Reflections on AGING

From join1440.com

“Background

Aging is the progressive decline of the human body’s function that results from a combination of genetic, environmental, and metabolic factors. As our cells accumulate damage, important systemic processes within the body become dysregulated, leading to an increased rate of disease and mortality (see overview here).

The global population is aging at an unprecedented rate, a phenomenon that carries significant social and economic challenges. Societies are investing heavily in the fight against aging—a recent analysis revealed that a slowdown of aging by just one year could be worth $38T in the US alone.

What Happens to the Body

As we age, our cells accumulate damage on many fronts, including mutations in DNA (the information code of our cells), shortening of telomeres (protective end caps on DNA strands), and epigenetic alterations (changes in how our cells read DNA information).

This causes our microscopic machinery to go awry. The result is decreased cellular function, impaired mitochondrial energy production, and less efficient repair mechanisms. Read more about the causes of cellular aging.

As our body’s building blocks break down, our organs and tissues experience an associated loss of structure and function. This results in a cycle of inflammation and tissue fibrosis that reduces the functional capacity of our vital organs.

All of these microscopic changes add up to what we see as “getting older.” Our bones lose the ability to resist stress (i.e., osteoporosis), the structural integrity of our skin fails (i.e., wrinkles), our heart no longer pumps with the necessary strength (i.e., heart failure), and we are more at risk of injury and disease.

What Happens to the Brain

The same cellular- and tissue-level changes associated with aging have a particularly destructive effect on our brains.

As cellular function decreases, inflammation rises and the accumulation of cellular waste disrupts the ability of our brain cells to talk to each other. This impairs our processing of complex cognitive tasks and weakens our memory (what happens to your brain through life).

These neurologic changes often translate to depression, social withdrawal, and increased susceptibility to diseases like Alzheimer’s and Parkinson’s dementia.

Chronological Versus Biological Aging

While the most familiar convention of measuring age is “chronological” (that is, measuring age in years), there is an emerging interest in determining “biological age.”

This method uses formulas or blood test results to estimate the cellular age of a person. In other words, biological age is not a function of time but rather of how well cellular and organ systems are functioning in each individual. In this way, interventions such as exercise, healthy lifestyles, and perhaps even medications could reverse one’s biological age—all while their chronological age increases.

While some testable biomarkers have emerged as candidates (e.g., the epigenetic clock), there is ongoing research to uncover simple, reliable means to measure and track one’s biological age over time.

Lifespan Versus Healthspan

While tremendous recent progress has been made in the field of aging, the emphasis has begun to shift from extending lifespan (the number of years one is alive) to maximizing an individual’s healthspan (the number of years one is active and without disease).

Researchers emphasize a holistic approach to nurturing your healthspan, including consistent daily movement and exercise, high-quality sleep hygiene, a balanced diet with whole foods, and more.”

 

Patient Compliance, Investigator Compliance, and More Compliance

  1. Importance of Compliance: Compliance (adherence to the study protocol by participants and researchers) is a cornerstone of successful clinical trials. Poor compliance can lead to unreliable results, increased costs, and even trial failure.
  2. Types of Compliance:
    • Participant Compliance: Refers to how well participants follow the trial protocol, including taking medications as prescribed, attending scheduled visits, and completing required procedures.
    • Investigator Compliance: Involves adherence by researchers to the trial protocol, including proper data collection, reporting, and ethical conduct.
  3. Consequences of Non-Compliance:
    • Non-compliance by participants can lead to biased outcomes, reduced statistical power, and difficulty in interpreting results.
    • Non-compliance by investigators can result in protocol violations, ethical issues, and compromised data integrity.
  4. Factors Affecting Compliance:
    • Participant Factors: Lack of understanding, forgetfulness, side effects, and personal beliefs can reduce participant compliance.
    • Trial Design Factors: Complex protocols, frequent visits, and burdensome procedures can discourage participation and adherence.
    • Investigator Factors: Inadequate training, lack of resources, and poor communication can lead to non-compliance by researchers.
  5. Strategies to Improve Compliance:
    • Participant Engagement: Educating participants about the importance of the trial, simplifying protocols, and providing reminders (e.g., phone calls, text messages) can enhance adherence.
    • Investigator Training: Ensuring researchers are well-trained and motivated to follow protocols strictly.
    • Monitoring and Feedback: Regular monitoring of compliance and providing feedback to participants and investigators can help identify and address issues early.
    • Incentives: Offering incentives (e.g., financial compensation, travel reimbursement) can improve participant retention and adherence.
  6. Technological Solutions: Leveraging technology, such as electronic monitoring devices and mobile apps, to track and improve compliance.
  7. Ethical Considerations: Ensuring compliance should not compromise ethical standards. Participants must provide informed consent, and their autonomy and well-being should always be prioritized.
  8. Conclusion: Compliance is not just a minor detail but a fundamental aspect of clinical trial success. Addressing compliance proactively through thoughtful trial design, participant engagement, and investigator training is essential for generating reliable and valid results.

