Skip to main content

Home/ Dr. Goodyear/ Group items tagged features

Rss Feed Group items tagged

Filter: All | Bookmarks | Topics Simple Middle
Nathan Goodyear

Findings from Flawed Study Used To Discredit Multivitamin/Mineral Supplements - 0 views

www.lef.org/...itamin-Mineral-Supplements.htm

vitamins minerals supplements flawed research study

shared by Nathan Goodyear on 14 Oct 11 - No Cached
  • Nathan Goodyear on 14 Oct 11
     
    rebuttal to seriously flawed study recently released about vitamin/mineral supplements.  Much of scientific research published today is a rush to manipulate public opinion, rather than a rush to publish truth.  
Nathan Goodyear

Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk - 0 views

jme.endocrinology-journals.org/...R51.full

metabolic endotoxemia obesity insulin resistance cardiovascular disease LPS inflammation

shared by Nathan Goodyear on 04 Aug 14 - No Cached
  • Weight gain has been associated with a higher gut permeability
  • a high-fat diet promotes LPS absorption
  • higher concentrations of fatty acids impair intestinal barrier integrity
  • ...37 more annotations...
  • The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors
  • TLRs are PRRs that recognize microbe-associated molecular patterns
  • TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain
  • The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients
  • Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.
  • Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption
  • LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.
  • In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.
  • In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.
  • the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels
  • dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.
  • This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.
  • n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations
  • it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).
  • this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A
  • these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.
  • This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.
  • endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis
  • in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.
  • T2DM patients have mean values of LPS that are 76% higher than healthy controls
  • LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic
  • LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells
  • Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease
  • The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile
  • All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features
  • LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism
  • When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome
  • It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis
  • On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα
  • high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs
  • prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls
  • Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers
  • This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation
  • high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk
  • LPS has been shown to promote atherosclerosis
  • markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk
  • As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.
  • Nathan Goodyear on 04 Aug 14
     
    Very nice updated review on Metabolic endotoxemia
Nathan Goodyear

High Testosterone in Women Linked with Insulin Resistance and CVD - 0 views

www.diabetesincontrol.com/...8738-

Testosterone women female IR insulin resistance

shared by Nathan Goodyear on 26 Mar 15 - No Cached
  • Nathan Goodyear on 26 Mar 15
     
    High Testosterone in women associated with increased insulin resistance.
wheelchairindia9

Wheelchair Lightweight - 0 views

www.wheelchairindia.com/...Ultra-Lightweight-Wheelchair

Lightweight And Folding Transport Wheelchair Transport Wheelchair Wheelchair Lightweight Ultra Lightweight Wheelchair Lightweight Wheelchair Karma KM 2500 transport chair

shared by wheelchairindia9 on 06 May 15 - No Cached
  • wheelchairindia9 on 06 May 15
     
    Transport chairs, also known as companion wheelchairs, have four small wheels instead of two small and two large. A transport chair is designed to only be push by caregiver, other common names are 'companion chair' or 'rollabout chair'. A huge variety of different widths and weight capacities are available. A transport wheelchair is a mobility chair designed for convenience, short-distance use and easy handling by a caregiver. Lightweight and foldable, these wheelchairs are easily moved and typically fit in the trunk of most vehicles. There is even a model designed to fold into a bag to be carried over the shoulder. They are much smaller than standard manual wheelchairs and similar in size to the front wheels. Without large rear wheels, the user must rely on someone else to push the chair, which is why the transport chair is often referred to as a companion wheelchair. Karma Travel Wheelchair KM TV 20.2: Karma Travel Wheelchair KM TV 20.2 - 606 T-6 aircraft-grade aluminum-alloy frame provides incredible strength. Easy-to-fold in three seconds. Karma Travel Wheelchair KM TV 20.2 Features: Type: Travel Wheelchair T-6 aircraft-grade aluminum Secure brake improve safety Padded flip back armrest PU front caster & rear wheel Karma Travel Wheelchair KM TV 20.2 Measurements: Weight: 8.9kg Seat width: 39.5cm Tyre: PU front casters and rear wheels Capacity: 100kg Folded size: (L/W/H): 610mm x 350mm x710mm. Ultra Lightweight Wheelchair: Its compact design and feather light weight makes it suitable for people on the go. Ultra Lightweight Wheelchair Specifications: Frame Style : Foldable Frame Material : Aluminium (Light weight) Rear wheel to wheel width in open position (inches) : 20" Handle to Handle : 16" Seat Width (inches): 13" Rear Wheel Size: 7" Front Wheel Size: 5" Seat to floor height (inches): 19" Seat Depth (inches): 13" Back height (inches): 16" Total height (inches): 35" Max User Weight Capacity (kgs): 80 k.g. Net Weigh
Nathan Goodyear

