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Electrochemical pH-swing strategies offer a promising avenue for cost-effective and energy-efficient carbon dioxide (CO2) capture, surpassing the traditional thermally activated processes and humidity-sensitive techniques. The concept of elevating seawater's alkalinity for scalable CO2 capture without introducing additional chemical as reactant is particularly intriguing due to its minimal environmental impact. However, current commercial plants like chlor-alkali process or water electrolysis demand high thermodynamic voltages of 2.2 V and 1.23 V, respectively, for the production of sodium hydroxide (NaOH) from seawater. These high voltages are attributed to the asymmetric electrochemical reactions, where two completely different reactions take place at the anode and cathode. Here, we developed a symmetric electrochemical system for seawater alkalization based on a highly reversible and identical reaction taking place at the anode and cathode. We utilize hydrogen evolution reaction at the cathode, where the generated hydrogen is looped to the anode for hydrogen oxidation reaction. Theoretical calculations indicate an impressively low energy requirement ranging from 0.07 to 0.53 kWh/kg NaOH for established pH differences of 1.7 to 13.4. Experimentally, we achieved the alkalization with an energy consumption of 0.63 kWh/kg NaOH, which is only 38% of the theoretical energy requirements of the chlor-alkali process (1.64 kWh/kg NaOH). Further tests demonstrated the system's potential of enduring high current densities (~20 mA/cm²) and operating stability over an extended period (>110 h), showing its potential for future applications. Notably, the CO2 adsorption tests performed with alkalized seawater exhibited remarkably improved CO2 capture dictated by the production of hydroxide compared to the pristine seawater. [ABSTRACT FROM AUTHOR]

This study analyzes "selective exposure" to online news media (i.e., preferential exposure to congenial and trusted media) by comparing the behavioral and declarative data of 1,536 participants over a one-month period. We recorded their Internet activity over a one-month period and then asked them about their level of trust in several news media outlets, the frequency with which they had been exposed to them, and their political position and orientation along a progressive-conservative axis.. Results show that 1) participants' trust in the different news media varies according to their political attitudes, 2) participants' probability of declaring exposure to a specific news media is impacted by their trust in this media, as well as by their political attitudes, 3) these effects are much weaker when considering participants' effective exposure to news media. Overall, these results indicate that selective exposure to online news media exists, but it is exaggerated when studied only by means of declarative data. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent research has helped us understand more about the role of microbes in the health and disease of the lungs. The detection of microbes and microbial products in sputum may improve early lung cancer diagnosis. The monitoring of the microbiome of the lungs over time may help predict the response to and side effects of treatment. However, studies have not yet examined how diet and air pollution affect the lung microbiome and how it might be linked to the development and progression of lung cancer. By examining the lung microbiome, dietary patterns, and air pollutants, we hope to prevent and manage lung cancer in the future. The past several years have provided a more profound understanding of the role of microbial species in the lung. The respiratory tract is a delicate ecosystem of bacteria, fungi, parasites, and viruses. Detecting microbial DNA, pathogen-associated molecular patterns (PAMPs), and metabolites in sputum is poised to revolutionize the early diagnosis of lung cancer. The longitudinal monitoring of the lung microbiome holds the potential to predict treatment response and side effects, enabling more personalized and effective treatment options. However, most studies into the lung microbiota have been observational and have not adequately considered the impact of dietary intake and air pollutants. This gap makes it challenging to establish a direct causal relationship between environmental exposure, changes in the composition of the microbiota, lung carcinogenesis, and tumor progression. A holistic understanding of the lung microbiota that considers both diet and air pollutants may pave the way to improved prevention and management strategies for lung cancer. [ABSTRACT FROM AUTHOR]