Best podcast episode of all the podcasts in 2024

The best single episode of any podcast (subscribe to 70) that I have heard this year. The episode is so good, I will probably repost this message a couple times in 2025.

“In 1962, President John F. Kennedy said, “Those who make peaceful revolution impossible will make violent revolution inevitable.”

It was a recognition of a universal truth in human history: Social stability, the rule of law, and civilization will eventually break down if a population is immiserated for too long while a handful of elites profit. And just two months after that speech, Kennedy honed in on the health care crisis in America, pressing for the passage of what would become Medicare. ”

“What we are now talking about doing, most of the countries of Europe did years ago,” he said at a Madison Square Garden rally. “We are behind every country, pretty nearly, in Europe, in this matter of medical care for our citizens.”

I’ve been thinking a lot about that moment in history in light of the news over the past week. All of a sudden, after the murder of UnitedHealthcare CEO Brian Thompson, everyone is talking about health care, even though almost nobody was talking about it during the presidential campaign.

David Sirota reflects on the shocking murder of United Health CEO Brian Thompson and the surge of public anger it unleashed against America’s broken health insurance system. Why hasn’t this longstanding outrage translated into universal health care — a system every other wealthy nation already has?

Tracing decades of broken promises and corporate influence — from the Clinton and Obama administrations to today — Sirota looks at how political corruption has trapped Americans in a system that profits from their suffering. Drawing on JFK’s 1960s warnings about social stability and justice, this audio essay explores the health care crisis as a symptom of a deeper democracy crisis — and asks what it will take for Americans to finally demand change.

https://podbay.fm/p/lever-time/e/1734429600

Surgical Implantation of Autologous Dopamine Neuron Progenitor Cells (DANPCs) Into the Putamen of Patients with Parkinson’s Disease