Androgen receptor positive triple negative breast cancer: Clinicopathologic, prognostic... - 0 views

journals.plos.org/...article

"Breast cancer" androgen receptor AR HER-2

shared by Nathan Goodyear on 19 Nov 18 - No Cached
  • Nathan Goodyear on 19 Nov 18
     
    Androgen receptor status helps to determine prognosis in breast cancer. High risk is AR-/HER-2+ and low risk is AR+/HER-2-
Nathan Goodyear

Lytic Bone Lesions as a Prominent Feature in Waldenstrom's Macroglobulinemia. - PubMed ... - 0 views

www.ncbi.nlm.nih.gov/...19078464

Waldenstrom lymphoma cancer bone

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • Nathan Goodyear on 24 Sep 18
     
    Waldentstrom's macroglobulinemia with lytic bone lesions.  Only abstract available here.  Treatment, other than chemo, is radiation to effected site.
Nathan Goodyear

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical respo... - 0 views

www.ncbi.nlm.nih.gov/...PMC6114970

cancer metabolism breast cancer glutamine glutamate aspartate oncogenes

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
  • RAS, PI3K, TP53 and MYC
  • The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
  • ...16 more annotations...
  • The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
  • The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
  • four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
  • growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
  • glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
  • blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
  • glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
  • Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
  • changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
  • lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes
  • the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
  • these metabolic disturbances would be expected to remain extant after therapeutic interventions
  • accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
  • Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
  • liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
  • cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
  • Nathan Goodyear on 24 Sep 18
     
    Breast cancer is a metabolic disease.  Now, where have I heard that cancer is a metabolic disease?
Nathan Goodyear

Evolution of the Cancer Stem Cell Model: Cell Stem Cell - 0 views

www.cell.com/...S1934-5909(14)00057-5

CSC cancer stem cells cancer

shared by Nathan Goodyear on 01 Feb 18 - No Cached
  • cancer is widely understood to be a heterogeneous disease and there is increasing awareness that intratumoral heterogeneity contributes to therapy failure and disease progression
  • Evidence from both experimental models and clinical studies indicate that CSCs survive many commonly employed cancer therapeutics
  • both CSCs and normal tissue stem cells possess self-renewal capacity; however, self-renewal is typically deregulated in CSCs
  • ...2 more annotations...
  • the properties and transcriptional signatures specific to CSC are highly predictive of overall patient survival pointing to their clinical relevance
  • CSCs represent a distinct population that can be prospectively isolated from the remainder of the tumor cells and can be shown to have clonal long-term repopulation and self-renewal capacity—the defining features of a CSC
  • Nathan Goodyear on 01 Feb 18
     
    Great review on Cancer Stem Cells
Nathan Goodyear

Cancer stem cells in the development of liver cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC3635728

cancer liver cancer CSC cancer stem cells liver

shared by Nathan Goodyear on 01 Feb 18 - No Cached
  • the finding of a stem cell–like gene expression signature is of great interest because it reflects the malignant nature of a tumor with poor survival outcome
  • poor prognosis of HCC in patients with stemness-associated gene expression traits is assumed to reflect the abundance of liver CSCs with highly tumorigenic and/or metastatic features
  • CSCs have a highly invasive and metastatic capacity
  • ...1 more annotation...
  • The discovery and exploration of liver CSCs has expanded our knowledge of the mechanisms by which liver cancers obtain tumorigenic, metastatic, and chemotherapy- and radiation-resistant capacities
  • Nathan Goodyear on 01 Feb 18
     