The evolution of threats and scenarios requires continuous performance improvements of ballistic protections for armed forces. From a modeling point of view, it is necessary to use sufficiently precise material behavior models to accurately describe the phenomena observed during the impact of a projectile on a protective equipment. In this context, the goal of this paper is to characterize the behavior of a small caliber steel jacket by combining experimental and numerical approaches. The experimental method is based on the lateral compression of ring specimens directly machined from the thin and small ammunition. Various speeds and temperatures are considered in a quasi-static regime in order to reveal the strain rate and temperature dependencies of the tested material. The Finite Element Updating Method (FEMU) is used. Experimental results are coupled with an inverse optimization method and a finite element numerical model in order to determine the parameters of a constitutive model representative of the jacket material. Predictions of the present model are verified against experimental results and a parametric study as well as a discussion on the identified material parameters are proposed. The results indicate that the strain hardening parameter can be neglected and the behavior of the thin steel jacket can be described by a modeling without strain hardening sensitivity. [ABSTRACT FROM AUTHOR]

Background: Programmed death ligand‐1 (PD‐L1) expression is a well‐known predictive biomarker of response to immune checkpoint blockade in non‐small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD‐L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. Methods: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD‐L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. Results: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD‐L1 expression was categorized as PD‐L1 negative (45.1%), PD‐L1 positive low‐expression 1%–49% (32.3%), and PD‐L1 positive high‐expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD‐L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non‐adenocarcinoma histology had a significantly higher median PD‐L1 expression (p < 0.001). Additionally, PD‐L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14–2.25, p < 0.01]). In the multivariate analysis, EGFR‐positive tumors were more commonly associated with PD‐L1 low expression (OR 0.62 [95% CI: 0.51–0.75], p < 0.01), while ALK‐positive tumors had a significant risk of being PD‐L1 positive (OR 1.81 [95% CI: 1.30–2.52], p < 0.01). Conclusions: PD‐L1 expression was associated with well‐defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD‐L1 in patients with advanced NSCLC in a large Latin American cohort. [ABSTRACT FROM AUTHOR]

Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight themajor role played by B-cells in breaking immune tolerance by epitope spreading. Activated B-cells are key Antigen-Presenting Cells (APC) that diversify the T-cell response against self-antigens, such as ribonucleoproteins, in autoimmunity but also during successful cancer immunotherapy. This has important implications for the design of future cancer vaccines. [ABSTRACT FROM AUTHOR]

The Li-S battery is a promising next-generation battery chemistry that offers high energy density and low cost. The Li-S battery has a unique chemistry with intermediate sulphur species readily solvated in electrolytes, and understanding their implications is important from both practical and fundamental perspectives. In this study, we utilise the solvation free energy of electrolytes as a metric to formulate solvation-property relationships in various electrolytes and investigate their impact on the solvated lithium polysulphides. We find that solvation free energy influences Li-S battery voltage profile, lithium polysulphide solubility, Li-S battery cyclability and the Li metal anode; weaker solvation leads to lower 1st plateau voltage, higher 2nd plateau voltage, lower lithium polysulphide solubility, and superior cyclability of Li-S full cells and Li metal anodes. We believe that relationships delineated in this study can guide the design of high-performance electrolytes for Li-S batteries. In the Li-S battery, a promising next-generation battery chemistry, electrolytes are vital because of solvated polysulfide species. Here, the authors investigate solvation-property relationships via the measurement of solvation free energy of the electrolytes, guiding advanced electrolyte design for Li-S batteries. [ABSTRACT FROM AUTHOR]

Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma. Synopsis: Most patients with metastatic uveal melanoma die within a year from diagnosis, highlighting an unmet clinical need. A genetic screen was launched to identify actionable vulnerabilities and uncovered the critical role of the kinases LKB1 and SIK2 in constraining metastatic uveal melanoma cell growth. The sodium/calcium exchanger SLC8A1 mediated the effect of the LKB1‐SIK2 module.Loss of the LKB1‐SIK2 module and increased SLC8A1 expression were associated with enhanced mitochondrial level of calcium and ROS and increased metastatic uveal melanoma cell growth.SLC8A1 and mitochondrial ROS were validated as relevant therapeutic target as their combined inhibition induced cell death with a higher sensitivity in LKB1 or SIK2‐depleted metastatic uveal melanoma cells.A molecular signature related to LKB1 loss was identified as a prognosis biomarker and a predictor of the response to SLC8A1 and mitochondrial ROS inhibition. [ABSTRACT FROM AUTHOR]

