Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.
Cariprazine as a therapeutic option for schizophrenia: a drug evaluation

ABSTRACT Introduction: Schizophrenia is a very disabling condition that may result in a significant impairment of individual, professional, and social adjustments. Antipsychotics (APs), the first-line treatment for schizophrenia, in many cases modify the course of the disease, by reducing the institutionalization risk, at the price of severe and invalidating side effects. Cariprazine is one of the latest second-generation APs (SGAs) acting as a partial agonist of type 2 and 3 dopamine receptors, which was recently approved for the treatment of adult schizophrenia. Areas covered: The authors provide a critical review and commentary on the currently available data on the effectiveness and tolerability of cariprazine in schizophrenic patients, with a particular focus on its specific target symptoms. Expert opinion: Cariprazine appears significantly effective on both acute and maintenance treatment of schizophrenia, and in improving positive, negative, and cognitive symptoms, slightly more than other SGAs. It shows a good safety and tolerability profile, with akathisia being its most common side effect. Although further independent studies are needed to clarify its precise advantages over other SGAs, cariprazine seems a promising compound not only in schizophrenia, but also in a broad range of psychiatric conditions, including perhaps bipolar and addictive disorders.
Acceptance and Potential Impact of the eWALL Platform for Health Monitoring and Promotion in Persons with a Chronic Disease or Age-Related Impairment

Pervasive health technologies can increase the effectiveness of personal health monitoring and training, but more user studies are necessary to understand the interest for these technologies, and how they should be designed and implemented. In the present study, we evaluated eWALL, a user-centered pervasive health technology consisting of a platform that monitors users’ physical and cognitive behavior, providing feedback and motivation via an easy-to-use, touch-based user interface. The eWALL was placed for one month in the home of 48 subjects with a chronic condition (chronic obstructive pulmonary disease—COPD or mild cognitive impairment—MCI) or with an age-related impairment. User acceptance, platform use, and potential clinical effects were evaluated using surveys, data logs, and clinical scales. Although some features of the platform need to be improved before reaching technical maturity and making a difference in patients’ lives, the real-life evaluation of eWALL has shown how some features may influence patients’ intention to use this promising technology. Furthermore, this study made it clear how the free use of different health apps is modulated by the real needs of the patient and by their usefulness in the context of the patient’s clinical status.
YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes

Simple Summary Colorectal cancer (CRC) is a heterogeneous disease that can be divided into 4 consensus molecular subtypes (CMS) according to molecular profiling. The CMS classification is now considered as a reference framework for understanding the heterogeneity of CRC and for the implementation of precision medicine. Although the contribution of YAP/TAZ signalling to CRC has been intensively studied, there is little information on its role within each CMS subtype. This article aims to provide an overview of our knowledge of YAP/TAZ in CRC through the lens of the CMS classification. Abstract Recent advance in the characterization of the heterogeneity of colorectal cancer has led to the definition of a consensus molecular classification within four CMS subgroups, each associated with specific molecular and clinical features. Investigating the signalling pathways that drive colorectal cancer progression in relation to the CMS classification may help design therapeutic strategies tailored for each CMS subtype. The two main effectors of the Hippo pathway YAP and its paralogue TAZ have been intensively scrutinized for their contribution to colon carcinogenesis. Here, we review the knowledge of YAP/TAZ implication in colorectal cancer from the perspective of the CMS framework. We identify gaps in our current understanding and delineate research avenues for future work.
A cross-sectional study

