Searching across-cohort relatives in 54,092 GWAS samples via encrypted genotype regression.

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier.

The Dawn of a New Era: Targeting the "Undruggables" with Antibody-Based Therapeutics.

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more "undruggable" targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

Asymmetric Cross-Coupling of Aldehydes with Diverse Carbonyl or Iminyl Compounds by Photoredox-Mediated Cobalt Catalysis.

The asymmetric cross-coupling of unsaturated bonds, hampered by their comparable polarity and reactivity, as well as the scarcity of efficient catalytic systems capable of diastereo- and enantiocontrol, presents a significant hurdle in organic synthesis. In this study, we introduce a highly adaptable photochemical cobalt catalysis framework that facilitates chemo- and stereoselective reductive cross-couplings between common aldehydes with a broad array of carbonyl and iminyl compounds, including N-acylhydrazones, aryl ketones, aldehydes, and α-keto esters. Our methodology hinges on a synergistic mechanism driven by photoredox-induced single-electron reduction and subsequent radical-radical coupling, all precisely guided by a chiral cobalt catalyst. Various optically enriched ß-amino alcohols and unsymmetrical 1,2-diol derivatives (80 examples) have been synthesized with good yields (up to 90% yield) and high stereoselectivities (up to >20:1 dr, 99% ee). Of particular note, this approach accomplishes unattainable photochemical asymmetric transformations of aldehydes with disparate carbonyl partners without reliance on any external photosensitizer, thereby further emphasizing its versatility and cost-efficiency.

Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome.

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i-Arrhythmias and Sudden Cardiac Death).

OBJECTIVE: We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs). BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk. METHODS: We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated. RESULTS: 33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78-1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77-0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found. CONCLUSIONS: SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

Nupr1-mediated vascular smooth muscle cell phenotype transformation involved in methamphetamine induces pulmonary hypertension.

AIMS: Nuclear protein 1 (Nupr1) is a multifunctional stress-induced protein involved in the regulation of tumorigenesis, apoptosis, and autophagy. However, its role in pulmonary hypertension (PH) after METH exposure remains unexplored. In this study, we aimed to investigate whether METH can induce PH and describe the role and mechanism of Nupr1 in the development of PH. METHODS AND RESULTS: Mice were made to induce pulmonary hypertension (PH) upon chronic intermittent treatment with METH. Their right ventricular systolic pressure (RVSP) was measured to assess pulmonary artery pressure. Pulmonary artery morphometry was determined by H&E staining and Masson staining. Nupr1 expression and function were detected in human lungs, mice lungs exposed to METH, and cultured pulmonary arterial smooth muscle cells (PASMCs) with METH treatment. Our results showed that chronic intermittent METH treatment successfully induced PH in mice. Nupr1 expression was increased in the cultured PASMCs, pulmonary arterial media from METH-exposed mice, and METH-ingested human specimens compared with control. Elevated Nupr1 expression promoted PASMC phenotype change from contractile to synthetic, which triggered pulmonary artery remodeling and resulted in PH formation. Mechanistically, Nupr1 mediated the opening of store-operated calcium entry (SOCE) by activating the expression of STIM1, thereby promoting Ca2+ influx and inducing phenotypic conversion of PASMCs. CONCLUSIONS: Nupr1 activation could promote Ca2+ influx through STIM1-mediated SOCE opening, which promoted METH-induced pulmonary artery remodeling and led to PH formation. These results suggested that Nupr1 played an important role in METH-induced PH and might be a potential target for METH-related PH therapy.

Impact of COVID-19 on temporal trends and health risks of urinary metal concentrations among residents of Guangzhou, China.

Long-term biomonitoring of urinary metal ions is an essential tool for the epidemiological assessment of chronic exposure levels, enabling us to track changes in metal exposure over time and better understand its health implications. In this study, we evaluated the temporal trends of urinary metal ions among 1962 residents of Guangzhou, China, from 2018 to 2022. The total metal ion concentrations in the urine of the population did not change significantly between 2018 and 2019. With the onset of the COVID-19 pandemic in 2020, urinary total metal ion concentrations began to decline dramatically, reaching their lowest level in 2021. A rebound in concentrations was observed in 2022, which returned to the initial levels observed in 2018. Urine chromium and cadmium concentrations peaked in 2020, while urinary lead levels were the highest in 2021, and urinary nickel concentrations were the highest in 2022. Males consistently displayed higher urinary concentrations of lead and arsenic throughout each year of the study. Furthermore, minors consistently had higher urinary nickel levels than adults, whereas adults consistently had higher urinary cadmium concentrations than minors. Cluster analyses were conducted annually on urinary metal ions to examine the differences in their distribution and to evaluate changes in metal exposure patterns over time. The Monte Carlo simulations indicate that the whole population exhibits a high non-carcinogenic risk from arsenic exposure and significant carcinogenic risks associated with exposure to nickel, arsenic, chromium, and cadmium. The next two years were predicted by a gray prediction model, and the results are tested using mean absolute percentage error which demonstrating high accuracy.

