overall mortality and CV mortality were inversely associated with serum T concentrations.
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shared by Nathan Goodyear on 01 Dec 14
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Testosterone deficiency and cardiovascular mortality Morgentaler A, - Asian J Androl - 0 views
www.ajandrology.com/preprintarticle.asp
testosterone low t low Testosterone CVD cardiovascular mortality therapy
shared by Nathan Goodyear on 01 Dec 14
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men with low serum T, defined as < 8.7 nmol l−1 (250 ng dl−1 ), demonstrated significantly greater all-cause mortality than men with higher serum T (hazard ratio [HR]: 2.24; 95% CI: 1.41-3.57), as well as greater CV mortality
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lower T levels were significantly associated with the presence of any CV disease
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more than 30 years of studies suggesting that low levels of T represent an increased risk for CV and overall mortality,
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lower serum T concentrations also are associated with CV disease, including incident coronary artery disease [17],[18],[19] and atherosclerosis,
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the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk = 10.1%) as in the untreated group (1587 events in 7486 men = 21.2%)
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The study by Vigen et al. [7] has already undergone two published corrections,
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29 medical societies have called for retraction of the article, asserting "gross data mismanagement and contamination," that rendered the study "no longer credible
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Mortality in T-treated men was reduced by approximately half in treated men compared with untreated men, at 10.3% versus 20.7%, respectively
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The mortality rate for men who received TTh was 3.4 deaths per 100 person-years, and 5.7 deaths per 100 person-years in untreated men
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HR of 0.61 (95%CI: 0.42-0.88; P = 0.008), indicating a significant reduction in mortality with TTh
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men in the highest prognostic MI risk quartile, treatment with TTh was associated with reduced risk
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tripling in T prescriptions in the US over the last decade
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a majority of observational studies have found that low endogenous serum T levels are associated with increased mortality.
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Men who received TTh were able to exercise significantly longer without ischemia compared with men who received placebo
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In men with congestive heart failure, those who received T demonstrated greater walking distance and other functional endpoints compared with those who received placebo
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TTh has been shown uniformly and repeatedly to improve several known CV risk factors, including reduced fat mass, body fat percent, and waist circumference, and increased lean mass
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improved glycemic control
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reductions in insulin resistance.
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the evidence strongly points to improved CV status with normal serum T or treatment with TTh in men with TD
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analysis of health insurance claims data that reported a 36% increased rate of nonfatal MI in the 90d following receipt of a T prescription compared with the 12 prior months.
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Comparison with men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) revealed no increased rate of MI following the prescription
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Great review by Morgentaler of Testosterone and CVD. He highlights the significant flaws in the JAMA and the NEJM articles of Testosterone therapy risks. Morgentaler highlights the significant evidence that points to low T and increased risk of CVD. On contention I have, is Morgantaler seems to flip aside the massive uptick of Testosterone use in the US as compared to other countries. The evidence definitely points to Testosterone therapy as being safe in those with low T, but there is definitely a problem of significant Testosterone doping that is taking place as well.
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shared by Nathan Goodyear on 12 Nov 14
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Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxid... - 0 views
www.ncbi.nlm.nih.gov/...PMC3180189
cancer reverse warburg effect warburg effect NF-kapppB HIF-1alpha Cav-1 H2O2
shared by Nathan Goodyear on 12 Nov 14
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reducing oxidative stress with powerful antioxidants, is an important strategy for cancer prevention, as it would suppress one of the key early initiating steps where DNA damage and tumor-stroma metabolic-coupling begins. This would prevent cancer cells from acting as metabolic “parasites
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Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the “reverse Warburg effect.
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Then, oxidative stress, in cancer-associated fibroblasts, triggers the activation of two main transcription factors, NFκB and HIF-1α, leading to the onset of inflammation, autophagy, mitophagy and aerobic glycolysis in the tumor microenvironment
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oxidative stress and ROS, produced in cancer-associated fibroblasts, has a “bystander effect” on adjacent cancer cells, leading to DNA damage, genomic instability and aneuploidy, which appears to be driving tumor-stroma co-evolution
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tumor cells produce and secrete hydrogen peroxide, thereby “fertilizing” the tumor microenvironment and driving the “reverse Warburg effect.”
