Miracle-dz/UniFAR-FTUs huggingface dataset:
The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors.

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. Clinical Trial Registration: NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).
The blood cerebrospinal fluid barrier orchestrates immunosurveillance, immunoprotection, and immunopathology in the central nervous system

Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology.
Spinal dopaminergic mechanisms regulating the micturition reflex in male rats with complete spinal cord injury.

Traumatic spinal cord injury (SCI) often causes micturition dysfunction. We recently discovered a low level of spinally-derived dopamine (DA) that regulates recovered bladder and sphincter reflexes in SCI female rats. Considering substantial sexual dimorphic features in the lower urinary tract, it is unknown if the DA-ergic mechanisms act in the male. Histological analysis showed a similar distribution of tyrosine hydroxylase (TH)+ neurons in the lower cord of male rats and the number increased following thoracic SCI. Subsequently, focal electrical stimulation in slices obtained from L6/S1 spinal segments of SCI rats elicited detectable DA release with fast scan cyclic voltammetry. Using bladder cystometrogram and external urethral sphincter (EUS) electromyography in SCI male rats, intravenous (i.v.) administration of SCH 23390, a D1-like receptor (DR1) antagonist, induced significantly increased tonic EUS activity and a trend of increased residual volume, whereas activation of these receptors with SKF 38393 did not influence the reflex. Meanwhile, blocking spinal D2-like receptors (DR2) with remoxipride had no effect but stimulating these receptors with quinpirole elicited EUS bursting to increase voiding volume. Furthermore, intrathecal (i.t.) delivery of SCH 23390 and quinpirole resulted in similar responses to those with i.v. delivery, respectively, which indicates the central action regardless of delivery route. In addition, metabolic cage assays showed that quinpirole increased the voiding frequency and total voiding volume in spontaneous micturition. Collectively, spinal DA-ergic machinery regulates recovered micturition reflex following SCI in male rats; spinal DR1 tonically suppress tonic EUS activity to enable voiding and activation of DR2 facilitates voiding.
Data-driven development of the Meal-based Diet History Questionnaire for Japanese adults

Abstract FFQ, the primary method of dietary assessment in large-scale nutritional epidemiological studies, preclude an informed evaluation of the timing of dietary intake and meal-specific dietary intake. In this study, we developed the Meal-based Diet History Questionnaire (MDHQ), a self-administered questionnaire designed for estimating food and nutrient intakes for each meal type separately. The development was done based on a 16-d dietary record obtained from 242 Japanese adults. The MDHQ consisted of the three different parts, with a total of 196 items. Part 1 of the MDHQ asks about consumption frequency of generic food groups (n 24) for each meal type: breakfast, morning snack, lunch, afternoon snack, dinner and night snack. Part 2 of the MDHQ asks about relative consumption frequency of sub-food groups within one of the generic food groups which are asked in Part 1. Combining information derived from Parts 1 and 2 enables us to increase the number of foods we can estimate efficiently but within a limited number of questions. Part 3 of the MDHQ asks about general eating behaviours, which are intended to use in a variety of ways during dietary intake calculation. A series of calculation algorithms for food groups, energy and nutrients was also prepared. Given that the MDHQ was empirically developed based on comprehensive information on actual food consumption, this innovative tool may be promising for future epidemiological research on meal patterns and time of day of dietary intake, or chrono-nutrition research. A rigorous evaluation of validity of the MDHQ is warranted.
Change in hospital antibiotic use and acquisition of multidrug-resistant gram-negative organisms after the onset of coronavirus disease 2019

Abstract Interrupted time series segmented regression was conducted to trend antibiotic use and multidrug-resistant gram-negative (MDRGN) acquisition relative to COVID-19 in an academic hospital. Total antibiotic use and antibiotic use related to pneumonia was higher in the period after the onset of COVID-19 compared to the similar calendar period in 2019. Furthermore, MDRGN acquisition increased 3% for every increase in positive COVID-19 tests per week.
Potential roles of neuronal nitric oxide synthase and the PTEN-induced kinase 1 (PINK1)/Parkin pathway for mitochondrial protein degradation in disuse-induced soleus muscle atrophy in adult rats

