Prognostic or predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1

Next generation sequencing studies in Chronic lymphocytic leukemia (CLL) have revealed novel genetic variants that have been associated with disease characteristics and outcome. The aim of this study was to evaluate the prognostic value of recurrent molecular abnormalities in patients with CLL. Therefore, we assessed their incidences and associations with other clinical and genetic markers in the prospective multicenter COMPLEMENT1 trial (treatment naive patients not eligible for intensive treatment randomized to chlorambucil (CHL) vs. ofatumumab-CHL (O-CHL)). Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by amplicon-based targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation and the incidence was highest in NOTCH1 (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT1 (7.0%), RPS15 (4.4%), FBXW7 (3.4%), MYD88 (2.6%) and BIRC3 (2.3%). While most mutations lacked prognostic significance, TP53 (HR2.02,p<0.01), SF3B1 (HR1.66,p=0.01) and NOTCH1 (HR1.39,p=0.03) were associated with inferior PFS in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71,p=0.04) and OS (HR2.78,p=0.02) and of SF3B1 for PFS only (HR1.52,p=0.02). Notably, NOTCH1 mutation status separates patients with a strong and a weak benefit from ofatumumab addition to CHL (NOTCH1wt:HR0.50,p<0.01, NOTCH1mut:HR0.81,p=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo (immune)therapy CLL trial. These results validate NGS-based mutation analysis in a multicenter trial and provide a basis for expanding molecular testing in the prognostic workup of patients with CLL. ClinicalTrials.gov registration number: NCT0074818

Геофізична модель мантійної рудообразующего системи

The paper deals with a generalized geophysical model of the mantle ore-forming system that covers three main parts: a) the area of origin of the ore substance; b) its transportation zone and c) the area of concentrated ore-formation ― a deposit. The essence of the model uses the modern achievements of metallogeny and deep geophysics on one hand, as well as original quantitative data on the structure of the astenosphere in the regions of large deposits of non-ferrous and metal ores deposits in Central Srednogorie and the Central Rhodopes on the other. As a result of geophysical studies longitudinal and transversal mantle faults have been tracked as well as the lifting of the heated roof of the asthenospheric layer. In addition quantitative data have been obtained on considerable vertical amplitudes of tectonic ruptures both on the Moho division of more than 7―14 km and on the upper boundary of asthenospheric layer where the amplitude is more than 60 km. The structure of endogenous ore-forming system described shows that two of its main parts, namely origination and localization of ore-bearing products are completely situated in asthenosphere and earth crust respectively. The third main part ― the transporting one occupies some restricted area of the upper mantle and the whole vertical size of the earth crust coincident with crust-mantle nods. The features of tectonosphere revealed within the limits of the mantle ore areas as well as specific geophysical character of asthenospheric layer certificate that within these areas favorable conditions were generated for emergence and functioning of convecting cells and ascending magmo-fluid flows. All the mentioned, stimulated origination of ore-bearing magma in asthenosphere layer and their movement to the surface, where in the Late Cretaceous (Srednogorie) and Paleogenic (Rhodopes) the mantle deposits were formed. The results of the studies conducted are the important step in clearing the problem of origination of the ore matter realized in asthenosphere.Рассмотрена геофизическая модель мантийной рудо-образовательной системы, которая состоит из трех частей: а) район зарождения рудного вещества; б) зона его транспортировки; в) ареал рудовидкладення - месторождение. Модель основывается, с одной стороны, на использовании современных достижений металлогении и методов глубинной геофизики, а с другой - на оригинальных данных по строения тектоносферы в пространстве больших рудных районов цветных и благородных металлов, расположенных в Центральном среднегорье и Центральных Родопах. В результате геофизических исследований прослежена продольные и поперечные мантийные разломы, а также поднятия разогретой кровли астеносферном слоя. Получены количественные данные о значительных вертикальных амплитуд (7-14 км и более) тектонических разрывов, происходящих как на разделении Мохо, так и на верхней границе астеносферном слоя (амплитуда более 60 км). В описанной структуре эндогенной рудоутворювальнои системы две из его основных частей, а именно зарождения и локализация рудоносных продуктов, полностью размещаются в астеносфере и земной коре соответственно. Третья основная часть - транспортная - занимает ограниченный участок верхней мантии и по вертикали охватывает земную кору, которая совпадает с коромантийный узлами.Выявлены особенности тектоносферы в пределах мантийных рудных районов, а также специфическая геофизическая характеристика астеносферном слоя свидетельствуют, что в их пространстве существовали благоприятные условия для возникновения и функционирования конвективных ячеек и восходящих магмофлюидних потоков. Все это повлекло зарождения рудоносных магм в астеносферном слое и их передвижения к земной поверхности, где в верхней мелу (Среднегорье) и палеогене (Родопы) формировались мантийные месторождения. Результаты исследований важны для выяснения проблемы зарождения рудного вещества, которое происходит в астеносфере.Розглянуто геофізичну модель мантійної рудоутворювальної системи, яка складається з трьох частин: а) район зародження рудного речовини; б) зона його транспортування; в) ареал рудовідкладення — родовище. Модель ґрунтується, з одного боку, на використанні сучасних досягнень металогенії і методів глибинної геофізики, а з іншого — на оригінальних даних щодо будови тектоносфери у просторі великих рудних районів кольорових і благородних металів, розташованих у Центральному Середньогір’ї і Центральних Родопах. У результаті геофізичних досліджень простежено поздовжні і поперечні мантійні розломи, а також підняття розігрітої покрівлі астеносферного шару. Отримано кількісні дані щодо значних вертикальних амплітуд (7—14 км і більше) тектонічних розривів, що відбуваються як на поділі Мохо, так і на верхній межі астеносферного шару (амплітуда понад 60 км). В описаній структурі ендогенної рудоутворювальної системи дві з її основних частин, а саме зародження і локалізація рудоносних продуктів, повністю розміщуються в астеносфері й земній корі відповідно. Третя основна частина — транспортна — займає обмежену ділянку верхньої мантії і за вертикаллю охоплює земну кору, яка збігається з коромантійними вузлами.Виявлені особливості тектоносфери в межах мантійних рудних районів, а також специфічна геофізична характеристика астеносферного шару засвідчують, що в їх просторі існували сприятливі умови для виникнення і функціонування конвективних комірок і висхідних магмофлюїдних потоків. Все це спричинило зародження рудоносних магм в астеносферному шарі і їх пересування до земної поверхні, де у верхній крейді (Середньогір’я) і палеогені (Родопи) формувалися мантійні родовища. Результати досліджень важливі для з’ясування проблеми зародження рудної речовини, яке відбувається в астеносфері

