Saturday, January 15, 2011
Crossroads
I posted an academic piece I wrote on cancer biology recently...and despite intentions of transitioning the blog to a more critical look at biology with a sprinkle of my own life, it isn't there yet.
I got a great ride in today. Columbia is really a fantastic place to live. With that in mind, last weekend while Maggie and I were trying to make a final decision about whether we're moving or not, I had a bit of an epiphany: what I do on a daily basis has profound effects on my health and I need to do everything I can to protect my health.
With that said, I'll continue with my PhD and graduate school here at MU. No move. Possibly no MD and no med school for the time being. As crazy as it sounds, but proper sleep, time with family, good nutriton, time spent outside, and riding my bike are something I just won't compromise right now. Returning to medical school in June and then starting a residency in 2 years, too high of a portion of my day will be at work. It isn't that a PhD is any easier, but I can get my stuff done and be serious about it in a confined period of time.
Friday, January 7, 2011
My thoughts on cancer biology
Cancer is a global challenge. An overwhelming amount of scientific, medical, and social progress has been achieved in the last 30 years with respect to cancer. However, cancer remains a vexing economic, health, and community challenge around the world. It is estimated that 1,529,560 Americans (789,620 men and 739,940 women) will be diagnosed with and 569,490 men and women will die of cancer of all sites in 2010.(1) Indeed, the lifetime risk of being faced with a cancer diagnosis is ~1 out of 2 for every man and women, i.e. 40.77% of men and women born today will be diagnosed with cancer of all sites at some time during their lifetime. On January 1, 2007 there were 11,713,736 living US citizens, 5,353,054 men and 6,360,682 women, who had a history of cancer of any site.1 Globally, the statistics are staggering. It is estimated that 12.9 million new cancer cases were diagnosed in 2009 and this number is expected to rise to 16.8 million by 2020.(3) It is the second leading cause of death and disability both in the US and worldwide.
The global burden of cancer, based on the incidence of new cases and deaths, has doubled within the last 30 years.2 The costs associated with this burden include medical spending such as costs of diagnosis, in-patient treatment and care, and out-patient treatment, in addition to productivity losses such as lost income due to cancer morbidity associated with new cancer cases. The worldwide cancer costs, excluding research expenditures have been estimated to be at least $286 billion in 2009 alone.(3) That sum does not include the topic of this document; the amount spent on cancer research, which totals at least $19 billion worldwide.(3) Lastly, it should be emphasized that although the disease is indiscriminate with respect to socio-economic boundaries, the global funding for cancer research is almost entirely accounted for by developed nations.
The infrastructure of the scientific and research communities of the US and the personel have contributed immensely to our current understanding of cancer biology.
This post will follow an outline format to provide an overview of the following:
I. Our understanding of cancer biology in 2010
II. Major accomplishments of academic, biotechnology, and pharmaceutical research on cancer
III. Remaining problems for scientists and physicians working in cancer biology
IV. Specific areas of high priority research
V. Concluding remarks and overall progress report
I . Cancer is the common term for all malignant tumors. There are >100 types of cancer, each classified according to the types of cells from which they develop. We understand cancer to be an abnormal mass of tissue, compromised of cells, the growth of which exceeds and is uncoordinated with that of the normal tissues.4 Most affect solid tissues, but some such as leukemias and lymphomas can be distributed throughout the circulatory system.
The mechanism of disease is incredibly complex and not fully understood. The growth of cancers is often described as occurring without restraint because of, when left to their own natural history, the ability to colonize and invade foreign tissues. This persistence of growth and inability to undergo normal processes of restraint results from somatic genes (although occasional germline mutations are present) inside the tumor cells that are heritable elements passed down to the progeny of the tumor cells. Often, the genes of tumor cells are in fact the driving force that allows for autonomous, excessive, and unregulated growth. Despite the knowledge that cancer is a genetic disease, we also know that only a minority of cancer syndromes are heritable.
Fundamental to cancer biology is the notion that the entire population of cells forming a tumor arises from a microevolutionary process whereby a single cell experiences an initial insult, often genetic damage acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or inherited in the germ line. This damage leads to dysregulation of the cellular machinery controlling replication, the integrity or fidelity of the genomes, adherence to surrounding cells, and the biochemical/physical communication with the organism at large. This event is termed transformation.(5, 6)
The progeny of the transformed cell has the same or similar alterations and therefore are known to be clonal.11 As tumors grow, local invasion of a tissue can occur. In a process that is now understood to be multi-step, as time passes (depending on the context the scale ranges from days to up to years or decades), tumor progression occurs where further alterations and mutations accumulate and may lead to the ability of some cells within the tumor to enter into the circulatory system and eventually invade distant areas of the body, i.e. metastasize. This process is the subject of intense scientific scrutiny. And there is substantial evidence to support that there are steps leading to the phenomena of metastasis and that these steps reflect accumulating genetic alterations.7, 8, 9, 10 In other words, the temporal progression of a cell from a normal differentiated epithelial cell to a life threatening carcinoma requires multiple and successive mutations and/or alterations working under the selective pressures of a permissive microenvironment, each of which conferring growth advantage and laying the foundation for metastatic potential.16
Metastatic cancer represents the major cause of cancer-related morbidity and mortality. Metastatic disease can be thought of as monoclonal, because at any point in time, one sick cell gave rise to all subsequent cells, in addition to being heterogeneous, because progeny cells can undergo further alterations. This is to say that cancer is a disease with dynamic changes to its genome and behavior, and that each case of cancer is characterized by its own array of genetic lesions, e.g. recently completed genome-wide sequencing analysis of breast and colon cancers has revealed that individual tumors accumulate an average of 90 mutant genes.10
To summarize the above, the behavior of malignant tumors can be divided into four phases: (1) transformation; (2) local growth; (3) local invasion; and (4) distant metastases. Each of these phases is now better understood because of rigorous study in multiple fields of scientific inquiry at the level of molecular mechanisms. This growing understanding holds incredible promise for the future in reducing disease burden and mortality from cancer because the scientific body of knowledge is the source upon which medical advances are drawn. Indeed, the rational design of drugs and treatment of cancer at all levels, including diagnosis, surgery, chemotherapy, radiation, recovery, and remission demands an understanding of the properties that cancer cells acquire as they grow, evolve, and spread.
