Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.
We conducted a multicenter, ...retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).
A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1–60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line hazard ratios (HR) 2.8, CI 1.3–6.3, P = 0.01, relapsed-refractory (HR 2.8, CI 1.9–4.1, P < 0.001), del17p (HR 2.0, CI 1.2–3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2–5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3–1.0, P = 0.06).
In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
Consequences of reef phase shifts on fish communities remain poorly understood. Studies on the causes, effects and consequences of phase shifts on reef fish communities have only been considered for ...coral-to-macroalgae shifts. Therefore, there is a large information gap regarding the consequences of novel phase shifts and how these kinds of phase shifts impact on fish assemblages. This study aimed to compare the fish assemblages on reefs under normal conditions (relatively high cover of corals) to those which have shifted to a dominance of the zoantharian Palythoa cf. variabilis on coral reefs in Todos os Santos Bay (TSB), Brazilian eastern coast. We examined eight reefs, where we estimated cover of corals and P. cf. variabilis and coral reef fish richness, abundance and body size. Fish richness differed significantly between normal reefs (48 species) and phase-shift reefs (38 species), a 20% reduction in species. However there was no difference in fish abundance between normal and phase shift reefs. One fish species, Chaetodon striatus, was significantly less abundant on normal reefs. The differences in fish assemblages between different reef phases was due to differences in trophic groups of fish; on normal reefs carnivorous fishes were more abundant, while on phase shift reefs mobile invertivores dominated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Wine industry is one of the food industries that most generate residues around the world.•Environmental benefits can be achieved with a waste management policy.•Grape pomace can be a source of ...healthy and technological compounds.•Seedless grape pomace is generally rich in phenolic compounds and fibres.•Grape seeds are mainly explored for their oil and phenolic compounds.
Grape is the main fruit crop in several countries. Although many grape-based food products can be found in the market, studies have shown that around 75% of the world grape production is destined for the wine industry. Grape pomace is an abundant by-product from the wine industry, which consists of the remaining skin, seeds and stalks and represents around 25% of total grape weight used in the winemaking process. In countries such as Italy, France and Spain, where wine production is more relevant, the annual grape pomace generation can reach nearly 1200 tonnes per year. In order to reach a sustainable winemaking process there is a need of a waste reduction policy. Several studies explore this subject using grape pomace as a source of healthy and technological compounds that could be applied in animal feed, pharmaceutical, cosmetic or food industry to improve stability and nutritional characteristics, and in cosmetic industry, where grape seeds oil is widely used. This review aims to approach the recent winemaking scenario and the benefits achieved when a waste management policy is implemented, as well as to compare available extractive technologies and a wide alternative of uses for grape pomace.
The environmental severity of large impacts on Earth is influenced by their impact trajectory. Impact direction and angle to the target plane affect the volume and depth of origin of vaporized ...target, as well as the trajectories of ejected material. The asteroid impact that formed the 66 Ma Chicxulub crater had a profound and catastrophic effect on Earth's environment, but the impact trajectory is debated. Here we show that impact angle and direction can be diagnosed by asymmetries in the subsurface structure of the Chicxulub crater. Comparison of 3D numerical simulations of Chicxulub-scale impacts with geophysical observations suggests that the Chicxulub crater was formed by a steeply-inclined (45-60° to horizontal) impact from the northeast; several lines of evidence rule out a low angle (<30°) impact. A steeply-inclined impact produces a nearly symmetric distribution of ejected rock and releases more climate-changing gases per impactor mass than either a very shallow or near-vertical impact.
MSCs derived from the umbilical cord tissue, termed UCX, were investigated for their immunomodulatory properties and compared to bone marrow-derived MSCs (BM-MSCs), the gold-standard in ...immunotherapy. Immunogenicity and immunosuppression were assessed by mixed lymphocyte reactions, suppression of lymphocyte proliferation and induction of regulatory T cells. Results showed that UCX were less immunogenic and showed higher immunosuppression activity than BM-MSCs. Further, UCX did not need prior activation or priming to exert their immunomodulatory effects. This was further corroborated in vivo in a model of acute inflammation. To elucidate the potency differences observed between UCX and BM-MSCs, gene expression related to immune modulation was analysed in both cell types. Several gene expression profile differences were found between UCX and BM-MSCs, namely decreased expression of HLA-DRA, HO-1, IGFBP1, 4 and 6, ILR1, IL6R and PTGES and increased expression of CD200, CD273, CD274, IL1B, IL-8, LIF and TGFB2. The latter were confirmed at the protein expression level. Overall, these results show that UCX seem to be naturally more potent immunosuppressors and less immunogenic than BM-MSCs. We propose that these differences may be due to increased levels of immunomodulatory surface proteins such as CD200, CD273, CD274 and cytokines such as IL1β, IL-8, LIF and TGFβ2.
Phase shift, resulting from coral reef degradation, has been frequently recorded on reefs in optimal conditions, while marginal reefs were considered more resistant due to few records. Noting the ...lack of marginal reef phase shift studies, we quantitatively assessed their geographic extent in the Southwest Atlantic. Using metadata and a calculated phase shift index, we identified phase shifts from corals to both zoanthid and macroalgal dominance. Positive correlations existed between phase shift and local human impacts for zoanthids: proximity to human populations >100,000 inhabitants, urbanized surfaces and dredged ports and a negative relationship to the endurance of SST >1 °C above normal. Macroalgal shifts positively correlated to ports and urbanized surfaces, higher latitudes and shore proximity, indicating a possible link to nutrient runoff. The high frequency of these phase shifts suggests greater degradation than reported for Caribbean reefs, suggesting that marginal reefs do not have higher natural resistance to human impacts.
