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A 2-year dataset of a stand-alone mooring, deployed in November 2020 down the Levante Canyon in the eastern Ligurian Sea, is presented. The Levante Canyon Mooring (LCM) is a deep submarine multidisciplinary observatory positioned at 608 m depth in a key ecosystem area. The Levante Canyon hosts a valuable and vulnerable ecosystem of deep-living cold-water corals (CWCs), studied and monitored since 2013 through integrated mapping of the seabed and water column. The 2-year dataset, acquired on the mooring and presented here (data from November 2020 to October 2022), includes measurements conducted with both current meters and conductivity–temperature–depth (CTD) probes and provides information about the hydrodynamics and thermohaline properties across almost the entire water column. The observatory is still ongoing, and the dataset is regularly updated. All the described data are publicly available from https://doi.org/10.17882/92236 (Borghini et al., 2022). They must therefore be preserved and are of considerable scientific interest.

One-year time-lapse images acquired via an autonomous photo imaging device positioned at a depth of 20 m in Tethys Bay (Ross Sea, Antarctica) on a rocky bottom colonized by the sponge Mycale (Oxymycale) acerata were analysed. Monthly changes in the abundance and activity of the sea star Odontaster validus and sea urchin Sterechinus neumayeri on the sponge and nearby rocky bottom were compared with respect to environmental variables such as pack-ice presence/absence, temperature, salinity and photosynthetically active radiation. Sea urchins were more abundant on the rocky bottom and sponge during the summer and winter, respectively. Sea stars showed a decrease in the number of individuals on the sponge from January to December. The grazing activity of both species reached its maximum in January–April, when increased sunlight contributed to the phytoplankton bloom. The winter months were critical both for O. validus and S. neumayeri; although the red sea star maintained its pattern of activity on the rocky bottoms in terms of searching for food, the sea urchin reduced its activity. Time-lapse monitoring systems coupled with physicochemical sensors showed potential for revealing species behaviour in polar environments, contributing to the elucidation of future changes in coastal communities facing climate change.

Background Congenital prekallikrein deficiency has been associated with increased risk of thrombosis in a few uncontrolled studies. Prekallikrein levels were reduced by 36-94% (median 75%) in a phase 2 study with the prekallikrein specific antisense oligonucleotide, donidalorsen, in patients with hereditary angioedema (HAE). Objectives To estimate the effects of plasma prekallikrein reduction on coagulation and fibrinolysis. Methods Plasma samples were obtained from 16 HAE patients treated with donidalorsen and six placebo-treated patients. Calibrated automated thrombogram (CAT), clot lysis time, high-molecular-weight kininogen activity, factor XI activity, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes, D-dimer, plasminogen activity, plasmin-α2-antiplasmin complexes, and α2-antiplasmin activity were measured before and after four months of treatment. Results No significant changes following donidalorsen treatment were observed between baseline and after four months of treatment: CAT lag time 3.0 min and 3.0 min, CAT peak thrombin concentration 109% and 129%, CAT endogenous thrombin potential 98% and 108%, factor XI activity 110% and 115%, F1+2 levels 251 pMol/L and 161 pMol/L, thrombin-antithrombin complexes 2.6 μg/L and 1.9 μg/L, high-molecular-weight kininogen activity 87% and 93%, clot lysis time 92% and 99%, D-dimer levels 0.65 μg/L and 0.36 μg/L, plasminogen activity 116% and 125%, plasmin-α2-antiplasmin complexes 533 ng/mL and 328 ng/mL, and α2-antiplasmin activity 122% and 127%, respectively. There were also no differences between donidalorsen and placebo treatment. Conclusions Reduction of plasma prekallikrein by donidalorsen in HAE patients neither affected thrombin formation nor fibrinolytic activity. Our data suggest that partial plasma prekallikrein reduction does not influence thrombotic risk.

