subjects with hyperandrogenemic phenotypes displayed the greatest degree of hyperinsulinemia, β-cell function,
and chronic inflammation
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shared by Nathan Goodyear on 10 Mar 15
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Spectrum of metabolic dysfunction in relationship with hyperandrogenemia in obese adole... - 0 views
eje-online.org/...1093.long
PCOS polycystic ovarian syndrome CRP inflammation insulin insulin resistance women female hormone hormones androgens Testosterone hyperandrogenism
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The rise in serum androgens is accompanied by excess insulin secretion, suggesting that insulin directly stimulates ovarian androgen production
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HA has been identified as an important risk factor for MS and dyslipidemias in premenopausal women and adolescents
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In our study, HA was found to be an independent risk factor for MS as previously reported by Coviello et al.
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obesity and HA, and not insulin resistance, are the major determinants of chronic inflammation and risk of atherosclerosis in adolescents with PCOS
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hyperandrogenemic PCOS phenotypes have greatest degree of hyperinsulinemia, insulin resistance, and inflammation
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shared by Nathan Goodyear on 05 Mar 15
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Relationship between Low Free Testosterone Levels and Loss of Muscle Mass : Scientific ... - 0 views
www.nature.com/...srep01818.html
muscle men male hormone Testosterone free Testosterone low T low Testosterone
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Our data confirm that a low FT level is a significant predictor of a risk for loss of appendicular muscle
- ...11 more annotations...
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These results suggest that a threshold level of FT exists for muscle loss, rather than a dose-response relationship
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In the previous cross-sectional and longitudinal studies of French and American men, no dose-response relationships were reported between T and muscle mass
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A minimal serum level of FT may be needed to preserve muscle mass in men, regardless of race/ethnicity.
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Our result is in line with previous studies that reported a relationship between low FT and low muscle mass in men
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Although a progressive decrease in TT levels with ageing is observed in middle-aged and elderly American men16, 17, the TT levels do not change during ageing in Japanese men
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shared by Nathan Goodyear on 20 Nov 14
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Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and... - 0 views
ard.bmj.com/...annrheumdis-2014-205675
inflammation cardiovascular RA rheumatoid arthritis psoriasis disease CVD
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shared by Nathan Goodyear on 10 Nov 14
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Oxidative Stress and Its Relationship With Adenosine Deaminase Activity in Various Stag... - 0 views
www.ncbi.nlm.nih.gov/...PMC3547448
Adenosine Deaminase ADA cancer breast cancer superoxide disumutase glutathione peroxidase oxidative stress inflammation
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Reduced SOD activity might be responsible for excessive accumulation of superoxide anions leading to increased free radical mediated injury. Increased free radical production has been shown to be responsible for chromosomal damage leading to mutagenecity, cell proliferation and carcinogenesis. SOD activity showed marked improvement after mastectomy indicating the lowering of oxidative stress.
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The increased production of reactive oxygen species causes oxidative stress leading to cell proliferation and hence increased inflammatory conditions
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Superoxide dismutase is an important antioxidant enzyme which decomposes the harmful superoxide anions into hydrogen peroxide thus protects the body from the action of free radicals
- ...20 more annotations...
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Females suffering from breast cancer had significantly decreased Superoxide dismutase (SOD) and reduced glutathione (GSH) levels in comparison to normal females
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ADA seems to be a promising marker of inflammation in breast cancer thereby suggesting that it can be used as a diagnostic tool to detect the stage of breast cancer along with cytopathological studies
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In conclusion, our study confirmed the role of oxidative stress in the pathogenesis of breast cancer.
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Another potent antioxidant molecule is reduced glutathione. It acts as reductant which converts hydrogen peroxide into water and reduces lipid peroxidation products into their corresponding alcohols and thus mediates protective action.
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In the present study, significantly low SOD activity has been observed in female patients suffering from carcinoma breast both pre as well as post operative in comparison to healthy females.
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We observed significantly decreased SOD activity and GSH levels in patients belonging to clinical stage 4 as compared to those having stages 1, 2 or 3 of breast cancer.
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The compromised antioxidant defence system produces the oxidative stress which in turn creates the inflammatory response shown by concomitant increased adenosine deaminase (ADA) activity in female patients.
