Is Weak Acid Beneficial for Addressing Checkpoint Inhibitor-Triggered Cancer Hyper Progression in Anti-PD1/PD-L1 Immunotherapies?

Numerous cases of checkpoint inhibitor-triggered cancer hyperprogression have been documented. A previous hypothesis attributes cancer onset to the local buildup of hydrogen chloride, jointly mediated by hydrogen bond donors and acceptors and basic amino acids. The anti-PD1/PD-L1 immunotherapies may have caused a surge of protons or chloride ions for the effective treatment of neoplasm, thus giving rise to the local formation of hydrogen chloride and subsequently cancer hyperprogression in some susceptible individuals. It was postulated that the local strength of acidity is critical for tumor growth and metastasis, as the intake of weak organic acids reduces cancer risks. The anti-PD1/PD-L1 immunotherapies can be integrated with weak organic acids to reduce adverse reactions and generate better anticancer outcomes.

A Solo Dance or a Tango?

Previous studies have identified genetic factors and Epstein-Barr virus underlying nasopharyngeal carcinoma. A hypothesis postulated that the local buildup of HCl, mediated by hydrogen bond donors and acceptors and basic amino acids, causes cancer. Nasopharyngeal carcinoma incidences are high in the humid southern coastal China, Southeast Asia, and Mediterranean regions, but not in the noncoastal and nonhumid southern Yunnan Province, China, and nonhumid Central China. The nearly saturated humidity in the Huinan period in Guangdong can trigger the expression of proteins with extensive hydrogen bonding to protons, augmenting the formation of HCl that is mutagenic. Given that the Epstein-Barr virus carries high content of hydrogen bond donors and acceptors, the moist environment in the nasal cavity may enable the virus to colonize the site, compounding pertinent investigations as both virus and high humidity are likely to trigger carcinogenesis. Therefore, the phenomena of exceptionally high humidity in regions with high nasopharyngeal cancer rates warrant further investigations.

How Hepatitis B virus causes cirrhosis and liver cancer.

Hepatitis B virus is a major pathogen infecting the liver, causing high morbidity and mortality worldwide, particularly in developing countries. The mechanism underlying progression from infections of Hepatitis B virus to cirrhosis and liver cancer is not fully determined. Here we propose that the HBV X protein traps protons and Cl-, and induces the expression of collagen in the liver, which forms potent hydrogen bonds with trapped protons. The presence of collagen in the liver marks the progression to fibrosis. The X protein and collagen concertedly build up HCl locally, triggering disease advances to liver cancer in some patients with liver cirrhosis. The hypothesis can be tested in Hepatitis B primate model with the administration of calcium and weak acids to ascertain physiological changes and monitor tumorigenesis rate. The experiments will pave the way for better intervention of human infections with Hepatitis B virus.

Heat conjugation of antibacterial agents from amino acids and plant oil.

Antimicrobial peptides are components of the innate immune systems in animals and plants as natural defense against pathogens. Critical issues like manufacturing costs have to be addressed before mass production of these peptides for agriculture or community sterilizations. Here, we report a cost-effective chemical synthesis method to produce antimicrobial cocktails, which was based on the heat conjugation of amino acids in the presence of phosphoric acid and plant oil at 150 °C. The conjugates showed potent biological activities against all tested bacteria including a multi-drug resistant Staphylococcus aureus strain Y5 and ampicillin resistant Pseudomonas aerugenosa ATCC9027 strain, demonstrating potential in agriculture, and prophylactic applications in hospital and community settings.

Conditional potency is a hallmark of viral protein-derived toxic peptides.

Viral infections are major ongoing challenges to mankind. The theory of cytokine storm cannot fully account for the virulence of some highly infectious viruses with high mortality rates. Although numerous viruses are capable of lysing animal and human cells in vivo, viral protein-derived peptides are mostly mild in standard culture conditions in in vitro assays. A hypothesis is postulated that conditional potency of viral protein-derived toxic peptides could at least in part explain cell senescence upon viral infections. The hypothesis can be tested with full length viral proteins against microbial and mammalian cells in various media. Viral protein injections to live animals may reveal that they are critical factors underlying cell destructions when protein degradation pathways and cytokine levels are controlled. Stimulation of autophagy could enhance current viral therapies by recycling toxic viral proteins.

Hydrogen donors and acceptors and basic amino acids jointly contribute to carcinogenesis.

A hypothesis is postulated that high content of hydrogen donors and acceptors, and basic amino acids cause the intracellular trapping of the H+ and Cl- ions, which increases cancer risks as local formation of HCl is mutagenic to DNA. Other cations such as Ca2+, and weak acids such as short-chain organic acids may attenuate the intracellular gathering of the H+ and Cl-, two of the most abundant ions in the cells. Current data on increased cancer risks in diabetic and obese patients are consistent with the assumption that hydrogen bonding propensity on glucose, triglycerides and other molecules is among the causative factors.