A large group of countries constitute Latin American (LATAM) countries, where hemophilia care is as varied as the landscape of this region. To better understand the care provided to persons with bleeding disorders, especially hemophilia, a symposium was organized as part of the CLAHT Congress 2021 in Colombia to highlight the issues of hemophilia care and challenges faced by persons with hemophilia in four LATAM countries, Colombia, Peru, Argentina, and Mexico. A summary of the symposium is provided. Four clinicians highlighted the issues in their own country, the status, and the path forward to bring the standard of care to the international level in each of these countries. The geography of the country, the health infrastructure, and the resources available are obstacles in these countries to provide state-of-the-art care to the bleeding disorder community. However, depending on the country, its infrastructure and the resources available, progress is being made to upend the care provided. Indeed, the care of persons with hemophilia has been greatly improved, including personalized prophylaxis. The information summarized here first emphasizes how the geography of a country and the different healthcare infrastructures play a major role in how care is offered. It also provides a path for other countries to evaluate these issues in their own realities. In parallel, these data provide hope to many developing countries; despite obstacles, strides can be made in the care of the bleeding disorder community.

The bone tissue can regenerate itself completely and continuously; however, large-scale bone defects may overpower this self-regenerative process. Furthermore, the aging population, the increment in obesity incidence, and the sedentary lifestyles are serious risk factors for bone diseases' development which are associated with the self-regenerative process's failure, high morbidity, and mortality rates. Thus, there is an ever-growing need for strategic approaches targeting bone replacement, its remodelling, and its regeneration. Bone scaffolds have successfully been used as synthetic bone grafts for many years, yet recent bone tissue engineering strategies attempt to explore their multifunctionality by investigating them as drug delivery systems. Bone diseases' treatments can be substantially difficult due to the avascular nature of the surrounding cartilage; thus, targeted drug delivery to the bone can be advantageous: it provides local high drug concentrations and minimizes adverse effects while securing a space for new, healthy tissue growth. Despite the promising scientific progress, studies underlining bone scaffolds' use as local drug delivery systems are not abundant. Hence, this work reviews bone scaffolds' therapeutic interest for local drug delivery in five distinct bone disorders-osteomyelitis, osteoporosis, osteoarthritis, osteosarcoma, and cancer bone metastasis. Additionally, it presents the challenges of this possible therapeutic approach and its future perspectives. Albeit bone scaffolds present therapeutic benefits by acting as drug delivery systems, further pre-clinical and clinical assessments are needed to strengthen their understanding and enable research evidence translation into clinical practice. The mismatch between scientific evolution and regulatory frameworks remains one of the major future challenges.

Baseline gene expression analysis of B cell lymphoma cell lines with higher (IC50 < 200 nM) or lower sensitive (IC50 > 400 nM) to PQR309.

PQR309 activity, combinations of PQR309 with additional drugs, BCL2, MYC and TP53 status in lymphoma cell lines.

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120–9. ©2017 AACR.

Baseline gene expression analysis of B cell lymphoma cell lines sensitive to PQR309 and idelalisib (dual sensitive) or to PQR309 only (discordant).

Phosphopeptide changes induced by PQR309 in B cell lymphoma cell lines revealed using mass spectrometry analysis.

Phosphoprotein changes induced by PQR309 in B cell lymphoma cell lines revealed using Reverse Phase Protein Array (RPPA) analysis.