The residual risk of inflammation and remnant cholesterol in acute coronary syndrome patients on statin treatment undergoing percutaneous coronary intervention.

BACKGROUND: Residual risk assessment for acute coronary syndrome (ACS) patients after sufficient medical management remains challenging. The usefulness of measuring high-sensitivity C-reactive protein (hsCRP) and remnant cholesterol (RC) in assessing the level of residual inflammation risk (RIR) and residual cholesterol risk (RCR) for risk stratification in these patients needs to be evaluated. METHODS: Patients admitted for ACS on statin treatment who underwent percutaneous coronary intervention (PCI) between March 2016 and March 2019 were enrolled in the analysis. The included patients were stratified based on the levels of hsCRP and RC during hospitalization. The primary outcome was ischemic events at 12 months, defined as a composite of cardiac death, myocardial infarction, or stroke. The secondary outcomes included 12-month all-cause death and cardiac death. RESULTS: Among the 5778 patients, the median hsCRP concentration was 2.60 mg/L and the median RC concentration was 24.98 mg/dL. The RIR was significantly associated with ischemic events (highest hsCRP tertile vs. lowest hsCRP tertile, adjusted hazard ratio [aHR]: 1.52, 95% confidence interval [CI]: 1.01-2.30, P = 0.046), cardiac death (aHR: 1.77, 95% CI:1.02-3.07, P = 0.0418) and all-cause death (aHR: 2.00, 95% CI: 1.24-3.24, P = 0.0048). The RCR was also significantly associated with these outcomes, with corresponding values for the highest tertile of RC were 1.81 (1.21-2.73, P = 0.0043), 2.76 (1.57-4.86, P = 0.0004), and 1.72 (1.09-2.73, P = 0.0208), respectively. The risks of ischemic events (aHR: 2.80, 95% CI: 1.75-4.49, P < 0.0001), cardiac death (aHR: 4.10, 95% CI: 2.18-7.70, P < 0.0001), and all-cause death (aHR: 3.00, 95% CI, 1.73-5.19, P < 0.0001) were significantly greater in patients with both RIR and RCR (highest hsCRP and RC tertile) than in patients with neither RIR nor RCR (lowest hsCRP and RC tertile). Notably, the RIR and RCR was associated with an increased risk of ischemic events especially in patients with adequate low-density lipoprotein cholesterol (LDL-C) control (LDL-C < 70 mg/dl) (Pinteraction=0.04). Furthermore, the RIR and RCR provide more accurate evaluations of risk in addition to the GRACE score in these patients [areas under the curve (AUC) for ischemic events: 0.64 vs. 0.66, P = 0.003]. CONCLUSION: Among ACS patients receiving contemporary statin treatment who underwent PCI, high risks of both residual inflammation and cholesterol, as assessed by hsCRP and RC, were strongly associated with increased risks of ischemic events, cardiac death, and all-cause death.

Intestinal metaplasia in follow-up endoscopies among Asian patients with short-segment Barrett's esophagus: Regression, sampling error, and associated factors.