    Good review and discussion of liver cancer Cancer Stem cells.
Nathan Goodyear

Doxycycline Decreases Tumor Burden in a Bone Metastasis Model of Human Breast Cancer | ... - 0 views

cancerres.aacrjournals.org/...1588

doxycycline cancer breast cancer

shared by Nathan Goodyear on 08 May 18 - No Cached
  • it appears more likely that the effectiveness relies on the properties of doxycycline as an inhibitor of tumor cell proliferation and less on its effect as a MMP inhibitor
  • Our results suggest that doxycycline may be useful not only for the treatment of osteolytic but also for the treatment of osteoblastic bone metastasis
  • A prominent feature of bone metastasis of breast cancer is the uncoupling of bone remodeling
  • ...3 more annotations...
  • doxycycline can improve this to some extent by increasing bone formation
  • the current study clearly demonstrates the benefit of doxycycline when administered from the time of the development of the tumor
  • In conclusion, doxycycline greatly reduced tumor burden and could also compensate for the increased bone resorption frequently associated with bone metastasis from breast cancer
  • Nathan Goodyear on 08 May 18
     
    doxycycline useful in breast cancer animal model to reduce tumor burden through inhibition of tumor cell proliferation and inhibition of MMP.
Nathan Goodyear

Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine | PNAS - 0 views

www.pnas.org/10238

AML leukemia acute myeloid leukemia MDS vitamin C cancer

shared by Nathan Goodyear on 12 May 18 - No Cached
  • Vitamin C alone at concentrations up to 57 μM had little effect on cell growth but was toxic at 228 μM (SI Appendix, Fig. S1B), in line with recent studies of high vitamin C concentrations (125–2,000 μM)
  • In our combination approach, vitamin C increased the effects of low doses of 5-aza-CdR, with 57 μM vitamin C almost doubling the growth inhibition
  • Using the Chou–Talalay method (28), we found that the two compounds indeed acted synergistically, rather than additively, to inhibit cancer cell growth over the physiological ranges of vitamin C in healthy individuals (26–84 μM)
  • ...12 more annotations...
  • These results show that targeting the cancer DNA methylome by combining low-dose 5-aza-CdR and vitamin C stimulates the expression of ERVs, the induction of a cell-autonomous immune activation response, and increased apoptosis of cancer cells
  • The addition of vitamin C to treatment protocols therefore may be a straightforward way to increase the clinical efficacy of such drugs in MDS and leukemia patients
  • Vitamin C deficiency has been seen previously in patients with multiple types of cancer, including hematological malignancies (35⇓–37). We predict that these patients might receive the most benefits from the combination treatment.
  • induction of an innate immune response
  • We therefore measured plasma concentrations of vitamin C in a small number of patients with miscellaneous hematologic malignancies. Strikingly, 58% of patients with hematological neoplasia who were not taking vitamin C supplements had severe vitamin C deficiency (serum concentration <11.4 μM, at which clinical features of scurvy may be manifested) (34), and 33% had vitamin C levels below the normal range
  • it is possible that vitamin C was oxidized to DHA before it was transported into the cells
  • Oral administration of vitamin C should be sufficient for the therapeutic strategy, because the concentrations reported in this study would not require i.v. administration.
    • Nathan Goodyear
      Nathan Goodyear on 12 May 18
       
      This statement lacks a basic understanding of vitamin C pharmacokinetics.
  • Vitamin C is an essential nutrient for humans and has been reported to increase IFN levels in human cells upon virus infection
  • daily treatment with vitamin C alone at physiological concentrations enhanced the expression of viral-defense genes relative to untreated cells
  • When combined with low-dose 5-aza-CdR, physiological concentrations of vitamin C synergistically inhibited cancer-cell growth and induced apoptosis. Such synergy was associated with increased ERV expression and dsRNA in treated cells. The mechanism of action differs from that of vitamin C at higher doses, which involves its pro-oxidant activity, including GSH inhibition, to generate reactive oxygen species
  • This activity has been shown to induce DNA damage and to enhance the sensitivities of myeloid malignancies, multiple myeloma, and cutaneous T-cell lymphoma to arsenic trioxide (41⇓⇓–44). It also can increase chemosensitivity of ovarian cancer cells (27) and selectively kill KRAS or BRAF mutant colorectal cancer cells by inhibiting GAPDH
  • reactive oxygen species
  • Nathan Goodyear on 12 May 18
     