Parkinson’s Disease

  • Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Performed market assessment for some of the latest (2024) treatments for PD. (1) Produodopa—a new treatment approved by NICE for people with PD who experience movement-related symptoms. It’s delivered continuously by a small pump that’s inserted under the skin. (2) Vyalev—(foscarbidopa and foslevodopa) is a solution of carbidopa and levodopa prodrugs for 24-hour continuous subcutaneous infusion that’s been approved for PD motor fluctuations. (3) Crexont—a new formulation of immediate- and extended-release levodopa with carbidopa. (Levodopa is converted in the brain to dopamine, the chemical that goes missing in PD; carbidopa helps levodopa get into the brain and decreases side effects.) (4) Safinamide— a novel experimental drug that shows potential in the treatment of PD and epilepsy. It works by blocking voltage-dependent sodium and N-type calcium channels, inhibiting glutamate release. (5) Methylphenidate and atomoxetine—noradrenaline reuptake inhibitors that are being investigated for their effects on balance and gait. (6) Levodopa inhalation powder—a formulation of levodopa that can be used as needed when medication effects wear off. (7) Focused ultrasound—a minimally invasive treatment that uses beams of heat to generate acoustic energy and precisely target areas of the brain that control voluntary movement. (8) Deep brain stimulation—a surgical procedure that involves implanting electrodes in the brain to deliver electrical impulses and disrupt abnormal circuitry. (9) Bemdaneprocel—a cell therapy that’s showing positive results in clinical trials, including improved motor function and symptom control.
  • ASPIRO Clinical Trial (Phase 1 & 2a). Autologous dopamine neuron progenitor cells (DANPCs) are surgically implanted into the putamen of patients with PD. The putamen is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. The putamen is a subcortical structure that is part of a group of structures known as the basal ganglia or basal nuclei. (“Basal nuclei” is technically more accurate, because “ganglia” usually refers to clusters of nerve cell bodies outside the central nervous system.) The putamen is adjacent to the globus pallidus and together they are sometimes referred to as the lentiform or lenticular nucleus. The putamen is involved in (reward-related) learning and motor control, including speech articulation, language functions, reward, cognitive functioning, and addiction.
    • PD affects the putamen in several ways, including Dopamine depletion—PD causes a gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which leads to a depletion of dopamine in the putamen. This depletion causes motor dysfunction. Atrophy—the putamen can undergo atrophy, which is associated with motor symptoms and cognitive status.  Shape changes—The putamen can undergo shape changes, particularly in the right putamen. Decreased activity.
  • Other parts of the brain that are affected by PD include the caudate and nucleus accumbens, which can also experience dopamine depletion. Dopamine replacement therapy can partially restore motor function, but long-term treatment can lead to motor complications.
  • The effect on PD symptoms, safety and tolerability, and cell survival are assessed for 5 years post-transplant (with MRI and PET imaging scans of the brain). Safety and tolerability are assessed annually for an additional 10 years via telephone call (total follow-up of 15 years).
  • The biologic implanted, ANPD001, is an experimental product derived from autologous skin cells converted to induced pluripotent stem cells. The stem cells were differentiated into DANPCs. Dose escalation will be achieved by bilateral injection of these DANPCs into the putamen.
  • Primary outcome measures: incidence and severity of treatment emergent adverse events (TEAE) and serious adverse events. Secondary outcome measures: “ON” time without troublesome dyskinesia [Time Frame: 1 year (primary follow up) and 5 years (long term follow up)]. Post-injection change in Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (Activities of Daily Living – ADL) and Part III (motor score) in the ON state. “ON” time or ON state simply means the period when the Parkinson’s medication is effectively managing symptoms, allowing for normal movement with minimal side effects.
  •  The anterior commissure (AC) is a bundle of nerve fibers that connects different parts of the brain and is important for communication between the brain and the body. The AC is a white matter tract that connects the two cerebral hemispheres across the midline, in front of the fornix columns. Although PD is primarily considered a gray matter (GM) disease, alterations in white matter (WM) have gained increasing attention in PD research recently. Recent evidence from MRI scans reveals correlations between WM changes and specific PD symptoms, and these WM abnormalities may be caused by changes of oligodendrocyte (OLs)/myelin in PD.

An Independent Review of Camrelizumab-Rivoceranib Combination Therapy for the Treatment of Hepatocellular Carcinoma and Rivoceranib for Gastric Cancer

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf 

https://www.researchgate.net/publication/383861594_An_Independent_Review_of_Camrelizumab-Rivoceranib_Combination_Therapy_for_the_Treatment_of_Hepatocellular_Carcinoma_and_Rivoceranib_for_Gastric_Cancer/

Abstract: The CARES-310 clinical trial compared the safety and efficacy of camrelizumab, an anti-PD-1 antibody, combined with rivoceranib, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted tyrosine kinase inhibitor (TKI), versus the obsolete standard of care sorafenib as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC). In this independent analysis of the CARES-310 trial, potential bias in the choice of comparator and the clinical significance of the results are reexamined. Although rivoceranib (also known as “apatinib”) is approved in China to treat patients with advanced gastric cancer, the clinical trial conducted in the USA for patients with gastric cancer seems to indicate missed endpoints and weak evidence to justify FDA approval. Due to a nondisclosure agreement, the principal investigators are unable to comment on these results. However, from a table of functional benefits and harms, readers might well conclude that palliative hospice care is non-inferior to rivoceranib for patients with Stage 4 gastric cancer.

RCCEP can cause red-nevus-like, pearl-like, mulberry-like, patch-like, and even tumor-like skin lesions in patients with HCC

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf

Conclusion

The CARES-310 clinical trials produced a new longest median OS of 23.8 months for patients with uHCC treated with C-R.  However, the CARES-310 clinical trial may have been overweighted with an Asian population with preexposure to antiviral therapy and better preservation of liver function at time of HCC diagnosis. Conversely, the CARES-310 trial was underweighted with Western patients who have NAFLD, diabetes, obesity, and other co-morbidities and confounding factors.  Oncologists already have 1L patient treatment experience for uHCC with Roche’s FDA-approved anti-PD-L1/VEGF combination Tecentriq and Avastin and with AstraZeneca’s CTLA-4 checkpoint inhibitor Imjudo combined with its PD-L1 antagonist Imfinzi for treatment of uHCC. It would be useful to compare the C-R proposed therapy with these drug combinations and determine if C-R maintains an 8.6-month median OS advantage over the new comparator(s).

