Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to
gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor ...2α (HIF-2α).
In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.
After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients 77%) and central nervous system hemangioblastomas (15 of 50 patients 30%). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
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•Neurotrophins (NTs) play important role in maintaining neuro-endocrine homeostasis.•NTs mediate their effects through hypothalamo-pituitary-adrenal (HPA)-axis activation.•Their ...unique interplay might be implicated in stress induced genesis of psychiatric disorders.•Epigenetics plays orchestrating role in NTs mediated HPA axis dysregulation.
Apart from their established role in embryonic development, neurotrophins (NTs) have diverse functions in the nervous system. Their role in the integration of physiological and biochemical aspects of the nervous system is currently attracting much attention. Based on a systematic analysis of the literature, we here propose a new paradigm that, by exploiting a novel role of NTs, may help explain the genesis of stress-related psychiatric disorders, opening new avenues for better management of the same. We hypothesize that NTs as an integrated network play a crucial role in maintaining an indivdual’s psychological wellbeing. Given the evidence that stress can induce chronic disruption of the hypothalamic-pituitary-adrenal (HPA) axis which, in turn, is causally linked to several psychiatric disorders, this function may be mediated through the homeostatic mechanisms governing regulation of this axis. In fact, NTs, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are known to participate in neuroendocrine regulation. Recent studies suggest epigenetic modification of NT-HPA axis interplay in the precipitation of psychiatric disorders. Our article highlights why this new knowledge regarding NTs should be considered in the etiogenesis and treatment of stress-induced psychopathology.
The Ectopia cordis is a rare congenital condition. It is characterized by the abnormal position of the heart outside the thoracic cavity, associated with defects in the parietal pericardium, ...diaphragm, sternum, and, in most cases, cardiac malformations. The reported prevalence is 5.5 to 7.9 per million live births. The designation Ectopia cordis was first proposed by Abott in 1998, although cases of patients with similar defects had been reported in past. Only 267 cases have been reported as of 2001, most (95%) associated with other cardiac abnormalities. A 10 hour old, normal, vaginally delivered, full-term male neonate, weighing 2020 grams was brought with an externally visible, beating heart over the lower chest wall. The antenatal period was uneventful, though no ultrasonography was done. The beating heart was covered with a membrane with greenish purulent matter over it, most probably, due to pseudomonas/proteus infection. Rest of the anterior abdominal wall was intact. Ectopia cordis is produced by segmental defects in mesodermal development in the third week of intrauterine life, and/or amniotic band syndrome that causes simultaneous cerebral and Thoraco-abdominal malformations. The existence of Ectopia cordis with severe congenital heart disease may be confirmed in the prenatal period by vaginal echocardiography at 10-12 weeks of gestation or by abdominal echocardiography by 20-22 weeks. Surgery is the only hope of survival, for such patients, although the overall success rate is very poor. In recent years, surgery has been attempted in one or two phases with variable results that depend, mainly on the type of associated heart disease.
Research aimed at improving spacecraft attitude estimation using stand-alone star trackers has focused upon the measurement of star image on CMOS APS array. The precision and speed of the star ...identification process from the image of stars is the critical issue. An algorithm for star pattern identification, using a star catalog, the database with information about individual stars, and a set of derived catalogs to provide information regarding the attributes of star pairs, is presented. A star pair is designated with the inter-star angular displacement and the scaled difference between their corresponding visual magnitudes. This algorithm is developed for general lost-in-space conditions and further extended for normal mode of operation to track the stars in the field of view.
The specificity of hydrotropes in solubilization has been successfully employed for the separation of close-boiling isomeric components from their binary mixtures forming simple eutectics, in some ...cases even at the eutectic compositions. The purpose of this paper is to propose a novel technique of crystallizing 6-aminopenicillanic acid (6-APA) in a good quality and pure crystalline form from product reaction mixture in a hydrotrope environment. The remaining mother liquor may be used to recover crystalline phenoxyacetic acid (PAA) by dilution with water and subsequently to concentrate hydrotrope solution for recycle. Semibatch crystallization experiments for 6-APA in a 2
l laboratory-scale agitated crystallizer with controlled acid addition from product reaction mixture in hydrotrope solution yield better quality crystalline product than that in absence of hydrotrope. The present study demonstrates the potential efficacy of sodium butyl monoglycol sulphate (NaBMGS) hydrotrope in the separation of 6-APA in pure crystalline form from the product reaction mixture.
To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.
In a ...multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.
The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%-17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.
On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management.
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Green electronics is a trending and cost-effective method with potential application in health care monitoring and wearable electronics. We present a piezo resistive wearable pressure sensor using ...Polyaniline (PANI) incorporated with cellulose paper (CP) substrate. The ultralow-cost sensor is prepared by coating the sensing material on the paper using simple dip coating method. On stacking multiple PANI-CPs one upon another, the obtained flexible sensor demonstrates excellent sensitivity of 2.23 kPa−1, fast response of 70 ms and wide working range from 2 to 90 kPa. Furthermore, the sensor manifest excellent flexibility, outstanding stability up to 800 loading–unloading cycles and biodegradability. In addition, the pressure sensor can also be used for detecting rapid finger tapping. Apart from the other pressure sensors, this work mainly focusses on fabricating wearable piezo resistive sensors with low cost, facile fabricating process and shows potential for future applications in flexible wearable sensors.
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•Piezo resistive wearable pressure sensor was fabricate using PANI decorated on CP substrate.•The pressure sensor is prepared by coating the sensing material on to the paper using simple dip coating method.•The sensor demonstrates excellent sensitivity of 2.23 kPa−1, fast response of 70 ms and wide working range.•This work mainly focusses on fabricating wearable piezo resistive sensors with low cost, facile fabricating process.
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