Adjuvant dabrafenib and trametinib for patients with resected BRAF-mutated melanoma: DESCRIBE-AD real-world retrospective observational study

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF-V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF-mutated melanoma patients aged & GE;18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations

Congenital leptin deficiency and leptin gene missense mutation found in two colombian sisters with severe obesity

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Measurement of the Lambda(b) cross section and the anti-Lambda(b) to Lambda(b) ratio with Lambda(b) to J/Psi Lambda decays in pp collisions at sqrt(s) = 7 TeV

The Lambda(b) differential production cross section and the cross section ratio anti-Lambda(b)/Lambda(b) are measured as functions of transverse momentum pt(Lambda(b)) and rapidity abs(y(Lambda(b))) in pp collisions at sqrt(s) = 7 TeV using data collected by the CMS experiment at the LHC. The measurements are based on Lambda(b) decays reconstructed in the exclusive final state J/Psi Lambda, with the subsequent decays J/Psi to an opposite-sign muon pair and Lambda to proton pion, using a data sample corresponding to an integrated luminosity of 1.9 inverse femtobarns. The product of the cross section times the branching ratio for Lambda(b) to J/Psi Lambda versus pt(Lambda(b)) falls faster than that of b mesons. The measured value of the cross section times the branching ratio for pt(Lambda(b)) > 10 GeV and abs(y(Lambda(b))) < 2.0 is 1.06 +/- 0.06 +/- 0.12 nb, and the integrated cross section ratio for anti-Lambda(b)/Lambda(b) is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are statistical and systematic, respectively.Comment: Submitted to Physics Letters

Nonperturbative study of the four gluon vertex

In this paper we study the nonperturbative structure of the SU(3) four-gluon vertex in the Landau gauge, concentrating on contributions quadratic in the metric. We employ an approximation scheme where 'one-loop' diagrams are computed using fully dressed gluon and ghost propagators, and tree-level vertices. When a suitable kinematical configuration depending on a single momentum scale p is chosen, only two structures emerge: the tree-level four-gluon vertex, and a tensor orthogonal to it. A detailed numerical analysis reveals that the form factor associated with this latter tensor displays a change of sign (zero-crossing) in the deep infrared, and finally diverges logarithmically. The origin of this characteristic behavior is proven to be entirely due to the masslessness of the ghost propagators forming the corresponding ghost-loop diagram, in close analogy to a similar effect established for the three-gluon vertex. However, in the case at hand, and under the approximations employed, this particular divergence does not affect the form factor proportional to the tree-level tensor, which remains finite in the entire range of momenta, and deviates moderately from its naive tree-level value. It turns out that the kinematic configuration chosen is ideal for carrying out lattice simulations, because it eliminates from the connected Green's function all one-particle reducible contributions, projecting out the genuine one-particle irreducible vertex. Motivated by this possibility, we discuss in detail how a hypothetical lattice measurement of this quantity would compare to the results presented here, and the potential interference from an additional tensorial structure, allowed by Bose symmetry, but not encountered within our scheme

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess.</p> <p>Methods/design</p> <p>Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.</p> <p>The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints.</p> <p>Discussion</p> <p>In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism.</p> <p>Trial registration</p> <p>ISRCTN33941607</p

The First Habitable-Zone Earth-Sized Planet From TESS. I. Validation Of The TOI-700 System

We present the discovery and validation of a three-planet system orbiting the nearby (31.1 pc) M2 dwarf star TOI-700 (TIC 150428135). TOI-700 lies in the TESS continuous viewing zone in the Southern Ecliptic Hemisphere; observations spanning 11 sectors reveal three planets with radii ranging from 1 R⊕ to 2.6 R⊕ and orbital periods ranging from 9.98 to 37.43 days. Ground-based follow-up combined with diagnostic vetting and validation tests enables us to rule out common astrophysical false-positive scenarios and validate the system of planets. The outermost planet, TOI-700 d, has a radius of 1.19 ± 0.11 R⊕ and resides within a conservative estimate of the host star\u27s habitable zone, where it receives a flux from its star that is approximately 86% of Earth\u27s insolation. In contrast to some other low-mass stars that host Earth-sized planets in their habitable zones, TOI-700 exhibits low levels of stellar activity, presenting a valuable opportunity to study potentially rocky planets over a wide range of conditions affecting atmospheric escape. While atmospheric characterization of TOI-700 d with the James Webb Space Telescope (JWST) will be challenging, the larger sub-Neptune, TOI-700 c (R = 2.63 R⊕), will be an excellent target for JWST and future space-based observatories. TESS is scheduled to once again observe the Southern Hemisphere, and it will monitor TOI-700 for an additional 11 sectors in its extended mission. These observations should allow further constraints on the known planet parameters and searches for additional planets and transit timing variations in the system