Supplementary figures, table legends, Table S1, S9 Figure S1. In vitro antitumor activity of the dual PI3K/mTOR inhibitor apitolisib and its correlation with PQR309. Figure S2. Antitumor In vivo activity of PQR309 in the treatment of RI-1 and SU-DHL-6 xenograft model. Figure S3. Apoptosis is induced by co-treatment of PQR309 with venetoclax or panobinostat in primary cells and in the DLBCL SU-DHL-6 cell line. Figure S4. Specific baseline gene expression signatures are associated with higher or lower sensitivity to PQR309. Figure S5. In vitro antitumor activity of the PI3K� inhibitor idelalisib and its correlation with PQR309. Figure S6. PQR309 induced decrease in phosphorylation of AKT-Ser473 and p70S6K-Thr389 in DLBCL cell lines. Figure S7. PQR309 reduces AKT-Ser473 phosphorylation in lymphoma cell lines. Figure S8. Transcriptional expression signature of ABC DLBCL cell lines induced by PQR309. Figure S9. ABC and GCB DLBCL PQR309-treated signatures were highly overlapping. Figure S10. Transcript expression levels of PQR309-treated samples. Figure S11. Changes in protein phosphorylation and RNA expression differently contribute to PQR309 affected biologic pathways in ABC DLBCL. Figure S12. PQR309 can largely regulate the same genes affected by the BTK inhibitor ibrutinib, the PI3K� idelalisib, the dual PI3K�/� inhibitor duvelisib (A), the dual PI3K�/� inhibitor AZD8835 or the AKT inhibitor AZD5363 (B). Figure S13. BCR pathway signature is similarly affected after ibrutinib, idelalisib and duvelisib treatments in ABC DLBCL cell lines. Figure S14. The dual PI3K/mTOR inhibitor PQR309 and the PIM inhibitor AZD1208 synergize in DLBCL cell lines. Supplementary Table 1. List of phosphoresidues investigated by Carna Bioscience to perform RPPA analysis. Supplementary Table 9. Transcripts differentially expressed in ABC DLBCL cell lines treated with ibrutinib (A), idelalisib (B) or duvelisib (C) versus DMSO.

Phosphoproteins changes induced by PQR309 in B cell lymphoma cell lines revealed using Pathscan Akt Signaling Antibody Array Kit.

Gene expression changes in DLBCL cell lines after exposure to PQR309.

Information extraction from synthetic aperture radar (SAR) images is heavily impaired by speckle noise, and hence, despeckling is a crucial preliminary step in scene analysis algorithms. The recent success of deep learning envisions a new generation of despeckling techniques that could outperform classical model-based methods. However, current deep learning approaches to despeckling require supervision for training, whereas clean SAR images are impossible to obtain. In the literature, this issue is tackled by resorting to either synthetically speckled optical images, which exhibit different properties with respect to true SAR images, or multitemporal SAR images, which are difficult to acquire or fuse accurately. In this article, inspired by recent works on blind-spot denoising networks, we propose a self-supervised Bayesian despeckling method. The proposed method is trained by employing only noisy SAR images and can, therefore, learn features of real SAR images rather than synthetic data. Experiments show that the performance of the proposed approach is very close to the supervised training approach on synthetic data and superior on real data in both quantitative and visual assessments.

In the chapter, childcare by grandparents reflects downward intergenerational support in families. The authors aim to understand the ways that policy, structure, and culture shape the extent to which grandparents provide care for their grandchildren. According to common approaches to the role of family policy, a strong welfare state may replace family arrangements and thus “crowd out” intergenerational solidarity within the family, or it may stimulate and thus “crowd in” intergenerational solidarity within the family. The authors suggest the concept of mixed responsibilities, according to which family and state provisions interact. Using this framework, the chapter provides an overview of grandparental childcare in different welfare state contexts (namely Europe, the United States, China, and South Korea). It concludes that a mix of demographic trends, cultural norms, and welfare state policies contributes to explaining cross-national differences in the provision of childcare by grandparents.

A 2 years dataset of a stand-alone mooring placed, deployed in November 2020 down the Levante Canyon in the Eastern Ligurian Sea, is presented. The Levante Canyon Mooring (LCM) is a deep submarine multidisciplinary observatory deployed at 608 m depth, in a key ecosystem area. The Levante Canyon hosts a valuable and vulnerable ecosystem of deep-living Cold-Water Corals (CWC), studied and monitored since 2013 through the integrated mapping of seabed and water column. The 2 years dataset, acquired on the mooring and presented here (data from November 2020 to October 2022), includes measurements conducted with both currentmeters and CTD probes, and provides information about the hydrodynamics and thermohaline properties across almost the entire water column. The observatory is still on-going and the dataset is regularly updated. All the described data are publicly available from https://doi.org/10.17882/92236 (Borghini et al., 2022). They must therefore be preserved and are of considerable scientific interest.