The combination of immune checkpoint inhibitors and anti-angiogenic agents is a promising new approach in cancer treatment. Immune checkpoint inhibitors block the signals that help cancer cells evade the immune system, while anti-angiogenic agents target the blood vessels that supply the tumour with nutrients and oxygen, limiting its growth. Importantly, this combination triggers synergistic effects based on molecular and cellular mechanisms, leading to better response rates and longer progression-free survival than treatment alone. However, these combinations can also lead to increased side effects and require close monitoring. [ABSTRACT FROM AUTHOR]

Nearly fifty million older people suffer from neurodegenerative diseases, including Alzheimer (AD) and Parkinson (PD) disease, a global burden expected to triple by 2050. Such an imminent "neurological pandemic" urges the identification of environmental risk factors that are hopefully avoided to fight the disease. In 2022, strong evidence in mouse models incriminated defective lysosomal acidification and impairment of the autophagy pathway as modifiable risk factors for dementia. To date, the most prescribed lysosomotropic drugs are proton pump inhibitors (PPIs), chloroquine (CQ), and the related hydroxychloroquine (HCQ), which belong to the group of disease-modifying antirheumatic drugs (DMARDs). This commentary aims to open the discussion on the possible mechanisms connecting the long-term prescribing of these drugs to the elderly and the incidence of neurodegenerative diseases. Abbreviations: AD: Alzheimer disease; APP-βCTF: amyloid beta precursor protein-C-terminal fragment; BACE1: beta-secretase 1; BBB: brain blood barrier; CHX: Ca2+/H+ exchanger; CMI: cognitive mild impairment; CQ: chloroquine; DMARD: disease-modifying antirheumatic drugs; GBA1: glucosylceramidase beta 1; HCQ: hydroxychloroquine; HPLC: high-performance liquid chromatography; LAMP: lysosomal associated membrane protein; MAPK/JNK: mitogen-activated protein kinase; MAPT: microtubule associated protein tau; MCOLN1/TRPML1: mucolipin TRP cation channel 1; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NRBF2: nuclear receptor binding factor 2; PANTHOS: poisonous flower; PD: Parkinson disease; PIK3C3: phosphatIdylinositol 3-kinase catalytic subunit type 3; PPI: proton pump inhibitor; PSEN1: presenilin 1, RUBCN: rubicon autophagy regulator; RUBCNL: rubicon like autophagy enhancer; SQSTM1: sequestosome 1; TMEM175: transmembrane protein 175; TPCN2: two pore segment channel 2; VATPase: vacuolar-type H+-translocating ATPase; VPS13C: vacuolar protein sorting ortholog 13 homolog C; VPS35: VPS35 retromer complex component; WDFY3: WD repeat and FYVE domain containing 3; ZFYVE1: zinc finger FYVE-type containing 1. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer therapies directly targeting the mitogen-activated protein kinase (MAPK) pathway lead to cancer drug resistance. Resistance has been linked to compensatory RAS overexpression, but the mechanisms underlying this overexpression remain unclear. Here, we find that MEK inhibitors (MEKi) increases translation of the KRAS and NRAS oncogenes through a mechanism involving liquid–liquid phase separation (LLPS), and more particularly processing body (P-body) dissolution. Overall, we describe a new feedback loop mechanism involving P-bodies and phase separation that regulates RAS translation. Identification of key components that regulate LLPS will be important for future targeted therapeutic strategies. Overactivation of the mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies directly targeting this pathway lead to cancer drug resistance. Resistance has been linked to compensatory RAS overexpression, but the mechanisms underlying this response remain unclear. Here, we find that MEK inhibitors (MEKi) are associated with an increased translation of the KRAS and NRAS oncogenes through a mechanism involving dissolution of processing body (P-body) biocondensates. This effect is seen across different cell types and is extremely dynamic since removal of MEKi and ERK reactivation result in reappearance of P-bodies and reduced RAS-dependent signaling. Moreover, we find that P-body scaffold protein levels negatively impact RAS expression. Overall, we describe a new feedback loop mechanism involving biocondensates such as P-bodies in the translational regulation of RAS proteins and MAPK signaling. [ABSTRACT FROM AUTHOR]

