and that cancer can exist without resulting in clinical disease.

Polyak, K. & Kalluri, R. The role of the microenvironment in mammary gland development and cancer. Cold Spring Harb. Perspect. Biol. 2, a003244 (2010).

Erez, N., Truitt, M., Olson, P., Arron, S. T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010). An interesting study indicating that CAFs aquire a pro-inflammatory gene expression programme in the early stages of neoplasia.

Dolberg, D. S., Hollingsworth, R., Hertle, M. & Bissell, M. J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).

Schuh, A. C., Keating, S. J., Monteclaro, F. S., Vogt, P. K. & Breitman, M. L. Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice. Nature 346, 756–760 (1990).

Li, J. et al. Idiopathic pulmonary fibrosis will increase the risk of lung cancer. Chinese Med. J. 127, 3142–3149 (2014).

Park, J. et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 17, 1216–1219 (2001).

Samet, J. M. Does idiopathic pulmonary fibrosis increase lung cancer risk? Am. J. Respir. Crit. Care Med. 161, 1–2 (2000).

Sangiovanni, A. et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 126, 1005–1014 (2004).

Wang, H. M. et al. Liver stiffness measurement as an alternative to fibrotic stage in risk assessment of hepatocellular carcinoma incidence for chronic hepatitis C patients. Liver Int. 33, 756–761 (2013).

Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

Brown, L. F. et al. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin. Cancer Res. 5, 1041–1056 (1999).

Feng, D. et al. Ultrastructural localization of the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) receptor-2 (FLK-1, KDR) in normal mouse kidney and in the hyperpermeable vessels induced by VPF/VEGF-expressing tumors and adenoviral vectors. J. Histochem. Cytochem. 48, 545–556 (2000).

Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

Giussani, M., Merlino, G., Cappelletti, V., Tagliabue, E. & Daidone, M. G. Tumor–extracellular matrix interactions: Identification of tools associated with breast cancer progression. Semin. Cancer Biol. 35, 3–10 (2015).

Chiquet-Ehrismann, R., Mackie, E. J., Pearson, C. A. & Sakakura, T. Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 47, 131–139 (1986).

Mackie, E. J. et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc. Natl Acad. Sci. USA 84, 4621–4625 (1987).

Kyutoku, M. et al. Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int. J. Mol. Med. 28, 181–186 (2011).

Ruan, K., Bao, S. & Ouyang, G. The multifaceted role of periostin in tumorigenesis. Cell. Mol. Life Sci. 66, 2219–2230 (2009).

Abdollahi, A. et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J. Exp. Med. 201, 925–935 (2005).

Pietras, K., Pahler, J., Bergers, G. & Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 5, e19 (2008).

Paulsson, J., Ehnman, M. & Ostman, A. PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncol. 10, 1695–1708 (2014).

Strutz, F. et al. Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol. 130, 393–405 (1995).

Osterreicher, C. H. et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl Acad. Sci. USA 108, 308–313 (2011).

Kikuchi, N. et al. Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression. Cancer Sci. 97, 1061–1069 (2006).

Arnold, J. N., Magiera, L., Kraman, M. & Fearon, D. T. Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol. Res. 2, 121–126 (2014).

Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014). This paper shows that depletion of α SMA + stromal cells promotes an immunosupressive tumour milieu and exacerbates cancer progression with diminished survival.

Sugimoto, H., Mundel, T. M., Kieran, M. W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006).

Guido, C. et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: connecting TGF-β signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle 11, 3019–3035 (2012).

Simpkins, S. A., Hanby, A. M., Holliday, D. L. & Speirs, V. Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J. Pathol. 227, 490–498 (2012).

Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).

Li, P. et al. Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. Cell Res. 25, 588–603 (2015).

Mrazek, A. A. et al. Colorectal cancer-associated fibroblasts are genotypically distinct. Curr. Cancer Ther. Rev. 10, 97–218 (2014).

Hu, M. et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat. Genet. 37, 899–905 (2005).

Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544–550 (2010). The first study to implicate epigenetic control of fibroblast activation.

Huang, S. K. et al. Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis. 4, e621 (2013).

He, Z. et al. Epigenetic regulation of Thy-1 gene expression by histone modification is involved in lipopolysaccharide-induced lung fibroblast proliferation. J. Cell. Mol. Med. 17, 160–167 (2013).

Robinson, C. M., Neary, R., Levendale, A., Watson, C. J. & Baugh, J. A. Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir. Res. 13, 74 (2012).

Zong, Y. et al. Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling. Proc. Natl Acad. Sci. USA 109, E3395–E3404 (2012). This study shows that overexpression of the chromatin remodeller HMGA2 in stroma initiates neoplasia of prostate epithelium.

Albrengues, J. et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204 (2015).

Madar, S. et al. Modulated expression of WFDC1 during carcinogenesis and cellular senescence. Carcinogenesis 30, 20–27 (2009).

Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

Dimanche-Boitrel, M. T. et al. In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of tumor-associated myofibroblasts. Int. J. Cancer 56, 512–521 (1994).

Scherz-Shouval, R. et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158, 564–578 (2014).

Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).

Procopio, M. G. et al. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat. Cell Biol. 17, 1193–1204 (2015).

Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313 (2005).

Stetler-Stevenson, W. G., Aznavoorian, S. & Liotta, L. A. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol. 9, 541–573 (1993).

Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).

Lochter, A. et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872 (1997).

Borges, F. T. et al. TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J. Am. Soc. Nephrol. 24, 385–392 (2013).

Kahlert, C. & Kalluri, R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. (Berl.) 91, 431–437 (2013).

Luga, V. & Wrana, J. L. Tumor–stroma interaction: revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res. 73, 6843–6847 (2013).

Hu, Y. et al. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 10, e0125625 (2015).

Shimoda, M. et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat. Cell Biol. 16, 889–901 (2014).

Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012).

Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

Del Pozo Martin, Y. et al. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13, 2456–2469 (2015).

Chen, W. J. et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 5, 3472 (2014).

Elkabets, M. et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J. Clin. Invest. 121, 784–799 (2011).

Bruzzese, F. et al. Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Res. 74, 3408–3417 (2014).

Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007). This paper reports ECM remodelling by CAFs to engineer tracks used by cancer cells to migrate.

O'Connell, J. T. et al. VEGF-A and Tenascin-C produced by S100A4 + stromal cells are important for metastatic colonization. Proc. Natl Acad. Sci. USA 108, 16002–16007 (2011). This study reports that FSP1 + stromal cells remodel the metastatic soil.

Olaso, E. et al. Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis. Hepatology 26, 634–642 (1997).

Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

Pena, C. et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 73, 1287–1297 (2013).

Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

Grum-Schwensen, B. et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res. 65, 3772–3780 (2005).

Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

Martinez-Outschoorn, U. E., Lisanti, M. P. & Sotgia, F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin. Cancer Biol. 25, 47–60 (2014).

Zhang, D. et al. Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell Rep. 10, 1335–1348 (2015).

Chaudhri, V. K. et al. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol. Cancer Res. 11, 579–592 (2013).

Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009). This study indicates that Cav1 -knockout fibroblasts metabolically cooperate with cancer cells.

LeBleu, V. S. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–1003, 1001–1015 (2014).

Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).

Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).