Excessive nitric oxide (NO) production and mitochondrial dysfunction can activate protein degradation in disuse-induced skeletal muscle atrophy. However, the increase in NO production in atrophied muscles remains controversial. In addition, although several studies have investigated the PTEN-induced kinase 1 (PINK1)/Parkin pathway, a mitophagy pathway, in atrophied muscle, the involvement of this pathway in soleus muscle atrophy is unclear. In this study, we investigated the involvement of neuronal nitric oxide synthase (nNOS) and the PINK1/Parkin pathway in soleus muscle atrophy induced by 14 days of hindlimb unloading (HU) in adult rats. HU lowered the weight of the soleus muscles. nNOS expression showed an increase in atrophied soleus muscles. Although HU increased malondialdehyde as oxidative modification of the protein, it decreased 6-nitrotryptophan, a marker of protein nitration. Additionally, the nitrosocysteine content and S-nitrosylated Parkin were not altered, suggesting the absence of excessive nitrosative stress after HU. The expression of PINK1 and Parkin was also unchanged, whereas the expression of heat shock protein 70 (HSP70), which is required for Parkin activity, was reduced in atrophied soleus muscles. Moreover, we observed accumulation and reduced ubiquitination of high molecular weight mitofusin 2, which is a target of Parkin, in atrophied soleus muscles. These results indicate that excessive NO is not produced in atrophied soleus muscles despite nNOS accumulation, suggesting that excessive NO dose not mediate in soleus muscle atrophy at least after 14 days of HU. Furthermore, the PINK1/Parkin pathway may not play a role in mitophagy at this time point. In contrast, the activity of Parkin may be downregulated because of reduced HSP70 expression, which may contribute to attenuated degradation of target proteins in the atrophied soleus muscles after 14 days of HU. The present study provides new insights into the roles of nNOS and a protein degradation pathway in soleus muscle atrophy.
Week 96 resistance analyses of the once‐daily, single‐tablet regimen (STR) darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV‐1 from the phase 3 randomized AMBER and EMERALD trials

In AMBER and EMERALD, darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg demonstrated high virological response and low virological failure (VF) through week 96. Week 96 resistance analyses are presented. Post‐baseline samples for genotyping/phenotyping were analyzed from protocol‐defined‐VFs with viral load (VL) ≥ 400 copies/ml at failure/later time points. Post‐hoc analyses were deep sequencing (AMBER) and HIV‐1 proviral DNA sequencing from baseline samples (VL < 50 copies/ml) (EMERALD). Through week 96 across studies, no darunavir, primary protease inhibitor (PI), or tenofovir resistance‐associated‐mutations (RAMs) occurred in patients continuing (N = 1125) or switching to D/C/F/TAF (N = 715). M184I/V (emtricitabine RAM) was detected in one patient in each arm of AMBER. In EMERALD D/C/F/TAF patients with prior VF and baseline genoarchive data (N = 98), 4% had darunavir RAMs, 36% emtricitabine RAMs, mainly at position 184 (32%), 4% tenofovir RAMs, and 19% ≥3 thymidine‐analogue‐associated‐mutations at screening. The predicted phenotype showed 0% had reduced susceptibility to darunavir, 37% to emtricitabine, and 22% to tenofovir. All achieved VL < 50 copies/ml at week 96/prior discontinuation, with no VF. D/C/F/TAF has a high barrier to resistance; no darunavir, primary PI, or tenofovir RAMs occurred through 96 weeks in AMBER and EMERALD. In EMERALD, baseline archived darunavir, emtricitabine, and tenofovir RAMs in patients with prior VF did not preclude virologic response.
Risk Factors Associated With In-Hospital Mortality in a US National Sample of Patients With COVID-19

Key Points Question What are the epidemiologic characteristics of patients with coronavirus disease 2019 (COVID-19) treated in US hospitals, and what risk factors are associated with mortality? Findings In this cohort study of 64 781 patients with COVID-19 treated in 592 US hospitals during April and May 2020, the in-hospital mortality rate was 20.3% among inpatients, and severe complications were common. Receipt of statin, angiotensin-converting enzyme inhibitors, and calcium channel blockers were associated with decreased odds of mortality, but the combination use of hydroxychloroquine and azithromycin was associated with increased odds of mortality. Meaning In this study, COVID-19 was associated with severe complications and deaths among patients hospitalized in the United States; certain medications may be associated with decreased odds of mortality.
Xpert MTB/XDR: a 10-Color Reflex Assay Suitable for Point-of-Care Settings To Detect Isoniazid, Fluoroquinolone, and Second-Line-Injectable-Drug Resistance Directly from Mycobacterium tuberculosis-Positive Sputum

