Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.

BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS: At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).

Improved efficacy and safety of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) in China: a subgroup of ALPINE.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has different epidemiology in Chinese vs. Western patients, but there are few studies of CLL/SLL in large populations of Chinese patients. ALPINE is a global phase 3 trial investigating Bruton tyrosine kinase inhibitors zanubrutinib vs. ibrutinib to treat relapsed/refractory (R/R) CLL/SLL. Here we report results from the subgroup of Chinese patients. Adults with R/R CLL/SLL were randomized 1:1 to receive zanubrutinib (160 mg twice-daily) or ibrutinib (420 mg once-daily) until disease progression or unacceptable toxicity. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively. Ninety patients were randomized in China (zanubrutinib, n = 47; ibrutinib, n = 43). Baseline characteristics were balanced between groups, with fewer male patients in the zanubrutinib vs. ibrutinib group (55.3% vs. 69.8%). Median age was 60.5 years, 11% had del(17p) mutation, and 32% had tumor protein 53 (TP53) mutation. With median 25.3 months follow-up, ORR was 80.9% with zanubrutinib vs. 72.1% with ibrutinib. PFS was improved with zanubrutinib vs. ibrutinib (HR = 0.34 [95% CI, 0.15, 0.77]), and the HR for OS was 0.45 (95% CI, 0.14, 1.50). Rates of Grade ≥ 3 treatment-emergent adverse events (TEAEs; 64.4% vs. 72.1%), AEs leading to discontinuation (6.4% vs. 14.0%), and serious TEAEs (35.6% vs. 51.2%) were lower with zanubrutinib vs. ibrutinib. Zanubrutinib demonstrated improved ORR, PFS, and OS vs. ibrutinib and a more favorable safety profile in patients with R/R CLL/SLL in China. These results are consistent with the full global population of ALPINE. ClinicalTrials.gov: NCT03734016, registered November 7, 2018.

Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).

Characterization of newly diagnosed type 1 diabetes in children and adolescents from 2017 to 2022 in China: a single-center analysis.

OBJECTIVE: This study investigated the characteristics of newly diagnosed type 1 diabetes mellitus (T1DM) related to autoimmunity and the frequency of diabetic ketoacidosis (DKA) in children and adolescents from 2017-2022 in China. RESEARCH DESIGN AND METHODS: Single-center regional data from the Department of Pediatric Endocrinology, Tongji Hospital, were used to compare 88 children and adolescents newly diagnosed with T1DM from 2020 to 2022 (i.e. during the COVID-19 pandemic in China) and 76 children and adolescents diagnosed with T1DM from 2017 to 2019. Auto-antibodies, including glutamic acid decarboxylase-65 and insulin auto-antibodies, were detected by enzyme-linked immunoassays. DKA was defined as a pH < 7.3 and/or a bicarbonate level < 15 mmol/L. RESULTS: The median age of the 164 children and adolescents newly diagnosed with T1DM from 2017 to 2022 was 7.0 years (interquartile range [IQR]: 3.8-10.0 years; 51.83% male). The mean annual incidence of T1DM was 2.98 per 1,000,000 child years. The estimated frequency of auto-antibody positivity was 51.22% (n = 84), and there was no difference between the 2020-2022 group and 2017-2019 group (55.68% [n = 49] vs. 46.5% [n = 35]; p = 0.219). The frequency of DKA among the entire cohort was 57.93% (n = 95), and peaked in 2020 at 78.9% (15/19 patients). The frequency of DKA was not significantly higher in the 2020-2022 group compared with the 2017-2019 group (60.23% [n = 53] vs. 55.26% [n = 42]; p = 0.521). We found no significant difference in the frequency of DKA between patients who were negative vs. positive for auto-antibodies in the 2020-2022 group (64.10% [n = 25] vs. 57.14% [n = 28], p > 0.05). The C-peptide level and HbA1c (%) were positively correlated with onset age (R1 = 0.389, p < 0.01; R2 = 0.371, p < 0.01), and the estimated mean C-peptide level was 0.26 ng/ml (IQR: 0.2-0.4 ng/ml) in patients with DKA and 0.370 ng/ml (IQR: 0.2-0.6 ng/ml) in patients without DKA (p = 0.044). CONCLUSIONS: This study showed the annual incidence of T1DM was 2.98 per 1,000,000 child years, gradually increased over the study period, and there was no significant increase in T1DM with auto-antibody positivity in children and adolescents newly diagnosed from 2020-2022 in China compared with the previous 3 years. Furthermore, the frequency of DKA was peaked in 2020, and were not significantly different between patients who were negative vs. positive for auto-antibodies.

Assessment of the Relationship Between Genetic Determinants of Obesity, Unhealthy Eating Habits and Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study.