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Experimental and epidemiological evidences implicate the involvement of oxygen derived free radical in the pathogenesis of breast cancer.
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Antioxidant status was highly depressed in advanced stages of breast cancer as compared to initial stage.
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In the present study, significantly low GSH levels were observed in female patients of carcinoma breast as compared to normal females
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Walia et al. (1995) reported increased ADA activity in breast cancer patients as compared to age matched normal subjects.
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These free radicals are able to cause damage to membrane, mitochondria and macromolecules including proteins, lipids and DNA and actively take part in cell proliferation. This cascade in turn generates the inflammatory response and causes the progression of the disease.
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Marked oxidative stress in stage 4 of breast cancer indicated advancement of the disease, hence checking oxidative stress at initial stage could be helpful for controlling the progression of the disease.
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Adenosine deaminase enzyme (ADA) catalyzes the conversion of adenosine to inosine which finally gets converted to uric acid
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Study finds a reduction in SuperOxide Dismutase and Glutathione Perioxidase in advancing breast cancer. Cancer is a high oxidative stress disease that results in inflammation, mitochondrial dysfunction and proliferation. Adenosine Deaminase (ADA) is proposed to be another biomarker to assess tumor stage.
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shared by Nathan Goodyear on 10 Nov 14
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Implications of free radicals and antioxidant levels in carcinoma of the breast: A neve... - 0 views
www.indianjcancer.com/article.asp
SOD superoxide disumutase catalase antioxidants antioxidant breast cancer cancer malondialdehyde MDA lipid peroxides oxidative stress inflammation
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Experimental investigations as well as clinical and epidemiological findings have provided evidence supporting the role of reactive oxygen metabolites or free radicals such as singlet oxygen O 2 - , superoxide anions (O 2 ), hydrogen peroxide (H2 O2 ) and hydroxyl radical in the etiology of cancer.
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Certain aldehydes such as Malonyldialdehyde (MDA), the end product of lipid peroxidation arising from free radical degeneration of polyunsaturated fatty acids can cause cross linking in lipids, proteins and nucleic acids leading to cellular damage.
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In this study, patients with cancer exhibited higher levels of MDA, both in tissues and serum (p<0.001) compared to the control group [Table 1]. In tissue, the MDA level in stage IV was significantly higher as compared to stage I indicating increased free radical activity with increasing severity of cancer
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From these observations, it can be concluded that MDA levels play an important role in assessing the outcome of cancer
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SOD and CAT are considered primary antioxidant enzymes, since they are involved in direct elimination of reactive oxygen metabolites. [13-16] They also act as anti-carcinogens and inhibitors at initiation and promotion/transformation stage in carcinogenesis
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In our study, SOD and CAT levels were found to be low in all cancer patients as compared to controls
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Fridovich and Tayarani have demonstrated in their respective studies that the reduction in SOD activity increases the toxic effects of O2 - and this might lead to severe cellular damage.
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Mehrotra et al. in their study also observed high levels of MDA and low levels of SOD and CAT in patients of cancer cervix which is in sync with our observations.
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This study finds a strong correlation between advancing breast cancer, decreased catalase and SOD with increasing MDA. The authors of this study conclude this is a key factor in carcinogenesis and not a by-product of cancer. This flies in the face of traditional medicines fear of antioxidant therapy in cancer.
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shared by Nathan Goodyear on 11 Nov 14
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Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Prog... - 0 views
www.ncbi.nlm.nih.gov/...PMC3950899
cancer oxidative stress warburg effect reverse warburg effect ROS
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Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
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increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
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Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
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Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
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metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
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Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
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secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
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oxidative stress has an important role in the initiation and preservation of breast cancer progression
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the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
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Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
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cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
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Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
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hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
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It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
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It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
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obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
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Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
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Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.
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shared by Nathan Goodyear on 30 Mar 15
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Testosterone level in men with type 2 diabetes mellitus and related metabolic... - 0 views
www.ncbi.nlm.nih.gov/...PMC4364844
low T low Testosterone Diabetes Testosterone men male hormones metabolic syndrome
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defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
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the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
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most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
- ...57 more annotations...