We describe the design, development, analytical performance, and a limited clinical evaluation of the 10-color Xpert MTB/XDR assay (CE-IVD only, not for sale in the United States). This assay is intended as a reflex test to detect resistance to isoniazid (INH), fluoroquinolones (FLQ), ethionamide (ETH), and second-line injectable drugs (SLIDs) in unprocessed sputum samples and concentrated sputum sediments which are positive for Mycobacterium tuberculosis. ABSTRACT We describe the design, development, analytical performance, and a limited clinical evaluation of the 10-color Xpert MTB/XDR assay (CE-IVD only, not for sale in the United States). This assay is intended as a reflex test to detect resistance to isoniazid (INH), fluoroquinolones (FLQ), ethionamide (ETH), and second-line injectable drugs (SLIDs) in unprocessed sputum samples and concentrated sputum sediments which are positive for Mycobacterium tuberculosis. The Xpert MTB/XDR assay simultaneously amplifies eight genes and promoter regions in M. tuberculosis and analyzes melting temperatures (Tms) using sloppy molecular beacon (SMB) probes to identify mutations associated with INH, FLQ, ETH, and SLID resistance. Results can be obtained in under 90 min using 10-color GeneXpert modules. The assay can differentiate low- versus high-level resistance to INH and FLQ as well as cross-resistance versus individual resistance to SLIDs by identifying mutation-specific Tms or Tm patterns generated by the SMB probes. The assay has a limit of detection comparable to that of the Xpert MTB/RIF assay and successfully detected 16 clinically significant mutations in a challenge set of clinical isolate DNA. In a clinical study performed at two sites with 100 sputum and 214 clinical isolates, the assay showed a sensitivity of 94% to 100% and a specificity of 100% for all drugs except for ETH compared to that of sequencing. The sensitivity and specificity were in the same ranges as those of phenotypic drug-susceptibility testing. Used in combination with a primary tuberculosis diagnostic test, this assay should expand the capacity for detection of drug-resistant tuberculosis near the point of care.
Association of Apolipoprotein E Polymorphism with Adipokines and Cardiovascular Disease Risk in Rheumatoid Arthritis Patients

Apolipoprotein E (ApoE) polymorphism and adipokines are linked to atherosclerosis. We aimed to investigate the associations of apoE genotypes with adipokines, inflammatory parameters, and cardiovascular disease (CVD) risks in rheumatoid arthritis (RA) patients. We enrolled 152 RA patients and 49 healthy control (HC) subjects. The apoE genotyping was determined by a polymerase chain reaction, while plasma levels of adipokines and inflammatory cytokines were measured with ELISA. Although apoE genotypes distributions were indistinguishable between RA patients and HC, we found significantly higher levels of apoE and adipokines in RA patients compared with HC. RA patients with ε2ε3 genotype had lower levels of TNF-α, IL-6, resistin, and visfatin, but higher leptin levels compared with ε3ε3 genotype patients. Patients with ε3ε4 genotype had significantly higher low-density lipoprotein-cholesterol (LDL-C) levels and atherogenic index scores compared with ε2ε3 genotype carriers. Moreover, patients with ε2ε3 genotype had significantly lower 10-year CVD risk than ε3ε3 or ε3ε4 genotype patients. ε3ε4 genotype and adiponectin levels were independent predictors of a high 10-year CVD risk. RA patients with ε2ε3 genotype are associated with lower levels of TNF-α, IL-6, resistin, visfatin, and CVD risk, while RA patients with ε3ε4 genotype exhibited higher levels of LDL-C, insulin resistance, and higher CVD risks.
Intimate Partner Violence and Sexual Agency in a Nationally Representative Sample of Women and Girls in the Philippines

This study examined the prevalence of intimate partner violence (Intimate Partner Violence) and its associations with sexual agency among women and adolescent girls in the Philippines. Data came from the 2017 Philippines National Demographic and Health Survey (DHS), a nationally representative, cross-sectional survey of women and girls ages 15–49. Participants included 11,727 women and girls who reported having a current male partner. Survey measures included three indicators of Intimate Partner Violence (physical, sexual, emotional), ability to refuse sex, ability to insist on condom use, perception that a husband/boyfriend can be justified in hitting or beating his wife/girlfriend, and sociodemographic characteristics. Descriptive and multivariable statistical analyses were conducted, with survey weightings used to account for the complex survey design. Overall, 23.9% reported Intimate Partner Violence in their current partnership (10.1% physical violence, 3.4% sexual violence, 19.0% emotional violence), 11.2% believed a husband or partner could be justified in hitting or beating their wife, 10.5% reported being unable to refuse sex with their partner, and 20.4% were unable to ask their partner to use a condom. In multivariable analyses, experiences of sexual (OR .68; 95% CI .50, .92), physical (OR .83; 95% CI .68, 1.02), and emotional violence (OR .69; 95% CI .58, .81) were associated with lower adjusted odds of being able to ask a partner to use a condom. When placed in the same model, emotional violence had the strongest association with lower odds of negotiating condom use with partner (OR .70; 95% CI .57, .85). Perception that a husband/boyfriend can be justified in hitting or beating his wife/girlfriend was associated with lower ability to refuse sex and ask a partner to use a condom. Findings indicate a need for further investment in interventions to prevent Intimate Partner Violence and support the sexual health and agency of women and girls who have experienced Intimate Partner Violence in the Philippines.
Gentiopicroside prevents alcoholic liver damage by improving mitochondrial dysfunction in the rat model

