Great diagram of the pH in/around solid tumors. Cancer exists in an obvious hypoxic environment which favors the HIF-1alpha which favors lactate production which drops the pH in the tumor extracellular environment effecting chemoresistance, radioresistance, angiogenesis, invasion, aggressiveness, metastasis, immune evasion...
Only abstract available here. Study finds association between high tumor burden, more aggressive disease, and lower NK cell numbers. In addition, inverse assocation with CD16/56 and LDH found. Most likely direct tumor suppression as cause.
The obesity epidemic is increasing cancer risk and changing the cancer aggressiveness in younger and younger adults. The cancer of today is different than the cancer of yesterday. It behaves differently.
Average progression-free time and percentage of patients alive at 1 year was significantly higher in those using IL-2 and melatonin compared to chemotherapy in aggressive NSCLC. Of note, in this study, they used a repeat cycle of IL-2 and MLT as well as a once/week maintenance IL-2 and MLT.
glucose deprivation triggers apoptosis47 and vitamin C treatment kills RAS-oncogene expressing tumor cells, but not wild-type RAS containing cells, by inhibition of GAPDH
New study out of the UK supports the role of glucose in cancer growth and aggressiveness. This research found that high influx of glucose into the glycolysis pathway upregulated the RAS oncogene via accumulation of the Fructose 1,6 bisphosphonate through the enzyme phosphofructokinase..
"Cells are more responsive and sensitive to heat under oxygen-deprived and highly acidic conditions, which are common in cancer tissue due to aggressive growth and enhanced glycolysis"
Increased demand and shortages of lateral flow tests are pushing staff at pharmacies to bear the brunt from frustrated customers who are unable to get their free lateral flow tests, Daily Mail reported.
Some Britons claimed that they have been unable to get lateral flow tests at their local pharmacies for up to a fortnight while some pharmacies were forced to put up sign warning stating they have run out of free tests.
Given the patchy supply of test kits, pharmacy bosses warned that staff are facing 'unfair' and 'abusive' behaviour by customers, the newspaper reported.Dr Leyla Hannbeck, chief executive of the Association of Independent Multiple Pharmacies (AIMP), told the newspaper: "Up until yesterday the supply to pharmacies was still patchy. The past few days the situation has not improved.
"Pharmacies are having to put up with a lot of abuse and aggressive behaviours by members of the public because of this situation which is unfair.
"The demand is still very high now because the governments guidelines put a lot of emphasis on testing as a key out of self isolation, so naturally as Omicron cases are high people are reliant on tests to get on with daily life."
high dose IV vitamin C shown to be treatment option in Cancer. Granted in a mouse study, but high dose IV vitamin C shown to decrease growth rates of ovarian, pancreatic, and glioblastoma cancers.
Rugby training resulted in a decrease in T:C salivary ratio through a decline in resting testosterone level. In contrast, competition events increased the T:C ratio primarily through an increase in Cortisol production.
in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
about 90% of normal proliferating breast epithelial cells are receptor negative
Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure (Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
serum from mice with tumors had significantly more 5αP than 3αHP
the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
breast carcinomas are able to synthesize progesterone
The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
5α-reductase and 5αPR levels are upregulated by 5αP
in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
Nice study that reveals the pharmacologic mechanism of vitamin C as a pro-oxidant in cancer cells. Obviously, this effect is opposite that found blood. In this study they looked at high dose IV vitamin C in the treatment of ovarian, pancreatic, and glioblastoma cancer. Treatment was beneficial and well tolerated.
Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally [39] and to produce modest but consistent improvement in exercise-induced angina and reverse associated ECG changes [40]. The mechanism of action is via blockade of calcium channels with effect of similar magnitude to nifedipine
Testosterone acts as a calcium channel blocker inducing vasodilation.
men with chronic stable angina pectoris, the ischaemic threshold increased after 4 weeks of TRT and a recent study demonstrates improvement continuing beyond 12 months [
Exercise capacity in men with chronic heart failure increased after 12 weeks
Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels
Medications such as chronic analgesics, anticonvulsants, 5ARIs, and androgen ablation therapy are associated with increased risk of testosterone deficiency and insulin resistance
Women with T2D or metabolic syndrome characteristically have low SHBG and high free testosterone
Hypogonadism is a common feature of the metabolic syndrome
The precise interaction between insulin resistance, visceral adiposity, and hypogonadism is, as yet, unclear but the important mechanisms are through increased aromatase production, raised leptin levels, and increase in inflammatory kinins
levels of testosterone are reduced in proportion to degree of obesity
Men should be encouraged to combine aerobic exercise with strength training. As muscle increases, glucose will be burned more efficiently and insulin levels will fall. A minimum of 30 minutes exercise three times weekly should be advised
Testosterone increases levels of fast-twitch muscle fibres
By increasing testosterone, levels of type 2 fibres increase and glucose burning improves
Weight loss will increase levels of testosterone
studies now clearly show that low testosterone leads to visceral obesity and metabolic syndrome and is also a consequence of obesity
In the case of MMAS [43], a baseline total testosterone of less than 10.4 nmol/L was associated with a greater than 4-fold incidence of type 2 diabetes over the next 9 years
There is high level evidence that TRT improves insulin resistance
Low testosterone predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes
A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% (
) in the treated group with the greatest effect in younger men and those with type 2 diabetes
the presence of ED has been shown to be an independent risk factor, particularly in hypogonadal men, increasing the risk of cardiac events by over 50%
A recent online publication on ischaemic heart disease mortality in men concluded optimal androgen levels are a biomarker for survival
inverse associations between low TT or FT (Table 2) and the severity of CAD
A recent 10 year study from Western Australia involving 3690 men followed up from 2001–2010 concluded that TT and FT levels in the normal range were associated with decreased all-cause and cardiovascular mortality, for the first time suggesting that both low and DHT are associated with all-cause mortality and higher levels of DHT reduced cardiovascular risk
TDS is associated with increased cardiovascular and all-cause mortality
The effect of treatment with TRT reduced the mortality rate of treated cohort (8.4%) to that of the eugonadal group whereas the mortality for the untreated remained high at 19.2%
hypogonadal men had slightly increased triglycerides and HDL
Men with angiographically proven CAD (coronary artery disease) have significantly lower testosterone levels [29] compared to controls (
) and there was a significant inverse relationship between the degree of CAD and TT (total testosterone) levels
TRT has also been shown to reduce fibrinogen to levels similar to fibrates
men treated with long acting testosterone showed highly significant reductions in TC, LDL, and triglycerides with increase in HDL, associated with significant reduction in weight, BMI, and visceral fat
Low androgen levels are associated with an increase in inflammatory markers
A decline was noted in IL6 and TNF-alpha
In some studies, a decline in diastolic blood pressure has been observed, after 3–9 months [24, 26] and in systolic blood pressure
In the Moscow study, C-reactive protein was reduced by TRT at 30 weeks versus placebo
No studies to date show an increase in LUTS/BPH symptoms with higher serum testosterone levels
TRT has been shown to upregulate PDE5 [65] and enhance the effect of PDE5Is (now an accepted therapy for both ED and LUTS), it no longer seems logical to advice avoidance of TRT in men with mild to moderate BPH.
What about just starting with normalization of Testosterone levels first.
Several meta-analyses have failed to show a link between TRT and development of prostate cancer [66] but some studies have shown a tendency for more aggressive prostate cancer in men with low testosterone
And if one would have looked at their estrogen levels, I guarantee they would have been found to be elevated.
low bioavailable testosterone and high SHBG were associated with a 4.9- and 3.2-fold risk of positive biopsy
Current EAU, ISSAM, and BSSM guidance [1, 2] is that there is “no evidence TRT is associated with increased risk of prostate cancer or activation of subclinical cancer.”
Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass with an altered lipid profile
Erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone
great review of data on cardiac damage associated with extreme endurance training. These EEEs, that they are called, are rare in those < 40 and usually involved genetic defects. This article points to aggressive preventive testing in those > 50.