BACKGROUND: The percentage of and factors associated with the regression of Barrett's esophagus (BE) or its characteristic intestinal metaplasia (IM) remain unclear, and conflicting results have been reported because of diverse regression and sampling error definitions. Thus, we investigated the rates of IM regression, sampling error, and associated factors. METHODS: Forty-two patients with proven short-segment BE with IM who underwent two follow-up endoscopies with biopsies of Barrett's mucosa were retrospectively analyzed. Additional Alcian blue and MUC2 staining were done on the biopsy specimens without IM in hematoxylin-eosin staining. Only patients with negative hematoxylin-eosin, Alcian blue, and MUC2 staining for IM in both follow-up endoscopies were considered to have true regression. When all three stains were negative for IM in the first, but positive in the second follow-up endoscopy, we considered IM persisting and declared sampling error. RESULTS: Among the 18 patients without IM at the first follow-up endoscopy, only five (11.9%) were judged to have true regression. Prolonged proton-pump inhibitor use was significantly associated with regression. Limited experience of the endoscopist, and insufficient biopsy number were significantly related to sampling error. Receiver operating characteristic (ROC) curve analysis showed the best cut-off value of the biopsy number/maximal-length (cm) ratio to predict sampling error was 2.25. CONCLUSION: In our patients with short-segment BE, 11.9% experienced regression of IM. Prolonged proton-pump inhibitors treatment was associated with regression. An insufficient biopsy number was related to a missed IM, which may be eliminated by maintaining biopsy number/maximal-length (cm) ratio ≥2.25.

Disease Duration Affects the Clinical Phenotype of Primary Sjögren Syndrome: A Medical Records Review Study of 952 Cases.

OBJECTIVES: To investigate the impact of disease duration on clinical phenotypes in Chinese patients with primary Sjögren syndrome (pSS) and examine the correlation between clinical phenotypes and onset age, age at diagnosis, and disease duration. METHODS: Data from 952 patients diagnosed with pSS in China between January 2013 and March 2022 were analyzed based on medical records. Patients were categorized into 3 groups based on disease duration: short (<5 years), moderate (≥5 and <10 years), and long (≥10 years) group. Clinical characteristics were compared among the 3 groups, and pSS patients with a long disease duration were compared with the other patients after matching age at diagnosis and age at onset. RESULTS: Among the patients, 20.4% had a disease duration over 10 years. After matching for age at onset and age at diagnosis, pSS patients with a long disease duration exhibited a significantly higher prevalence of dry mouth ( p <0.001), dry eyes ( p <0.001), fatigue ( p <0.001), arthralgia ( p <0.001), and dental caries ( p <0.001) and higher rates of anti-Sjögren syndrome A ( p < 0.05), anti-Ro52 ( p < 0.05), and anti-SSB ( p < 0.05) positivity than their control groups, with prevalence increasing with disease duration ( ptrend < 0.001). However, no differences were noted in the prevalence of interstitial lung disease and leukopenia between different disease duration groups after matching for age at onset, although differences were shown when matching for age at diagnosis. CONCLUSION: Longer disease duration in pSS patients correlates with increased prevalence of sicca symptoms, fatigue, and arthralgia and higher positivity of autoantibodies associated with pSS. However, the prevalence of interstitial lung disease and leukopenia did not correlate with disease duration after matching for age at onset.

[Identification and expression of genome of uridine diphosphate glycosyltransferase (UGT) gene family from Chrysanthemum indicum].

Uridine diphosphate glycosyltransferase(UGT) is involved in the glycosylation of a variety of secondary metabolites in plants and plays an important role in plant growth and development and regulation of secondary metabolism. Based on the genome of a diploid Chrysanthemum indicum, the UGT gene family from Ch. indicum was identified by bioinformatics methods, and the physical and chemical properties, subcellular localization prediction, conserved motif, phylogeny, chromosome location, gene structure, and gene replication events of UGT protein were analyzed. Transcriptome and real-time fluorescence quantitative polymerase chain reaction(PCR) were used to analyze the expression pattern of the UGT gene in flowers and leaves of Ch. indicum. Quasi-targeted metabolomics was used to analyze the differential metabolites in flowers and leaves. The results showed that a total of 279 UGT genes were identified in the Ch. indicum genome. Phylogenetic analysis showed that these UGT genes were divided into 8 subfamilies. Members of the same subfamily were distributed in clusters on the chromosomes. Tandem duplications were the main driver of the expansion of the UGT gene family from Ch. indicum. Structural domain analysis showed that 262 UGT genes had complete plant secondary metabolism signal sequences(PSPG box). The analysis of cis-acting elements indicated that light-responsive elements were the most ubiquitous elements in the promoter regions of UGT gene family members. Quasi-targeted metabolome analysis of floral and leaf tissue revealed that most of the flavonoid metabolites, including luteolin-7-O-glucoside and kaempferol-7-O-glucoside, had higher accumulation in flowers. Comparative transcriptome analysis of flower and leaf tissue showed that there were 72 differentially expressed UGT genes, of which 29 genes were up-regulated in flowers, and 43 genes were up-regulated in leaves. Correlation network and phylogenetic analysis showed that CindChr9G00614970.1, CindChr2G00092510.1, and CindChr2G00092490.1 may be involved in the synthesis of 7-O-flavonoid glycosides in Ch. indicum, and real-time fluorescence quantitative PCR analysis further confirmed the reliability of transcriptome data. The results of this study are helpful to understand the function of the UGT gene family from Ch. indicum and provide data reference and theoretical basis for further study on the molecular regulation mechanism of flavonoid glycosides synthesis in Ch. indicum.