II. The major accomplishments in cancer research include the discovery of the critical genes involved in cancer and the development of effective treatment strategies for some patients with metastatic disease. Both of these broad categories of advancement were made possible by the inquiry into the molecular basis of cancer cell behavior, i.e. cellular and molecular biology and the tools that those fields of study have developed. The technologic progress accomplished in these fields is massive. To name a few; we can now amplify, copy, and read gene sequences in a matter of hours with incredible fidelity; We can query proteins expressed by cells accurately and with confidence; Cells can be sorted on the basis of specific expression markers; human cell lines can be used to test drug efficacy; and many other revolutionary technologies. Through the techniques of molecular biology, in the 1970s, scientists became aware of two families of genes that are predominately involved in transformation:
(1) Oncogenes, which are genes involved in growth and when mutated or altered cause normal cells to proliferate. No single oncogene can fully transform cells in vitro, but cells can be transformed by combinations of oncogenes. Such cooperation is required because each oncogene is specialized to induce part of the phenotype necessary for full transformation.7
(2) Tumor suppressor genes, which are regulatory elements within cells to oversee and coordinate cell division, repair mistakes in DNA replication, and to initiate programmed cell death or apoptosis if needed. We now know that the emergence of malignant tumors requires mutational loss of many genes, including those that regulate apoptosis and senescence.8
We also now know DNA repair genes can be mutated but do not directly transform cells by affecting proliferation or apoptosis. Instead, they affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes.14, 15 Additionally, a new class of regulatory molecules, called microRNAs has recently been discovered. Although they do not encode proteins, different families have been shown to act as either oncogenes or tumor suppressors.12, 13
Another area of accomplishment, made possible by cell cultures is the discovery that mutations that cause cancer are often induced by carcinogens acting as mutagens. The mechanism can vary from viral insertional mutagenesis (about 1/5 of the worlds cancers are caused by viruses), to carcinogenic chemicals causing DNA adducts, and ionizing radiation acting to induce breaks in DNA strands.
The model that has been produced from research proposes a set of rules, including 6 hallmarks listed below, helping us understand how cancer cells differ from normal. This knowledge can lead to targeting therapies, such as the development of Gleevec to treat the specific oncogenic event in chronic myelogenous leukemia.17 These physiologic changes of cancer cells include:6, 9
• Self-sufficient growth signals or constitutively activated growth factor signaling.7, 9, 18, 19
• Resistance to anti-growth signals or inactivated cell cycle checkpoint20, 21
• Immortality or limitless replicative potential22, 23
• Resistance to cell death via activated anti-cell death signaling24, 25, 26
• Sustained angiogenesis via activated VEGF signalling27, 28
• Tissue invasion and metastasis by multiple mechanisms including loss of cell-to-cell interactions29
III. The principles above provide a foundation of strength in moving forward and working on cures for various cancers. However, a major challenge stems from the diversity of the >100 cancers known and because of this diversity, progress in the clinic has been slow. Although there are unifying principles, there will almost certainly never be a single cure. The spectrum of cellular pathophysiology is too broad. Moreover, as living cells with remarkable growth advantage, the microevolutionary process creates a difficult problem, e.g. a patient with breast cancer can have their original tumor tested for a specific oncogenic aberration and can be found to be negative in their primary tumor but positive in a distant metastasis. The current targeted drug for this mutation is also known to make the disease worse in people who lack the mutation, so what should be done in that scenario? It is also known that tumors can become treatment resistant and that even some of the new targeted agents such as VEGF inhibitors, over time, select for even more aggressive disease.
Cancer is indeed a terrible disease and although there have been successes with hematologic malignancies (especially amongst children) and germ cell tumors, many carcinomas are still very difficult to treat. The oncology literature generally proclaims statistical victories with P<.05 despite only weeks of survival gains. Indeed, it has been said that the clinical research efficacy bar is currently set too low, therefore hindering progress and that the “objectives, methods, and regulation of clinical trials need to change so that we can rapidly move drugs from the lab into the clinic, and then define those drugs that are effective and those patients who are most likely to benefit”.30
IV. Future areas of research ought to lead to substantial improvements in patient care and be conducted with that purpose in mind. Although many unanswered biological questions remain and represent missing links in a comprehensive understanding, with limited funding, the eventual contribution to patient care should at least be considered in deciding which questions to pursue. Promising areas include:
• Using viruses to treat cancer
• Gene therapy
• Helping the bodies immune system destroy cancer cells
• Designing drugs that target malignant cells
• Starving tumors of their blood supply and taking advantage of cancers’ altered metabolism
• Improving diagnostic tests
• Improving/reducing costs of care
• Helping the developing world with their cancer burden
V. Despite the complexities involved in understanding cancer, there is a concept amongst the experts of the cancer biology community, that cancer research is a logical science, “where the complexities of the disease, described in the laboratory and clinic, will become understandable in terms of a small number of underlying principles”.6 There is a notion that various aspects of tumor biology, although diverse and complex in scope, are supported in the literature to be “acquired capabilities-shared by most and perhaps all types of human cancer”.6 This guiding principle is the conclusion drawn from the observations made by the field of cellular biology and indeed fundamental to biology itself, that virtually all mammalian cells share similar processes and machinery which regulates proliferation, death, and differentiation.6
Figure references:
Table page 1- Reference #3
Figure 1, 2, 3- Reference #5
Table page 5- Reference #30
Text References:
1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/ based on November 2009 SEER data submission, posted to the SEER web site, 2010.