When rivoceranib plus hospice care was compared to hospice care alone in a clinical trial of patients with advanced gastric cancer or gastroesophageal adenocarcinoma, the results data were mixed. For some measures of functional benefits and harms, the patients with hospice care alone had higher percentages for certain functional benefits and lower percentages for some harms and adverse events.  The rivoceranib-treated group failed to consistently outperform hospice care alone using these measures.  Based on those benefits and harms, hospice care alone was not inferior to rivoceranib + hospice care, which calls into question the underlying clinical value, if any, of rivoceranib to the American patient population with advanced gastric cancer.  The fact that rivoceranib, known as apatinib, is approved in China for treatment of advanced gastric raises anew questions about fundamental differences in patient populations between China and the USA or Europe for medical conditions such as uHCC and advanced gastric cancer.

References

  1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003 May 31;326(7400):1167-70. (“Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.”)
  2. Sismondo S. Epistemic Corruption, the Pharmaceutical Industry, and the Body of Medical Science. Front Res Metr Anal. 2021 Mar 8;6:614013 (“Put simply, if a pharmaceutical company funds a trial, the chances of results and conclusions in that company’s favor are increased.”)
  3. Bradley SH, DeVito NJ, Lloyd KE, Richards GC, Rombey T, Wayant C, Gill PJ. Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps. J R Soc Med. 2020 Nov;113(11):433-443 (“[A]voidable methodological failings and biases lead to ‘research waste’, which is estimated to account for 85% of all medical research funding.”)
  4. Sismondo S (2007) Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Med 4(9): e286. https://doi.org/10.1371/journal.pmed.0040286[1]
  5. Mann H, Djulbegovic B. Comparator bias: why comparisons must address genuine uncertainties. J R Soc Med. 2013 Jan;106(1):30-3.
  6. Setoguchi S, Gerhard T. Comparator Selection. In: Velentgas P, Dreyer NA, Nourjah P, et al., editors. Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. Chapter 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126184/
  7. Pinato DJ, D’Alessio A, Celsa C, Manfredi GF, Fulgenzi CAM. The price and value of therapeutic synergy in liver cancer. Lancet. 2023 Sep 30;402(10408):1108-1110.
  8. Lee, W.S., Yang, H., Chon, H.J. et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485 (2020). https://doi.org/10.1038/s12276-020-00500-y
  9. Qin S, Chan SL, Gu S, et al., CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146.
  10. Supplement to: Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet 2023; published online July 24. https://doi.org/10.1016/S0140-6736(23)00961-3.
  11. Wang, F., Qin, S., Sun, X. et al. Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial. J Hematol Oncol 13, 47 (2020).
  12. Liu Y, Chen T, Zhang C, Pan W. Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation. Indian J Dermatol. 2023 Jan-Feb;68(1):85-90.
  13. Vogel A., Chan SL, Ren Z et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study. Journal of Clinical Oncology 42(16_suppl) https://doi.org/10.1200/JCO.2024.42.16_suppl.4110.
  14. Li, J., Qin, S., Wen, L. et al.Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study. BMC Med 21, 173 (2023). https://doi.org/10.1186/s12916-023-02841-7
  15. Liu, Angus, “FDA snubs another China-made PD-1 with rejection of Elevar, Hengrui’s liver cancer combo,” Fierce Pharma. 2024 May 17.https://www.fiercepharma.com/pharma/fda-pd-1-combo-elevar-hengrui-camrelizumab-liver-cancer
  16. Kansteiner, Fraiser, “Elevar commits $600M-plus to take Hengrui’s liver cancer cocktail to market in US and beyond,” Fierce Pharma. 2023 Oct 17. https://www.fiercepharma.com/ pharma/elevar-ponies-600m-take-hengruis-investigational-liver-cancer-cocktail-market-us-and-beyond
  17. Elevar Therapeutics, “Elevar Therapeutics Reports Plans for Near-Term Resubmission of NDA for First-Line Treatment Option for Unresectable Hepatocellular Carcinoma Following Type A FDA Meeting,” Press Release. 2024 Jul 9. https://elevartherapeutics.com/2024/07/09/ elevar-therapeutics-first-line-treatment-option/
  18. Liu, Angus, “UPDATED: Elevar, Hengrui eye accelerated refile for PD-1 liver cancer combo after surprise FDA rejection” Fierce Pharma. 2024 Jul 12. https://www.fiercepharma.com/ pharma/elevar-hengrui-eye-quick-refile-pd-1-liver-cancer-combo-after-surprise-fda-rejection