To evaluate the performance of different blood cells-derived indexes in the diagnosis of rheumatoid arthritis (RA). Neutrophil-to-lymphocyte ratio (NLR), lymphocyte to monocyte ratio, platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and aggregate inflammation systemic index were calculated in 199 consecutive RA patients and 283 sex and age-matched controls (147 healthy donors and 136 patients with other rheumatic diseases). Area under the curve (AUCs), sensitivity and specificity were calculated to evaluate the accuracy of indexes in discriminating between RA and controls. Association between indexes and RA variables was explored by multiple linear regression analyses. Blood cells-derived indexes did not demonstrate good accuracy in differentiating RA from controls with lymphocyte to monocyte ratio, the index with the best diagnostic performance, having 63.6% of sensitivity and 65.3% specificity [AUC (95%CI)=0.67 (0.62– 0.72]. The accuracy of the indexes in differentiating RA from healthy donors was significantly higher than that (AUCs<0.6 for all comparisons) differentiating RA from rheumatic diseases. In RA, SIRI and aggregate inflammation systemic index showed significant association with C-reactive protein and erythrocyte sedimentation rate. Our results do not support the use of blood cells-derived indexes for the diagnosis of RA, suggesting that they might reflect chronic inflammatory burden in rheumatic diseases rather than, specifically, in RA. Abbreviations: ACR/EULAR = American College of Rheumatology/European League against Rheumatisms, AISI = aggregate inflammation systemic index, AUC = area under the curve, CRP = C-reactive protein, HD = healthy donors, LMR = lymphocyte to monocyte ratio, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet to lymphocyte ratio, RA = rheumatoid arthritis, RDs = other rheumatic diseases.
Clinical practice during the COVID‐19 pandemic: A cross‐sectional survey of attending dermatologists

Dear Editor, The COVID-19 pandemic has necessitated significant modifications in clinical practice. Our objectives were to understand the effect of the pandemic on practice management, including changes in staffing, use of teledermatology and in-person visits, and clinical decision making. After receiving Institutional Review Board exempt status from Weill Cornell Medicine (Protocol No: 20-04021753), an anonymous 31-question survey was emailed to attending dermatologists at our institution who were encouraged to distribute the survey to dermatology colleagues. Surveys were collected from 26 May 2020 to 25 June 2020 and there were 113 respondents (estimated 65% response rate). Demographic characteristics of respondents and survey responses are summarized in Table 1. Free-text responses are summarized in Table 2. There was a significant increase in telemedicine utilization across the country during the study period (Table 1). Only 25.0% of dermatologists reported utilizing telemedicine prior to the COVID-19 pandemic, and 93.2% reported use during the study period, a 272.7% increase. While insurance companies reported expansion of telehealth coverage during the pandemic, the majority of respondents (51.9%) were unsure about telemedicine reimbursement. Dermatologists queried reported variability in clinical staffing changes by region (Table 1). While all regions had similar rates of dermatologists practicing in areas with stay at home orders, those in the Northeast were more likely to report that staff were laid off (78.9% of all layoffs) or terminated (91.7% of all terminations). Additionally, only dermatologists in the Northeast had been terminated. Given the recent upsurge in COVID-19 cases in the Southeast and West US, future investigation of these trends is warranted. Skin cancer management was similar between dermatologists practicing in different geographical regions. We found that melanoma treatment by dermatologist participants was consistent with published expert recommendations. However, when stratifying by region, Northeast dermatologists were less likely to manage melanoma in situ as scheduled (50.0%) than those in the Midwest (55.6%, P = .68), Southeast (64.7%, P = .23) or West (77.8%, P = .06), however, these findings did not reach statistical significance (Table 1). Management of T1/T2 and T3/T4 melanomas were similar across geographic regions. Average number of years practicing did not differ between expedited treatment vs delayed treatment (18.05 ± 12.62 vs 19.27 ± 11.5, P = .7). This study is subject to several limitations. The data collected represents a small proportion of the dermatologic community. Additionally, the cross-sectional nature of the study reflects only a snapshot of TABLE 1 Trends in practice management during COVID-19
Impact of Preoperative Low Prognostic Nutritional Index and High Intramuscular Adipose Tissue Content on Outcomes of Patients with Oral Squamous Cell Carcinoma