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This type of stromal metabolism then produces high-energy nutrients (lactate, ketones and glutamine), as well as recycled chemical building blocks (nucleotides, amino acids, fatty acids), to literally “feed” cancer cells
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loss of stromal caveolin (Cav-1) is sufficient to drive mitochondrial dysfunction with increased glucose uptake in fibroblasts, mimicking the glycolytic phenotype of cancer-associated fibroblasts.
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oxidative stress initiated in tumor cells is transferred to cancer-associated fibroblasts.
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Then, cancer-associated fibroblasts show quantitative reductions in mitochondrial activity and compensatory increases in glucose uptake, as well as high ROS production
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These findings may explain the prognostic value of a loss of stromal Cav-1 as a marker of a “lethal” tumor microenvironment
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aerobic glycolysis takes place in cancer-associated fibroblasts, rather than in tumor cells, as previously suspected.
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our results may also explain the “field effect” in cancer biology,5 as hydrogen peroxide secreted by cancer cells, and the propagation of ROS production, from cancer cells to fibroblasts, would create an increasing “mutagenic field” of ROS production, due to the resulting DNA damage
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Interruption of this process, by addition of catalase (an enzyme that detoxifies hydrogen peroxide) to the tissue culture media, blocks ROS activity in cancer cells and leads to apoptotic cell death in cancer cells
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In this new paradigm, cancer cells induce oxidative stress in neighboring cancer-associated fibroblasts
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cancer-associated fibroblasts have the largest increases in glucose uptake
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cancer cells secrete hydrogen peroxide, which induces ROS production in cancer-associated fibroblasts
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Then, oxidative stress in cancer-associated fibroblast leads to decreases in functional mitochondrial activity, and a corresponding increase in glucose uptake, to fuel aerobic glycolysis
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cancer cells show significant increases in mitochondrial activity, and decreases in glucose uptake
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fibroblasts and cancer cells in co-culture become metabolically coupled, resulting in the development of a “symbiotic” or “parasitic” relationship.
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cancer-associated fibroblasts undergo aerobic glycolysis (producing lactate), while cancer cells use oxidative mitochondrial metabolism.
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We have previously shown that oxidative stress in cancer-associated fibroblasts drives a loss of stromal Cav-1, due to its destruction via autophagy/lysosomal degradation
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a loss of stromal Cav-1 is sufficient to induce further oxidative stress, DNA damage and autophagy, essentially mimicking pseudo-hypoxia and driving mitochondrial dysfunction
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loss of stromal Cav-1 is a powerful biomarker for identifying breast cancer patients with early tumor recurrence, lymph-node metastasis, drug-resistance and poor clinical outcome
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this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks
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the upstream tumor-initiating event appears to be the secretion of hydrogen peroxide
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one such enzymatically-active protein anti-oxidant that may be of therapeutic use is catalase, as it detoxifies hydrogen peroxide to water
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numerous studies show that “catalase therapy” in pre-clinical animal models is indeed sufficient to almost completely block tumor recurrence and metastasis
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by eliminating oxidative stress in cancer cells and the tumor microenvironment,55 we may be able to effectively cut off the tumor's fuel supply, by blocking stromal autophagy and aerobic glycolysis
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breast cancer patients show systemic evidence of increased oxidative stress and a decreased anti-oxidant defense, which increases with aging and tumor progression.68–70 Chemotherapy and radiation therapy then promote further oxidative stress.69 Unfortunately, “sub-lethal” doses of oxidative stress during cancer therapy may contribute to tumor recurrence and metastasis, via the activation of myofibroblasts.