This paper proposes a hybrid machine translation (HMT) system that improves the quality of neural machine translation (NMT) by incorporating statistical machine translation (SMT). Therefore, two NMT systems and two SMT systems were built for the Slovenian–English language pair, each for translation in one direction. We used a multilingual language model to embed the source sentence and translations into the same vector space. From each vector, we extracted features based on the distances and similarities calculated between the source sentence and the NMT translation, and between the source sentence and the SMT translation. To select the best possible translation, we used several well-known classifiers to predict which translation system generated a better translation of the source sentence. The proposed method of combining SMT and NMT in the hybrid system is novel. Our framework is language-independent and can be applied to other languages supported by the multilingual language model. Our experiment involved empirical applications. We compared the performance of the classifiers, and the results demonstrate that our proposed HMT system achieved notable improvements in the BLEU score, with an increase of 1.5 points and 10.9 points for both translation directions, respectively. [ABSTRACT FROM AUTHOR]

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At a time when complex diseases affect globally 280 million people and claim 14 million lives every year, there is an urgent need to rapidly increase our knowledge into their underlying etiologies. Though critical in identifying the people at risk, the causal environmental factors (microbiome and/or pollutants) and the affected pathophysiological mechanisms are not well understood. Herein, we consider the variations of autophagy-related (ATG) genes at the heart of mechanisms of increased susceptibility to environmental stress. A comprehensive autophagy genomic resource is presented with 263 single nucleotide polymorphisms (SNPs) for 69 autophagy-related genes associated with 117 autoimmune, inflammatory, infectious, cardiovascular, neurological, respiratory, and endocrine diseases. We thus propose the term 'autophagopathies' to group together a class of complex human diseases the etiology of which lies in a genetic defect of the autophagy machinery, whether directly related or not to an abnormal flux in autophagy, LC3-associated phagocytosis, or any associated trafficking. The future of precision medicine for common diseases will lie in our ability to exploit these ATG SNP x environment relationships to develop new polygenetic risk scores, new management guidelines, and optimal therapies for afflicted patients. Abbreviations: ATG, autophagy‐related; ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementia; ccRCC, clear cell renal cell carcinoma; CD, Crohn disease; COPD, chronic obstructive pulmonary disease; eQTL, expression quantitative trait loci; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; GTEx, genotype-tissue expression; GWAS, genome-wide association studies; LAP, LC3-associated phagocytosis; LC3-II, phosphatidylethanolamine conjugated form of LC3; LD, linkage disequilibrium; LUAD, lung adenocarcinoma; MAF, minor allele frequency; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NSCLC, non-small cell lung cancer; OS, overall survival; PtdIns3K CIII, class III phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; SLE, systemic lupus erythematosus; SNPs, single-nucleotide polymorphisms; mQTL, methylation quantitative trait loci; ULK, unc-51 like autophagy activating kinase; UTRs, untranslated regions; WHO, World Health Organization. [ABSTRACT FROM AUTHOR]

Microbial processes can be involved in the remobilization of uranium (U) from reduced sediments under O2 reoxidation events such as water table fluctuations. Such reactions could be typically encountered after U-bearing sediment dredging operations. Solid U(IV) species may thus reoxidize into U(VI) that can be released in pore waters in the form of aqueous complexes with organic and inorganic ligands. Non-uraninite U(IV) species may be especially sensitive to reoxidation and remobilization processes. Nevertheless, little is known regarding the effect of microbially mediated processes on the behaviour of U under these conditions. [ABSTRACT FROM AUTHOR]