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Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
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−0.124 nmol/L/year in serum total testosterone
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In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
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In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
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testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
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testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
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In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
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independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
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Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
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In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
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leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
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Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
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Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
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As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
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alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
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A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
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Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
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subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
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In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
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Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
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HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
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pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
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In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
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Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
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Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
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The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
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In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
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a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
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the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
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assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
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In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
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a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
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A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
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most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
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MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
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Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
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In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
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weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
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To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
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In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
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low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
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Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
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low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
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European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
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Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
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serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
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Nice review of Testosterone levels and some of the evidence linking Diabetes with low T. However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling. The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
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shared by Nathan Goodyear on 18 Jan 16
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Prevalence of chronic hypopituitarism after blast concussion -- Wilkinson et al. 27 (1)... - 1 views
www.fasebj.org/...935.3
PCS TBI head trauma traumatic brain injury post concussion syndrome concussion hormones pituitary
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shared by Nathan Goodyear on 10 Feb 16
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The Role of Post-Exercise Nutrient Administration on Muscle Protein Synthesis and Glyco... - 0 views
www.ncbi.nlm.nih.gov/...PMC3761704
exercise athlete athletes recovery exercise recovery training protein carbohydrates glycogen muscle
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Free form amino acid ingestion acts similarly to whey by displaying a rapid and strong increase in aminoacidemia
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it appears that protein synthesis rapidly increases for up to two hours after amino acid administration
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The intervention of dietary protein or amino acid supplementation in conjunction with resistance training has proven to effectively increase protein synthesis rates
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291% increase in protein synthesis following the exercise bout, while protein degradation remained unchanged from baseline quantities
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it has been established that post-exercise EAA supplementation stimulates protein synthesis, in conjunction with a positive protein balance, comparable to that of intravenous infusion of amino acids
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Casein and whey protein ingestion yielded similar values of net positive protein balance, and thus an overall increase in protein synthesis
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A later analysis revealed that soy protein increased protein synthesis in rats similar to that of whey after a treadmill exercise protocol
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A human trial, however, concluded that milk proteins (caseins and whey) in comparison to soy promoted greater muscle protein accretion when they were ingested after regular resistance training
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Whey hydrolysate ingested after a resistance exercise bout acutely stimulated mixed muscle protein synthesis 31% greater than soy
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adequate amount of protein (20 g) is ingested (Tipton et al., 2009) immediately before or after a resistance exercise bout
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slow phase, which can last up to several hours if carbohydrate availability is high and insulin levels remain elevated
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Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells |... - 0 views
15More
Ki-67 is a prognostic parameter in breast cancer patients: results of a large populatio... - 0 views
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A wide range of techniques is available to assess tumor cell proliferation such as calculating mitotic figures in stained tissue segments, flow cytometric analysis to determine the proportion of cells being in the S phase of the cell cycle, examination of thymidine-labeling index, proliferating cell nuclear antigen (PCNA), or cyclins E and D
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Ki-67 is a nuclear protein being associated with cellular proliferation and was originally identified by Gerdes et al.
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Ki-67 nuclear antigen is expressed in certain phases of the cell cycle namely S, G1, G2, and M phases, but is nonexisting in G0
- ...11 more annotations...
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Ki-67 is also expressed at low levels (<3 % of cells) in ER-negative cells, but not in ER-positive cells
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A meta-analysis involving 12,155 patients demonstrated that the Ki-67 positivity confers a higher risk of recurrence and a worse survival rate in patients with early breast cancer.