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a loss of stromal Cav-1 is associated with the increased expression of gene profiles associated with normal aging, oxidative stress, DNA damage, HIF1/hypoxia, NFκB/inflammation, glycolysis and mitochondrial dysfunction
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cancer-associated fibroblasts show the largest increases in glucose uptake, while cancer cells show corresponding decreases in glucose uptake, under identical co-culture conditions
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Thus, increased PET glucose avidity may actually be a surrogate marker for a loss of stromal Cav-1 in human tumors, allowing the rapid detection of a lethal tumor microenvironment.
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it appears that astrocytes are actually the cell type responsible for the glucose avidity.
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In the brain, astrocytes are glycolytic and undergo aerobic glycolysis. Thus, astrocytes take up and metabolically process glucose to lactate.7
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Then, lactate is secreted via a mono-carboxylate transporter, namely MCT4. As a consequence, neurons use lactate as their preferred energy substrate
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both astrocytes and cancer-associated fibroblasts express MCT4 (which extrudes lactate) and MCT4 is upregulated by oxidative stress in stromal fibroblasts.34
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In accordance with the idea that cancer-associated fibroblasts take up the bulk of glucose, PET glucose avidity is also now routinely used to measure the extent of fibrosis in a number of human diseases, including interstitial pulmonary fibrosis, postsurgical scars, keloids, arthritis and a variety of collagen-vascular diseases.
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PET glucose avidity and elevated serum inflammatory markers both correlate with poor prognosis in breast cancers.
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PET signal over-estimates the actual anatomical size of the tumor, consistent with the idea that PET glucose avidity is really measuring fibrosis and inflammation in the tumor microenvironment.
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human breast and lung cancer patients can be positively identified by examining their exhaled breath for the presence of hydrogen peroxide.
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tumor cell production of hydrogen peroxide drives NFκB-activation in adjacent normal cells in culture6 and during metastasis,103 directly implicating the use of antioxidants, NFκB-inhibitors and anti-inflammatory agents, in the treatment of aggressive human cancers.
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Good description of the communication between cancer cells and fibroblasts. This theory is termed the "reverse Warburg effect".
35More
The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views
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WNT signaling
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early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
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Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
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In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
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beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
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The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
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involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
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the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
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Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
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Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig(Fig2C).2C). All changes were significative
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The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
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Pre-established H358 tumors responded to Ivermectin showing a ˜ 50% repression of growth
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Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
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Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
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these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
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anti-WNT-TCF activities of Ivermectin and Selamectin
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Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
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the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
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What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
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Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
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Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
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(i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
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(ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
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(iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
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(iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
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(v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
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These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
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the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
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If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
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Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
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previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
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Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
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Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
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they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
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Ivermectin, a common anti-parasitic, found to inhibit WTF-TCF pathway and decrease c-terminal phosophorylaiton of Beta-CATENIN all resulting in increased aptosis and inhibition of cancer growth in colon cancer cell lines and lung cancer cell lines.
26More
In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epitheli... - 0 views
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we functionally validated a potent EOC oncogene, KPNB1, and showed its clinical relevance to human EOC
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a well-established antiparasitic drug, ivermectin, has antitumor effects on EOC through its inhibition of KPNB1
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EOC has high intertumor and intratumor heterogeneity at the molecular and epigenetic levels
- ...22 more annotations...
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the mortality rate of EOC has not been significantly changed for several decades
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Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer
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Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations
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KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3
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Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC
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KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition
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KPNB1 functions as an antiapoptotic and proproliferative oncogene in EOC.
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Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1
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KPNB1 acts as an oncogene in human EOC and represents a promising therapeutic target.
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ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC
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ivermectin also induced apoptosis
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ivermectin increased the expression levels of BAX, and cleaved PARP, as well as p21 and p27
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KPNB1 inhibition is responsible for the antitumor effect of ivermectin
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we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells
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Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth
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ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types
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KPNB1 was the second-highest-ranked gene identified in our screen
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Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types
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our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members
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higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans
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none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event
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we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone
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Ivermectin found to be pro-apoptotic for the epithelial ovarian cancer oncogene, KPNB1 in in Vivo study. This effective anti-parasitic drug inhibits the KPNB1 oncogene.