Objective: To analyze the frequency of KRAS, NRAS and BRAF hotspot mutations in circulating tumor DNA (ctDNA) from patients with metastatic colorectal cancer (mCRC). Methods: Observational, descriptive and retrospective study in mCRC patients with available ctDNA-based genotype of KRAS, NRAS and BRAF. Results: The frequencies of plasma mutations for KRAS, NRAS and BRAF were 34% (± 7), 4% (± 3) and 4% (± 3), respectively. Median overall survival of plasma-tested RAS/BRAF-mutated patients was 26.6 months (95% CI: 14.4-not estimable [NE]), while RAS/BRAF wild-type patients did not reach the median survival during follow-up. Median progression-free survival for RAS/BRAF wild-type and RAS/BRAF-mutated patients was 12 (95% CI: 7-NE) and 4 months (95% CI: 4-NE), respectively. Conclusion: Our work supports the utility of KRAS, NRAS and BRAF analysis in liquid biopsy from mCRC patients. [ABSTRACT FROM AUTHOR]

Dear Editor, This pilot study suggests the presence of two different profiles of patients with advanced non-small cell lung cancer (aNSCLC), responding to immune checkpoint inhibitors (ICIs). These results suggest a difference in T-cell activity in TruCulture (e.g. the "high concentrations" group with a high T-cell activity, and the "low concentrations" group with low T-cell activity). The correlation heat map is calculated in order to classify the patients and/or the analytes using a dendrogram gathering the patients/analytes having correlated profiles, the distance chosen being 1 - R, R being the correlation coefficient. [Extracted from the article]

The article informs on the stage adaptation of the play "L'Annuncio a Maria" by Paul Claudel. It mentions the linguistic choices are examined such as Casnati and Vigini's aged lexicon, Sinisi's updated lexico, the adaptation and the cuts, and the performance, created in 2017 under the sign of poetry and scenic imagination.

Simple Summary: RAS mutation is the most frequent oncogenic alteration in human cancers and KRAS is the most frequently mutated, notably in non-small cell lung carcinomas (NSCLC). Various attempts to inhibit KRAS in the past were unsuccessful in these latter tumors. However, recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target KRAS G12C-mutated tumors, which seems promising for patient treatment and should soon be administered in daily practice for non-squamous (NS)-NSCLC. In this context, it will be mandatory to systematically assess the KRAS status in routine clinical practice, at least in advanced NS-NSCLC, leading to new challenges for thoracic oncologists. KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment. [ABSTRACT FROM AUTHOR]

Background: Little is known about the real‐world care of young adult (YA) females (aged 20‐39 years) with breast cancer. This study describes factors associated with the receipt of guideline‐concordant care (GCC) among YAs. Methods: The authors identified 1259 YA women with invasive breast cancer diagnosed in 2013 in the National Cancer Institute's Patterns of Care study. Hospital records were re‐abstracted, and treatment was verified. Using the National Comprehensive Cancer Network's 2013 breast cancer guidelines, the authors assessed the receipt of GCC by cancer subtype among a subset of YAs (n = 952). Associations between sociodemographic and clinical factors and GCC receipt were examined. Results: Most YAs were 35 to 39 years old (51.2%) and partnered (56.4%); half had hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) tumors. GCC was found for 81.7% of YAs. Relationships between sociodemographic and clinical factors and GCC receipt differed by subtype. Stage was the only significant predictor of GCC receipt for all subtypes (stage II vs III: odds ratio [OR] for HR+/HER2+, 0.20; 95% confidence interval [CI], 0.08‐0.50; OR for HR−/HER2+, 0.13; 95% CI, 0.07‐0.25; OR for HR−/HER2−, 3.86; 95% CI, 1.55‐9.62; OR for HR+/HER2−, 2.81; 95% CI, 1.63‐5.80). Conclusions: GCC is high among YAs with breast cancer. The effects of sociodemographic factors and treatment facility size on GCC differ by subtype. Consistent with recommendations, tumor biology, not age, is associated with GCC for all subtypes. Future studies should assess the effect of GCC on survival among YAs. Guideline‐concordant care is high among young adult women with breast cancer. Consistent with recommendations, tumor biology, not age, is associated with guideline‐concordant care for all subtypes. [ABSTRACT FROM AUTHOR]