    91% of patients with hematologic malignancies have vitamin C levels that are either low or severly deficient. This study found that vitamin C plus low dose DNA methyltransferase inhibitors have synergistic inhibition of cancer cell proliferation and increased apoptosis.  Unfortunately, the authors claimed that oral vitamin C would be sufficient which indicates an incredible lack of understanding of vitamin C pharmacokinetics.
fnfdoc

What Causes Hiccups And Treatment | Health Blog - 0 views

www.fnfdoc.com/...causes-hiccups-treatment

Causes Hiccups Treating

shared by fnfdoc on 22 May 18 - No Cached
  • fnfdoc on 22 May 18
     
    Hiccups are an uncontrollable reflex of the human body. What exactly goes on within the body to generate this weird sound is highly debated. The fact that hiccups can be heard and seen from fetuses suggests that the central circuit involved in producing hiccups...
  • fnfdoc on 22 May 18
     
    Hiccups are unwanted contractions of the diaphragm - the muscle that participates in breathing. Although evolutionary scientists have a few theories, the exact cause and purpose of hiccups is unknown. They remain a unique and age-old feature of the human physiology that continues to elude scientists to this day.
trungtamnamkhoa

Penis enlargement due to where? Cause And Treatment - 1 views

trungtamnamkhoa.com/n-duong-vat-noi-mun-trang.html

penis pimples white acne male men health healthy cancer Testosterone hormone

shared by trungtamnamkhoa on 25 Jun 19 - No Cached
  • trungtamnamkhoa on 25 Jun 19
     
    The body of the white pimples is a common feature of boys entering puberty. Understanding their nature will help you no longer worry. White pimples on the penis and pores, squeezing out with a white core. Do these acne affect fertility? This top concern in many young people will be answered right after.
Nathan Goodyear

Availability of evidence of benefits on overall survival and quality of life of cancer ... - 0 views

www.bmj.com/bmj.j4530

cancer cancer treatment survival quality of life

shared by Nathan Goodyear on 20 Dec 17 - No Cached
  • Although the goal of cancer treatment is to improve the quantity and quality of life,123 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4567891011 or quality of life46111213
  • two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low
  • Available data from the US show that only a small proportion of cancer treatments approved by the US Food and Drug Administration (FDA) unequivocally show benefits on survival or quality of life.30
  • ...16 more annotations...
  • We sought to systematically evaluate the evidence base for all new drugs and new indications for the treatment of solid tumours and haematological malignancies approved by the EMA in the five year period 2009-13
  • Three investigators (AP, EP, and EG) independently extracted data on and descriptively analysed the following trial features: characteristics of the participant population, study design (randomisation, crossover from experimental to control group, and blinding of investigators and participants), experimental and control groups, enrolment, primary and secondary endpoints, magnitude of benefit on survival and quality of life, and narrative interpretation of the findings
  • Only 18 of the 68 (26%) were supported by a pivotal study powered to evaluate overall survival as the primary outcome
  • From 2009 to 2013, the EMA approved use of 48 oncology drugs
  • Seventeen drugs were approved for treatment of haematological malignancies and 51 for treatment of solid tumours
  • Overall, 72 clinical trials supported the approval of 68 novel drug uses
  • Our scoring was limited to drugs for solid tumours
  • Among 68 cancer drug indications approved by the EMA in the period 2009-13, and with a median of 5.4 years’ follow-up, only 35 (51%) were associated with a significant improvement in survival (26/35) or quality of life (9/35) over existing treatment options, placebo, or as add on treatment
  • Only two of the 26 drugs shown to extend life also showed benefits on quality of life
  • 33 (49%) had not shown any improvement on survival or quality of life
  • This systematic evaluation of oncology drug approvals by the EMA in 2009-13 shows that most of the drugs (39/68, 57%) entered the market without evidence of improved survival or quality of life
  • At a minimum 3.3 years after market entry, there was still no conclusive evidence that 33 of these 39 cancer drugs either extended or improved life
  • What are potential reasons for the paucity of drug approvals with demonstrable survival advantages over existing treatments?
  • Firstly, only 18 (26%) indications for use in our cohort were supported by trials in which extension of life was the primary outcome
  • None of the pivotal studies supporting oncology drug approvals from 2009 to 2013 included quality of life as a primary outcome measure
  • Most new oncology drugs authorised by the EMA in 2009-13 came onto the market without clear evidence that they improved the quality or quantity of patients’ lives
  • Nathan Goodyear on 20 Dec 17
     