Fiaschi, T. et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 72, 5130–5140 (2012).

Valencia, T. et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26, 121–135 (2014).

Kuchnio, A. et al. The cancer cell oxygen sensor PHD2 promotes metastasis via activation of cancer-associated fibroblasts. Cell Rep. 12, 992–1005 (2015).

Madsen, C. D. et al. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO Rep. 16, 1394–1408 (2015).

Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015). This paper implicates PDL1 in the control of metabolic competition in the TME to mediate T cell hyper-responsiveness.

Ghesquiere, B., Wong, B. W., Kuchnio, A. & Carmeliet, P. Metabolism of stromal and immune cells in health and disease. Nature 511, 167–176 (2014).

Molon, B., Cali, B. & Viola, A. T. Cells and cancer: how metabolism shapes immunity. Front. Immunol. 7, 20 (2016).

Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015).

Lisanti, M. P., Martinez-Outschoorn, U. E. & Sotgia, F. Oncogenes induce the cancer-associated fibroblast phenotype: metabolic symbiosis and “fibroblast addiction” are new therapeutic targets for drug discovery. Cell Cycle 12, 2723–2732 (2013).

Costea, D. E. et al. Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 73, 3888–3901 (2013).

De Boeck, A. et al. Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics 13, 379–388 (2013).

Koczorowska, M. M. et al. Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations. Mol. Oncol. 10, 40–58 (2015).

Lotti, F. et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 210, 2851–2872 (2013).

Raffaghello, L. & Dazzi, F. Classification and biology of tumour associated stromal cells. Immunol. Lett. 168, 175–182 (2015).

Harper, J. & Sainson, R. C. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin. Cancer Biol. 25, 69–77 (2014).

Patel, R., Filer, A., Barone, F. & Buckley, C. D. Stroma: fertile soil for inflammation. Best practice and research. Clin. Rheumatol. 28, 565–576 (2014).

Poggi, A., Musso, A., Dapino, I. & Zocchi, M. R. Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells. Immunol. Lett. 159, 55–72 (2014).

Soleymaninejadian, E., Pramanik, K. & Samadian, E. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Am. J. Reprod. Immunol. 67, 1–8 (2012).

Park, S. J. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173, 3844–3854 (2004).

Chomarat, P., Banchereau, J., Davoust, J. & Palucka, A. K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 1, 510–514 (2000).

Hugo, H. J. et al. Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment. Cancer Microenviron. 5, 83–93 (2012).

Wan, Y. Y. & Flavell, R. A. 'Yin-Yang' functions of transforming growth factor-β and T regulatory cells in immune regulation. Immunol. Rev. 220, 199–213 (2007).

Bailey, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Front. Immunol. 5, 276 (2014). A detailed review on T H 17 cells in the TME.

Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).

Kim, J. H. et al. The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem. Biophys. Res. Commun. 423, 60–66 (2012).

Augsten, M. et al. Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res. 74, 2999–3010 (2014).

Mishra, P., Banerjee, D. & Ben-Baruch, A. Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy. J. Leukoc. Biol. 89, 31–39 (2011).

Van Linthout, S., Miteva, K. & Tschope, C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc. Res. 102, 258–269 (2014).

Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

Silzle, T. et al. Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur. J. Immunol. 33, 1311–1320 (2003).

Barnas, J. L., Simpson-Abelson, M. R., Yokota, S. J., Kelleher, R. J. & Bankert, R. B. T cells and stromal fibroblasts in human tumor microenvironments represent potential therapeutic targets. Cancer Microenviron. 3, 29–47 (2010).

Pinchuk, I. V. et al. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4 + T-cell activity. Gastroenterology 135, 1228–1237 (2008).

Nazareth, M. R. et al. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J. Immunol. 178, 5552–5562 (2007).

Augsten, M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 4, 62 (2014).

Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).

Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827–830 (2010). This article shows that depletion of FAP + stromal cells enables immunological control of tumour growth.

Wen, Y. et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci. 101, 2325–2332 (2010).

Liao, D., Luo, Y., Markowitz, D., Xiang, R. & Reisfeld, R. A. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4, e7965 (2009).

Ohshio, Y. et al. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci. 106, 134–142 (2015).

Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).

Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).

Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat. Rev. Cancer 9, 665–674 (2009). A review on the role of the TME in drug resistance.

Paraiso, K. H. & Smalley, K. S. Fibroblast-mediated drug resistance in cancer. Biochem. Pharmacol. 85, 1033–1041 (2013).

Heldin, C. H., Rubin, K., Pietras, K. & Ostman, A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806–813 (2004).

Correia, A. L. & Bissell, M. J. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist. Updat. 15, 39–49 (2012).

Dittmer, J. & Leyh, B. The impact of tumor stroma on drug response in breast cancer. Semin. Cancer Biol. 31, 3–15 (2015).

Mori, Y. et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 104, 2149–2154 (2004).

Park, C. C., Zhang, H. J., Yao, E. S., Park, C. J. & Bissell, M. J. β1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 68, 4398–4405 (2008).

Hazlehurst, L. A., Damiano, J. S., Buyuksal, I., Pledger, W. J. & Dalton, W. S. Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19, 4319–4327 (2000).

White, D. E., Rayment, J. H. & Muller, W. J. Addressing the role of cell adhesion in tumor cell dormancy. Cell Cycle 5, 1756–1759 (2006).

Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27, 574–588 (2015).

Flach, E. H., Rebecca, V. W., Herlyn, M., Smalley, K. S. & Anderson, A. R. Fibroblasts contribute to melanoma tumor growth and drug resistance. Mol. Pharmaceut. 8, 2039–2049 (2011).

Li, G., Satyamoorthy, K. & Herlyn, M. N-Cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 61, 3819–3825 (2001).

Sui, H., Zhu, L., Deng, W. & Li, Q. Epithelial-mesenchymal transition and drug resistance: role, molecular mechanisms, and therapeutic strategies. Oncol. Res. Treat. 37, 584–589 (2014).

Mitra, A., Mishra, L. & Li, S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 6, 10697–10711 (2015).

Chang, J. T. & Mani, S. A. Sheep, wolf, or werewolf: cancer stem cells and the epithelial-to-mesenchymal transition. Cancer Lett. 341, 16–23 (2013).

Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

Kumari, N., Dwarakanath, B. S., Das, A. & Bhatt, A. N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. http://dx.doi.org/10.1007/s13277-016-5098-7 (2016).

Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

Wang, W. et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 15, 6630–6638 (2009).

McMillin, D. W., Negri, J. M. & Mitsiades, C. S. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat. Rev. Drug Discov. 12, 217–228 (2013).

Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

Madden, J. I. Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. Infinity Pharmaceuticals http://phx.corporate-ir.net/phoenix.zhtml?c=121941&p=irol-newsArticle&ID=1653550 (27 January 2012).

Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

Goel, S., Wong, A. H. & Jain, R. K. Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb. Perspect. Med. 2, a006486 (2012).

Huang, Y., Goel, S., Duda, D. G., Fukumura, D. & Jain, R. K. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 73, 2943–2948 (2013).

Kuperwasser, C. et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc. Natl Acad. Sci. USA 101, 4966–4971 (2004).

Cheng, N. et al. Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene 24, 5053–5068 (2005).