2. Boyle P, Levin B (eds.) World Cancer Report 2008, Lyon: International Agency for Research on Cancer. 2008.
3. The Economist. “Breakaway: The Global Burden of Cancer-challenges and opportunities”, a report from the Economist Intelligence Unit 2009. Sponsored by LiveStrong. http://www.livestrong.org/What-We-Do/Our-Approach/Reports-Findings/Economic-Impact-Report
4. Willis R: The Spread of Tumors in the Human Body, London, Butterworth, 1952.
5. Kumar et al. Robbins Pathological basis of Disease. 7th Edition. Elsevier Saunders
6. Weinberg RA, Hanahan D: The hallmarks of cancer. Cell 2000; 100:57.
7. Halazonetis TD, et al: An oncogene-induced DNA damage model for cancer. Science 2008; 319:1352.
8. Knudson A: Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157.
9. Hahn W, Weinberg R: Rules for making human tumor cells. N Engl J Med 2002; 347:1593.
10. Wood LD, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007; 318(5853):1108.
11. Gale RE: Evaluation of clonality in myeloid stem-cell disorders. Semin Hematol 1999; 36:361.
12. Zhang W, et al: MicroRNAs in tumorigenesis: a primer. Am J Pathol 2007; 171:728
13. Rana TM: Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8:23.
14. Jiricny J, Marra G: DNA repair defects in colon cancer. Curr Opin Genet Dev 2003; 13:61.
15. Friedberg EC: How nucleotide excision repair protects against cancer. Nat Rev Cancer 2001; 1:22.
16. Loeb LA, et al: Multiple mutations and cancer. Proc Natl Acad Sci U S A 2003; 100:776.
17. Kurzrock R, et al: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003; 138:819.
18. Sharma SV, Settleman J: Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes and Development 2007; 21:3214.
19. Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17:45.
20. Kastan MB, Bartek J: Cell cycle checkpoints and cancer. Nature 2004; 432:316.
21. Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2002; 2:103.
22. Deng Y, et al: Telomere dysfunction and tumor suppression: the senescence connection. Nature Rev. Cancer 2008; 8:450.
23. Sharpless N, DePinho R: Telomeres, stem cells, senescence, and cancer. J Clin Invest 2004; 113:160.
24. Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell 2004; 116:205.
25. Korsmeyer SJ: Programmed cell death and the regulation of homeostasis. Harvey Lect 1999; 95:21.
26. Igney FH, Krammer PH: Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2:277.
27. Nagy J, et al: VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2007; 2:251.
28. Bergers G, Benjamin L: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401.
29. Fidler IJ: The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nat Rev Cancer 2003; 3:453.
30. Stewart DJ, Kurzrock R.Cancer: The Road to Amiens. J Clin Oncol. 2009 Jan 20;27(3):328-33.
The global burden of cancer, based on the incidence of new cases and deaths, has doubled within the last 30 years.2 The costs associated with this burden include medical spending such as costs of diagnosis, in-patient treatment and care, and out-patient treatment, in addition to productivity losses such as lost income due to cancer morbidity associated with new cancer cases. The worldwide cancer costs, excluding research expenditures have been estimated to be at least $286 billion in 2009 alone.(3) That sum does not include the topic of this document; the amount spent on cancer research, which totals at least $19 billion worldwide.(3) Lastly, it should be emphasized that although the disease is indiscriminate with respect to socio-economic boundaries, the global funding for cancer research is almost entirely accounted for by developed nations.
The infrastructure of the scientific and research communities of the US and the personel have contributed immensely to our current understanding of cancer biology.
This post will follow an outline format to provide an overview of the following:
I. Our understanding of cancer biology in 2010
II. Major accomplishments of academic, biotechnology, and pharmaceutical research on cancer
III. Remaining problems for scientists and physicians working in cancer biology
IV. Specific areas of high priority research
V. Concluding remarks and overall progress report
I . Cancer is the common term for all malignant tumors. There are >100 types of cancer, each classified according to the types of cells from which they develop. We understand cancer to be an abnormal mass of tissue, compromised of cells, the growth of which exceeds and is uncoordinated with that of the normal tissues.4 Most affect solid tissues, but some such as leukemias and lymphomas can be distributed throughout the circulatory system.
The mechanism of disease is incredibly complex and not fully understood. The growth of cancers is often described as occurring without restraint because of, when left to their own natural history, the ability to colonize and invade foreign tissues. This persistence of growth and inability to undergo normal processes of restraint results from somatic genes (although occasional germline mutations are present) inside the tumor cells that are heritable elements passed down to the progeny of the tumor cells. Often, the genes of tumor cells are in fact the driving force that allows for autonomous, excessive, and unregulated growth. Despite the knowledge that cancer is a genetic disease, we also know that only a minority of cancer syndromes are heritable.
Fundamental to cancer biology is the notion that the entire population of cells forming a tumor arises from a microevolutionary process whereby a single cell experiences an initial insult, often genetic damage acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or inherited in the germ line. This damage leads to dysregulation of the cellular machinery controlling replication, the integrity or fidelity of the genomes, adherence to surrounding cells, and the biochemical/physical communication with the organism at large. This event is termed transformation.(5, 6)
The progeny of the transformed cell has the same or similar alterations and therefore are known to be clonal.11 As tumors grow, local invasion of a tissue can occur. In a process that is now understood to be multi-step, as time passes (depending on the context the scale ranges from days to up to years or decades), tumor progression occurs where further alterations and mutations accumulate and may lead to the ability of some cells within the tumor to enter into the circulatory system and eventually invade distant areas of the body, i.e. metastasize. This process is the subject of intense scientific scrutiny. And there is substantial evidence to support that there are steps leading to the phenomena of metastasis and that these steps reflect accumulating genetic alterations.7, 8, 9, 10 In other words, the temporal progression of a cell from a normal differentiated epithelial cell to a life threatening carcinoma requires multiple and successive mutations and/or alterations working under the selective pressures of a permissive microenvironment, each of which conferring growth advantage and laying the foundation for metastatic potential.16
Metastatic cancer represents the major cause of cancer-related morbidity and mortality. Metastatic disease can be thought of as monoclonal, because at any point in time, one sick cell gave rise to all subsequent cells, in addition to being heterogeneous, because progeny cells can undergo further alterations. This is to say that cancer is a disease with dynamic changes to its genome and behavior, and that each case of cancer is characterized by its own array of genetic lesions, e.g. recently completed genome-wide sequencing analysis of breast and colon cancers has revealed that individual tumors accumulate an average of 90 mutant genes.10
To summarize the above, the behavior of malignant tumors can be divided into four phases: (1) transformation; (2) local growth; (3) local invasion; and (4) distant metastases. Each of these phases is now better understood because of rigorous study in multiple fields of scientific inquiry at the level of molecular mechanisms. This growing understanding holds incredible promise for the future in reducing disease burden and mortality from cancer because the scientific body of knowledge is the source upon which medical advances are drawn. Indeed, the rational design of drugs and treatment of cancer at all levels, including diagnosis, surgery, chemotherapy, radiation, recovery, and remission demands an understanding of the properties that cancer cells acquire as they grow, evolve, and spread.