    New study from European Medicines Agency questions alot of the new cancer drugs brought to the market 2009-2013.  57% of the new drugs (39/68) were brought to the market without evidence of improved survival or quality of life.
Nathan Goodyear

Statins use and coronary artery plaque composition: Results from the International Mult... - 0 views

www.ncbi.nlm.nih.gov/...PMC4277888

statin statins plaque CAD coronary artery disease coronary artery calcium cardiovascular disease

shared by Nathan Goodyear on 17 Oct 17 - No Cached
  • Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium
  • As compared with individuals not taking statins, those taking statins possessed a significantly higher prevalence of obstructive CAD, as well as higher numbers of vessels with obstructive CAD
  • non-calcified plaques (NCP)
  • ...11 more annotations...
  • non-calcified (NCP), mixed (MP), or calcified (CP) plaque
  • statin use was each associated with a significantly higher prevalence of NCP, MP and CP
  • statin use was associated with increased presence of MP [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.27–1.68, p < 0.001] and CP (OR 1.54, 95% CI 1.36–1.74, p < 0.001], but not NCP
  • statin use was associated with increasing numbers of coronary segments possessing MP and CP but not associated with increasing numbers of coronary segments possessing NCP
  • North America, Europe and Asia
  • A total of 6673 individuals (2413 on statin therapy and 4260 not on statin therapy) comprised the study population
  • we identified a strong association of statin use to coronary artery plaque features
  • statin use was associated with a differentially increased prevalence and extent of MP and CP
  • one potential unifying hypothesis is that rather than regression of coronary plaque, statins may contribute to the conversion of coronary plaque constituents, perhaps by conversion of NCP to plaque possessing calcium
  • Coronary computed tomographic angiography (CCTA)
  • Statin use was associated with a higher frequency of severe coronary artery stenoses as well as numbers of coronary vessels with obstructive CAD
  • Nathan Goodyear on 17 Oct 17
     
    Study finds statin therapy associated with increased coronary plaque with calcium.
Nathan Goodyear

Substantial contribution of extrinsic risk factors to cancer development - 0 views

www.ncbi.nlm.nih.gov/...PMC4836858

cancer lifestyle

shared by Nathan Goodyear on 03 Jan 18 - No Cached
  • Here we provide evidence that intrinsic risk factors contribute only modestly (<10~30%) to cancer development
  • we conclude that cancer risk is heavily influenced by extrinsic factors. These results carry immense consequences for strategizing cancer prevention
  • cancers are proposed to originate from the malignant transformation of normal tissue progenitor and stem cells
  • ...14 more annotations...
  • “Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens
  • intrinsic factors do not play a major causal role.
  • intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions
  • if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case)
  • Particularly, for breast and prostate cancers, it has long been observed that large international geographical variations exist in their incidences (5-fold for breast cancer, 25-fold for prostate cancer)14, and immigrants moving from countries with lower cancer incidence to countries with higher cancer rates soon acquire the higher risk of their new country
  • Colorectal cancer is another high-incidence cancer that is widely considered to be an environmental disease17, with an estimated 75% or more colorectal cancer risk attributable to diet
  • melanoma, its risk ascribed to sun exposure is around 65–86%
  • non-melanoma basal and squamous skin cancers, ~90% is attributable to UV
  • 75% of esophageal cancer, or head and neck cancer are caused by tobacco and alcohol
  • HPV may cause ~90% cases in cervical cancer23, ~90% cases in anal cancer24, and ~70% in oropharyngeal cancer
  • HBV and HCV may account for ~80% cases of hepatocellular carcinoma
  • H pylori may be responsible for 65–80% of gastric cancer
  • While a few cancers have relatively large proportions of intrinsic mutations (>50%), the majority of cancers have large proportions of extrinsic mutations, for example, ~100% for Myeloma, Lung and Thyroid cancers and ~80–90% for Bladder, Colorectal and Uterine cancers, indicating substantial contributions of carcinogen exposures in the development of most cancers
  • onsistent estimate of contribution of extrinsic factors of >70–90% in most common cancer types. This concordance lends significant credibility to the overall conclusion on the role of extrinsic factors in cancer development
  • Nathan Goodyear on 03 Jan 18
     