Lewis, D. A., Travers, J. B., Machado, C., Somani, A. K. & Spandau, D. F. Reversing the aging stromal phenotype prevents carcinoma initiation. Aging 3, 407–416 (2011).

Paulsson, J. & Micke, P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin. Cancer Biol. 25, 61–68 (2014).

Wang, W. Q. et al. Intratumoral α-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. PLoS One 8, e71189 (2013).

Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).

Frings, O. et al. Prognostic significance in breast cancer of a gene signature capturing stromal PDGF signaling. Am. J. Pathol. 182, 2037–2047 (2013).

Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

Takeda, Y., Tsujino, K., Kijima, T. & Kumanogoh, A. Efficacy and safety of pirfenidone for idiopathic pulmonary fibrosis. Patient Prefer. Adherence 8, 361–370 (2014).

Wang, X. M., Yu, D. M., McCaughan, G. W. & Gorrell, M. D. Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line. Hepatology 42, 935–945 (2005).

Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

Kim, H. Y. et al. Localized smooth muscle differentiation is essential for epithelial bifurcation during branching morphogenesis of the mammalian lung. Dev. Cell 34, 719–726 (2015).

Shyer, A. E., Huycke, T. R., Lee, C., Mahadevan, L. & Tabin, C. J. Bending gradients: how the intestinal stem cell gets its home. Cell 161, 569–580 (2015).

Selman, M. & Pardo, A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir. Res. 3, 3 (2002).

Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009). A review of EMT in development and pathology.

Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).

Jolly, M. K. et al. Towards elucidating the connection between epithelial-mesenchymal transitions and stemness. J. R. Soc. Interface 11, 20140962 (2014).

Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).

Hematti, P. Mesenchymal stromal cells and fibroblasts: a case of mistaken identity? Cytotherapy 14, 516–521 (2012).

Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international Society for Cellular Therapy postition statement. Cytotherapy 8, 315–317 (2006).

Albrengues, J. et al. LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep. 7, 1664–1678 (2014).

Avgustinova, A. et al. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat. Commun. 7, 10305 (2016).

Rajaram, M., Li, J., Egeblad, M. & Powers, R. S. System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity. PLoS Genet. 9, e1003789 (2013).


What is the actual impact of chronic stress on health?

When considering the numerous cellular targets of the chemical mediators of stress, one would expect that protracted, stress-dependent neuroendocrine dysregulation may damage directly or through functional circuits practically all organs and tissues. To clarify this assumption and identify the biochemical pathways significantly impaired by chronic stress to the extent of producing illness, researchers have on one hand searched for putative morphological tissue alterations associated with stress, and on the other analyzed the molecular mechanisms of action of the main stress hormones.

Effects of chronic stress on brain structure

It has been shown that chronic stress is linked to macroscopic changes in certain brain areas, consisting of volume variations and physical modifications of neuronal networks. For example, several studies in animals have described stress-related effects in the prefrontal cortex (PFC) and limbic system, characterized by volume reductions of some structures, and changes in neuronal plasticity due to dendritic atrophy and decreased spine density [4]. These morphological alterations are similar to those found in the brains of depressed patients examined postmortem, suggesting that they could also be at the basis of the depressive disorders that are often associated with chronic stress in humans. This hypothesis is supported by imaging studies that evidenced structural changes in the brain of individuals suffering from various types of stress-related disorders, such as those linked to severe traumas, major negative life events or chronic psychosocial strain. In particular, Blix and colleagues observed atrophy of the basal ganglia and significantly reduced gray matter in certain areas of the PFC in subjects afflicted with long-term occupational stress [5]. In general, the consequences of these alterations in a brain region can expand to other functionally connected areas, and potentially cause those cognitive, emotional and behavioral dysfunctions that are commonly associated with chronic stress, and that may increase vulnerability to psychiatric disorders.

Interlink between the brain & the immune system

The understanding of the molecular circuits that underlie brain architectural changes and medical conditions linked to chronic stress is just at the beginning. Research in this area has centered primarily on the signaling functions of those molecules that are directly induced by stress through the activation of the sympathetic-adrenal-medullary and HPA networks, focusing on their possible cellular targets. Since receptors for stress neuropeptides and hormones are broadly expressed in immune cells [6], most studies have concentrated on the effects of stress on the immune system (IS). In fact, psychological stress can induce the acute phase response commonly associated with infections and tissue damage, and increase the levels of circulating cytokines and of various biomarkers of inflammation [2]. As suggested by Maier and Watkins, the interlink between the stress response and inflammation elicited by the IS can be explained from the evolutionary perspective by considering that the stress response is an adaptive process developed by co-opting the IS mechanisms of defense [7]. In this frame, a psychological stressor, perceived by the brain as �nger’, that is, potentially harming, sets in motion a neuroimmune circuit that stimulates the IS to mount a protective reaction intended to prevent damage, repair it and restore homeostasis.

This neuroimmune communication is bidirectional because the cytokines produced by stress-stimulated immune cells also convey a feedback to the nervous system, further modulating the release of stress hormones in the brain, as well as brain activity that regulates behavior and cognitive functions. In a situation of chronic stress, the neuroimmune axis can be overstimulated and breaks down, thus causing neuroendocrine/immune imbalances that establish a state of chronic low-grade inflammation, a possible prelude to various illnesses [8].

Diseases whose development has been linked to both stress and inflammation include cardiovascular dysfunctions, diabetes, cancer, autoimmune syndromes and mental illnesses such as depression and anxiety disorders.

Persistent, abnormal levels of cytokines and stress chemical mediators in the brain may also damage the parenchyma and cause neuronal death, thus contributing to the brain structural changes associated with chronic stress that are described above [9].

Despite the large number of studies that have addressed the biological effects of chronic stress and their impact on human health, the emerging picture still merely outlines the biochemical and functional responses of the nervous and immune systems to long-term stress, highlighting some nodes of information exchange between the two networks, but still lacking essential elements concerning additional cellular players, and functional and molecular mechanisms.

Some recent studies have, however, significantly improved our knowledge of how chronic stress promotes two of the diseases that have long been associated with it: atherosclerosis and depression.

Effects of chronic stress on hematopoietic stem cells in cardiovascular diseases

Heidt and colleagues demonstrated how stress increases the levels of circulating inflammatory leukocytes by direct stimulation of hematopoietic stem cell proliferation [10]. In this new pathway, stress induces the release of noradrenaline by sympathetic nerve fibers targeting blood vessels in the bone marrow of mice. The catecholamine then acts on mesenchymal stem cells located in the hematopoietic niche, which express high levels of the 㬣 adrenergic receptors. One of the consequences of this interaction is the downregulation of the chemokine CXCL12, a known target of noradrenaline, which is normally produced by several types of niche cells, including mesenchymal stem cells. This releases the inhibition typically exerted by CXCL12 on the proliferation of hematopoietic stem and progenitor cells and on leukocyte migration, thus promoting cell division and leukocyte mobilization into the bloodstream.

Predictably, the inflammatory response induced by the activation of this neuroimmune pathway may have adverse health effects, in particular by exacerbating pre-existing medical conditions. Specifically, the study demonstrated that this mechanism became activated when atherosclerosis-prone mice ApoE -/- were subjected to long-term stress, leading to enhanced recruitment of inflammatory cells in atherosclerotic plaques, higher levels of proteases and increased plaque fragility. Most interestingly, 㬣-adrenergic receptor blockers opposed leukocyte production and mobilization, thus counteracting plaque inflammation.