II. The major accomplishments in cancer research include the discovery of the critical genes involved in cancer and the development of effective treatment strategies for some patients with metastatic disease. Both of these broad categories of advancement were made possible by the inquiry into the molecular basis of cancer cell behavior, i.e. cellular and molecular biology and the tools that those fields of study have developed. The technologic progress accomplished in these fields is massive. To name a few; we can now amplify, copy, and read gene sequences in a matter of hours with incredible fidelity; We can query proteins expressed by cells accurately and with confidence; Cells can be sorted on the basis of specific expression markers; human cell lines can be used to test drug efficacy; and many other revolutionary technologies. Through the techniques of molecular biology, in the 1970s, scientists became aware of two families of genes that are predominately involved in transformation:
(1) Oncogenes, which are genes involved in growth and when mutated or altered cause normal cells to proliferate. No single oncogene can fully transform cells in vitro, but cells can be transformed by combinations of oncogenes. Such cooperation is required because each oncogene is specialized to induce part of the phenotype necessary for full transformation.7
(2) Tumor suppressor genes, which are regulatory elements within cells to oversee and coordinate cell division, repair mistakes in DNA replication, and to initiate programmed cell death or apoptosis if needed. We now know that the emergence of malignant tumors requires mutational loss of many genes, including those that regulate apoptosis and senescence.8
We also now know DNA repair genes can be mutated but do not directly transform cells by affecting proliferation or apoptosis. Instead, they affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes.14, 15 Additionally, a new class of regulatory molecules, called microRNAs has recently been discovered. Although they do not encode proteins, different families have been shown to act as either oncogenes or tumor suppressors.12, 13
Another area of accomplishment, made possible by cell cultures is the discovery that mutations that cause cancer are often induced by carcinogens acting as mutagens. The mechanism can vary from viral insertional mutagenesis (about 1/5 of the worlds cancers are caused by viruses), to carcinogenic chemicals causing DNA adducts, and ionizing radiation acting to induce breaks in DNA strands.
The model that has been produced from research proposes a set of rules, including 6 hallmarks listed below, helping us understand how cancer cells differ from normal. This knowledge can lead to targeting therapies, such as the development of Gleevec to treat the specific oncogenic event in chronic myelogenous leukemia.17 These physiologic changes of cancer cells include:6, 9
• Self-sufficient growth signals or constitutively activated growth factor signaling.7, 9, 18, 19
• Resistance to anti-growth signals or inactivated cell cycle checkpoint20, 21
• Immortality or limitless replicative potential22, 23
• Resistance to cell death via activated anti-cell death signaling24, 25, 26
• Sustained angiogenesis via activated VEGF signalling27, 28
• Tissue invasion and metastasis by multiple mechanisms including loss of cell-to-cell interactions29
III. The principles above provide a foundation of strength in moving forward and working on cures for various cancers. However, a major challenge stems from the diversity of the >100 cancers known and because of this diversity, progress in the clinic has been slow. Although there are unifying principles, there will almost certainly never be a single cure. The spectrum of cellular pathophysiology is too broad. Moreover, as living cells with remarkable growth advantage, the microevolutionary process creates a difficult problem, e.g. a patient with breast cancer can have their original tumor tested for a specific oncogenic aberration and can be found to be negative in their primary tumor but positive in a distant metastasis. The current targeted drug for this mutation is also known to make the disease worse in people who lack the mutation, so what should be done in that scenario? It is also known that tumors can become treatment resistant and that even some of the new targeted agents such as VEGF inhibitors, over time, select for even more aggressive disease.
Cancer is indeed a terrible disease and although there have been successes with hematologic malignancies (especially amongst children) and germ cell tumors, many carcinomas are still very difficult to treat. The oncology literature generally proclaims statistical victories with P<.05 despite only weeks of survival gains. Indeed, it has been said that the clinical research efficacy bar is currently set too low, therefore hindering progress and that the “objectives, methods, and regulation of clinical trials need to change so that we can rapidly move drugs from the lab into the clinic, and then define those drugs that are effective and those patients who are most likely to benefit”.30
IV. Future areas of research ought to lead to substantial improvements in patient care and be conducted with that purpose in mind. Although many unanswered biological questions remain and represent missing links in a comprehensive understanding, with limited funding, the eventual contribution to patient care should at least be considered in deciding which questions to pursue. Promising areas include:
• Using viruses to treat cancer
• Gene therapy
• Helping the bodies immune system destroy cancer cells
• Designing drugs that target malignant cells
• Starving tumors of their blood supply and taking advantage of cancers’ altered metabolism
• Improving diagnostic tests
• Improving/reducing costs of care
• Helping the developing world with their cancer burden
V. Despite the complexities involved in understanding cancer, there is a concept amongst the experts of the cancer biology community, that cancer research is a logical science, “where the complexities of the disease, described in the laboratory and clinic, will become understandable in terms of a small number of underlying principles”.6 There is a notion that various aspects of tumor biology, although diverse and complex in scope, are supported in the literature to be “acquired capabilities-shared by most and perhaps all types of human cancer”.6 This guiding principle is the conclusion drawn from the observations made by the field of cellular biology and indeed fundamental to biology itself, that virtually all mammalian cells share similar processes and machinery which regulates proliferation, death, and differentiation.6
Figure references:
Table page 1- Reference #3
Figure 1, 2, 3- Reference #5
Table page 5- Reference #30
Text References:
1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/ based on November 2009 SEER data submission, posted to the SEER web site, 2010.