    Really great read.  Cancer is a majority lifestyle disease.
Nathan Goodyear

Ibuprofen alters human testicular physiology to produce a state of compensated hypogona... - 0 views

www.pnas.org/...1715035115.full

ibuprofen Testosterone epigenetics hormones low Testosterone low T

shared by Nathan Goodyear on 09 Jan 18 - No Cached
  • The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
  • This increase was even more pronounced at 44 d, at 33%
  • We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial, which occurred as early as 14 d and was maintained until the end of the trial at 44 d
  • ...27 more annotations...
  • We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
  • The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration
  • Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
  • Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA
  • Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.
  • Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
  • A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
  • We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
  • the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.
  • Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
  • ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
  • The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action
  • AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
  • ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis
  • a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human
  • The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription
  • Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
  • ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected
  • short-term exposure
  • In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality
  • compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
  • an inverse relationship was recently reported between endurance exercise training and male sexual libido
  • AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels
  • inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
  • the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
  • after administration of 600 mg of ibuprofen to healthy volunteers
  • 14 d or at the last day of administration at 44 d
  • Nathan Goodyear on 09 Jan 18
     
    ibuprofen alters genetic expression that results in decreased Testosterone production.
Nathan Goodyear

"BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical fea... - 0 views

pubmed.ncbi.nlm.nih.gov/18955455

platinum cancer chemotherapy BRCA

shared by Nathan Goodyear on 14 May 21 - No Cached
  • Nathan Goodyear on 14 May 21
     
    Improved survival with platinum chemotherapy with BRCA.
Nathan Goodyear

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis - 1 views

www.ncbi.nlm.nih.gov/...PMC3937164

sepsis IV vitamin C vitamin C CRP

shared by Nathan Goodyear on 11 Oct 17 - No Cached
  • Padayatty and colleagues showed that high-level ascorbic acid plasma concentrations could only be achieved by intravenous administration
  • No patient in the low or high dose ascorbic acid treatment arms of this study suffered any identifiable adverse event
  • a pharmacologic ascorbic acid treatment strategy in critically ill patients with severe sepsis appears to be safe
  • ...7 more annotations...
  • subnormal plasma ascorbic acid levels are a predictable feature in patients with severe sepsis
  • Ascorbic acid depletion in sepsis results from ascorbic acid consumption by the reduction of plasma free iron, ascorbic acid consumption by the scavenging of aqueous free radicals (peroxyl radicals), and by the destruction of the oxidized form of ascorbic acid dehydroascorbic acid
  • Sepsis further inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion
  • Ascorbic acid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every six hours administration protocol
  • Septic ascorbic acid-deficient neutrophils fail to undergo normal apoptosis. Rather, they undergo necrosis thereby releasing hydrolytic enzymes in tissue beds, thus contributing to organ injury
  • We speculate that intravenous ascorbic acid acts to restore neutrophil ascorbic acid levels
  • Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging hydrolytic enzymes.
  • Nathan Goodyear on 11 Oct 17
     
    Study finds IV vitamin C in patients with sepsis is very safe and blunts the effects (endothelial damage, end organ damage...) of sepsis.  Of note, the IV vitamin C group reached serum levels of ascorbic acid of 1,592 to 5,722 micromol/L.  The IV groups maintained elevated serum C levels for up to 96 hours post infusion.  
« First ‹ Previous 201 - 220 of 224 Next ›
Showing 20▼ items per page