Simple Summary Oral squamous cell carcinoma (OSCC) has the highest mortality rate among all head and neck cancers. To date, the impact of preoperative malnutrition and sarcopenia on survival in OSCC patients remains controversial. The aim of our study was to investigate the effects of preoperative nutritional status and abnormalities in body composition on the mortality of OSCC patients. The disease-specific survival (DSS) rate among patients with a high intramuscular adipose tissue content (IMAC) and a low psoas muscle mass index was significantly lower than that in controls. Multivariate analysis revealed that a low preoperative Prognostic Nutritional Index (PNI) and high IMAC were independent risk factors. We demonstrated that preoperative malnutrition and abnormal body composition, such as abnormal preoperative skeletal muscle quality, are associated with DSS in OSCC patients. Our study suggests that the evaluation of preoperative malnutrition and skeletal muscle quality would be useful for predicting mortality in patients with OSCC. Abstract The impact of preoperative malnutrition and sarcopenia on survival in oral squamous cell carcinoma (OSCC) patients remains controversial. We investigated the effects of the preoperative nutritional status and abnormalities in body composition on the mortality of OSCC patients. A retrospective study involving 103 patients with OSCC was conducted. Disease-specific survival (DSS) according to the preoperative psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) was evaluated. Univariate and multivariate analyses were performed to determine the predictive performance of the covariates with respect to DSS. The DSS rate in patients with high IMAC and low PMI was significantly lower than that in controls. Multivariate analysis revealed that a low preoperative Prognostic Nutritional Index (PNI) and high IMAC were independent risk factors. We demonstrated that preoperative malnutrition and abnormal body composition, such as preoperative skeletal muscle quality, are associated with DSS in OSCC patients. Our study suggests that the evaluation of preoperative malnutrition and skeletal muscle quality would be useful for predicting mortality in patients with OSCC.
The role of loneliness as a mediator between autism features and mental health among autistic young adults

Autistic adults commonly experience anxiety and depression. These mental health concerns are often tied to social experiences, such that mental well-being can be supported by social connection and deteriorated by loneliness. The mediating role of social and emotional loneliness (i.e. social isolation and lack of emotional attachment, respectively) between autism features and mental health has yet to be empirically tested among autistic adults. Here, 69 autistic young adults completed self-report questionnaires assessing social contact (Friendship Questionnaire), autism features (Autism Quotient), mental health (Liebowitz Social Anxiety Scale, Social Phobia Inventory, Beck Depression Inventory), and loneliness (Social and Emotional Loneliness Scale for Adults). Positive associations emerged between autism features, social loneliness, family loneliness, social anxiety, and depression. In addition, more social contact was related to less social and family loneliness and less social anxiety but was not related to depression. Mediation analyses indicated significant indirect effects of social contact and autism features on mental health through social loneliness. Indirect effects partially held substituting family loneliness for social loneliness and did not hold using romantic loneliness. In light of these results, the scientific and clinical implications of the role of loneliness for autistic young adults are discussed and recommendations provided. Lay abstract Autistic adults commonly experience mental health concerns including social anxiety and depression, which can have negative effects on their quality of life. It is not completely clear, however, why rates of mental health concerns are so high. Some evidence suggests that social connectedness might play a key role. The goal of this study was to explore links between loneliness, mental health concerns, autism features, and social contact among autistic adults and test whether the links between mental health with autism features and social contact can be explained by loneliness. Researchers in this study collected data using questionnaires completed by 69 autistic young adults. Autistic adults who reported more autism features also reported more social and family loneliness, higher levels of social anxiety and depression, and fewer initiated social contacts. In addition, adults with more social contact initiations were likely to report lower levels of social and family loneliness and social anxiety but not depression. Results showed that the link from social engagement and autism features to social anxiety and depression symptoms could be mostly explained by loneliness. The results of this study expand previous findings by illustrating one factor (loneliness) that might be responsible for the high rates of mental health concerns among adults on the autism spectrum. These findings highlight the importance of studying factors related to mental health concerns among autistic adults and ways to best support social connectedness for the mental well-being of autistic young adults.
The Separative Performance of Modules with Polymeric Membranes for a Hybrid Adsorptive/Membrane Process of CO2 Capture from Flue Gas

Commercially available polymeric membrane materials may also show their potential for CO2 capture by the association of the membrane process with other separation techniques in a hybrid system. In the current study, PRISM PA1020/Air Products and UBE UMS-A5 modules with membrane formed of modified polysulfone and polyimide, respectively, were assessed as a second stage in the hybrid vacuum swing adsorption (VSA)–membrane process developed in our laboratory. For this purpose, the module permeances of CO2, N2, and O2 at different temperatures were determined, and the separation of CO2/N2 and CO2/N2/O2 mixtures was investigated in an experimental setup. An appropriate mathematical model was also developed and validated based on experimental data. It was found that both modules can provide CO2-rich gas of the purity of > 95% with virtually the same recovery (40.7−63.6% for maximum carbon dioxide content in permeate) when fed with pre-enriched effluent from the VSA unit. It was also found that this level of purity and recovery was reached at a low feed to permeate the pressure ratio (2−2.5) in both modules. In addition, both modules reveal stable separation performance, and thus, their applicability in a hybrid system depends on investment outlays and will be the subject of optimization investigations, which will be supported by the model presented and validated in this study.
Serum miRNAs associated with tumor-promoting cytokines in non-small cell lung cancer