Gentianae Radix et Rhizoma is a medical plant that is widely cultivated in China, North Korea, Japan, and Russia, and gentiopicroside is one of its major active compounds. In this study, the hepatoprotective activity of gentiopicroside on rats with alcoholic liver damage (ALD) was evaluated using the transaminase and blood lipid levels and antioxidant capacity. The potential mechanism of hepatoprotective effect of gentiopicroside was evaluated by mitochondrial function detection, gas chromatography–mass spectrometry (GC–MS) metabolomic analysis, and anti‐apoptosis analysis. Results showed that the gentiopicroside exhibited good hepatoprotective activity on rats with ALD by decreasing the transaminase levels, regulating the blood lipid levels, and increasing the antioxidant capacity. The potential mechanisms were related to regulating mitochondrial dysfunction by recovering mitochondrial membrane potential level, adenosine triphosphate concentration, activities of key enzymes in tricarboxylic acid cycle, and activities of complex I‐V, regulating micromolecular metabolism and anti‐apoptosis. These findings supported the further exploration of Gentianae Radix et Rhizoma as effective phytotherapy to prevent and treat ALD.
Simultaneous Ultrasound and Heat Enhance Functional Properties of Glycosylated Lactoferrin

Protein-polysaccharide covalent complexes exhibit better physicochemical and functional properties than single protein or polysaccharide. To promote the formation of the covalent complex from lactoferrin (LF) and beet pectin (BP), we enhanced the Maillard reaction between LF and BP by using an ultrasound-assisted treatment and studied the structure and functional properties of the resulting product. The reaction conditions were optimized by an orthogonal experimental design, and the highest grafting degree of 55.36% was obtained by ultrasonic treatment at 300 W for 20 min and at LF concentration of 20 g/L and BP concentration of 9 g/L. The formation of LF-BP conjugates was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Fourier transform infrared (FTIR) spectroscopy. Ultrasound-assisted treatment can increase the surface hydrophobicity, browning index, 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and 2,2’-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) free radicals scavenging activity of LF due to the changes in the spatial configuration and formation of Maillard reaction products. The thermal stability, antioxidant activity and emulsifying property of LF were significantly improved after combining with BP. These findings reveal the potential application of modified proteins by ultrasonic and heat treatment.
Critical Success Factors of Data Integration on Digital Human Capital Information System to Support Digital Transformation - A Case Study at PTXYZ

The Human Capital paradigm, used as a catalyst for digital transformation, aims to increase the company's competitive value. The paradigm is outlined in the form of a Digital Human Capital Information System (HCIS) to support digital transformation at PT XYZ. However, this implementation raises a gap with legacy systems that have been running before, so data integration between the two systems is needed. This study aims to determine the critical success factor (CSF) of data integration in HCIS implementation. This study uses the HOT-fit model and TOE framework to determine the factors that influence the success of implementation, then the analytical hierarchy process (AHP) is used to determine the factor that has the greatest influence. The results found that these factors are classified into four criteria: human, technology, organization, and environment. Among the four criteria, the environment is the most important criterion, followed by human, technology, and organization. CSF in each criterion are government regulations and support, innovativeness of senior executives, perceived compatibility, and relative advantage.
Deciphering the Relevance of Bone ECM Signaling

Bone mineral density, a bone matrix parameter frequently used to predict fracture risk, is not the only one to affect bone fragility. Other factors, including the extracellular matrix (ECM) composition and microarchitecture, are of paramount relevance in this process. The bone ECM is a noncellular three-dimensional structure secreted by cells into the extracellular space, which comprises inorganic and organic compounds. The main inorganic components of the ECM are calcium-deficient apatite and trace elements, while the organic ECM consists of collagen type I and noncollagenous proteins. Bone ECM dynamically interacts with osteoblasts and osteoclasts to regulate the formation of new bone during regeneration. Thus, the composition and structure of inorganic and organic bone matrix may directly affect bone quality. Moreover, proteins that compose ECM, beyond their structural role have other crucial biological functions, thanks to their ability to bind multiple interacting partners like other ECM proteins, growth factors, signal receptors and adhesion molecules. Thus, ECM proteins provide a complex network of biochemical and physiological signals. Herein, we summarize different ECM factors that are essential to bone strength besides, discussing how these parameters are altered in pathological conditions related with bone fragility.