Background: Clinical studies have shown that the onset and exacerbation of chronic obstructive pulmonary disease (COPD) are related to obesity and dietary behaviours, but the genetic relationship between them is not clear.Aims: To investigate the relationship between the genetic determinants of obesity, dietary habits (alcohol consumption, intake of sweets, salt intake) and COPD.Methods: Exposure and outcome datasets were obtained from the IEU Open GWAS project. The exposure dataset includes dietary habits (Salt added to food, Sweets intake, Alcohol consumption), obesity level (represented by body mass index (BMI) and body fat percentage (BFP) data sets.). The outcome dataset includes COPD and acute COPD admissions. The collected data were imported into the RStudio software and conducted Mendelian randomisation analysis. Additionally, heterogeneity and horizontal pleiotropy tests were conducted on the data to ensure the veracity of the results.Results: The results showed that BMI was positively correlated with the risk of acute COPD admission (OR = 1.74, 95% CI 1.39-2.18) and COPD (OR = 1.81, 95%CI 1.41-2.33). In addition, BFP was also a risk factor for COPD (OR = 1.98, 95% CI 1.42-2.77) and acute exacerbation of COPD admission (OR = 1.99, 95%CI 1.43-2.77). The increase of salt, sugar and alcohol consumption will not increase the risk of COPD and the risk of hospitalisation due to COPD.Conclusion: Therefore, we should strengthen the guidance of diet and living habits of obese patients. For patients with heavier weight and higher body fat rate, they should be instructed to lose weight and fat to prevent the occurrence of COPD. For obese patients with COPD, more attention should be paid to prevent the occurrence of acute exacerbation of COPD in advance.

Effects of accelerated rehabilitation surgical care on the surgical site wound infection and postoperative complications in patients of lung cancer: A meta-analysis.

To comprehensively evaluate the effect of accelerated rehabilitation surgical care on perioperative wound infections and complications in patients undergoing lung cancer surgery. A comprehensive computerised search for randomised controlled trials (RCTs) of accelerated rehabilitative surgical care applied to patients undergoing lung cancer surgery was conducted using the Web of Science, PubMed, Cochrane Library, Embase, Wanfang and China National Knowledge Infrastructure databases from inception to September 2023. The literature was screened and evaluated by two investigators, and data were extracted from the final included literature. Stata software (version 17.0) was used for data analysis. Overall, 21 RCTs involving 2187 patients were included, including 1093 cases in the accelerated rehabilitation surgical care group and 1094 cases in the conventional care group. The analyses revealed that patients with lung cancer surgery who implemented accelerated rehabilitation surgical care were significantly less likely to develop postoperative wound infections (odds ratio [OR] = 0.29, 95% confidence interval [CI]: 0.17-0.49, p < 0.001) and postoperative complications (OR = 0.26, 95% CI: 0.20-0.34, p < 0.001) and shortened the hospital length of stay (standardised mean differences [SMD] = -1.93, 95% CI: -2.32 to -1.53, and p < 0.001) compared with conventional care. The effect of accelerated rehabilitation surgical care intervention in the perioperative period of lung cancer surgery patients is remarkable, as it can effectively reduce the incidence of wound infection and complications, shorten hospitalisation time and promote patient recovery.

Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis.

Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.

Decreased circulating levels of free triiodothyronine in Sepsis children and correlation analysis.

BACKGROUND: Intensive physical stress in sepsis can induce the disorder of endocrine function and impact the clinical course and prognosis. Low T3 syndrome has been verified to be the predictive indicator of poor prognosis in several researches. Reports on the influence factors of thyroid hormonal levels in children with severe sepsis are rare. We aim to investigate the thyroid hormonal variations in the course of sepsis and analyze that how to be affected by clinical data and inflammatory biomarkers. METHODS: In the case-control study, 184 children with sepsis and 323 controls were included in Tongji Hospital, Wuhan, China, in 2019. Data on clinical and inflammatory parameters were collected from all participants. Circulating FT3(Free Triiodothyronine) levels were measured by Electrochemiluminescence immunoassay. Finally, we investigated the correlation between FT3 and related variables with linear regression analysis. RESULTS: Serum FT3 was lower in the sepsis group than in control group(2.59 + 1.17 vs 2.83 + 1.01 pg/mL, p < 0.05). Significant moderately negative correlations(|r| > 0.3) of FT3 levels with ferritin, PCT, duration of symptoms, SOFA score, and mortality were revealed. Moreover, we observed that FT3 had the positive correlation with albumin, as well as white blood cell count. CONCLUSIONS: Concentrations of serum FT3 are dramatically declined in sepsis children than in control children. Our results demonstrate that recognizing the potential abnormality of thyroid hormones in sepsis patients and examine timely through abnormal common clinical data and inflammatory biomarkers is a fine option.