8More
Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skelet... - 0 views
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short-term HFO introduces DNA methylation changes on a genome-wide scale in human skeletal muscle
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These changes were only partly reversed after 6–8 weeks
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The induction of DNA methylation changes after 5 days of HFO supports the growing awareness of DNA methylation as a dynamic signal that is possibly relevant to short-term day-to-day metabolic adaptations, including acute exercise
- ...4 more annotations...
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Diverging DNA methylation levels between elderly, but not young, genetically identical twins indicate that environmental exposures throughout life may permanently influence DNA methylation, suggesting some preservation of de novo DNA methylation in adults
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our finding of a slow reversibility rate indicates the demethylation process may be somewhat impeded compared with the induction of methylation changes by diet, which could have implications for the preservation or build-up of CpG methylation over time
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A slow reversibility of DNA methylation induced by carcinogenic agents has likewise been observed due to ingestion of high-fat diets in rodents
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the relationship between DNA methylation and gene expression is not always straightforward
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Study finds variability of methylation and some genetic expression alteration with high fat diet. Restated, what you eat interacts with your DNA to alter genetic expression. This has implications on initiation of therapy as well as response to therapy.
67More
Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil... - 0 views
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tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure.
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NETosis, which is the process of forming neutrophil extracellular traps (NETs)
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surgery-induced metastasis
- ...61 more annotations...
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surgery per se can promote cancer metastasis through a series of local and systemic events
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surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers
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After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear
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infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients
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Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis
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Surgery-induced cancer metastasis has been well established in animal models
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tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis
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the surgical resection of primary tumors is beneficial is controversial
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CTCs abruptly increase just after surgery
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Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer
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excessive glucocorticoids negatively modulate immune functions
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immune surveillance against tumors is considered to be impaired by surgical stress
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In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla
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NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids
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In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases
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primary tumors may secrete angiogenic inhibitors as well as angiogenic activators
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second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.
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double-edged sword
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HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity
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neutrophils play various roles in the initiation and progression of cancer
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NETosis
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many inflammatory and neoplastic diseases
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formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1
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NETosis has been highlighted as an inflammatory event that promotes cancer metastasis
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Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves
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A series of these events is called NETosis.
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neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins
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innate immune response against infection
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Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells
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two types of NEToses, suicidal (or lytic) NETosis and vital NETosis
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Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)
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Since neutrophils die during this process, it is called suicidal NETosis.
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vital NETosis
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vital NETosis occurs independently of ROS production
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Vital NETosis can be induced by Gram-negative bacteria. LPS
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NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia
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neutrophils actively undergo NETosis in the tumor microenvironment
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Hypoxia
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NETosis plays a pivotal role in noninfectious autoimmune diseases,
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cytokines
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tumor-derived proteases
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tumor exosomes
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NETosis generally actively progresses in the tumor microenvironment.
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the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
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NETosis is a defense system to protect the body from invading pathogens
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when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences
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plasma levels of NETosis markers are elevated after major surgeries
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local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases
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NETs promote metastasis at multiple steps
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NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells
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NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow
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NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)
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neutrophil elastase, matrix metalloproteinase 9, and cathepsin G
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NETs also promote the intravasation of cancer cells
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millions of tumor cells are released into the circulation every day,
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NETs can wrap up CTCs with platelets
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β1-integrin plays an important role in the interaction between CTCs and NETs
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NET-platelet-CTC aggregates.
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After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late
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NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions
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NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells
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shared by Nathan Goodyear on 13 Nov 12
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Testosterone, the male hormone connection: treating diabetes and heart disease. - 0 views
www.worldhealth.net/...thera6_ch7.pdf
testosterone low T low testosterone CVD cardiovascular disease diabetes insulin leptin ghrelin PAI-1 obesity adiponectin type II diabetes DM atherosclerosis
shared by Nathan Goodyear on 13 Nov 12
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good, well referenced discussion of how Testosterone support for those with low T can improve Diabetes, insulin function, improve energy balance, and reduce cardiovascular disease risk. The discussion discusses many of the moving parts in how testosterone improves CVD risk.