2. Boyle P, Levin B (eds.) World Cancer Report 2008, Lyon: International Agency for Research on Cancer. 2008.
3. The Economist. “Breakaway: The Global Burden of Cancer-challenges and opportunities”, a report from the Economist Intelligence Unit 2009. Sponsored by LiveStrong. http://www.livestrong.org/What-We-Do/Our-Approach/Reports-Findings/Economic-Impact-Report
4. Willis R: The Spread of Tumors in the Human Body, London, Butterworth, 1952.
5. Kumar et al. Robbins Pathological basis of Disease. 7th Edition. Elsevier Saunders
6. Weinberg RA, Hanahan D: The hallmarks of cancer. Cell 2000; 100:57.
7. Halazonetis TD, et al: An oncogene-induced DNA damage model for cancer. Science 2008; 319:1352.
8. Knudson A: Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157.
9. Hahn W, Weinberg R: Rules for making human tumor cells. N Engl J Med 2002; 347:1593.
10. Wood LD, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007; 318(5853):1108.
11. Gale RE: Evaluation of clonality in myeloid stem-cell disorders. Semin Hematol 1999; 36:361.
12. Zhang W, et al: MicroRNAs in tumorigenesis: a primer. Am J Pathol 2007; 171:728
13. Rana TM: Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8:23.
14. Jiricny J, Marra G: DNA repair defects in colon cancer. Curr Opin Genet Dev 2003; 13:61.
15. Friedberg EC: How nucleotide excision repair protects against cancer. Nat Rev Cancer 2001; 1:22.
16. Loeb LA, et al: Multiple mutations and cancer. Proc Natl Acad Sci U S A 2003; 100:776.
17. Kurzrock R, et al: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003; 138:819.
18. Sharma SV, Settleman J: Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes and Development 2007; 21:3214.
19. Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17:45.
20. Kastan MB, Bartek J: Cell cycle checkpoints and cancer. Nature 2004; 432:316.
21. Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2002; 2:103.
22. Deng Y, et al: Telomere dysfunction and tumor suppression: the senescence connection. Nature Rev. Cancer 2008; 8:450.
23. Sharpless N, DePinho R: Telomeres, stem cells, senescence, and cancer. J Clin Invest 2004; 113:160.
24. Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell 2004; 116:205.
25. Korsmeyer SJ: Programmed cell death and the regulation of homeostasis. Harvey Lect 1999; 95:21.
26. Igney FH, Krammer PH: Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2:277.
27. Nagy J, et al: VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2007; 2:251.
28. Bergers G, Benjamin L: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401.
29. Fidler IJ: The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nat Rev Cancer 2003; 3:453.
30. Stewart DJ, Kurzrock R.Cancer: The Road to Amiens. J Clin Oncol. 2009 Jan 20;27(3):328-33.
Thursday, December 30, 2010
o ¡por fin!
I'm really glad this year is over.
We still haven't made a final decision regarding accompanying my mentor to Notre Dame, but at this point we're leaning towards staying in Columbia. The unfortunate consequence of that decision is that I'll probably discontinue my graduate school (abandon the PhD) and head back to finish med school...which although that won't be good for competitive cycling, I'm actually super motivated to get back to medicine!
I just read my friend's blog about his awesome accomplishments in bike racing this year and felt like writing my own version of a 2010 reflection. However as I sat down, I don't think I have enough to say about bike racing to write much. I had 2 goals for racing: 1. To win a bubba A race and 2. Top 5 in the state race
Other than that, here is a year in pictures:
Next year, more camping and more mountain biking are my goals. The end. Thanks for reading.
We still haven't made a final decision regarding accompanying my mentor to Notre Dame, but at this point we're leaning towards staying in Columbia. The unfortunate consequence of that decision is that I'll probably discontinue my graduate school (abandon the PhD) and head back to finish med school...which although that won't be good for competitive cycling, I'm actually super motivated to get back to medicine!
I just read my friend's blog about his awesome accomplishments in bike racing this year and felt like writing my own version of a 2010 reflection. However as I sat down, I don't think I have enough to say about bike racing to write much. I had 2 goals for racing: 1. To win a bubba A race and 2. Top 5 in the state race
Other than that, here is a year in pictures:
Next year, more camping and more mountain biking are my goals. The end. Thanks for reading.
Wednesday, December 22, 2010
Huge life decision ahead and winter training
After returning from Oregon, my PhD mentor with whom I've worked for this last year sat me down and told me that she got an incredible job offer as the director of a new cancer research institute at Notre Dame.
Now, the question of British punk band The Clash is on our mind.
There are lots of incredible career advancing and debt reliving benefits to accompanying her. But, it ain't so bad around here either. Anyway, big decision.
In terms of winter time and physical activity, I always hit the weight room this time of year. When I played Lacrosse in college, I learned how to squat, deadlift, press, and clean and IMHO those are about all you need in terms of lifting weight. One thing I learned early, is that even if I'm eating 4000-6000cal/day, I don't build ridiculous amounts of muscle...I just get stronger. Which for a power-endurance athlete is great.
Over the last year I have gotten much better at assessing weaknesses and understanding what I need to do to correct them. In general, I find that the key to a cyclist's lifting program is mobilizing the tissues which limit range of motion, e.g. hips (mostly stretching flexors and strengthening/activating extensors and rotators), ankles, and shoulders.
My sessions consists of about 10 minutes of foam rolling and digging into any tight areas with a lacrosse ball...see here. Then some dynamic exercises like high knee walks, lunging around, push-ups, etc. Next lifting. Right now my goal is to strengthen just about everything and stretch/mobilize the hell out of my hip flexors and quads.