Suicidality is a serious concern in this country. In the U.S. nearly 40,000 people die by suicide each year. It is the 10th leading cause of death. For those 15–24, it is the 2nd leading cause of death. Using data from the Add Health Longitudinal data set and data gathered from a local organization an examination of suicidality among African American youth was conducted. Given the trauma and low resourced situations many African American adolescents find themselves in, interventions are needed to address these health concerns before other issues such as education and other life options (i.e., careers) are addressed. Questions that participants were asked related to suicidal ideation and suicide attempts; did you ever seriously consider attempting suicide and did you attempt suicide? The results showed that the local sample had higher suicidal ideation than the Add health national sample (20% vs. 13.6%), respectively. The local sample had higher percentages of suicide attempts in the past twelve months compared to the National sample. There was a statistically significant difference between females and males in the sample. Limitations and future research are found in the discussion. [ABSTRACT FROM AUTHOR]

Summary: There is currently a strong development of therapeutic combinations with checkpoint inhibitors (CPIs). The most promising combinations with CPIs concern anti-angiogenic agents and BRAF/MEK inhibitors. The timing of the initiation of the combination should be particularly well investigated for chemotherapy. Combinations between CPIs raise questions about risk/benefit ratio and overall clinical activity. [ABSTRACT FROM AUTHOR]

There is currently a strong development of therapeutic combinations with checkpoint inhibitors (CPIs). The most promising combinations with CPIs concern anti-angiogenic agents and BRAF/MEK inhibitors. The timing of the initiation of the combination should be particularly well investigated for chemotherapy. Combinations between CPIs raise questions about risk/benefit ratio and overall clinical activity. [ABSTRACT FROM AUTHOR]

Corrections are needed to the original version of this article. [ABSTRACT FROM AUTHOR]

In less than eleven months, the world was brought to a halt by the COVID-19 outbreak. With hospitals becoming overwhelmed, one of the highest priorities concerned critical care triage to ration the scarce resources of intensive care units. Which patient should be treated first? Based on what clinical and biological criteria? A global joint effort rapidly led to sequencing the genomes of tens of thousands of COVID-19 patients to determine the patients' genetic signature that causes them to be at risk of suddenly developing severe disease. In this commentary, we would like to consider some points concerning the use of a multifactorial risk score for COVID-19 severity. This score includes macroautophagy (hereafter referred to as autophagy), a critical host process that controls all steps harnessed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Abbreviation list: ATG5: autophagy related 5; BECN1: beclin 1; COVID-19: coronavirus infectious disease-2019; EGR1: early growth response 1; ER: endoplasmic reticulum; DMVs: double-membrane vesicles; IBV: infectious bronchitis virus; MAP1LC3: microtubule associated protein 1 light chain 3; LC3-I: proteolytically processed, non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; MEFs: mouse embryonic fibroblasts; MERS-CoV: Middle East respiratory syndrome-coronavirus; MHV: mouse hepatitis virus; NSP: non-structural protein; PEDV: porcine epidemic diarrhea virus; PLP2-TM: membrane-associated papain-like protease 2; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TGEV: transmissible gastroenteritis virus. [ABSTRACT FROM AUTHOR]

At a time when the world faces an emotional breakdown, crushing our dreams, if not, taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined at home. Every day, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of the articles promoting the use of CQ in the current pandemic evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss the pros, but also the cons concerning the current therapeutic options targeting this process. [ABSTRACT FROM AUTHOR]

The combination of COVID-19 vaccination with immunotherapy by checkpoint inhibitors in cancer patients could intensify immunological stimulation with potential reciprocal benefits. Here, we examine more closely the possible adverse events that can arise in each treatment modality. Our conclusion is that caution should be exercised when combining both treatments. [ABSTRACT FROM AUTHOR]