Hole-spin qubits in semiconductors represent a mature platform for quantum technological applications. Here we consider their use as quantum sensors, and specifically for inferring the presence and estimating the distance from the qubit of a remote charge. Different approaches are considered - based on the use of single or double quantum dots, ground and out-of-equilibrium states, Rabi and Ramsey measurements - and comparatively analyzed by means of the discrimination probability, of the classical and quantum Fisher information. Detailed quantitative aspects result from the multiband character of the hole states, which we account for by means of the Luttinger-Kohn Hamiltonian. Furthermore, general conclusions can be drawn on the relative efficiency of the above options, and analytical expressions are derived for the Fisher information of a generic qubit within the Rabi and Ramsey schemes., Comment: 16 pages, 14 figures

Several new physics scenarios that address anomalies in $B$-physics predict an enhancement of $b \rightarrow s ττ$ with respect to its Standard Model prediction. Such scenarios necessarily imply modifications of the lifetime ratio $τ_{B_{s}}/τ_{B_{d}}$ and the lifetime difference $ΔΓ_{s}$. In this work, we explore indirect bounds provided by these observables over new physics scenarios. We also estimate future projections, showing that future experimental and theoretical improvements on both $τ_{B_{s}}/τ_{B_{d}}$ and $ΔΓ_{s}$ have the potential to provide bounds competitive with those directly extracted from $b\rightarrow s ττ$ transitions. After performing a model-independent analysis, we apply our results to the particular case of leptoquark mediators proposed to address the $R_{D^{(*)}}$ anomalies., 12 pages + Appendix, 4 Figures

We synthesized new aroyl diheterocyclic pyrrole (ARDHEP)

Graphene nanoribbons provide an ideal platform for electronic interferometry in the Integer Quantum Hall regime. Here, we solve the time-dependent four-component Schroedinger equation for single carriers in graphene and expose several dynamical effects of the carrier localization on their transport characteristics in pn junctions. We simulate two kinds of Mach-Zender Interferometers (MZI). The first is based on Quantum Point Contacts and is similar to traditional GaAs/AlGaAs interferometers. As expected, we observe Aharonov-Bohm oscillations and phase averaging. The second is based on Valley Beam Splitters, where we observe unexpected phenomena due to the intersection of the Edge Channels that constitute the MZI. Our results provide further insights into the behavior of graphene interferometers. Additionally, they highlight the operative regime of such nanodevices for feasible single-particle implementations., 14 pages, 7 figures

This study investigates the impact of non-intensive and intensive supplementary grandparental child care on grandparents’ involvement in leisure activities. Three aspects of leisure activities are investigated: the number/frequency of activities, with whom they are carried out and the subjective satisfaction with them. Beside the possibility of a cumulation effect, the literature suggests that providing grandparental child care might compete with other activities, especially for women. Thus, we consider role enhancement and role strain theories to derive our hypotheses. We use longitudinal data from the German Ageing Survey (DEAS) which contains rich information on the leisure activities of people aged 40 and older. To account for selection into the provision of grandparental child care, we use a within-unit estimation approach (fixed-effects panel models). Our results show that both grandfathers and grandmothers tend to engage in more leisure activities when they provide grandparental child care. While care-giving grandfathers become more likely to engage in activities with family members without changing their engagement outside the family, we found no effect for women in this respect. Nevertheless, grandparental child-care provision modifies satisfaction with leisure activities only for women, reducing it, independently from with whom leisure activities are carried out. These findings suggest that a higher quantity of leisure activities does not necessarily imply higher quality.