When shifting their attention to human subjects, the scientists determined that individuals under considerable occupational stress had significantly more circulating leukocytes compared with when they were not working, suggesting that the neuroimmune mechanism they discovered might be set off by chronic stress and sustain an inflammatory reaction also in humans. If demonstrated, this would open the way to conceptually new therapeutic possibilities not only for atherosclerosis and its related complications, but also for other stress-related diseases that are aggravated by chronic inflammation.

Mechanisms of chronic stress-associated depression & brain–skeletal muscle communication

The mechanisms by which stress chemicals may induce depression are mostly undetermined. Research in this field is starting to define how multiple, independent, though often interconnected biochemical pathways affected by chronic stress concur to promote this disease.

Ota and colleagues have identified a molecular mechanism triggered by chronic stress that contributes to neuronal atrophy in specific brain areas, an anomaly that is typically observed in depressed patients, independent of the cause of depression [11]. In their study, they observed that persistent high levels of GCs, resulting from stress-induced hyperactivation of the HPA axis, stimulate the production of the molecule REDD1 in the PFC of rodents subjected to prolonged stress. REDD1 is generally induced by a variety of stressors – from energy stress, to hypoxia, to DNA damage – in most tissues and inhibits the kinase mTORC1, thus altering the phosphorylation state and function of its targets. In the brain, the interference of REDD1 with mTORC1 signaling ultimately impinges on neuronal protein synthesis, spine formation and synaptic plasticity. The inhibition of mTORC is pivotal for synaptic impairment and appears to be a central endpoint of molecular pathways turned on by chronic stress. In fact, also the decrease of brain-derived neurotrophic factor levels in response to chronic stress disrupts mTORC1 function.

Proinflammatory cytokines induced by stress are also involved in the development of chronic stress-associated depression [12]. The acute phase response generally triggered by a harmful factor implies the so-called sickness behavior that includes symptoms similar to those typical of depressive disorders, like social withdrawal, decreased physical activity, fatigue, somnolence, mood and cognitive alterations. This adaptive response is orchestrated by cytokines, and is meant to divert an individual from normal activities in order to save energy, thus facilitating a reaction against the challenge, and subsequent recovery. In the case of chronic inflammation that may set in with prolonged stress, persisting cytokine signaling in the brain prevents the resolution of sickness behavior that consequently can degenerate into depression. The biochemical mechanisms underlying cytokine-induced depression are not well defined, but they may involve alterations of serotonin and glutamatergic transmission, and induction of GC resistance [12].

One of the pathways that are implicated drives the oxidation of tryptophan (a precursor of serotonin) to Kynurenin (Kyn) and results in the brain production of several neuroactive molecules ( Figure 1 ) [12]. The enzymes tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase trigger the Kyn pathway in the liver and extrahepatically respectively, and can both be activated by chronic stress: tryptophan 2,3-dioxygenase in fact responds to GCs, while indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines. The Kyn pathway not only affects the brain levels of serotonin and thus serotonergic transmission and its mood and behavioral effects, but it is also responsible for the production of tryptophan metabolites that have neuroinflammatory properties or can affect glutamatergic neurotransmission in the brain either positively or negatively. It follows that a shift in the pathway that favors the production of 3-hydroxykynurenine – an inducer of reactive oxygen species and inflammation – and quinolinic acid – an N-methyl- d -aspartate receptor agonist – over the antioxidant and N-methyl- d -aspartate receptor inhibitor kynurenic acid, may promote depression [12].

There is evidence that physical exercise can sustain brain health by regulating the production of neurotrophic factors, neurotransmitters, as well as inflammatory molecules. This can translate in a general enhancement of cognitive abilities, a reduced risk of neurodegenerative diseases and a mitigation of depression [13].

An interesting study has recently demonstrated that a key mechanism by which physical exercise counteracts chronic stress-dependent depression is the modulation of the Kyn pathway of tryptophan degradation [14]. In this work, Agudelo and colleagues demonstrated that skeletal muscle contraction during protracted training induces locally the interaction of the transcriptional coactivator PGC-1㬑 with the transcription factors PPARα/δ, thus increasing in the muscles the expression and activity of a set of kynurenin aminotransferases (KAT). KATs catalyze the peripheral transformation of tryptophan-derived Kyn into kynurenic acid, causing a drop in the levels of circulating Kyn. Since Kyn can cross the blood𠄻rain barrier, its peripheral catabolism has the effect to reduce also its brain concentration and so the production of neurotoxic molecules along the 3-hydroxykynurenine and quinolinic acid branch of the degradation pathway. In mice, under conditions that mimic chronic stress, the overexpression in skeletal muscles of PGC-1㬑 prevents neuroinflammation, synapses impairment and depression-like behaviors that are instead observed in control animals. Similarly, the scientists found that exercise training stimulates the PGC-1㬑-KAT pathway also in humans, and through this mechanism, potentially regulates those Kyn-dependent toxic effects in the brain that contribute to chronic stress-associated depression.

By identifying new signaling cascades implicated in the regulation of depression caused by chronic stress, Ota's and Agudelo's studies suggest novel areas of investigation for therapy development. Drugs that inhibit REDD1 effects on mTORC1, or that modulate brain levels of Kyn by enhancing its peripheral metabolism could improve the treatment of depression maybe also when it is not stress related. Since depressed individuals are usually reluctant to carry out regular physical exercise, drugs that mimic exercise training and reduce the plasma concentration of Kyn by acting peripherally would be of particular interest.

Biological & social implications of the latest findings in chronic stress research

These studies significantly improve our understanding of the interactions between the nervous systems and peripheral tissues and organs, and how their alterations can cause illness ( Figure 2 ). An important discovery is that if on one hand chronic stress can cause immune dysfunctions, that is, impair a peripheral function, on the other hand proper stimulation of a peripheral tissue like skeletal muscles can relieve stress symptoms and protect the brain, possibly favoring recovery. This suggests that programs of physical exercise should be formally proposed as a preventive measure to people known to be exposed to intense stress (eg., work-related stress), and could be prescribed as a form of therapy in combination with other treatments to ease mood and cognitive deficits caused by chronic stress.

In addition, Heidt's study suggests another intriguing possibility: if chronic stress can stimulate hematopoietic stem and progenitor cells through the activation of the peripheral nervous system, it is plausible that it can activate also other types of stem cells in other tissues by a similar mechanism. Bidirectional communication could in principle exist between the nervous system and every organ and tissue, and represents a general mechanism of nervous control of tissue homeostasis. A few recent studies have provided evidence that supports this hypothesis [15�]. One of the resulting and provoking implications is that chronic stress could promote cancer development also by direct induction of uncontrolled cell proliferation.

The recognition that chronic stress can cause serious diseases has intensified research to determine the biochemical perturbations that compromise homeostasis to a degree that prevents spontaneous recovery. The picture is very complex because chronic stress appears to affect organ and system functions at multiple levels. Yet, it is by pinpointing specific biochemical processes affected by chronic stress that it will be possible to envisage solutions to stimulate resilience and control stress-dependent diseases.