IL-27 overexpression alleviates inflammatory response in allergic asthma by inhibiting Th9 differentiation and regulating Th1/Th2 balance.

OBJECTIVE: To investigate the effect of IL-27 on Th9 differentiation and Th1/Th2 balance. METHODS: C57BL/6 (B6) mice were treated with ovalbumin to establish an allergic asthma (AA) model and subjected to IL-27 overexpression (OV) and empty vector (EV). Hematoxylin-eosin (HE) staining was performed to observe lung tissue inflammation. Flow cytometry was carried out to evaluate the percentage of Th9, Th1, and Th2 cells. The expression of IL-27, IL-27R, IL-9, T-bet, IFN-γ, and IgE was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot was conducted to observe the expression of pSTAT-1 and pSTAT-3. RESULTS: Compared with the Model group, the number of Th1 cells in the Model + OV group increased significantly (p < .05), while those of Th9 and Th2 cells decreased significantly (p < .05). The expression of IL-27, IL-27R, and IFN-γ in blood serum was increased (p < .05), and that of IL-9 and IgE was significantly decreased in the Model + OV group compared to the Model (p < .05). Western blot revealed that Model + OV exhibited lower expression of pSTAT-3 than that in the Model and Model + EV groups (p < .05), while pSTAT-1 expression was significantly increased (p < .05). Inflammatory infiltration in the Model + OV group was significantly reduced, and there was no significant difference between the Model and Model + EV groups. CONCLUSIONS: IL-27 OV inhibits Th9 differentiation and regulates the imbalance of Th1/Th2, thereby alleviating inflammatory response in AA. The findings suggest that IL-27 OV may be a potential strategy for clinical treatment of AA.

Adsorption behavior of organic pollutants on microplastics.

Microplastics (MPs) are emerging pollutants that act as a carrier of toxic pollutants, release toxic substances, and aggregate in biota. The adsorption behavior of MPs has recently become a research hot spot. The objective of this study was to summarize the main mechanisms by which MPs adsorb organic pollutants, introduce some mathematical models commonly used to study the adsorption behavior of MPs, and discuss the factors affecting the adsorption capacity from three perspectives, i.e., the properties of MPs and organic pollutants, and environmental factors. Adsorption kinetics and isothermal adsorption models are commonly used to study the adsorption of organic pollutants on MPs. We observed that hydrophobic interaction is the most common mechanism by which MPs adsorb organic pollutants, and also reportedly controls the portion of organic pollutants. Additionally, electrostatic interaction and other non-covalent forces, such as hydrogen bonds, halogen bonds, and π-π interactions, are also mechanisms of organic pollutant adsorption on MPs. The particle size, specific surface area, aging degree, crystallinity, and polarity of MPs, and organic pollutant properties (hydrophobicity and dissociated forms) are key factors affecting adsorption capacity. Changes in the pH, temperature, and ionic strength also affect the adsorption capacity. Current research on the adsorption behavior of MPs has mainly been conducted in laboratories, and in-depth studies on the adsorption mechanism and influencing factors are limited. Therefore, studies on the adsorption behavior of MPs in the environment are required, and this study will contribute to a better understanding of this topic.

Mutations in the PIGW gene associated with hyperphosphatasia and mental retardation syndrome: a case report.

BACKGROUND: Mutations in the PIGV, PIGO, PIGL, PIGY, PGAP2, PGAP3, and PIGW genes have recently been reported to cause hyperphosphatasia accompanied by mental retardation syndrome (HPMRS); the latter is an autosomal-recessive neurological disorder typically characterised by recurrent seizures, intellectual disability, and distinct facial features. Here, we report an extremely rare case of a Chinese boy with compound heterozygous PIGW mutations who suffers from severe pneumonia, mental retardation, and epilepsy. CASE PRESENTATION: A 70-day-old boy presented with fever and cough over 20 days in duration at the time of admission. At the age of 6 months, unusual facial features were apparent, and seizures were clinically observed, accompanied by obvious cognitive delay. Next-generation sequencing identified novel PIGW c.178G > A and c.462A > T mutations, confirmed by Sanger sequencing. CONCLUSIONS: Mutations in the PIGW gene in infants can cause various symptoms and multiple anomalies. Next-generation sequencing efficiently detects such mutations. The compound PIGW mutations that we describe expand the genotype/phenotype spectrum of HPMRS and may aid in clinical treatment.

[Etiology and risk factors for childhood unintentional injuries: a retrospective analysis of data at a pediatric intensive care unit].