Advising athletes how to improve their performance after a race is a very important aspect of sport training. It can also be called a post hoc analysis, which often includes a deep analysis of an athlete's performance, behavior and body characteristics after a race. These analyses help trainers to adapt their training plan according to the athlete's performance on the one hand, and to modify the strategy or tactic of the racing on the other. Until recently, rare solutions of automatic analysis, using modern artificial intelligence tools, were proposed. In this paper, recent solutions are reviewed and a novel solution is proposed, which relies on heart rate data for post hoc analysis. Here, the main focus is on individual sports, where the performed time determines the quality of results (e.g., running, cycling and triathlon). The proposed solution was tested on two case studies of running athletes. [ABSTRACT FROM AUTHOR]

Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR≥2. TGKR calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy. [ABSTRACT FROM AUTHOR]

Summary: Background Checkpoint inhibitors bring marked benefits but only in a minority of patients and may also be associated with severe adverse events. Treatment outcome still cannot be faithfully predicted. The following study hypothesized that host genetics could be applied as predictive biomarkers for checkpoint inhibitor response and immune-related adverse events. We conducted a study based on germinal polymorphisms from genes coding for proteins involved in immune regulation. Methods Germinal DNA was obtained from advanced cancer patients treated with anti-PD-1/PD-L1 checkpoint inhibitors. DNA was genotyped using a custom panel of 166 single nucleotide polymorphisms covering 86 preselected immunogenetic-related genes. Computational analysis using a GTEX portal was made to determine potential expression Quantitative Trait Loci in tissues. Results Ninety-four consecutive patients were included. Objective response rate (complete or partial response) was significantly correlated to tumor microenvironment-related SNPs concerning CCL2, NOS3, IL1RN, IL12B, CXCR3 and IL6R genes. Toxicity were linked to target-related gene SNPs including UNG, IFNW1, CTLA4, PD-L1 and IFNL4 genes. The Area Under the ROC curve (AUC) was 0.81 (95% CI: 0.72–0.9) for response and 0.89 (95% CI: 0.76–1.00) for toxicity. In silico functionality exploring pointed rs4845618 (IL6R), rs10964859 (IFNW1) and rs3087243 (CTLA4) as potentially impacting gene expression. Conclusion These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events. [ABSTRACT FROM AUTHOR]

Machine Translation has become an important tool in overcoming the language barrier. The quality of translations depends on the languages and used methods. The research presented in this paper is based on well-known standard methods for Statistical Machine Translation that are advanced by a newly proposed approach for optimizing the weights of translation system components. Better weights of system components improve the translation quality. In most cases, machine translation systems translate to/from English and, in our research, English is paired with a Slavic language, Slovenian. In our experiment, we built two Statistical Machine Translation systems for the Slovenian-English language pair of the Acquis Communautaire corpus. Both systems were optimized using self-adaptive Differential Evolution and compared to the other related optimization methods. The results show improvement in the translation quality, and are comparable to the other related methods. [ABSTRACT FROM AUTHOR]

The demand for translations is increasing at a rate far beyond the capacity of professional translators. It is too difficult, time consuming and expensive to translate everything from scratch in each language. Machine translation offers a solution, as it provides translation automatically. Until recently, statistical machine translation has proved to be one of the most successful approaches. However, a new approach to machine translation based on neural networks has emerged with promising results. The present paper concerns phrase-based statistical machine translation, an area that has been extensively studied in the literature. The translation system consists of many components built on the premise of probabilities. Each component is described separately. Although high quality translation systems have been developed for certain language pairs, there is still a large number of languages that cause many translation errors. Languages with a rich morphology pose an especially difficult challenge for research. We address one group of morphologically rich languages: Slavic languages, which constitute a relatively homogeneous family of languages characterized by rich, inflectional morphology. The present paper offers a comprehensive survey of approaches to coping with Slavic languages in different aspects of statistical machine translation. We observe that the interest of the community in research of more difficult languages is increasing and we believe that the translation quality of those languages will reach the level of practical use in the near future. [ABSTRACT FROM AUTHOR]

This essay shows how investors can create social value and explores that while it is relatively easy to achieve value alignment, creating social value is far more difficult for investors. Topics covered include terms that are commonly and confusedly used in the social investing community, a taxonomy of socially-motivated investments that identifies what should be considered as impact investing, and whether investments in public companies achieve value alignment or create social value.