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higher tumor stages and higher nodal status were associated with higher Ki-67 quartiles indicating that the more aggressive the tumor is the higher is the percentage of cells positively stained for Ki-67
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Previous studies were able to demonstrate that a prognostic model, the IHC 4 score, using ER, PR, HER2, and Ki-67 provides similar prognostic information to that in the 21-gene Genomic Health recurrence score
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ER status has been largely identified as being inversely correlated with Ki-67, with the higher rates of ER positivity shown in the lowest proliferating tumors
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Ki-67-labeling index was associated with larger tumors, higher tumor grade, peritumoral vascular invasion, and HER-2 positivity
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Statin use and risk of diabetes mellitus - 0 views
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An increase in new onset diabetes, i.e., 3% in statin arm and 2.4% in placebo arm was reported. This was accompanied by increase in median value of glycated haemoglobin and was one of the earlier studies to report the increase in new onset diabetes in patients on statins
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Even after adjustment for potential confounders, statin therapy was associated with an increased risk of new-onset diabetes mellitus
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Another study also reported that as compared to placebo, statin group showed a higher risk of physician reported incident diabetes and it was also observed that risk was higher in women as compared to men
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Meta-analysis of randomized controlled trials by Sattar et al[25] involving 91140 non-diabetic patients showed that statin therapy was associated with 9% increased risk of incident diabetes
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A number of studies showed dose dependent association between statin administration and incident diabetes
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Treatment with atorvastatin and simvastatin may be associated with an increased risk of new onset diabetes as compared to pravastatin
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Increased incidence of diabetes was seen with atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial
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Increased insulin resistance secondary to statins was demonstrated in a prospective non randomised study in patients with coronary bypass surgery
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Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial
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Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial
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Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expec... - 0 views
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Over the past few years, there have been steadily increasing reports that ivermectin may have varying uses as an anti-cancer agent, as it has been shown to exhibit both anti-cancer and anti-cancer stem cell properties
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In human ovarian cancer and NF2 tumor cell lines, high-dose ivermectin inactivates protein kinase PAK1 and blocks PAK1-dependent growth
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PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors
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Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression
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Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer
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Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10–20% of breast cancers and are associated with poor prognosis
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Ivermectin addition led to transcriptional modulation of genes associated with epithelial–mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo
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Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer
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ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells
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Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine,
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It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases
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In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects
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ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117
17More
Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor re... - 0 views
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Others have reported that niclosamide inhibits the NF-κB pathway in leukemia cell lines (26) or mTOR signaling in MCF-7 breast cancer cells
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In the more rapidly growing tumor (HCT116), a dose of 200 mg/kg of body weight was needed to suppress the tumor growth
- ...13 more annotations...
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however, 100 mg/kg of niclosamide could suppress the growth of the relatively slow-growing tumor (CRC039) to the same level
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The mechanism of action of the niclosamide in our studies is thought to be through internalization of Fzd1 and downregulation of Wnt pathway intermediaries
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Recently, Jin et al. (26) reported that niclosamide inhibited the NF-κB pathway and increased reactive oxygen species levels to induce apoptosis in AML cells. In contrast, we did not observe any inhibitory effect of niclosamide on NF-κB signaling in our CRC model
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oral administration of niclosamide does result in sufficient distribution of the drug into tumor tissue, to prove a prolonged inhibitory effect on Wnt/ß-catenin signaling, resulting in tumor growth inhibition
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we required higher doses (100 ~ 200 mg/kg body weight) of niclosamide in order to demonstrate significant inhibition of tumor growth in NOD/SCID mice
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niclosamide concentrations in tumor tissue showed good correlation with those in plasma, suggesting the efficient distribution of niclosamide from blood to tumor tissue
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we observed downregulation of Dvl2 and ß-catenin cytosolic expression in niclosamide-treated tumor cells in vivo
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One potential concern for the use of niclosamide as an anticancer therapy is the poor absorption of this drug
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The Wnt signaling pathway, fundamental to embryonic tissue patterning, is also activated in stem-like cells
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The canonical Wnt pathway is activated in approximately 80% of sporadic CRC primarily due to mutations in the APC gene
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recent observations reveal that Wnt ligands or inhibitors may affect the growth and survival of colon cancer cells in spite of the presence of APC or CTNNB1 mutations
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PET/CT Standardized Uptake Values (SUVs) in Clinical Practice and Assessing Response to... - 0 views
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In some cases, such as Hodgkins lymphoma, quantitative PET/CT imaging may not actually be needed, as success can be defined by the complETe absence of tracer uptake in the PET image following a course of standardized therapy
- ...9 more annotations...