Acknowledgments

Christopher Coleman, Pharm.D., provided useful comments.

Conflict of Interests

None.

Compounded Tirzepatide Therapy for Weight Loss: A Health Outcomes Researcher’s Perspective

Objective:  A male health outcomes researcher, age 55 – 65, with BMI ≥ 27 kg/m2, but without type 2 diabetes, took compounded tirzepatide 7.5 mg/week therapy with a goal of losing 10% of body weight over approximately four weeks and restoring BMI ≤ 25 kg/m2.  This study was also intended to offer a more sophisticated perspective of what compounded tirzepatide therapy entails and dispel some of the hype and myths currently circulating in popular media about tirzepatide and the glucagon-like peptide 1 (GLP-1) class of injectable drugs. All previous medical journals articles that mention tirzepatide have referred to the branded product, while this article is the first one focused solely on compounded tirzepatide.

 

Methods: The patient received subcutaneous injections of 7.5 mg compounded tirzepatide over four and a half weeks.  In the first, third, and fourth weeks, the patient received 7.5 mg of compounded tirzepatide as a bolus injection.  In week 2, the 7.5 mg dose was distributed over two injections of approximately 3.75 mg each given two days apart.  The primary end point in the trial was the percentage change in body weight from initiation to end of treatment.

 

Results: With a little over four weeks of compounded tirzepatide therapy, the patient achieved a 5% reduction in body weight and a BMI = 25.8. Despite having a healthy vegan diet and supplementing with many vitamins, minerals, electrolytes, and nutrients, the patient experienced most of the adverse events associated with the branded tirzepatide drug and the GLP-1 receptor agonist class of injectable drugs. However, the study revealed an undulating pattern  in which the compounded tirzepatide lost efficacy—or the patient built up resistance/tolerance for the drug—and also produced desirable side effects, both of which were findings not previously reported in the literature. 

 

Conclusions: Although compounded tirzepatide represents a welcome addition to the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist class of drugs in chronic weight management, a 7.5 mg weekly dose of compounded tirzepatide over four weeks is unlikely to produce a lasting 10% reduction in body weight over the course of a month even for average-weight (male) patients, even for those patients practicing intermittent fasting and choosing a vegan diet, let alone those patients with the typical American eating habits and diet. Neither the Center for Medicare and Medicaid Services (CMS) nor other payers should cover the ten times more expensive branded version of these drugs for weight loss until the manufacturers can prove with real-world evidence (RWE) that the patients’ weight losses are permanent as desired. In contrast, the compounded versions of these peptide drugs are affordable and reasonable tools for continued clinical study.  

Conflict of interest statement

The author has no affiliation with any pharmaceutical firm or compounding pharmacy and no financial or ownership interest in any pharmaceutical firm or compounding pharmacy.  He has no conflicts of interests that in any way affected the research or analysis reported in this article.

Current research on drug used for obesity and weight loss

In the obesity landscape, glucagoon-like peptide-1 (GLP-1) agonists dominate the weight loss market. Amylin agonists work differently from GLP-1s but may be able to induce similar weight loss with fewer adverse events. My client wanted to understand the molecular differences between various amylin assets and their hypothetical impacts on the efficacy / adverse event profile.

Project’s key research questions/topics include:
(1) Describe the medical literature as it pertains to Amylin for obesity specifically – e.g. years researching, articles on Amylin published, clinical trials, or other types of experience – please specify.

(2) Comment on the differences between cagrilintide, petrelintide, amycretin and any other amylin agonists?