Background: The umbilical coiling index (UCI) is a measure of the number of coils in the umbilical cord in relation to its length. Hypercoiled cords with a UCI of >0.3 coils/cm have been associated with adverse fetal and neonatal outcomes. Aims: The primary aim is to determine the accuracy of UCI measured on second trimester ultrasound in predicting UCI at birth. The secondary outcome is to investigate the association between hypercoiling of the umbilical cord on prenatal ultrasound and adverse maternal, fetal and neonatal outcomes. Methods: This was a prospective cohort study of uncomplicated singleton pregnancies. Seventy two patients were included in the study. UCI was measured in the second trimester ultrasound, and compared to UCI measured postnatally. Outcomes of patients with hypercoiled cords on ultrasound were compared to outcomes of patients with normocoiled cords. Results: Our results failed to show a strong correlation between the UCI determined with ultrasound, and the UCI determined with examination of the umbilical cord after delivery. We also did not demonstrate that measurement of the UCI on second trimester ultrasound is able to predict adverse maternal, fetal or neonatal outcomes. Conclusion: This study suggests that measurement of the umbilical coiling index should not be part of routine second trimester sonography in patients with uncomplicated singleton pregnancies, with no other medical or surgical comorbidities. [ABSTRACT FROM AUTHOR]

miR-34/449 micro RNAs are conserved regulators of multiciliated cell differentiation. Here, we evidence and characterize expression of two isomiR variant sequences from the miR-34/449 family in human airway epithelial cells. These isomiRs differ from their canonical counterparts miR-34b and miR-449c by one supplemental uridine at their 5′-end, leading to a one-base shift in their seed region. Overexpression of canonical miR-34/449 or 5′-isomiR-34/449 induces distinct gene expression profiles and biological effects. However, some target transcripts and functional activities are shared by both canonical micro RNAs and isomiRs. Indeed, both repress important targets that result in cell cycle blockage and Notch pathway inhibition. Our findings suggest that 5′-isomiR-34/449 may represent additional mechanisms by which miR-34/449 family finely controls several pathways to drive multiciliogenesis. [ABSTRACT FROM AUTHOR]

Circulating tumors cells ( CTCs) can be detected in the blood of metastatic melanoma patients ( MMPs) both as isolated circulating tumor cells ( iCTCs) and circulating tumor microemboli ( CTMs), but their clinical significance remains unknown. The aim of this work was to evaluate the prognostic impact in metastatic cutaneous melanoma of CTMs and iCTCs identified by a cytomorphological approach using the isolation by size of tumor cell ( ISET) method. We characterized the phenotype of CTCs using anti- PS100, anti- SOX10, anti- CD10, and anti- TRF2 antibodies. 128 MMPs and 37 control healthy individuals with benign nevi were included in this study. Results were compared to the follow-up of patients. 109/128 (85%) MMPs showed CTCs, 44/128 (34%) with 2 to 6 CTMs and 65/128 (51%) with 4 to 9 iCTCs. PS100 expression was homogeneous in iCTCs and heterogeneous in CTMs. SOX10, CD10, and TRF2 were mainly expressed in CTMs. None of the control subjects demonstrated circulating malignant tumor cells. Overall survival was significantly decreased in patients with CTMs, independently of the therapeutic strategies. In conclusion, the presence of CTMs is an independent predictor of shorter survival from the time of diagnosis of MMPs. [ABSTRACT FROM AUTHOR]