P2X7 receptor blockade reduces pyroptotic inflammation and promotes phagocytosis in Vibrio vulnificus infection.

Vibrio vulnificus, a gram-negative bacterium, causes serious wound infections and septicemia. Once it develops into early phase sepsis, hyperinflammatory immune responses result in poor prognosis in patients. The present study aimed to examine the possible underlying pathogenic mechanism and explore potential agents that could protect against V. vulnificus cytotoxicity. Here, we report that infection of mouse macrophages with V. vulnificus triggers antiphagocytic effects and pyroptotic inflammation via ATP-mediated purinergic P2X7 receptor (P2X7R) signaling. V. vulnificus promoted P2X7-dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 translocation, modulating the expression of the inflammasome sensor NLR family pyrin domain containing 3 (NLRP3), adaptor apoptosis-associated speck-like protein containing a card (ASC), and pyroptotic protein gasdermin D (GSDMD) in mouse macrophages. V. vulnificus induced the NLRP3/caspase-1 inflammasome signaling complex expression that drives GSDMD transmembrane pore formation and secretion of interleukin (IL)-1ß, IL-18, and macrophage inflammatory protein-2 (MIP-2). This effect was blocked by P2X7R antagonists, indicating that the P2X7R mediates GSDMD-related pyroptotic inflammation in macrophages through the NF-κB/NLRP3/caspase-1 signaling pathway. Furthermore, blockade of P2X7R reduced V. vulnificus-colony-forming units in the spleen, immune cell infiltration into the skin and lung tissues, and serum concentrations of IL-1ß, IL-18, and MIP-2 in mice. These results indicate that P2X7R plays a vital role in mediating phagocytosis by macrophages and pyroptotic inflammation during V. vulnificus infection and provides new opportunities for therapeutic intervention in bacterial infections.

On-Off Switching of a Photocatalytic Overall Reaction through Dynamic Spin-State Transition in a Hofmann Clathrate System.

Spin-state transition is a vital factor that dominates catalytic processes, but unveiling its mechanism still faces the great challenge of the lack of catalyst model systems. Herein, we propose that the {Fe-Pt} Hofmann clathrates, whose dynamic spin-state transition of metal centers can be chemically manipulated through iodine treatment, can serve as model systems in the spin-related structural-catalytic relationship study. Taking the photocatalytic synthesis of H2O2 as the basic catalytic reaction, when the spin state of Fe(II) in the clathrate is high spin (HS), sacrificial agents are indispensable to the photosynthesis of H2O2 because only the photocatalytic oxygen reduction reaction (ORR) occurs; when it is low spin (LS), both the ORR and water oxidation reaction (WOR) can take place, enabling a high H2O2 photosynthesis rate of 66 000 µM g-1 h-1 under visible-light irradiation. In situ characterizations combined with density functional theory calculations confirmed that, compared with the HS-state counterpart, the LS state can induce strong charge transfer between the LS Fe(II) and the iodide-coordinating Pt(IV) in the polymer and reduce the energy barriers for both the ORR and WOR processes, dominating the on-off switching upon the photosynthesis of H2O2 in O2-saturated water. What's more, the one-pot tandem reactions were conducted to utilize the synthesized H2O2 for transforming the low-value-added sodium alkenesulfonates into value-added bromohydrin products with decent conversion rates. This work provides a pioneering investigation into on-off switching the photocatalytic overall reaction through manipulating the metallic spin-state transition in spin-crossover systems.

Nickel-Catalyzed Reductive Cross-Coupling of Allylammonium Salts with Alkyl Iodides.

An unprecedented reductive cross-coupling reaction of allylammonium salts with alkyl electrophiles has been established through C-N bond cleavage. A range of allylammonium bromides smoothly participated in the nickel-catalyzed zinc-mediated allyl-alkyl cross-electrophile coupling reaction with alkyl iodides, delivering structurally diverse alkene products in moderate to good yields with high linear selectivity. Preliminary mechanistic experiments are consistent with the formation of an alkyl radical from the alkyl iodide.