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The utilization of PET/CT to assess response to therapy is increasing in the US related, in part, to the creation and subsequent favorable results of the National Oncologic PET Registry (NOPR)
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Changes in size as a result of therapy may take many months to develop and any opportunity to make early decisions about therapy success or failure is often unduly delayed or lost altogether
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measures of changes in metabolic activity via FDG Pet/CT can provide an alternate approach to assess response to therapy -- often very early in the course of treatment
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The true tracer uptake in a patient is composed of two components: the first being the amount of tracer uptake (e.g. FDG) associated with the disease status (the signal of interest), which can be modified by the biophysiological status of the patient. One of the more important patient parameters is the blood glucose level, which has been shown to inversely-linearly affect SUVs
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A prospective study by Crippa et al.30 in eight patients showed that as blood glucose levels were increased from 92.4 ±10.2 to 158 ± 13.8 mg/100 ml by glucose loading, the average SUV of 20 liver metastases decreased from 9.4 ± 5.7 to 4.3 ± 8.3
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chemotherapy can result in impaired renal function, significantly reducing the clearance of plasma FDG through the kidney and thus increasing tumor SUV relative to an initial PET scan
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The biological variability has been estimated in several test-retest studies7,32–35 at approximately 10% for scans repeated within a few days
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shared by Nathan Goodyear on 01 Oct 16
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Testosterone replacement therapy and the risk of prostate cancer - 0 views
www.ncbi.nlm.nih.gov/...PMC4814970
Testosterone testosterone therapy saturation theory cancer prostate cancer male hormones
![](/images/link.gif)
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When the level of circulating androgen is below normal, some androgen receptors are inactive, and the secondary downstream effects are decreased. Once androgen receptors within the prostate are saturated, however, increasing testosterone will no longer have an effect
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Only the subset of individuals with pretreatment testosterone level <250 ng dl−1 had PSA level correlating with free and total testosterone level
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none of the men stopped testosterone supplementation due to prostate cancer recurrence, and none demonstrated cancer progression
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PSA level did transiently rise in one patient; however, none exceeded a PSA of 1.5 ng ml−1 to raise concern for biochemical recurrence
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after 19 months on TRT, 10 hypogonadal patients with a history of undergoing a radical retropubic prostatectomy for prostate cancer had no PSA recurrence and had statistically significant improvements in serum total testosterone and hypogonadal symptoms
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Similarly, Kaufman and Graydon14 examined case records of seven hypogonadal men who had undergone curative RP with symptoms of hypogonadism and low serum testosterone levels treated with testosterone replacement. No biochemical or clinical evidence of cancer recurrence was noted
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In a much larger case series, Khera et al.15 reviewed the records of 57 men who received TRT following RP. After an average of 36 months following RP, testosterone replacement was initiated and followed for an average of 13 months. Mean testosterone values rose significantly and once again, there was no increase in PSA values and, therefore, no diagnosed biochemical recurrence
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Four of the patients in the treatment group were found to have cancer recurrence, compared with eight in the control group
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Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer - 0 views
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Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
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Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
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Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
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ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
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Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
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Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
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Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
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This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
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These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
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Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
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pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
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pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
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Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
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The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
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we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
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data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
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Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views
nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2
ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment
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A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
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“pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
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Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
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glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
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Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
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persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
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The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
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the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
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The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
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Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
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Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
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all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
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The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
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respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
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data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
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Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
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Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
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Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
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Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
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Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
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Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
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Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
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Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
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It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
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Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
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The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
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According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
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A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
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Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
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Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
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The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
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Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
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It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
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Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
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glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
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In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
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Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
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Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
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Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
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A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
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The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
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Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
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Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
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Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
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The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
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It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
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The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
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Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
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Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
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ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
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Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
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Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
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In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
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This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
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lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
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Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
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It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
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Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
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The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
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Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
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Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
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Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-Pet imaging, but could be detected under glutamine-based Pet imaging
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Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
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Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
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Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
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Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
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microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Co... - 0 views
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dysregulated miRNA could be involved in tumor cell proliferation and growth as well as cell cycle progression
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The upregulated miR-183 in our samples was predicted to be responsible for the decrease in expression of the BTG1 mRNA whose protein is involved in cell cycle arrest and apoptosis in breast cancer cells18.
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nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA
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the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest
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dysregulation in cancer particularly in breast cancer highlights their importance in tumor development
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mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration
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most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA
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microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases
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Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients