99 research outputs found

    Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

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    Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P G12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies

    TRPV1 Receptor Identification in Rainbow Trout (<i>Oncorhynchus mykiss</i>) and Evaluation of the Effects Produced by <i>Ocimum basilicum</i> Super Critical Fluid Extract

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    Transient receptor potential vanilloid type 1 (TRPV1) has been investigated in humans and mammals; in recent years, some researchers have focused on this receptor in fishes. The present study aimed to identify TRPV1 receptors in cultures of RT-gill W1 cells and in the organs of rainbow trout (Oncorhynchus mykiss), in addition to evaluating the possible modulation induced by super critical fluid extract of basil (Ocimum basilicum), named F1-BEO. In vitro evaluation consisted of cell cultures and immunocytochemistry assays. During in vivo experimental sessions, eighty trout were divided into five groups that received a fish diet supplemented with 0, 0.5, 1, 2 and 3% w/w F1-BEO. Forty trout were euthanized after 15 and 30 days; organs were collected and processed according to the immunohistochemistry technique. Receptor expression was quantitatively measured using Image Pro Plus software. TRPV1 was identified in RT-gill W1 cells and in all organs, with a higher positivity in the muscle layers of the stomach, intestine and kidneys. F1-BEO induced an increased expression of TRPV1 in the stomach while a lower expression was appreciated in the bowel. No morphological alterations have been highlighted in the liver or kidneys. Further investigation will be necessary to evaluate the functionality of this receptor in rainbow trout

    Comparative cardiac macroscopic and microscopic study in cats with hyperthyroidism vs. cats with hypertrophic cardiomyopathy

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    Hyperthyroidism is considered the most common endocrinopathy in middle-aged and old cats. The increased level of thyroid hormones influences many organs, including the heart. Cardiac functional and structural abnormalities in cats with hyperthyroidism have indeed been previously described. Nonetheless, myocardial vasculature has not been subjected to analysis. Also, no comparison with hypertrophic cardiomyopathy has been previously described. Although it has been shown that clinical alterations resolve after the treatment of hyperthyroidism, no detailed data have been published on the cardiac pathological or histopathological image of field cases of hyperthyroid cats that received pharmacological treatment. The aim of this study was to evaluate the cardiac pathological changes in feline hyperthyroidism and to compare them to alterations present in cardiac hypertrophy due to hypertrophic cardiomyopathy in cats. The study was conducted on 40 feline hearts divided into three groups: 17 hearts from cats suffering from hyperthyroidism, 13 hearts from cats suffering from idiopathic hypertrophic cardiomyopathy and 10 hearts from cats without cardiac or thyroid disease. A detailed pathological and histopathological examination was performed. Cats with hyperthyroidism showed no ventricular wall hypertrophy in contrast to cats with hypertrophic cardiomyopathy. Nonetheless, histological alterations were similarly advanced in both diseases. Moreover, in hyperthyroid cats more prominent vascular alterations were noted. In contrast to hypertrophic cardiomyopathy, the histological changes in hyperthyroid cats involved all ventricular walls and not mainly the left ventricle. Our study showed that despite normal cardiac wall thickness, cats with hyperthyroidism show severe structural changes in the myocardium.</p

    TRPV1 Receptor Identification in Bovine and Canine Mitral Valvular Interstitial Cells

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    Myxomatous mitral valve degeneration (MMVD) is the most common acquired cardiac disease in canine species, and valvular interstitial cells (VICs) are considered the main responsible for the development of this pathology. The scientific interest is focused on isolating and characterizing these cells. The aims of the present study were to verify a novel VICs mechanical isolation method and to characterize isolated cells using immunocytochemistry and immunofluorescence, with parallel histological and immunohistochemistry assays on bovine and canine healthy and MMVD mitral valves. Antibodies against vimentin (VIM), smooth muscle actin (SMA), von Willebrand (vW) factor, Transforming Growth Factor (TGF) β1, and Transient Receptor Potential Vanilloid 1 (TRPV1) were used. The isolation method was considered reliable and able to isolate only VICs. The different assays demonstrated a different expression of SMA in healthy and MMVD mitral valves, and TRPV1 was isolated for the first time from bovine and canine VICs and the correspondent mitral valve leaflets. The novelties of the present study are the new isolation method, that may allow correlations between laboratory and clinical conditions, and the identification of TRPV1, which will lead to further investigations to understand its function and possible role in the etiology of MMVD and to the design of new therapeutic strategies

    Left Pulmonary Artery Coarctation Associated with Pneumonia and Pulmonary Hypertension in a Cat

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    A five-month-old European shorthair female kitten was referred because of recurrent episodes of respiratory distress. Results of physical examination, thoracic radiography, and echocardiography led to a presumptive diagnosis of severe precapillary pulmonary hypertension (PH) and interstitial pneumonia associated with right-sided cardiac remodeling. The cat rapidly died because of respiratory insufficiency. Pulmonary and cardiovascular pathological findings evidenced left pulmonary artery coarctation, severe right-sided cardiac hypertrophy, and bilateral pneumonia. This is the first report of pulmonary artery coarctation associated with pneumonia and PH in a cat

    The Effect of the COVID-19 Lockdown on Melanoma Diagnosis in Italy

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    The coronavirus disease 2019 (COVID-19) pandemic has led to lockdowns for much of the world. In Italy, all health procedures not directly related to COVID-19 were reduced or suspended, thus limiting patient access to hospitals. Any delay in cancer treatment presents the additional risk of tumors progressing from being curable to incurable. Specifically, melanoma survival rate strictly de-pends on tumor thickness, which, in turn, is a function of time. To estimate the impact on melanoma progression caused by the reduction in dermatologic services during the COVID-19 lockdown, a retro-spective observational cohort study was conducted. This study was designed to compare the clinical and histologic characteristics of the primary melanomas removed in the first 2 months after the end of the lockdown (May-July 2020) in 12 Italian centers characterized by different COVID-19 case frequencies. The control group was represented by the melanomas removed during the same period in the previous 3 years. Overall, 1,124 melanomas were considered: 237 as part of the study group and 887 from the control group (average, 295), with a 20% reduction. Breslow thickness, as well as high-risk histotypes and melanomas with vertical growth, increased for all melanomas. Ulcerated and high mitotic index melanomas increased, particularly in northern Italy. In Italy, the lockdown led to a significant worsening of melanoma severity, causing a staging jump, with a consequent worsening of outcomes. (c) 2021 Elsevier Inc. All rights reserved

    Immunofluorescent Localization of Plakoglobin Is Altered in Endomyocardial Biopsy Samples from Dogs with Clinically Relevant Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

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    Diagnosing the early stages of canine Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is complicated by day-to-day arrhythmia variability, and absence of reliable, transthoracic echocardiographic features. Definitive diagnosis requires histopathologic identification of transmural fibrofatty replacement of the right ventricle. Reduction of immunofluorescent signal for plakoglobin (PG) at the intercalated disc (ID) is reported in ARVC-affected humans and boxers. Our objective was to determine whether reduced immunofluorescent signal for PG in endomyocardial biopsy samples (EMBs) correspond with a histopathologic diagnosis of ARVC. Here, 49 dogs were evaluated: 43 with advanced cardiac disease and 6 non-clinical boxers with mild to moderate ventricular arrhythmia (VA) burden. EMBs were obtained from all dogs; samples were prepared with antibodies recognizing cadherin (PC) and PG and evaluated with confocal microscopy. Investigators were blinded to breed and clinical status. ARVC was histopathologically diagnosed in 8 out of 49 dogs. Of these, three out of eight had clinical signs consistent with ARVC (two boxers, one English bulldog) and reduced PG signal at ID; five out of eight were non-clinical boxers with moderate VA and no reduction in PG. A total of 41 out of 49 dogs were histopathologically diagnosed with non-ARVC cardiac disease; 1 out of 41 showed reduction of PG at ID, while 40 out of 41 had no PG reduction. These results suggest that EMB PG signal is reduced in dogs with advanced ARVC, but not in the occult phase of the disease. Additionally, presence of PG at ID supports a diagnosis of non-ARVC cardiac disease in dogs with clinical signs. These results may offer an additional test that helps differentiate advanced ARVC from other myocardial diseases

    Comparison of two different barbed suture materials for end-to-end jejuno-jejunal anastomosis in pigs

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    Abstract Background Hand-sewn intestinal anastomoses are a fundamental procedure in both open and laparoscopic intestinal surgery. Self-retaining barbed suture devices have been tested for a variety of surgical applications. With the exception of clinical reports and various experimental studies on enterotomy, little has been published so far on the use of barbed suture for end-to-end intestinal anastomoses. The aim of the study was to compare two different barbed suture materials for end-to-end jejuno-jejunal anastomosis in pigs. End-to-end jejuno-jejunal anastomosis were performed with unidirectional barbed (A group), bidirectional barbed (B group) or normal (C group) sutures in each animal. A comparison was then made between the groups based on adhesions scoring, suturing time, bursting pressure and histopathology. Results Mean construction times in the A group (518 ± 40 s) and in the B group (487 ± 45 s) were significantly lower than in the C group (587 ± 63 s) but were not different between A and B group (P = 0.10). Mean bursting pressures were significantly higher in the intact intestine (197 ± 13 mmHg) than in any other group (group A 150 ± 16 mmHg, group B 145 ± 22 mmHg, group C 145 ± 24 mmHg). Among anastomotic techniques, the bursting pressures were not significantly different. Histologically no difference could be detected in the grade of inflammation, collagen deposition and neovascularization at the anastomotic sites. Conclusions Barbed sutures can be effectively used for handsewn end-to-end jejunojejunal anastomosis in pigs. They are comparable to normal suture but could provide a shorter surgical time
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