My plan is 6-8 weeks of a 4 day per week split. 2 days will be 'full-body' days, one dedicated upper body, and one lower body only. Here's a sample for those that care:
Full day 1:
A) Front Squat for Speed: 6x2 at 60-70% of 1RM, 45s rest between sets
B) Stiff leg romanian deadlift: 3x10/side, 40X0 tempo (time for: eccentric, bottom, concentric, top)
C1) Alternating Low Incline DB Bench Press: 3x6/side, 31X4
C2) Chest-Supported Row, Pronated Grip: 4x6, 40X0
Lower Day:
A) Snatch-Grip Deadlift on Podium- Initially perform 10 sets of 3 reps on a 50X0 tempo, resting 3 minutes between sets. Keep the weight constant until able to perform 10 sets of 5 reps; then add 5 to 10 kilos (11 to 22 pounds) to the bar so back to 10 sets of 3.
B) Barbell Reverse Lunge — Front Squat Grip: 3x8/side
C1) Pallof Press Isometric Hold: 3x3/side (10s hold at lockout)
C2) Glute-Ham Raise (un-assisted: 3x8
Upper:
A1) Bench Press: 5x5
A2) Neutral Grip Pull-up: 5x3
B1) 1-arm DB Push Press: 3x8/side
B2) Seated Cable Row — Neutral Grip: 3x8
C1) Ab Wheel Rollout: 3x8
C2) Side-Lying External Rotation: 3x10/side
Full:
A1) Back Squat: 4x6 (form just like that video, but slower eccentrics)
A2) Feet-Elevated Push-up: 3x12
B1) Standing 1-arm Cable Row: 3x12/side
B2) Walking DB Lunge: 3x6/side
C1) Landmines: 3x5/side
C2) Supine No Money w/Band: 3x4 (10s hold on each rep)
D) Farmer's Walk: 3x40yds
Since the role of abs/core in cycling is stabilization this program emphasizes that. Actually, I challenge you to find any sport or real life activity in which a crunch or sit-up actually leads to better performance. The anti-rotational and stabilization function of the 'core' absolutely trumps trunk flexion for injury prevention, low-back health, and performance.
Now, the question of British punk band The Clash is on our mind.
There are lots of incredible career advancing and debt reliving benefits to accompanying her. But, it ain't so bad around here either. Anyway, big decision.
In terms of winter time and physical activity, I always hit the weight room this time of year. When I played Lacrosse in college, I learned how to squat, deadlift, press, and clean and IMHO those are about all you need in terms of lifting weight. One thing I learned early, is that even if I'm eating 4000-6000cal/day, I don't build ridiculous amounts of muscle...I just get stronger. Which for a power-endurance athlete is great.
Over the last year I have gotten much better at assessing weaknesses and understanding what I need to do to correct them. In general, I find that the key to a cyclist's lifting program is mobilizing the tissues which limit range of motion, e.g. hips (mostly stretching flexors and strengthening/activating extensors and rotators), ankles, and shoulders.
My sessions consists of about 10 minutes of foam rolling and digging into any tight areas with a lacrosse ball...see here. Then some dynamic exercises like high knee walks, lunging around, push-ups, etc. Next lifting. Right now my goal is to strengthen just about everything and stretch/mobilize the hell out of my hip flexors and quads.
My plan is 6-8 weeks of a 4 day per week split. 2 days will be 'full-body' days, one dedicated upper body, and one lower body only. Here's a sample for those that care:
Full day 1:
A) Front Squat for Speed: 6x2 at 60-70% of 1RM, 45s rest between sets
B) Stiff leg romanian deadlift: 3x10/side, 40X0 tempo (time for: eccentric, bottom, concentric, top)
C1) Alternating Low Incline DB Bench Press: 3x6/side, 31X4
C2) Chest-Supported Row, Pronated Grip: 4x6, 40X0
Lower Day:
A) Snatch-Grip Deadlift on Podium- Initially perform 10 sets of 3 reps on a 50X0 tempo, resting 3 minutes between sets. Keep the weight constant until able to perform 10 sets of 5 reps; then add 5 to 10 kilos (11 to 22 pounds) to the bar so back to 10 sets of 3.
B) Barbell Reverse Lunge — Front Squat Grip: 3x8/side
C1) Pallof Press Isometric Hold: 3x3/side (10s hold at lockout)
C2) Glute-Ham Raise (un-assisted: 3x8
Upper:
A1) Bench Press: 5x5
A2) Neutral Grip Pull-up: 5x3
B1) 1-arm DB Push Press: 3x8/side
B2) Seated Cable Row — Neutral Grip: 3x8
C1) Ab Wheel Rollout: 3x8
C2) Side-Lying External Rotation: 3x10/side
Full:
A1) Back Squat: 4x6 (form just like that video, but slower eccentrics)
A2) Feet-Elevated Push-up: 3x12
B1) Standing 1-arm Cable Row: 3x12/side
B2) Walking DB Lunge: 3x6/side
C1) Landmines: 3x5/side
C2) Supine No Money w/Band: 3x4 (10s hold on each rep)
D) Farmer's Walk: 3x40yds
Since the role of abs/core in cycling is stabilization this program emphasizes that. Actually, I challenge you to find any sport or real life activity in which a crunch or sit-up actually leads to better performance. The anti-rotational and stabilization function of the 'core' absolutely trumps trunk flexion for injury prevention, low-back health, and performance.
Sunday, December 12, 2010
Bend and Cross nationals
A lot of time, money, and energy has been spent to get me and my wife to Bend, OR along with our friends Matt and Lizz James. When we first started talking about the trip back in August, we've gone back-and-forth about the affordability, feasibility, and utilitarian aspects of this undertaking. With a 2-year-old at home, a limited budget, demanding jobs, and having already spent a few months with bicycle racing dominating virtually every weekend from Sep-Dec, there were many reasons not to make this trip.
In September and October, it looked like it wasn't a good idea to make the trip. It would be too much to fly and then ship bikes, then requiring a rental car big enough to transport the bikes. Leaving out daughter also seemed like a terrible idea since she is every bit of a 'needy' 2-year-old right now (not sure if needy is the right word, but if you have kids or know many 2 year olds, you probably know what I mean).
Slowly however, we began coming up with solutions.
-First and foremost, grandparents offered to take time off work and come to our house too keep our daughter on her own turf. Unbelievably kind. Best christmas/bday present to us ever!
-Maggie and I got to use her parents frequent flyer miles for our plane tickets, again, an incredible bday/xmas present. Thank you SO much.