(3) Describe the theoretical physiologies of the various subsets within amylin receptors (calcitonin, AMY1R, AMY2R, AMY3R).

(4) Comment on whether the pH of the assets differ, and whether these could have material impacts on the drug profile?

(5) Comment on the solubility of cagrilintide and other amylin assets, as well as the corresponding impacts on the drug profile (e.g. half-life)?

Despite the similarities between GLP-1 and Amylin agonists (e.g. both molecular classes slow gastric emptying, decrease glucagon, and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on hyperglycemia and energy balance.

Can Proteins be Modified to Fight Diseases and Cancer?

Alternative Title: Medical Writer Michael A. S. Guth’s Summary of External Research on Cancer Treatment Using Proteolysis Targeting Chimera (PROTAC) Biochemistry and the Body’s Ubiquitin-Proteasome System (UPS) Natural Degradation Process to Eliminate Disease-Causing Proteins. Oral PROTACs have shown encouraging clinical trial results in the treatment of some genotypes (ER+/HER-) of breast cancer and in previously treated metastatic castration-resistant prostate cancer (mCRPC). PROTACs degrade a targeted protein by attaching ubiquitin molecules (a process called “ubiquitinating”) the target proteins and stopping tumor growth. PROTACs—which are bivalent chemical protein degraders—are multifunctional molecules that act on specific endogenous proteins through the E3 ubiquitin ligase pathway.

Protein degradation is required for maintaining homeostasis of cell proteins and to regulate numerous cell processes, such as gene transcription, DNA pairing, cell cycle control, and apoptosis. The UPS is a crucial way to specifically degrade proteins that are involved in various metabolic activities, mainly including cyclin, spindle related proteins, cell surface receptors (epidermal growth factor receptor, etc.), transcription factors (NF-κB, etc.), tumor suppressor factors such as p53, oncogene products, and intracellular denaturing proteins, whose deregulation is related to the pathogenesis of many diseases. UPS relies on adenosine triphosphate (ATP) and consists of two steps: polyubiquitination of target protein and proteolysis of polyubiquitin by 26S proteolytic enzyme complex. 

Compared to UPS, two conventional treatment methods, small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs), suffer from some inherent limitations due to their mechanisms of actions. The FDA has approved over 62 SMIs that target about 20 different protein kinases. However, for most protein kinases, there is a lack of suitable active sites to target. In addition, molecule-targeted therapy is easy to induce drug resistance. mAbs have a large molecular weight and mainly target proteins located at the plasma membrane.

Beautiful Reflection on Water House by a Lake

Heather Cox Richardson image (002)

Pictures shot by Heather Cox Richardson while kayaking.

The State of Cancer Research

From Jon Barron’s Lessons from the Miracle Doctors book.

“Most current research is a waste of time and money. It is magic bullet nonsense. Take the search for the cancer gene. Are there genes that give one a predisposition for getting cancer? Absolutely. This is exactly what the Baseline of Health talks about when it refers to your Personal Health Line at the time of birth.

But looking for a cancer cure by finding the cancer gene will do nothing to eliminate all of the other factors responsible for cancer. And we already know how small a role the cancer gene plays in the onset of cancer: there has been an 8-fold to 17-fold increase in the incidence of cancer in the last hundred years, but not even one-millionth of 1 percent of that increase can be related to genes.

Genes evolve over hundreds of thousands (if not millions) of years, which means that the so-called cancer gene has had no impact on the huge increase we’ve seen since 1900. Virtually 90 percent of the cancer that we see today cannot possibly have anything to do with genes. So, at best, genes are responsible for only a small percentage of the minimal cancer rates we had in the early 1900s, and finding the cancer gene will affect only that tiny percentage of cancer. Genes may create tendencies, but in most cases they are not the underlying cause. Bottom line: look not for a cure in the cancer gene.

There is, however, a ray of hope in the world of medical research. In the last few years, medical research has started committing resources to the development of methods to harness and enhance the body’s natural tendency to defend itself against malignant tumors. Immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments. Sometimes referred to as biological response modifiers or as biological therapies, these new treatments–such as interferons and other cytokines, monoclonal antibodies, and vaccine therapies–have generated renewed interest and research activity in immunology.”

From Jon Barron of jonbarron.org