Renal Changes in Cocaine Abuse and Addiction

Cocaine is a natural alkaloid extracted from the leaves of the South American plant Erythroxylum coca or synthesized chemically. After cannabis, it is the second most frequently abused recreational substance worldwide. Cocaine can affect every tissue and organ within the human body, including the kidneys, causing tissue ischemia due to vasoconstriction, endothelial dysfunction and damage, procoagulant activity and oxidative stress with subsequent ischemic infarctions and fibrosis. The renal changes in cocaine abuse and addiction are due to rhabdomyolysis, ischemic, hypertensive, and inflammatory changes with the development of cell proliferation and fibrosis. The authors present three patients with cocaine-associated renal damage and discuss the underlying mechanisms of cocaine-induces tissue changes

Rhabdomyolisys as a Cause of Acute Renal Injury

Rhabdomyolysis (RM) is defined as striate muscle-cell damage with disintegration of skeletal muscles and release of intracellular constituents to the circulation, with or without subsequent kidney injury. RM is one of the leading causes of acute kidney injury and is associated with substantial morbidity. The major signs of acute kidney injury in rhabdomyolysis are: pain, weakness and swelling of the injured muscle or muscle groups and myoglobinuria with reddish discoloration of the urine and decrease in urine output to anuria. The authors describe three cases of rhabdomyolysis with acute renal injury and discuss the current knowledge on the etiopathogenesis, clinical manifestations, diagnosis and treatment of this condition

Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: Results complement1 from the pivotal phase III study

Next generation sequencing studies in chronic lymphocytic leukemia (CLL) have revealed novel genetic variants that have been associated with disease characteristics and outcome. The aim of this study was to evaluate the prognostic value of recurrent molecular abnormalities in patients with CLL. Therefore, we assessed their incidences and associations with other clinical and genetic markers in the prospective multicenter COMPLEMENT1 trial [treatment naive patients not eligible for intensive treatment randomized to chlorambucil (CHL) vs. ofatumumab-CHL (O-CHL)]. Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by amplicon-based targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation; the incidence was highest in NOTCH1 (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT1 (7.0%), RPS15 (4.4%), FBXW7 (3.4%), MYD88 (2.6%), and BIRC3 (2.3%). While most mutations lacked prognostic significance, TP53 (HR2.02, P&amp;lt;0.01), SF3B1 (HR1.66, P=0.01), and NOTCH1 (HR1.39, P=0.03) were associated with inferior progression-free survival (PFS) in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71, P=0.04) and overall survival (OS) (HR2.78, P=0.02), and of SF3B1 for PFS only (HR1.52, P=0.02). Notably, NOTCH1 mutation status separates patients with a strong from those with a weak benefit from addition of ofatumumab to CHL (NOTCH1wt: HR0.50, P&amp;lt;0.01; NOTCH1mut: HR0.81, P=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic factors and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo/immunotherapy CLL trial. These results validate NGS-based mutation analysis in a multicenter trial and provide a basis for expanding molecular testing in the prognostic workup of patients with CLL. © 2020 Ferrata Storti Foundatio

A beamline for fundamental neutron physics at TRIUMF

This article describes the new primary proton beamline 1U at TRIUMF. The purpose of this beamline is to produce ultracold neutrons (UCN) for fundamental-physics experiments. It delivers up to 40 µA of 480 MeV protons from the TRIUMF cyclotron to a tungsten spallation target and uses a fast kicker to share the beam between the Center for Molecular and Materials Science and UCN. The beamline has been successfully commissioned and operated with a beam current up to 10 µA, facilitating first large-scale UCN production in Canada.This article describes the new primary proton beamline 1U at TRIUMF. The purpose of this beamline is to produce ultracold neutrons (UCN) for fundamental-physics experiments. It delivers up to 40 microA of 480 MeV protons from the TRIUMF cyclotron to a tungsten spallation target and uses a fast kicker to share the beam between the Center for Molecular and Materials Science and UCN. The beamline has been successfully commissioned and operated with a beam current up to 10 microA, facilitating first large-scale UCN production in Canada