-We'd find the cheapest rental house possible and split it with Matt and Lizz. We can cook, do laundry, and relax in our own space!
-Bikes would be provided for us by the Specialized demo truck! These were full sram force equipped Cruxes with Zipp 303s and Dugast Rhino tubulars! All, because Specialized is an amazing company with a ton of great people working for them.
-Because we'd have bikes waiting for us, we could split a cheaper and smaller rental car with Matt and Lizz! Amazors!
The lingering issue was the question Maggie and I had about the trips' selfishness with respect to our family and our jobs. Was it worth it? Should we devote so much time and energy to a weekend away at a huge bike race? I'm not a pro cyclist and have no intentions of ever being one. The chance of doing well in the race was realistically the chance of a top-20 finish in the Master's 30-34 category. If we're going to take a vacation, why not just a cozy weekend away at a B&B in Missouri?
At this point, the cyclocross aspects of the trip have made every ounce of energy poured into bike racing completely worth it. The race is over and now it is time to just enjoy this incredible state and town of Bend.
The race yesterday was unreal. Matt and I started in the 5th and 4th rows respectively and both battled our way to middle of the pack finishes (41st and 31st place out of 74 racers) and easily had one of the coolest cycling experiences I've ever had. There were 6in deep water puddles, long quick-sand mud sections, a drum core marching band, hundreds of cheering fans, tons of cow bell, and every person I raced with seemed to be very positive about it.
Plus, our biggest fans were there to support us and put up with our silly passion for riding curly bar road bikes around a small loop in the grass, cold, rain/snow, and mud. My stress level right now is zero. In my own crazy mind, that makes me better as a husband, father, scientist, and person.
In September and October, it looked like it wasn't a good idea to make the trip. It would be too much to fly and then ship bikes, then requiring a rental car big enough to transport the bikes. Leaving out daughter also seemed like a terrible idea since she is every bit of a 'needy' 2-year-old right now (not sure if needy is the right word, but if you have kids or know many 2 year olds, you probably know what I mean).
Slowly however, we began coming up with solutions.
-First and foremost, grandparents offered to take time off work and come to our house too keep our daughter on her own turf. Unbelievably kind. Best christmas/bday present to us ever!
-Maggie and I got to use her parents frequent flyer miles for our plane tickets, again, an incredible bday/xmas present. Thank you SO much.
-We'd find the cheapest rental house possible and split it with Matt and Lizz. We can cook, do laundry, and relax in our own space!
-Bikes would be provided for us by the Specialized demo truck! These were full sram force equipped Cruxes with Zipp 303s and Dugast Rhino tubulars! All, because Specialized is an amazing company with a ton of great people working for them.
-Because we'd have bikes waiting for us, we could split a cheaper and smaller rental car with Matt and Lizz! Amazors!
The lingering issue was the question Maggie and I had about the trips' selfishness with respect to our family and our jobs. Was it worth it? Should we devote so much time and energy to a weekend away at a huge bike race? I'm not a pro cyclist and have no intentions of ever being one. The chance of doing well in the race was realistically the chance of a top-20 finish in the Master's 30-34 category. If we're going to take a vacation, why not just a cozy weekend away at a B&B in Missouri?
At this point, the cyclocross aspects of the trip have made every ounce of energy poured into bike racing completely worth it. The race is over and now it is time to just enjoy this incredible state and town of Bend.
The race yesterday was unreal. Matt and I started in the 5th and 4th rows respectively and both battled our way to middle of the pack finishes (41st and 31st place out of 74 racers) and easily had one of the coolest cycling experiences I've ever had. There were 6in deep water puddles, long quick-sand mud sections, a drum core marching band, hundreds of cheering fans, tons of cow bell, and every person I raced with seemed to be very positive about it.
Plus, our biggest fans were there to support us and put up with our silly passion for riding curly bar road bikes around a small loop in the grass, cold, rain/snow, and mud. My stress level right now is zero. In my own crazy mind, that makes me better as a husband, father, scientist, and person.
Tuesday, December 7, 2010
MO state champs! Cat 1/2!
A year ago in Herman, Matt James and I crossed the line in the cat 3 race second and first respectively. This year, the race was in the birth place of Charlie Parker, home of Arthur Bryants, and after reading on wikipedia, apparently a large enclave of Irish Americans...KC, MO. Although we were only a stones throw away from Kansas, it was still the MO state championship.
I didn't know what to expect going into the race and was a bit disappointed that half of the KC cat1/2 field wasn't in attendance. Devin was sick, Jeff Yielding had already raced (and won) earlier, and Schottler resting. Plus, the race was on saturday so many folks, had to work. So it left Josh and I battling for the jersey. In addition, Andrew Coe was in attendance and proved to be a very worthy competitor as he pretty much crushed everyone there.
The race went something like this:
-1/2 lap in, Josh was at the front and I was on his wheel. Coming into the first set of barriers, there was a sidewalk crossing and unfortunately I slipped and scraped my knee pretty good but managed to recover and chase back onto Josh's wheel.
-Josh fell in the sandpit, just like in October ;) I passed and soon it was Andrew and me at the front. I haven't ridden with such a strong rider this year. He was attacking out of every corner and really riding well. A week ago, I think I could have ridden with him longer but this week, I just didn't feel on. It was a struggle and the hurt began early.
-After a few laps, I smacked the back of my knee with my pedal coming out of the sand and Andrew was gone. I hobbled around until Josh caught me and then tried to recover on his wheel for a few laps.
You can actually see the blood soaking through my right knee warmer here along with a cut on my shin. At this point, I'm not exactly sure what happened. Josh is my friend and I have a ton of respect for him but for some reason he and I have a hard time communicating non-verbally. I wasn't sure if we were working together to bring back Andrew or if he was trying to shake me off his wheel. All I knew was that I was hurting and wished my legs felt like the week before.
With 2 to go, Josh yelled at me to pull. So, I put in a big effort to try and catch Andrew. I guess my adrenaline got the best of me and I rode myself into a hole. With 1 to go, Josh came around me and I just couldn't match his pace. It was painful watching him ride away. Especially given the crappy week that preceded the race (had to travel to Houston to get another bump on my neck looked at).