We perform an analysis of $\Lb\to\L(1520)$ local form factors. We use dispersive techniques to provide a model-independent parametrisation of the form factors that can be used in the whole kinematic region. We use lattice QCD data to constrain the free parameters in the form factors expansion, which is further constrained by endpoint relations, dispersive bounds, and SCET relations. We analyse different scenarios, where we expand the form factors up to different orders, and their viability. Finally, we use our results to obtain predictions for some observables in $\Lb\to\L(1520)\ell^+\ell^-$ decays, as the differential branching ratio, the forward-backwards lepton asymmetry and the branching ratio of $\Lambda_b\to\L(1520)\gamma$. Finally, we provide a python notebook based on the software \texttt{EOS} to reproduce our result. We perform an analysis of Λ$_{b}$ → Λ(1520) local form factors. We use dispersive techniques to provide a model-independent parametrisation of the form factors that can be used in the whole kinematic region. We use lattice QCD data to constrain the free parameters in the form factors expansion, which is further constrained by endpoint relations, dispersive bounds, and SCET relations. We analyse different scenarios, where we expand the form factors up to different orders, and their viability. Finally, we use our results to obtain predictions for some observables in Λ$_{b}$ → Λ(1520)ℓ$^{+}$ℓ$^{−}$ decays, as the differential branching ratio, the forward-backwards lepton asymmetry and the branching ratio of Λ$_{b}$ → Λ(1520)γ. Finally, we provide a python notebook based on the software EOS to reproduce our result. We perform an analysis of $\Lambda_b\to\Lambda(1520)$ local form factors. We use dispersive techniques to provide a model-independent parametrisation of the form factors that can be used in the whole kinematic region. We use lattice QCD data to constrain the free parameters in the form factors expansion, which is further constrained by endpoint relations, dispersive bounds, and SCET relations. We analyse different scenarios, where we expand the form factors up to different orders, and their viability. Finally, we use our results to obtain predictions for some observables in $\Lambda_b\to\Lambda(1520)\ell^+\ell^-$ decays, as the differential branching ratio, the forward-backwards lepton asymmetry and the branching ratio of $\Lambda_b\to\Lambda(1520)\gamma$. Finally, we provide a python notebook based on the software EOS to reproduce our result.

Antarctica is a remote place, the continent is covered by ice and its surrounding coastal areas are frozen for the majority of the year. Due to its peculiarity the observation of the underwater organisms is particularly difficult, complicated by logistic factors. We present a long-term dataset consisting of 755 images acquired by using a non-invasive, autonomous imaging device and encompassing both the Antarctic daylight and dark periods, including the corresponding transition phases. All images have the same field of view showing the benthic fauna and part of the water column above, including fishes present in the monitored period. All the images are manually annotated after a visual inspection performed by expert biologists. The extended monitoring period and the annotated images make the dataset a valuable benchmark suitable for studying the dynamics of the long-term Antarctic underwater fauna as well as for developing and testing algorithms for automated image analysis focused on the recognition and classification of the Antarctic organisms and the automated analysis of their long-term dynamics.

The primary forms of cicatricial (scarring) alopecia (PCA) are a group of inflammatory, irreversible hair loss disorders characterized by immune cell infiltrates targeting hair follicles (HFs). Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and centrifugal cicatricial alopecia (CCCA) are among the main subtypes of PCAs. The pathogenesis of the different types of PCAs are poorly understood, and current treatment regimens yield inconsistent and unsatisfactory results. We performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures, trained into machine-learning-based predictive models and pathways associated with dysregulated gene expression. We performed morphological and cytokine analysis to define the immune cell populations found in PCA subtypes. We identified a common PCA gene signature that was shared between LPP, FFA, and CCCA, which revealed a significant over-representation of mast cell (MC) genes, as well as downregulation of cholesterogenic pathways and upregulation of fibrosis and immune signaling genes. Immunohistological analyses revealed an increased presence of MCs in PCAs lesions. Our gene expression analyses revealed common pathways associated with PCAs, with a strong association with MCs. The indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss.

EOS is an open-source software for a variety of computational tasks in flavor physics. Its use cases include theory predictions within and beyond the Standard Model of particle physics, Bayesian inference of theory parameters from experimental and theoretical likelihoods, and simulation of pseudo events for a number of signal processes. EOS ensures high-performance computations through a C++ back-end and ease of usability through a Python front-end. To achieve this flexibility, EOS enables the user to select from a variety of implementations of the relevant decay processes and hadronic matrix elements at run time. In this article, we describe the general structure of the software framework and provide basic examples. Further details and in-depth interactive examples are provided as part of the EOS online documentation., Comment: 32 pages, 8 figures, 4 ancillary Jupyter example notebooks

Los aceros TWIP, Twinning-Induced Plasticity (plasticidad inducida por maclado) están incluidos en el grupo de los denominados segunda generación de aceros avanzados de alta resistencia. Son aceros con alto contenido de manga- neso (20% en peso aproximadamente) y totalmente austeníticos a temperatura ambiente. Tienen, a priori, un elevado potencial de aplicación por la particularidad de presentar una excelente combinación de resistencia y ductilidad, a la que se suma su gran capacidad de deformación ante esfuerzos de impacto entre otras cualidades sobresalientes. Los principales tópicos contemplados en las investigaciones llevadas a cabo en los aceros TWIP corresponden al estudio de las propiedades mecánicas tradicionales y la correlación entre éstas y la microestructura. Existen estudios acerca de conformabilidad, soldabilidad y fatiga por citar algunos más particulares. El presente trabajo se enfoca en una ca- racterización mecánica-metalúrgica de un acero de composición base y la determinación de las propiedades a fractura, aspecto del que no se dispone de mucha información en la literatura. Palabras Clave: TWIP; Plasticidad inducida por trenza; Tenacidad a fractura; Curva J-R; JIc.

Grandparents play an important role in their family’s lives. However, little is known about the demography of grandparenthood. Given dramatic recent changes in fertility, we explore the role of number of children and age at first birth in the timing of the transition into grandparenthood focusing on Italy, a country with well-known North-South fertility differentials. We used data from the 2009 Italian Survey ‘Family and Social Relations’ (N = 10,186) to estimate median ages of grandparenthood across three birth cohorts of parents (1920–29; 1930–39; 1940–49). Findings show an overall postponement of age of grandparenthood of 5 years, shifting for women from early to mid- or late-50s (in the South and North, respectively). Such postponement is largely driven by family compositional changes: although the age of grandparenthood among mothers of three or more children has not changed much over cohorts, the percentage of mothers with such characteristic decreased significantly. The heterogeneity in experiencing the transition to grandparenthood has implications for intergenerational transfers and other roles in later life.

Lambert Wiesing et Jacques Ranciere ont chacun elabore une theorie du spectateur. Selon l’approche phenomenologique de Wiesing, le spectateur d’une image contemple un objet purement visible et artificiellement present qui lui permet de vivre une pause de participation. Selon Ranciere, l’experience theâtrale permet au spectateur d’user de maniere autonome de son intelligence afin de vivre un moment d’emancipation. En comparant les pensees de ces deux auteurs, il semble pertinent de decrire le propre de l’experience spectatorielle d’objets relevant des arts mimetiques comme une pause de participation emancipatrice.

Introduction International guidelines recommend BRAF mutational status assessment in treatment-naive advanced non-squamous non-small cell lung carcinoma (NSCLC) patients since the presence of a BRAFV600 mutation enables specific BRAF inhibitor treatment. For this purpose, the mutational status needs to be obtained in 10 working days. Herein, we prospectively evaluated the feasibility of systematic assessment of the BRAF status using immunohistochemistry (IHC) in a single institution (LPCE, Nice) at baseline for NSCLC diagnosed. Methods 1317 NSCLC were evaluated using BRAF IHC from 2011 to 2019. Initially the BRAF status was prospectively assessed using NGS and/or pyrosequencing in 618 consecutively diagnosed NSCLC patients from 2012 to 2016; BRAFV600E and BRAF nonV600E mutated tumors detected in this cohort were retrospectively evaluated using BRAF IHC. Secondarily, 699 biopsies of NSCLC were prospectively analyzed between 2017 and 2019 using BRAF IHC. BRAF IHC positive tumors were tested using a rapid BRAF specific PCR based assay. Results Initially, 21/618 (3%) of tumors (15 early and 6 late stage tumors) were BRAFV600E mutated according to the results of NGS and/or pyrosequencing. BRAF IHC was positive in 21/21 of these cases and negative in 51/51 (100 %) BRAF non V600E mutated cases. In the prospective BRAF IHC tested cohort of patients, 24/699 (3%) tumors (13 early and 11 late stage tumors) were positive with VE1 IHC. The BRAF PCR assay was positive in 20/24 (83 %) of these cases. Conclusion BRAFV600E IHC screening of treatment-naive NSCLC patients is a rapid, specific and very sensitive method which can lead in advanced stage positive NSCLC tumors to a BRAF inhibitor treatment. This test can be routinely integrated into mandatory predictive biomarker ‘testing of NSCLC. According to the organization of patient care and the physician’s request, this practice can be proposed as an alternative to NGS-based tissue biopsy made at baseline.