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Seafloor methane release can significantly affect the global carbon cycle and climate. Appreciable quantities of methane are stored in continental margin sediments as shallow gas and hydrate ...deposits, and changes in pressure, temperature and/or bottom-currents can liberate significant amounts of this greenhouse gas. Understanding the spatial and temporal dynamics of marine methane deposits and their relationships to environmental change are critical for assessing past and future carbon cycle and climate change. Here we present foraminiferal stable carbon isotope and sediment mineralogy records suggesting for the first time that seafloor methane release occurred along the southern Brazilian margin during the last glacial period (40-20 cal ka BP). Our results show that shallow gas deposits on the southern Brazilian margin responded to glacial-interglacial paleoceanographic changes releasing methane due to the synergy of sea level lowstand, warmer bottom waters and vigorous bottom currents during the last glacial period. High sea level during the Holocene resulted in an upslope shift of the Brazil Current, cooling the bottom waters and reducing bottom current strength, reducing methane emissions from the southern Brazilian margin.
Abstract
Introduction
Speckle-tracking echocardiography (STE) is an established tool to detect early myocardial contractile impairment. In Chagas disease patients, STE may be helpful to identify ...subtle myocardial damage with the potential of progression to heart failure.
Purpose
This study aimed to assess the value of STE in predicting heart failure in Chagas disease patients with preserved left ventricular ejection fraction (LVEF).
Methods
Patients with Chagas disease living in endemic area who had preserved LVEF (>50%) were selected for the study. Clinical evaluation, B-type natriuretic peptide (NT-ProBNP), electrocardiogram (ECG), and echocardiogram were performed at enrollment in 2015 to 2016 and in the follow-up visit between 2018 and 2019. Global longitudinal strain (GLS) derived from STE was analyzed offline. Peak GLS was calculated as the mean value from 18 segments of the left ventricle (Figure 1). The outcome was development of heart failure defined by elevation of NT-ProBNP levels, categorized according to age-specific cut-points for heart failure at the second evaluation. Patients with abnormal NT-ProBNP at baseline or those who died between the 2 visits were not included.
Results
A total of 692 were enrolled, mean age was 58 ± 12 years and 495 (72%) were women. Mean LVEF at baseline and follow-up visits were 63.4 ± 4.6% and 59.8 ± 11.2% (p<0.001). The median IQR time between visit 1 and visit 2 was 5.4 4.5 - 5.8 years. Among patients alive and attending the second visit, 48 patients (7%) developed overt heart failure with overall incidence rate of 14.1 events per 1000 patient-years (95% CI 10.4-18.6). On multivariable analysis, independent predictors of new-onset heart failure were male sex (OR 2.30, 95% CI 1.02-5.18), age (OR 1.04, 95% CI 1.01-1.07), QRS duration (OR 1.03, 95% CI 1.01-1.04), left atrial (LA) volume indexed (OR 1.05, 95% CI 1.01-1.09), and GLS (OR 0.90, 95% CI 0.81-0.98). LVEF did not remain in the model. The C-statistic of the final model was 0.80 (95% CI 71-88) showing a good discrimination.
Conclusions
In a cohort of patients with Chagas disease from remote areas with preserved ejection fraction, GLS was an important predictor of progression to overt heart failure, after adjustment for sex, age, QRS duration and LA volume. GLS was associated with further increased NT-ProBNP levels, which is useful to guide heart failure management, irrespective of systolic dysfunction.
Summary
Background
Prophylactic administration of mesenchymal stromal cells (MSCs) derived from adipose (AD‐MSC) and bone marrow tissue (BM‐MSC) in ovalbumin‐induced asthma hinders inflammation in a ...Treg‐dependent manner. It is uncertain whether MSCs act through Tregs when inflammation is already established in asthma induced by a clinically relevant allergen.
Objective
Evaluate the effect of therapeutic administration of MSCs on inflammation and Treg cells in house dust mite (HDM)‐induced asthma.
Methods
BM‐MSCs and AD‐MSCs were administered intratracheally to C57BL/6 mice 1 day after the last HDM challenge. Lung function, remodelling and parenchymal inflammation were assayed 3 or 7 days after MSCs treatment, through invasive plethysmography and histology, respectively. Bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes (mLNs) were assessed regarding the inflammatory profile by flow cytometry, ELISA and qRT‐PCR. MSCs were studied regarding their potential to induce Treg cells from primed and unprimed lymphocytes in vitro.
Results
BM‐MSCs, but not AD‐MSCs, reduced lung influx of eosinophils and B cells and increased IL‐10 levels in HDM‐challenged mice. Neither BM‐MSCs nor AD‐MSCs reduced lung parenchymal inflammation, airway hyperresponsiveness or mucus hypersecretion. BM‐MSCs and AD‐MSCs did not up‐regulate Treg cell counts within the airways and mLNs, but BM‐MSCs decreased the pro‐inflammatory profile of alveolar macrophages. Co‐culture of BM‐MSCs and AD‐MSCs with allergen‐stimulated lymphocytes reduced Treg cell counts in a cell‐to‐cell contact‐independent manner, although co‐culture of both MSCs with unprimed lymphocytes up‐regulated Treg cell counts.
Conclusions
MSCs therapeutically administered exert anti‐inflammatory effects in the airway of HDM‐challenged mice, but do not ameliorate lung function or remodelling. Although MSC pre‐treatment can increase Treg cell numbers, it is highly unlikely that the MSCs will induce Treg cell expansion when lymphocytes are allergenically primed in an established lung inflammation.
Abstract
Context
Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been ...reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.
Objective
To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.
Methods
We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.
Results
KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004).
Conclusion
The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
The impact of KCNJ5 somatic mutations on hypertension remission after adrenalectomy brings new insight into the postoperative follow-up of patients with PA.
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