It is clear that in the case of illnesses caused by heightened occupational stress, priority should be given to preventive interventions with the purpose of creating and maintaining work conditions respectful of human physiological, emotional and social needs: in other words, the work environment should stimulate growth and productivity while supporting each individual in their challenges. If certain measures could be implemented through official regulations that assure, for example, fair contracts, training, and sensible work schedules in relation to the type and load of responsibilities and the levels of physical and mental engagement implied by the job, others are less manageable because they strictly depend on human factors. Elements like discordant interactions with coworkers and superiors’ demands beyond formal agreements, that are quite common in very competitive work environments, can sharpen tensions and exaggerate the psychosocial strain to the point of causing illness, yet they usually remain overlooked and uncontrolled [17].


UG Legon Minimum Requirements For Undergraduate Bachelor Programmes

Ghana WASSCE/SSSCE

The University of Ghana announces for the information of the general public the minimum requirements are for the admission of prospective applicants into various undergraduate programmes for the academic year. Applicants should take note of the following minimum undergraduate programmes for the academic year before applying for admission:

GHANA WASSCE/SSSCE – Minimum/General Entry

Minimum Admission Requirements into Legon Campus, Accra City Campus and Korle Bu Campus.

An applicant for admission to a degree programme in the University of Ghana must have at least

  1. credits (A1 – C6 in WASSCE and A – D in SSSCE) in English, Core Mathematics and Integrated Science (for Science related programmes) or Social Studies (for non-Science related programmes) and three elective subjects in Science for applicants applying to Science or Agriculture related disciplines or three elective subjects in General Arts/Business for applicants applying to non-Science related disciplines, with the total aggregate not exceeding 24.
  2. In addition, Science applicants should have at least a grade C6 in WASSCE/D in SSSCE in Social Studies/Life Skills and non-Science applicants should also have at least a grade C6 in WASSCE/D IN SSSCE in Integrated Science/Core Science.

COLLEGE OF HEALTH SCIENCES

Ghana WASSCE/SSSCE Applicants

Short-listed applicants into programmes at the College of Health Sciences:

Entry Requirements For University of Ghana Medical School

Minimum Admission Requirements For Bachelor of Medicine and Bachelor of Surgery

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies
Electives: Credit passes in Chemistry and any two from Physics, Biology and Elective Mathematics

Entry Requirements For University of Ghana Dental School

Minimum Admission Requirements For Bachelor of Dental Surgery

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies
Electives: Credit passes in Chemistry and any two from Physics, Biology and Elective Mathematics

Entry Requirements For School of Pharmacy

Minimum Admission Requirements For Doctor of Pharmacy

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Chemistry, Biology and either Physics or Elective Mathematics

Entry Requirements For School of Biological & Allied Health Sciences

Minimum Requirements For Bachelor of Science in Dietetics, Medical Laboratory, Occupational Therapy, Physiotherapy, Radiography, Respiratory Therapy.

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Chemistry, Physics and either Biology or Elective Mathematics

Entry Requirements For School of Nursing and Midwifery

Minimum Requirements For Bachelor of Science in Nursing with options in:

Applicants are expected to select one (1) option

    1. General Nursing
    2. Community Health Nursing
    3. Paediatric Nursing
    4. Mental Health Nursing

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies.

Electives: Credit passes in three electives from any of the combinations below:

Chemistry, Physics, Biology or Elective Mathematics

General Agriculture, Physics & Chemistry

Three General Arts Electives

Two General Arts Electives plus Food & Nutrition

Any three of the following Electives: Economics, Management in Living, Food & Nutrition, Chemistry, General Knowledge in Art and French.

Minimum Requirements For Bachelor of Science in Midwifery

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in three electives from any of the combinations below:

  1. Chemistry, Physics, Biology or Elective Mathematics
  2. General Agriculture, Physics & Chemistry
  3. Three General Arts Electives
  4. Two General Arts Electives plus Food & Nutrition
  5. Any three of the following Electives: Economics, Management in Living, Food & Nutrition, Chemistry, General Knowledge in Art and French.

COLLEGE OF BASIC AND APPLIED SCIENCES GHANA WASSCE/SSSCE APPLICANTS

Note that the following programmes at the College of Basic and Applied Sciences are FIRST CHOICE programmes:

Doctor of Veterinary Medicine, Bachelor of Science in Information Technology, Bachelor of Science in Computer Engineering and Bachelor of Science in Biomedical Engineering.

Entry Requirements For School of Physical & Mathematical Sciences

Minimum Requirements For Bachelor of Science in Physical Sciences ( Physics, Chemistry, Geophysics )

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Minimum Requirements For Bachelor of Science in Mathematical Sciences ( Mathematics, Statistics, Actuarial Science, Computer Science, Biomathematics, Physics )

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies.

Electives: Credit passes in any three subjects with at least a B2 in Elective Mathematics.

Minimum Requirements For Bachelor of Science in Earth Sciences ( Geology, Applied Geology, Applied Geophysics )

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology/Geography and Elective Mathematics, with at least a C6 in Chemistry

Minimum Requirements For Bachelor of Science in Information Technology

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three subjects, with at least a B2 in Core Mathematics.

Entry Requirements For School of Biological Sciences

Minimum Requirements For Bachelor of Science in Biological Sciences ( Animal Biology and Conservation Science, Biochemistry Cell and Molecular Biology, Nutrition, Food Science, Plant and Environmental Biology, Marine Science, Fisheries Science, Microbiology )

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a C6 in Chemistry

Minimum Requirements Bachelor of Science in Psychology

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics

Entry Requirements For School of Agriculture

Minimum Requirements Bachelor of Science in Agriculture ( Animal Science, Crop Science, Soil Science, Agriculture Economics, Agribusiness, Agriculture Extension, Post-Harvest Technology )

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Chemistry, Physics, Biology/Agriculture Science, Geography and Elective Mathematics, with at least a C6 in Chemistry

Minimum Requirements For Bachelor of Science in Family and Consumer Sciences (Food and Clothing)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three subjects with at least a C6 in Chemistry

Minimum Requirements For Bachelor of Science in Family and Consumer Sciences (Family and Child Studies)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three electives from:

  • Science
  • General Arts (except Languages and Visual Arts)
  • Home Economics/Science (Credit pass in Management in Living and any two of Food and Nutrition, Textiles and Clothing, General Knowledge in Art, Biology or Chemistry.

Entry Requirements For School of Engineering Sciences

Minimum Requirements For Bachelor of Science in Agriculture Engineering

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Minimum Requirements For Bachelor of Science in Biomedical Engineering

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies.