Tumor-promoting cytokines are a cause of tumor progression; therefore, identifying key regulatory microRNAs (miRNAs) for controlling their production is important. The aim of this study is to identify promising miRNAs associated with tumor-promoting cytokines in non-small cell lung cancer (NSCLC). We identified circulating miRNAs from 16 published miRNA profiles. The selected miRNAs were validated in the serum of 32 NSCLC patients and compared with 33 patients with other lung diseases and 23 healthy persons using quantitative real-time PCR. The cytokine concentration was investigated using the enzyme-linked immunoassay in the same sample set, with clinical validation of the miRNAs. The correlation between miRNA expression and cytokine concentration was evaluated by Spearman’s rank correlation. For consistent direction, one up-regulated miRNA (miR-145) was found in four studies, and seven miRNAs were reported in three studies. One miRNA (miR-20a) and four miRNAs (miR-25-3p, miR-223, let-7f, and miR-20b) were reported in six and five studies. However, their expression was inconsistent. In the clinical validation, serum miR-145 was significantly down-regulated, whereas serum miR-20a was significantly up-regulated in NSCLC, compared with controls. Regarding serum cytokine, all cytokines [vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and transforming growth factor β (TGF-β)], except tumor necrosis factor-α (TNF-α), had a higher level in NSCLC patients than controls. In addition, we found a moderate correlation between the TGF-β concentration and miR-20a (r = −0.537, p = 0.002) and miR-223 (r = 0.428, p = 0.015) and a weak correlation between the VEGF concentration with miR-20a (r = 0.376, p = 0.037) and miR-223 (r = −0.355, p = 0.046). MiR-145 and miR-20a are potential biomarkers for NSCLC. In addition, the regulation of tumor-promoting cytokine, through miR-20a and miR-223, might be a new therapeutic approach for lung cancer.
Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

Background The study was conducted to investigate the effects of metformin treatment on the human gut microbiome’s taxonomic and functional profile in the Latvian population, and to evaluate the correlation of these changes with therapeutic efficacy and tolerance. Methods In this longitudinal observational study, stool samples for shotgun metagenomic sequencing-based analysis were collected in two cohorts. The first cohort included 35 healthy nondiabetic individuals (metformin dose 2x850mg/day) at three time-points during metformin administration. The second cohort was composed of 50 newly-diagnosed type 2 diabetes patients (metformin dose–determined by an endocrinologist) at two concordant times. Patients were defined as Responders if their HbA1c levels during three months of metformin therapy had decreased by ≥12.6 mmol/mol (1%), while in Non-responders HbA1c were decreased by <12.6 mmol/mol (1%). Results Metformin reduced the alpha diversity of microbiota in healthy controls (p = 0.02) but not in T2D patients. At the species level, reduction in the abundance of Clostridium bartlettii and Barnesiella intestinihominis, as well as an increase in the abundance of Parabacteroides distasonis and Oscillibacter unclassified overlapped between both study groups. A large number of group-specific changes in taxonomic and functional profiles was observed. We identified an increased abundance of Prevotella copri (FDR = 0.01) in the Non-Responders subgroup, and enrichment of Enterococcus faecium, Lactococcus lactis, Odoribacter, and Dialister at baseline in the Responders group. Various taxonomic units were associated with the observed incidence of side effects in both cohorts. Conclusions Metformin effects are different in T2D patients and healthy individuals. Therapy induced changes in the composition of gut microbiome revealed possible mediators of observed short-term therapeutic effects. The baseline composition of the gut microbiome may influence metformin therapy efficacy and tolerance in T2D patients and could be used as a powerful prediction tool.
Upfront or intermediate treatment of advanced ovarian cancer patients with cytoreduction plus HIPEC: Results of a retrospective study

Newly diagnosed advanced‐stage ovarian cancer patients are treated with neoadjuvant chemotherapy, primary or intermediate cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study is to evaluate the optimal timing of cytoreduction plus HIPEC for advanced ovarian cancer patients.