This week I've come down with a nasty cold and am really hoping to feel better before leaving for Bend on Thursday. Maggie, Matt James, and his wife Lizz are coming with. Cassidy is staying with GaGa...very nervous about leaving her for so long, but we're also really looking forward to the trip.
Congrats to Andrew, Josh, Jeff Yielding, and as always T-tocs and storm for some impressive races and superior attitudes and states of mind.
Sunday, November 28, 2010
Last bubba and what I learned this year in CX
This weekend's race was a flat venue, with the potential for some mud. I was a bit nervous about being in good standing in the series and tried not to think about the point situation. Competition is fun for me, but in the end it is just about a healthy race environment and keeping perspective on things.
Last week I managed to get the week off from school/research and so spent it in St Louis with just Cassidy (my 2 year old) and me hanging out with the grandparents.
It was really what I needed to be away from cancer biology for a week. We did normal stuff like cook, go to the zoo, coffee shop, playground, and of course I found some time to ride. Specifically, Tuesday was an easy 2hr mtn bike ride at Castlewood with my good buddy Matt James and Justin Neely. Wednesday, the weather was rainy and upper-30s. Really quite miserable for biking. But over the past season I didn't do much structured training with the exception of wednesday's in November...which were 2min, 1min, or 30sec intervals each until I felt like I was loosing it a bit. My goal was to increase the number of intervals each week and land at 6 of each (6x2min, 6x1min, 6x:30). On wednesday, I went out in the morning and got drenched and cold, finishing only a few of the 2 min intervals. So, I went and got a rain jacket/change of clothes only to head back out for the remainder of the workout.
It is for that reason that I've decided that 'training' isn't how I want to approach bike riding and racing. I'm too intense about it. Too much of a type-A personality. Too scientific. I've always used movement/exercise as a kind of escape and work hard at whatever it is, but over the past year I've learned a ton from riding my bike and find that I'm a lot happier just riding as opposed to training. Sunday morning I woke feeling great despite having done some serious beer drinking the night before (and all the preceding evenings the entire week).
During the race I was glad to have a little ring (39t), as I spent the majority of the race trying to keep my cadence and pace high. Devin, Jeff, and I got a gap early and I ended up going off the front for about 6 laps to take the win.
Race started out like this:
Honestly it feels kind-of crazy as I didn't expect to do as well as I have during the bubba series. I guess I just didn't have any expectations for myself and I came in with a solid base of road riding from last winter/spring, some short track mtn bike racing in July, then nothing but the weight room during August and most of September. I'm convinced that the weight room and time off the bike has been a tremendous benefit to this cross season. A little bit ironic that I say I don't train, but still lift I suppose. I think lifting heavy things is a part of our ancestral-past and helps keep us healthy. If I had to design a longevity exercise routine, it'd consist of lifting 2-4 days per week, one or two hard 'interval' type days at whatever modality enjoyable, and then 1-2 long meandering type days (endurance riding, long hikes, long walks, etc).
Every other year for cross, I didn't have time to do long rides whereas this year, every Tuesday I managed gravel loop before work (~3hrs). More than anything else, I rode this year because I loved it and found so much peace of mind, especially on my Tuesday long rides (Josh Johnson actually encouraged me to sell the power meter and ride in this way). Wednesday's were cross practice or intervals in November. Thursday was either rest or an easy ride, then race as much as possible as long as it is fun.
Last week I managed to get the week off from school/research and so spent it in St Louis with just Cassidy (my 2 year old) and me hanging out with the grandparents.
It was really what I needed to be away from cancer biology for a week. We did normal stuff like cook, go to the zoo, coffee shop, playground, and of course I found some time to ride. Specifically, Tuesday was an easy 2hr mtn bike ride at Castlewood with my good buddy Matt James and Justin Neely. Wednesday, the weather was rainy and upper-30s. Really quite miserable for biking. But over the past season I didn't do much structured training with the exception of wednesday's in November...which were 2min, 1min, or 30sec intervals each until I felt like I was loosing it a bit. My goal was to increase the number of intervals each week and land at 6 of each (6x2min, 6x1min, 6x:30). On wednesday, I went out in the morning and got drenched and cold, finishing only a few of the 2 min intervals. So, I went and got a rain jacket/change of clothes only to head back out for the remainder of the workout. It is for that reason that I've decided that 'training' isn't how I want to approach bike riding and racing. I'm too intense about it. Too much of a type-A personality. Too scientific. I've always used movement/exercise as a kind of escape and work hard at whatever it is, but over the past year I've learned a ton from riding my bike and find that I'm a lot happier just riding as opposed to training. Sunday morning I woke feeling great despite having done some serious beer drinking the night before (and all the preceding evenings the entire week).
During the race I was glad to have a little ring (39t), as I spent the majority of the race trying to keep my cadence and pace high. Devin, Jeff, and I got a gap early and I ended up going off the front for about 6 laps to take the win.
Race started out like this:
Honestly it feels kind-of crazy as I didn't expect to do as well as I have during the bubba series. I guess I just didn't have any expectations for myself and I came in with a solid base of road riding from last winter/spring, some short track mtn bike racing in July, then nothing but the weight room during August and most of September. I'm convinced that the weight room and time off the bike has been a tremendous benefit to this cross season. A little bit ironic that I say I don't train, but still lift I suppose. I think lifting heavy things is a part of our ancestral-past and helps keep us healthy. If I had to design a longevity exercise routine, it'd consist of lifting 2-4 days per week, one or two hard 'interval' type days at whatever modality enjoyable, and then 1-2 long meandering type days (endurance riding, long hikes, long walks, etc).
Every other year for cross, I didn't have time to do long rides whereas this year, every Tuesday I managed gravel loop before work (~3hrs). More than anything else, I rode this year because I loved it and found so much peace of mind, especially on my Tuesday long rides (Josh Johnson actually encouraged me to sell the power meter and ride in this way). Wednesday's were cross practice or intervals in November. Thursday was either rest or an easy ride, then race as much as possible as long as it is fun.
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