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Minimum Requirements For Bachelor of Science in Computer Engineering

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Minimum Requirements For Bachelor of Science in Food Processing Engineering

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Minimum Requirements For Bachelor of Science in Material Science Engineering

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a B3 in Elective Mathematics

Entry Requirements For School of Veterinary Medicine

Minimum Requirements For Doctor of Veterinary Medicine

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three of Physics, Chemistry, Biology and Elective Mathematics, with at least a C6 in both Biology and Chemistry

COLLEGE OF HUMANITIES

GHANA WASSCE/SSSCE APPLICANTS

Entry Requirements For School of Social Sciences/ School of Arts/ School of Languages

Minimum Requirements For Bachelor of Arts

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects

Applicants must have the following WASSCE subjects to qualify to read the under listed courses:

  • Economics, Mathematics or Statistics – Elective Mathematics
  • Computer Science – Elective Mathematics
  • French – French
  • English – English Literature
  • Geography Geography

Entry Requirements For University of Ghana Business School

Minimum Requirements For Bachelor of Science in Business Administration

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects

Entry Requirements For University of Ghana School of Law

Minimum Requirements For Bachelor of Laws (LLB)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects

Entry Requirements For School of Performing Arts

Minimum Requirements For Bachelor of Fine Arts

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three electives subjects.

The programme is open to applicants interested in the Performing Arts with aggregate 24 or better. They will be expected to attend an audition or interview.

COLLEGE OF EDUCATION

GHANA WASSCE/SSSCE APPLICANTS

Entry Requirements For School of Education & Leadership

Minimum Requirements For BA Education (English)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects including English Literature.

Minimum Requirements For BA Education (Non-Teaching)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects.

Minimum Requirements For BA Sport and Physical Culture Studies

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects

Minimum Requirements For B.Sc. Education (Mathematics)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Elective Mathematics and any other two elective subjects

Minimum Requirements For B.Sc. Education (Biology)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Biology and any other two elective subjects

Minimum Requirements For B.Sc. Education (Chemistry)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Chemistry and any other two elective subjects

Minimum Requirements For B.Sc. Education (Physics)

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in Physics and any other two elective subjects

Entry Requirements For School of Continuing &Distance Education

Minimum Requirements For Bachelor of Science in Business Administration

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects with the total aggregate not exceeding 24

Minimum Requirements For Bachelor of Arts

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects with the total aggregate not more than 30

Minimum Requirements For Bachelor of Science in Information Technology

Core: Credit passes in English, Core Mathematics, Integrated Science & Social Studies

Electives: Credit passes in any three elective subjects with the total aggregate not exceeding 30

Minimum Requirements For Bachelor of Science in Nursing

Applicants must be professional nurses who already have a Diploma in Nursing from a recognized Nursing Training College, with a Final Grade Point Average (FGPA) OF 2.5 or better.

All interested applicants can register at any of the Learning Centres of the School of Continuing and Distance Education below, after payment into the following account: Account Name and number: (UG Learning Centre A/C, ECOBANK. A/C Number 0160134485305902).

All interested applicants can register at any of the Accounts offices of the School of Continuing and Distance Education below, after payment into the following account: Account Name and number: College of Education, ECOBANK. A/C NUMBER 0160094485305901.


Adequate Outdoor Air Ventilation Can Improve Ability to Perform, Raise Test Scores and Reduce Airborne Transmission of Infection

Ventilation rates in most schools are below recommended levels. 8 Growing evidence of the positive impact of outdoor air ventilation suggests a clear opportunity for improving health and academic performance.

Ability to Perform

  • Studies demonstrate a connection between improvements in IAQ — either from increased outdoor air ventilation rates or from the removal of pollution sources — and improved performance of children and adults. 39, 70, 69, 31, 56, 3
  • Controlled studies show that children perform school work with greater speed as ventilation rates increase.
  • The performance of adults, including teachers and school staff, has also been shown to improve with higher ventilation rates. 77, 78

Test Scores

Children in classrooms with higher outdoor air ventilation rates tend to achieve higher scores on standardized tests in math and reading than children in poorly ventilated classrooms. 57

Transmission of Infection

Higher ventilation rates reduce the transmission and spread of infectious agents in buildings. This is the conclusion of a multidisciplinary expert panel after reviewing 40 studies conducted between 1960 and 2005.

  • In their report, the authors recommend schools and similar high-density facilities increase their ventilation rates during influenza peak season. 28
  • In addition, a controlled study in office buildings found a link between short-term sick leave, often associated with respiratory illness, and low ventilation rates. 37
  • Occupants of buildings with low ventilation rates and high occupant densities experienced far higher rates of respiratory illness than did occupants of similar buildings with higher ventilation rates. 56

15.16: Physical Evidence - Biology

Physical function (ie, aerobic capacity, gait speed, and muscle strength) has been proposed as a biomarker of healthy ageing, as it is predictive of adverse health events, disability, and mortality. The role of physical exercise as a therapeutic strategy for prevention of both disease and the associated decline in functional capacity has been emphasised repeatedly. Supervised exercise interventions in hospitalised older people (aged ≥75 years) have been proved to be safe and effective in preventing or attenuating functional and cognitive decline. Unfortunately, few studies have explored the potential role of tailored physical activity guidelines to maximise exercise-related effect on function. Also, exercise has not been fully integrated into primary or geriatric medical practice and is almost absent from the core training of most medical doctors and other health-care providers. Physical trainers should be included in health-care systems to help manage physical exercise programmes for older patients. Taking into consideration current evidence about the benefits of exercise for frail older adults, it is unethical not to prescribe physical exercise for such individuals. To promote healthy and dignified ageing, it is therefore essential to help health-care systems to more efficiently implement evidence-based exercise programmes for frail older adults in all community and care settings.


Moderate‐to‐Vigorous Physical Activity and All�use Mortality: Do Bouts Matter?

The 2008 Physical Activity Guidelines for Americans recommends that adults accumulate moderate‐to‐vigorous physical activity ( MVPA ) in bouts of ≥10 minutes for substantial health benefits. To what extent the same amount of MVPA accumulated in bouts versus sporadically reduces mortality risk remains unclear.

Methods and Results

We analyzed data from the National Health and Nutrition Examination Survey 2003–2006 and death records available through 2011 (follow‐up period of ≈6.6 years 700 deaths) to examine the associations between objectively measured physical activity accumulated with and without a bout criteria and all‐cause mortality in a representative sample of US adults 40 years and older (n=4840). Physical activity data were processed to generate minutes per day of total and bouted MVPA . Bouted MVPA was defined as MVPA accumulated in bouts of a minimum duration of either 5 or 10 minutes allowing for 1‐ to 2‐minute interruptions. Hazard ratios for all‐cause mortality associated with total and bouted MVPA were similar and ranged from 0.24 for the third quartile of total to 0.44 for the second quartile of 10‐minute bouts. The examination of jointly classified quartiles of total MVPA and tertiles of proportion of bouted activity revealed that greater amounts of bouted MVPA did not result in additional risk reductions for mortality.

Conclusions

These results provide evidence that mortality risk reductions associated with MVPA are independent of how activity is accumulated and can impact the development of physical activity guidelines and inform clinical practice.

Clinical Perspective

What Is New?

This study examines whether moderate‐to‐vigorous physical activity needs to be accumulated in bouts to provide mortality benefits.

Accelerometer‐measured physical activity data collected in 2003–2006 from a representative sample of US adults (n=4840) were classified as being accumulated sporadically or in bouts and linked to mortality records available through 2011.

Sporadic and bouted moderate‐to‐vigorous physical activity was similarly and strongly associated with mortality risk.

Mortality risk reductions associated with moderate‐to‐vigorous physical activity are independent of how activity is accumulated.

What Are the Clinical Implications?

