Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is ...an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
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•5/6 nephrectomy and LLC tumors trigger cachexia and adipose tissue browning•Elevated circulating PTH and PTHrP stimulate browning through their receptor PTHR•PTHR function in fat is required for adipose tissue browning and wasting•Loss of PTHR in fat tissue also attenuates skeletal muscle atrophy
Kir et al. reveal a role for the PTH/PTHrP pathway in cachexia driven by kidney failure or cancer and show how PTH and PTHrP stimulate adipose tissue browning through their receptor PTHR. Loss of PTHR in adipocytes blocks atrophy of not only fat tissue, but also skeletal muscle in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Precise diagnosis and prognosis are key in prevention and reduction of morbidity and mortality in all types of cancers. Here we show that changes in the collagen fibres in the main histological ...subtypes of canine mammary gland carcinomas are directly associated with the tumour behaviour and the animal survival time and could become a useful tool in helping with diagnosis. Imaging by second harmonic generation and multiphoton excited fluorescence microscopy were performed to evaluate the collagen and cellular segment parameters in cancer biopsies. We present a retrospective study of 45 cases of canine mammary cancer analysing 836 biopsies regions including normal mammary gland tissue, benign mixed tumours, carcinoma in mixed tumour, carcinosarcoma, micropapillary carcinoma and solid carcinoma. The image analyses and the comparison between the tumour types allowed to assess the collagen fibre changes during tumour progression. We demonstrate that the collagen parameters correlate with the clinical and pathological data, the results show that in neoplastic tissues, the collagen fibres are more aligned and shorter as compared to the normal tissues. There is a clear association of the mean fibre length with the dogs survival times, the carcinomas presenting shorter collagen fibres indicate a worse survival rate.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Obesity has been identified like as a risk factor of metabolic syndrome. The High‐Conductance Calcium‐Activated Potassium Channel (BKCa) in vascular smooth muscle cells regulates membrane potential ...and control myogenic tone.
Objective
evaluated the role of the BKCa channel in first order mesenteric arteries of rats feed with a hypercaloric diet for 18 and 28 weeks.
Methodology
We performed isometric tension experiments in first and second order mesenteric arteries rings and Patch Clamp recordings of vascular smooth muscle cells isolated of the same vascular bed.
Results
The rats feed with a hypercaloric diet for 18 weeks shows an augmented un percentage of adipose tissue, triglycerides, glucose tolerance curve, blood pressure and more relaxation to BKCa channel activator NS11021 un rings precontracted with phenylephrine. At 28 weeks of evolution, an increase in percentage of adipose tissue with respect to body weight was observed, as well as an increase in blood pressure, Regarding BKCa channel function, an increase in current density was observed in the experimental group with respect to the control group.
Conclusion
Changes have been developed at the metabolic level in the groups of the hypercaloric diet, with changes in the BKCa channels, a gain of function in first order mesenteric rings of the 18 weeks group and in cells isolated from these arteries at 28 weeks group. Nevertheless, at 28 weeks of evolution, first order mesenteric artery rings no longer showed the gain in function observed in the previous group, which suggest a compensatory mechanism maybe associated to aging.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We present nonlinear microscopy imaging results and analysis from canine mammary cancer biopsies. Second harmonic generation imaging allows information of the collagen structure in the extracellular ...matrix that together with the fluorescence of the cell regions of the biopsies form a base for comprehensive image analysis. We demonstrate an automated image analysis method to classify the histological type of canine mammary cancer using a range of parameters extracted from the images. The software developed for image processing and analysis allows for the extraction of the collagen fibre network and the cell regions of the images. Thus, the tissue properties are obtained after the segmentation of the image and the metrics are measured specifically for the collagen and the cell regions. A linear discriminant analysis including all the extracted metrics allowed to clearly separate between the healthy and cancerous tissue with a 91%-accuracy. Also, a 61%-accuracy was achieved for a comparison of healthy and three histological cancer subtypes studied.
Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) ...and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure.
A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration-time curve to the last observation point (AUC0-24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein-P and OATP1B1) were determined.
A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0-24 h of RMP and INH. Results indicated that RMP Cmax and AUC0-24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0-24 h for INH.
Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.
The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to ...combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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•A subset of neoantigen-expressing pancreas cancer evades immune surveillance•Markers of T cell exhaustion typify pancreas cancer tumor-infiltrating lymphocytes•The CD155/TIGIT axis promotes immune evasion in pancreas cancer•TIGIT/PD-1 co-blockade plus CD40 agonism reinvigorates tumor-reactive T cells
Freed-Pastor et al. identify the CD155/TIGIT axis as a key driver of immune evasion in pancreas cancer. Neoepitope prediction reveals a subset of human pancreas cancer patients with predicted high-affinity neoepitopes and functional interrogation using preclinical models identifies a combination immunotherapy approach (TIGIT/PD-1 co-blockade plus CD40 agonism) capable of eliciting profound anti-tumor responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The study of electroencephalographic (EEG) signals in nonhuman primates has led to important discoveries in neurophysiology and sleep behavior. Several studies have analyzed digital EEG data from ...primate species with prehensile tails, like the spider monkey, and principal component analysis has led to the identification of new EEG bands and their spatial distribution during sleep and wakefulness in these monkeys. However, the spatial location of the EEG correlations of these new bands during the sleep-wake cycle in the spider monkey has not yet been explored. Thus, the objective of this study was to determine the spatial distribution of EEG correlations in the new bands during wakefulness, rapid eye movement (REM) sleep, and non-REM sleep in this species. EEG signals were obtained from the scalp of six monkeys housed in experimental conditions in a laboratory setting. Regarding the 1-21 Hz band, a significant correlation between left frontal and central regions was recorded during non-REM 2 sleep. In the REM sleep, a significant correlation between these cortical areas was seen in two bands: 1-3 and 3-13 Hz. This reflects a modification of the degree of coupling between the cortical areas studied, associated with the distinct stages of sleep. The intrahemispheric EEG correlation found between left perceptual and motor regions during sleep in the spider monkey could indicate activation of a neural circuit for the processing of environmental information that plays a critical role in monitoring the danger of nocturnal predation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are ...responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low‐dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra‐performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real‐time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed‐effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1‐compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2) * (red blood cells/4.6 × 106 cells/μL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The American Heart Association's ideal cardiovascular health (ICH) define criteria for seven metrics, four classified as lifestyle factors (diet, physical activity, smoking and body-mass index) and ...four classified as health factors (smoking, blood pressure, fasting plasma glucose and total cholesterol). We aimed to analyze ICH scores at the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment and the associations with sociodemographic characteristics (age, sex, race, educational level, and family income).
We analyzed 13,356 ELSA-Brasil participants without cardiovascular disease using quasi-Poisson regression models to study the association between the ICH score and sociodemographic characteristics.
Mean ICH scores were 2.5±1.3. Only 1047 (7.8%) participants had 5 or more ICH metrics. In adjusted models, age 65–74years was associated with lower ICH scores (−35.4%; 95% confidence interval CI: −37.6% to −33.1%) compared to age 35–44years. Women had higher ICH scores compared to men (+13.8%; 95%CI: +11.8% to +15.7%), mainly due to differences in the health factor ICH metrics. Participants of Black race had lower ICH scores compared to those of White race (−9.4%; 95%CI: −11.8% to −7.0%). Individuals with less than high school education had lower ICH scores than college-educated individuals (−17.2%; 95%CI: −20.0% to −14.2%). Low (<1245 USD) family income was also associated with lower ICH scores compared to those with high (≥3320 USD) family income (−4.4%, 95%CI: −7.2% to −1.6%).
We found a low proportion of individuals with 5 or more ICH metrics. Age, sex, race, educational level and income were associated with ICH scores.
•We analyzed the 7 ICH metrics in 13,356 ELSA-Brasil participants at baseline.•Only 1047 (7.8%) individuals had five or more ICH metrics.•The least frequent ICH metrics were diet (1.3%) and physical activity (25.3%).•The most frequent ICH metric was smoking (84.9%).•Age, sex, race, educational level and income were associated with ICH scores.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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