Introduction: Deafness is the most frequent sensory deficit in humans. Incidence is estimated at 4:1000 births in Brazil. Specific programs for clinical care of patients with hearing loss are still scarce in Brazil and the issue is an important public health problem. Objective: To determine the frequency of 35delG and D13S1830 mutations in GJB2 and GJB6 genes respectively in patients with non-syndromic sensorineural hearing loss from Minas Gerais, Brazil. Methods: This research involved 53 individuals, who were assessed by a questionnaire for predicting the possibility of non-syndromic deafness and for data collecting. Samples were tested for the presence of the 35delG mutation in GJB2 gene and D13S1830 in GJB6 gene by polymerase chain reaction and restriction enzyme digestion. Results: Epidemiological research has shown that the majority of the subjects are unaware of the etiology and the pathogenesis of hearing loss. In 9 patients (16.98%), 35delG mutation was found in heterozygosis and the allele frequency was estimate to be around 8.5%. Although 9.61% of the patients reported having some degree of consanguinity between the parents and 12.08% reported other cases of deafness in their families, this mutation was not found in homozygosis. The D13S1830 mutation was not found in this study. Conclusion: This research describes for the first time the frequency of the 35delG and D13S1830 mutation in hearing-impaired individuals from Minas Gerais, Brazil, and the collected data reinforce the need for further studies in this population due to heterogeneity of hearing loss. Resumo Introdução: A surdez é o déficit sensorial mais frequente em humanos. Estima-se que a incidência seja de 4:1.000 nascimentos no Brasil. Programas específicos para atendimento clínico de pacientes com perda auditiva são escassos no Brasil e a questão é um importante problema de saúde pública. Objetivo: Determinar a frequência das mutações 35delG no gene GJB2 e D13S1830 no GJB6 em pacientes deficientes auditivos de origem neurossensorial e não sindrômica de Minas Gerais, Brasil. Método: A pesquisa envolveu 53 indivíduos selecionados por meio de questionário o qual avaliou a possibilidade de surdez não sindrômica entre outros dados. As amostras foram testadas quanto à presença da mutação 35delG no gene GJB2 e D13S1830 no gene GJB6 por reação em cadeia da polimerase e digestão com enzima de restrição. Resultados: A pesquisa epidemiológica mostrou que a maioria dos indivíduos desconhece a etiologia da perda auditiva. Em 9 pacientes (16,98%), a mutação 35delG foi encontrada em heterozigose e a frequência alélica foi estimada em 8,5%. Embora 9,61% das pessoas tenham relatado algum grau de consanguinidade entre os pais e 12,08% relatassem outros casos de surdez em suas famílias, essa mutação não foi encontrada em homozigose. A mutação D13S1830 não foi encontrada neste estudo. Conclusão: Este trabalho descreve pela primeira vez a frequência da mutação 35delG e D13S1830 em deficientes auditivos de Minas Gerais, Brasil, e os dados coletados reforçam a necessidade de mais estudos nessa população devido à heterogeneidade da perda auditiva.

Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.

BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease. METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety. RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P