Impact of body size on efficacy of high-dose dual therapy for Helicobacter pylori eradication.

BACKGROUND: High-dose dual therapy (HDDT) is an emerging and promising therapeutic regime for Helicobacter pylori (H. pylori) eradication. However, the pharmacokinetics of the components of HDDT, amoxicillin and proton pump inhibitor, are likely to be affected by body size. In this study, we aimed to find out the impact of body size on the efficacy of HDDT. METHODS: We collected the medical data of 385 treatment-naive patients infected with H. pylori who received HDDT (esomeprazole 20 mg and amoxicillin 750 mg four times daily) for 14 days from July 2020 to December 2021. The associations among the eradication efficacy, adverse events, and variables (sex, age, height, body weight, body mass index (BMI), body surface area (BSA), smoking, drinking, etc.) were analyzed respectively in our study. Among these factors, continuous variables were classified into categorical variables using the cut-off values which were calculated by receiver operating characteristic analysis. RESULTS: The eradication rate of HDDT was 89.9%. There were 55 (14.3%) patients who occurred adverse events during the treatment. Patients with height <170.5 cm, body weight <60.5 kg, BMI <20.55 kg/m2 , BSA <1.69 m2 had a higher eradication rate (92.1% vs. 84.0%, 93.1% vs. 86.8%, 96.0% vs. 87.8%, 93.4% vs. 84.8%, all p < .05). The multivariate analysis showed that BSA ≥1.69 m2 (OR 2.53, 95% CI: 1.28-4.99, p = .007) was the only independent predictor of eradication failure. CONCLUSION: HDDT could achieve better eradication efficacy in patients with small BSA. Clinicians should be aware of the impact of BSA on the H. pylori eradication rate and pay more attention to patients with large BSA.

Cryptogenic hepatocellular carcinoma: characteristics, outcome, and prognostic role of albumin-bilirubin (ALBI) grade vs easy ALBI grade.

BACKGROUND: The characteristics and prognosis of cryptogenic hepatocellular carcinoma (HCC) remain unclear. The albumin-bilirubin (ALBI) grade and its updated version, the easy ALBI (EZ-ALBI) grade, are important prognostic predictors for HCC. We aimed to investigate the long-term survival of patients with cryptogenic HCC and the prognostic role of ALBI and EZ-ALBI grade in these patients. METHODS: A prospective cohort of 2,937 HCC patients with viral or cryptogenic etiology were retrospectively analyzed. The multivariate Cox model was used to determine prognostic predictors. RESULTS: Cryptogenic HCC patients were often older and diabetic, had lower serum ɑ-fetoprotein (AFP) levels, larger tumor burden, poor performance status, advanced cancer stage, and received non-curative treatments compared with hepatitis B or C-related HCC. The Cox analysis showed that age > 65 years, serum AFP > 400 ng/mL, presence of vascular invasion or distant metastasis, presence of ascites, performance status 2-4, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatment, were independent predictors of decreased survival in cryptogenic HCC (p < .001). Significant survival differences were found across ALBI grade and EZ-ALBI grade in cryptogenic HCC and subgroup patients receiving curative or non-curative treatments. The Cancer of Liver Italian Program was the best staging system for patients with cryptogenic HCC. CONCLUSIONS: Patients with cryptogenic HCC have a larger tumor burden and advanced cancer stage at disease presentation compared with those with viral HCC. The ALBI and EZ-ALBI score are robust models to evaluate liver functional reserve for these patients independent of treatment modality.

Low neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict favorable outcomes after endovascular treatment in acute basilar artery occlusion: subgroup analysis of the BASILAR registry.

BACKGROUND: Recently, the BAOCHE trial and ATTENTION trial registry have demonstrated the efficacy of endovascular treatment (EVT) in patients with acute basilar artery occlusion (BAO), however, the proportion of patients with favorable post-EVT outcomes remains low. The present study aimed to investigate the individual and joint prognostic values of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with acute BAO who have undergone EVT. METHODS: We enrolled patients who underwent EVT from the BASILAR registry. Patients were divided into the following groups based on their modified Rankin Scale (mRS) scores at 90 days: favorable-outcome (mRS score: 0-3) and poor-outcome (mRS score: 4-6) groups. Multivariable logistic regression was performed to analyze the association of NLR and PLR with favorable post-EVT outcomes. RESULTS: In total, 585 patients with EVT were recruited. Of these, 189 and 396 patients were in the favorable-outcome and poor-outcome groups, respectively. According to the multivariable logistic regression analyses, both NLR (adjusted odds ratio [aOR], 0.950; 95% confidence interval [CI], 0.920-0.981; P = 0.002) and PLR (aOR, 0.997; 95% CI, 0.995-0.999; P = 0.002) were related to favorable post-EVT outcomes in patients with acute BAO. The optimal cutoff values for the NLR and PLR were 7.75 and 191, respectively. Furthermore, stratified analysis using the multivariable logistic regression model revealed that both NLR and PLR (NLR values ≥ 7.75 and PLR values ≥ 191) were associated with a low rate of favorable outcomes (aOR, 0.292; 95% CI, 0.173-0.494; P < 0.001). CONCLUSIONS: Low NLR and PLR were both associated with favorable post-EVT outcomes in patients with acute BAO. Furthermore, the combined value of both inflammatory markers is potentially reliable in predicting clinical post-EVT outcomes.

Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance.

As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

Effect of glutamine on the systemic innate immune response in broiler chickens challenged with Salmonella pullorum.

BACKGROUND: The objective of this study was to evaluate the effects of glutamine on the growth performance and systemic innate immune response in broiler chickens challenged with Salmonella pullorum. A total of 600 one-day-old Arbor Acres broiler chickens were assigned randomly to 6 dietary treatments with 10 replicates for a 21-day feeding experiment. The experimental treatments were as follows: the control treatment (birds fed the basal diet), the Gln1 treatment, and the Gln 2 treatment (birds fed the basal diet supplemented with 0.5%, and 1.0% Glutamine, respectively). At 3 d of age, half of the birds from each treatment were challenged oral gavage with 2.0 × 104 CFU/mL of S. pullorum suspension (1.0 mL per bird) or an equivalent amount of sterile saline alone, which served as a control. RESULTS: The results showed that S. pullorum infection had adverse effects on the average daily feed intake, average daily gain, and feed conversion ratio of broiler chickens compared with those of the CON treatment on d 7, decreased the spleen and bursa of fabricius relative weights (except on d 21), serum immunoglobulin A (IgA),immunoglobulin G (IgG), and immunoglobulin M (IgM) concentrations, and spleen melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology gene 2 (LGP2) mRNA expression levels, and increased the mRNA expression levels of spleen Nodinitib-1 (NOD1), Toll-like receptors 2,4 (TLR2, TLR4), DNA-dependent activator of IFN-regulatory factors (DAI), mitochondrial antiviral-signaling protein (MAVS), P50, P65, and RelB on d 4, 7, 14, and 21. Supplementation with Gln improved the relative weights of the spleen and bursa of Fabricius (except on d 21), increased the serum IgA, IgG, and IgM concentrations and the mRNA expression levels of spleen MDA5 and LGP2, and decreased the mRNA expression levels of spleen NOD1, TLR2, TLR4, DAI, MAVS, P50, P65, and RelB of S. pullorum-challenged broiler chickens. CONCLUSION: These results indicate that Gln might stimulate the systemic innate immune responses of the spleen in broiler chickens challenged with S. pullorum.

Vesicular Lymphomatoid Papulosis With DUSP22-IRF4 Rearrangement on Chromosome 6p25.3: A Case Report.

ABSTRACT: Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement on chromosome 6p25.3 is a newly identified subtype of LyP. It is characterized by an older age of onset, localized skin lesions, with good prognosis, and it resembles a hybrid of LyP types B and C in histopathology. A limited number of cases have been reported so far. In this article, we reported a case of a 72-year-old man with recurrent episodes of widespread multiple discrete papular or vesicular eruptions on a region of the head, trunk, and 4 extremities for about 3 years. Histopathological examination of a vesicle revealed a subepidermal blister with abundant atypical lymphocytes in the vesicular space, band-like infiltrates in the papillary dermis, along with epidermotropism and pilosebaceous structure involvement. Fluorescence in situ hybridization analysis further demonstrated DUSP22-IRF4 rearrangement on chromosome 6p25.3. A diagnosis of vesicular LyP with this rare subtype was made according to the clinical and pathological findings.