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shared by Nathan Goodyear on 12 Nov 12
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Testosterone and cardiovascular disease in men. [Asian J Androl. 2012] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...22522504
low T testosterone CAD coronary artery disease CVD cardiovascular men
shared by Nathan Goodyear on 12 Nov 12
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This article, abstract only, looks at the cause of low Testosterone. It is well known that low T increases CAD in men. But what causes the low T? Is the "normal" decline in testosterone actually normal or a product of accumulative dysfunction.
1More
Update in TSH Receptor Agonists and Antagonists - 0 views
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Just abstract is available to this just released article, but the opening sentence shows the importance of receptors: "the physiological role of the TSH receptor (TSHR) as a major regulator of thyroid functions is well understood..."
1More
CIRCULATING INFLAMMATORY MARKERS IN POLYCYSTIC OVARY SYNDROME: A SYSTEMATIC REVIEW AND ... - 0 views
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It is well known that obesity increases CRP. However, in this meta-analysis, CRP elevation in women with PCOS was found to be independent from obesity and as they concluded: "...chronic low-grade inflammation that may underpin the pathogenesis of this disorder".
1More
An Overview of Melatonin and Breast Cancer - Natural Medicine Journal: The Official Jou... - 0 views
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Great review on the anti-cancer properties of melatonin. Well referenced.
1More
Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity ... - 0 views
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N-acetylcysteine, also known as NAC, a precursor to glutathione, is shown to significantly reduce the incidence of flu symptoms. NAC should be taken through out the winter months as a flu prevention? Well, this study does not support that, but if one gets the flu, NAC will significantly reduce the flu symptoms.
1More
Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with s... - 0 views
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Sensitivity and specificity of saliva evaluation of cortisol approached 100%. Salivary cortisol correlates extremely well serum cortisol levels. Birth control pills did result in a decline, but still exceeded 95%.
1More
shared by Nathan Goodyear on 02 Mar 13
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Assessment of adrenal function by measurement of sa... [Steroids. 2007] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...17257634
cortisol hormone hormones salivary hormone salivary hormones' testing steroids
shared by Nathan Goodyear on 02 Mar 13
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Saliva shown to be "simple, safe, well-accepted and non-invasive" technique to evaluate cortisol levels.
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American College of Cardiology Foundation | Journal of the American College of Cardiolo... - 0 views
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Small study, but well designed study shows that statins inhibit CoQ10 mediated oxidative phosphorylation through decrease in CoQ10. This points directly at a decrease in mitochondrial function as a result of statin therapy.
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Indole-3-carbinol disrupts estrogen rece... [Mol Cell Endocrinol. 2012] - PubMed - NCBI - 0 views
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Indole-3-carbinol degrades ER alpha expression on breast cancer cells lines and down regulates ER alpha expression. Not only does I3C degrade ER alpha expression it inhibits its expression as well. Additionally, I3C interferes with signaling associated with ER alpha through IGF-1.
A Soothing, Tranquil Journey - 1 views
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Correlations between serum and salivary hormona... [J Sports Sci. 2008] - PubMed - NCBI - 0 views
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salivary cortisol and DHEA correlates well with serum levels before and after exercise. Testosterone, in this study did not.
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shared by Nathan Goodyear on 26 Feb 13
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Testosterone: a metabolic hormone in health and disease - 0 views
joe.endocrinology-journals.org/...JOE-12-0455.full.pdf
low T low testosterone testosterone metabolic syndrome MetS hormone hormones men male health disease
shared by Nathan Goodyear on 26 Feb 13
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Great, great read and review on the current understanding of testosterone and metabolic dysfunction. Very well referenced.