This finding can inform future physical activity guidelines and guide clinical practice when advising individuals about the benefits of physical activity.

The key message based on the results presented is that total physical activity (ie, of any bout duration) provides important health benefits.

Practitioners can promote either long single or multiple shorter bouts of activity in advising adults how to progress toward 150 min/wk of moderate‐to‐vigorous physical activity.

This flexibility may be particularly valuable for individuals who are among the least active and likely at greater risk for developing chronic conditions.

The 2008 Physical Activity Guidelines for Americans recommends that adults accumulate at least 150 min/wk of moderate or 75 min/wk of vigorous‐intensity physical activity for substantial health benefits. 1 The guidelines also direct that activity be performed in bouts of at least 10 minutes. The 10‐minute bout criterion originated in 1995 and was intended to provide flexibility in achieving the recommended dose. 2 This messaging shift emphasized the importance of accumulating a total volume of moderate‐to‐vigorous physical activity (MVPA) and has remained a central feature of guidelines as they evolved. Surprisingly, evidence supporting a minimum bout of 10 minutes is limited. 3 Recent studies comparing MVPA accumulated in bouts to total minutes regardless of bouts suggest that bouts provide no additional benefit regarding metabolic syndrome, waist circumference, and body mass index. 4 , 5 , 6 , 7 , 8 However, these studies are limited to cross‐sectional designs that evaluated risk factors, making it difficult to understand the temporal sequence for the observed associations or the influence of MVPA bouts on end points, such as all‐cause mortality. Thus, whether only bouts or total accumulated MVPA is more beneficial to mortality remains uncertain.

Methods

Study Population

The data, analytic methods, and study materials are available to other researchers for purposes of reproducing the results or replicating the procedure. Data are available at https://wwwn.cdc.gov/nchs/nhanes/Default.aspx and additional details about the analytical methods can be provided upon request. Study data are from NHANES (National Health and Nutrition Examination Survey) 2003–2006 cycles. NHANES samples noninstitutionalized US civilians using a multistage probability sampling design that considers geographical area and minority representation. Sample weights are generated to create nationally representative estimates for the US population and subgroups defined by age, sex, and race/ethnicity. See https://www.cdc.gov/nchs/nhanes/about_nhanes.htm for more details on NHANES sampling procedures. NHANES collects data on various health and behavior indicators, including physical activity and self‐reported diagnosis of prevalent health conditions such as diabetes mellitus, coronary artery disease, stroke, and cancer. These data were merged with mortality records from the National Death Index, available through December 2011. The National Center for Health Statistics links mortality records available through the National Death Index with individuals in the respective NHANES database using various individual information such as social security number, first name, month of birth, sex, race, and others. 9 The matching process/linkage provides vital status for each individual that has been shown to accurately identify 87% to 97% of the true death records and is fairly accurate across race/ethnicities. 10 , 11 , 12 Our study used linked mortality NHANES data released to the public by the National Center for Health Statistics and restricted the analytical sample to adults aged 40 years and older with complete data on all variables of interest (N=4840 respondents). Details of this cohort have been reported elsewhere. 13 The NHANES study was reviewed and approved by the National Center for Health Statistics Research Ethics Review Board and all participants provided signed consent for participation.

Assessment of Physical Activity

Physical activity was measured with a waist‐worn uniaxial accelerometer (AM‐7164 ActiGraph) for up to 7 days using a standardized protocol. 14 Data were initially screened for nonwear time using a previously developed algorithm for NHANES accelerometer data. 14 Days with fewer than 10 hours of wear time were excluded and participants with at least 1 valid day of accelerometer data were included in the analysis. A threshold of 760 counts per minute defined MVPA. This threshold was defined to capture a broader range of lifestyle and ambulatory activities and has been demonstrated to provide accurate estimates of time spent in MVPA. 15 , 16 , 17 Minutes of activity were computed for 3 measures of MVPA: total with no bout restriction, accumulated in ≥5‐minute bouts, and accumulated in ≥10‐minute bouts. MVPA accumulated in bouts of 5 or 10 minutes allowed for 1 and 2 minutes, respectively, of activity counts <760 counts per minute to accommodate real‐life activity patterns (eg, stopping at a crosswalk while walking).

Statistical Analysis

All analyses were conducted with Cox proportional hazard models using established covariates of the physical activity–mortality association 13 : age (years), sex, race‐ethnicity (non‐Hispanic white, non‐Hispanic black, Hispanic, other), education (less than high school, high school diploma, high school or more), alcohol consumption (never, former, current), smoking status (never, former, current), body mass index (<25, 25–29.9, ≥30 kg/m 2 ), and self‐reported diagnosis (yes/no) of diabetes mellitus, coronary artery disease, stroke, cancer, and mobility limitation.

First, we examined mortality associations by quartiles for each of the 3 MVPA measures: total, ≥5‐minute, and ≥10‐minute bouts, not accounting for differences in activity volume. Total MVPA was similar across the 3 measures and strongly correlated (r=0.7–0.9) (Table S1), suggesting that the measures were not independent and that individuals who accumulated the most total MVPA also accumulated high amounts of MVPA in 5‐ or 10‐minute bouts.

To account for the dependence between total and bouted activity, we jointly classified quartiles of total MVPA by bouted activity, based on tertiles of the proportion of total MVPA accumulated in bouts of ≥5 or ≥10 minutes. This resulted in 12 categories of total MVPA and relative contribution of bouted MVPA. Many participants, particularly in the lower quartiles of total MVPA, had 0 bouts of ≥10 minutes. This led to unstable estimates, so analyses focused on bouts of ≥5 minutes. In these analyses, evidence of greater benefit for bouted activity would be demonstrated by lower hazard ratios (HRs) as contribution of bouts to total MVPA increased. To further describe the relationship between these exposures we plotted the risk estimates for each of the 12 categories against total MVPA. The assumption of proportional hazards was tested and held true for our MVPA exposure. All analyses accounted for the complex survey design in NHANES and were conducted using the SAS version 9.3 (SAS Insistute Inc) and SUDAAN (RTI International) statistical packages.

Results

Over a mean follow‐up of 6.6 years, 700 deaths were recorded. Participants were 46.7% male and 77.4% non‐Hispanic white, 17.4% had less than a high school education, 21.1% were current smokers, and 62.0% reported drinking alcohol.

For each of the 3 MVPA measures, greater MVPA was associated with lower mortality (P trend <0.01 Figure 1). HRs ranged from 0.24 to 0.44 and were nearly identical for each measure. For example, risk was similar in the upper quartiles for total MVPA (HR, 0.27 95% confidence interval [CI], 0.16–0.45), 5‐minute bouts (HR, 0.28 95% CI, 0.17–0.45), and 10‐minute bouts (HR, 0.35 95% CI, 0.23–0.53) (Table S2). Among the categories jointly classified by quartiles of total MVPA and tertiles of bouted MVPA, greater total MVPA was associated with lower mortality, but greater proportions of bouted MVPA showed no additional risk reduction (Table). Specifically, within a given quartile of MVPA, HRs were similar across tertiles of bout proportion (Table, columns 2–4). For example, in the first MVPA quartile, higher contributions of bouted activity resulted in similar HRs for moderate (0.75 95% CI, 0.60–0.95) and high amounts of bouted activity (0.77 95% CI, 0.60–0.99). HRs across tertiles within each of the remaining quartiles were also similar. Analyses replicated with bouts of ≥10 minutes were unstable in the lowest 2 quartiles because >30% of the sample had no ≥10‐minute bouts, but showed the same pattern for quartiles 3 and 4 (data not shown). To visualize these relationships, we plotted the HRs for each of the 12 categories by total MVPA in each category (Figure 2). Overall, greater total MVPA was associated with lower mortality, reaching a plateau at about 100 min/d, with no appreciable additional benefit of greater relative contributions of bouted activity. It was also evident that accumulating greater total MVPA required continuous bouts of activity.

Figure 1. Main effects for quartile‐specific distributions of total minutes per day of moderate‐to‐vigorous physical activity (MVPA), and both ≥5‐ and ≥10‐minute bouts of accumulated minutes per day of MVPA. Quartiles: total MVPA (≤40.2, 40.2–79.5, 79.5–123.4, and >123.4 min/d) 5‐minute bouts MVPA (≤10.7, 10.7–34.3, 34.3–70.7, and >70.7 min/d) 10‐minute bouts MVPA (0.0, 0.0–5.1, 5.1–20.5, >20.5 min/d). Hazard ratios are adjusted for age, sex, race‐ethnicity, education, alcohol consumption, smoking status, body mass index, and self‐reported diagnosis of diabetes mellitus, coronary artery disease, stroke, cancer, and mobility limitation.

Table 1. Mortality HRs for Joint Effects of Total MVPA and Proportions of Bouted (≥5 Minutes) MVPA

CI indicates confidence interval.

a Computed as (minutes per day of moderate‐to‐vigorous physical activity [MVPA] in ≥5‐minute bouts per total minutes per day of MVPA)×100. Sum of sporadic and bouted MVPA may exceed total MVPA due to allowance for minutes below threshold in bouts. Hazard ratios (HRs) are adjusted for age, sex, race‐ethnicity, education, alcohol consumption, smoking status, body mass index, and self‐reported diagnosis of diabetes mellitus, coronary artery disease, stroke, cancer, and mobility limitation.

Figure 2. Distribution of hazard ratios provided in the Table by total duration of moderate‐to‐vigorous physical activity ( MVPA ) for jointly classified quartiles of total minutes and tertiles of relative contribution of bouted minutes. For example, 4,1 is equivalent to combined quartile 4 of total MVPA and tertile 1 (Table) of the relative contribution of bouted to total minutes. The relative contribution (%) of bouted MVPA minutes ranged from 3% (bright yellow) to 81% (dark red). The joint group 4,1 represents 150 minutes in total MVPA and ≈50% of the total duration was accumulated in bouts of ≥5 minutes. The remaining 50% was accumulated in sporadic activity. The grey error bars indicate the upper and lower 95% confidence intervals for respective hazard ratios. Hazard ratios are adjusted for age, sex, race‐ethnicity, education, alcohol consumption, smoking status, body mass index, and self‐reported diagnosis of diabetes mellitus, coronary artery disease, stroke, cancer, and mobility limitation.

Discussion

This prospective study examined the relative benefits of bouted versus sporadic MVPA on mortality in a representative sample of US adults, using an objective measure of physical activity. Greater total MVPA was strongly associated with lower mortality, and bouted activity conferred little additional benefit. Thus, these results provide evidence that mortality risk reductions associated with MVPA are independent of how activity is accumulated. These results can inform the development of the second edition of the Physical Activity Guidelines for Americans and other recommendations.

Several published studies have examined the associations between physical activity and mortality and were used to inform the current physical activity guidelines. 3 However, most of these studies relied on data obtained from self‐reports and only a few explored these associations using device‐based measures of physical activity. 13 , 18 , 19 , 20 , 21 , 22 , 23 Even though the current physical activity guidelines recommend that activity be accumulated in bouts of ≥10 minutes, most of these studies also examined the relative benefits of sporadic MVPA. The few studies specifically examining the value of bouted physical activity showed that sporadic versus bouted activity had similar associations with the metabolic syndrome, waist circumference, and body mass index. 4 , 5 , 6 , 7 , 8 However, all of these studies employed cross‐sectional designs and examined intermediate end points. Thus, these studies could not address the ancillary question of whether sporadic and bouted activity can provide similar health benefits. In our study, similar to earlier published NHANES studies, we found risk reductions for all‐cause mortality to range from 60% to 80% across increased amounts of accumulated sporadic MVPA. However, the key finding of our study was that lowered risk for all‐cause mortality associated with sporadic MVPA was no different than the lowered risk associated with activity accumulated in bouts of ≥5 minutes. This finding aligns with previous studies examining cross‐sectional associations of sporadic versus bouted activity with various health risk factors however, it provides new evidence that benefits for mortality, a robust health end point, are independent of how activity is accumulated.

Our study is the first to use data from a representative sample of US adults with device‐based estimates of physical activity to compare the benefits of sporadic with bouted activity. Our analyses provide a robust estimate of such benefits but include a few challenges that are worth mentioning. We found that total and bouted activity were highly correlated (r=0.7–0.9) and that few individuals in the United States accumulate activity in bouts of ≥10 minutes (>30% of the sample had no 10‐minute bouts detected). These preliminary findings shaped our efforts in modeling the associations among sporadic versus bouted activity and mortality. To address these challenges, we jointly classified quartiles of total MVPA at various contributions of bouted activity of ≥5 minutes. We were unable to fully analyze the effects of MVPA accumulated in bouts of ≥10 minutes however, where data were available, results for 5‐ and 10‐minute bouts were similar. We also recognize that a variety of published cut points are available to define MVPA intensity. 18 NHANES studies have commonly employed 2020 counts per minute, which is based on ambulatory calibration, to define MVPA however, we chose to use a cut point calibrated to capture a greater variety of lifestyle activities in addition to ambulatory movement. Our selected cut point has been extensively evaluated and demonstrated to provide valuable insights when examining the associations between physical activity and mortality. 13 , 15 , 16 , 17 , 23 We explored the use of the ambulatory MVPA threshold (ie, 2020 counts per minute) in our study but found limited utility as the majority of our sample did not accumulate any MVPA in bouts of 10 minutes with this threshold. We previously examined the associations of sporadic activity using either 760 or 2020 counts per minute and found similar associations with mortality (unpublished findings). Thus, we do not expect our conclusions to be dependent on our choice of the 760 cut point, and consider that the magnitude of our associations for both sporadic and bouted activity may be conservative.

Conclusions

Despite the historical notion that physical activity needs to be performed for a minimum duration to elicit meaningful health benefits, we provide novel evidence that sporadic and bouted MVPA are similarly associated with substantially reduced mortality. This finding can inform future physical activity guidelines and guide clinical practice when advising individuals about the benefits of physical activity. Practitioners can promote either long single or multiple shorter episodes of activity in advising adults on how to progress toward 150 min/wk of MVPA. This flexibility may be particularly valuable for individuals who are among the least active and likely at greater risk for developing chronic conditions.


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Comments:

  1. Zedekiah

    This extraordinarily your opinion

  2. Bhric

    This message is simply matchless ;)

  3. Haytham

    not everything is so simple, as it seems



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