OBJECTIVE: To investigate the etiology and risk factors for unintentional injuries in children admitted to the pediatric intensive care unit (PICU), and to provide a basis for preventing these injuries and decreasing the mortality rate. METHODS: A retrospective analysis was performed on the clinical data of children with unintentional injuries admitted to the PICU from December 2012 to December 2017. RESULTS: A total of 102 children with unintentional injuries were admitted to the PICU, which accounted for 3.30% (102/3 087) of the overall PICU patients. The top three causes of unintentional injuries were food or drug poisoning, drowning, and foreign body ingestion and aspiration. The proportion of unintentional injuries in boys was significantly higher than in girls (P<0.05). The younger children had a significantly higher proportion of unintentional injuries (P<0.05). The cause of unintentional injuries was also related to age, and the common causes of unintentional injuries varied between different age groups. The proportion of unintentional injuries was not significantly different between children from urban and rural areas (P>0.05). The logistic regression analysis showed that the number of organs with dysfunction after unintentional injuries, especially respiratory, cardiac, neurological, renal and hematological involvement, was closely associated with the mortality rate of children with unintentional injuries (P<0.05); however, it is not an independent risk factor (P>0.05). CONCLUSIONS: Prevention is the key to decreasing the incidence of childhood unintentional injuries. Preventive measures should be taken based on patient's sex and age and the cause of unintentional injuries. The spread of first aid knowledge, improvement in emergency transportation, and more attention to organ protection may be useful for decreasing the mortality rate of children with unintentional injuries.

An Optimized and Feasible Preparation Technique for the Industrial Production of Hydrogel Patches.

For hydrogel patches, the laboratory tests could not fully reveal the existing problems of full scale of industrial production, and there are few studies about the preparation technique for the industrial manufacturing process of hydrogel patches. So, the purpose of this work was to elucidate the effects of mainly technological operation and its parameters on the performance of hydrogel patches at the industrial-scale production. The results revealed the following: (1) the aqueous phase was obtained by polyvinylpyrrolidone (PVP) along with tartaric acid dissolved in purified water, then feeding this into a vacuum mixer as a whole in one batch, thus extended the crosslinking reaction time of hydrogel paste (matrix) and allowed the operation of coating/cutting-off to be carried out easily, and there was no permeation of backing layer; (2) the gel strength of the hydrogel patches increased with the increase of working temperature, however, once the temperature exceeded 35 ± 2 °C, the hydrogel paste would lose water severely and the resultant physical crosslinking structure which has lower gel/cohesive strength would easily bring gelatinization/residues during application; (3) the relative humidity (RH) of the standing-workshop was dynamically controlled (namely at 35 ± 2 °C, keeping the RH at 55 ± 5% for 4 days, then 65 ± 5% for 2 days), which would make patches with satisfactory characteristics such as better flexibility, higher adhesive force, smooth flat matrix surface, and without gelatinization/residues and warped edge during the using process; (4) the aging of the packaged hydrogel patches was very sensitive to storage temperature, higher temperature, higher gel strength and lower adhesiveness. The storage temperature of 10 ± 2 °C could effectively prevent matrix aging and adhesion losing, which would also facilitate the expiration date of patches extended obviously. In conclusion, this work provides an optimized and feasible preparation technique for the industrial production of the hydrogel patches and establishes the hydrogel patches as a novel carrier for transdermal drug delivery.

Antifungal and Biocontrol Evaluation of Four Lysobacter Strains Against Clubroot Disease.

The effect of crude extract (Ce), seed coating agent (SCA) and whole bacterial broth culture (WBC) of Lysobacter strains was evaluated against the causal agent of clubroot formation in Cruciferous vegetables. The ability of four Lysobacter strains (L. antibioticus 6-B-1, L. antibioticus 6-T-4, L. antibioticus 13-B-1 and L. capsici ZST1-2) inhibited Plasmodiophora brassicae of resting spores and disease. Application of WBC of four Lysobacter strains inhibited clubroot disease, indicating that the disease suppression was due to antifungal compounds produced by the biocontrol bacterium in the culture. Development of clubroot on Chinese cabbage was inhibited when the WBC and SCA were applied before P. brassicae inoculation. Crude extract (Ce) of culture filtrate was effective in arresting the germination of resting spores of P. brassicae on slides. However, Lysobacter strains differed in their biocontrol effects, the strain L. capsci ZST1-2 recorded a high level of disease limiting effect.

[Effects of bufalin combined with doxorubicin on the proliferation and apoptosis of human lung cancer cell line A549 in vitro].

OBJECTIVE: To explore the effects of bufalin (BUF) combined with doxorubicin (DOX) on the proliferation and apoptosis in human lung cancer cell line A549 in vitro.
 Methods: Methyl thiazolyl tetrazolium (MTT) assay was used to measure the inhibitory effects of BUF, DOX and their combination on the growth of A549 cells. Hoechst 33342 staining was used to observe the changes of nucleus. Flow cytometry was used to investigate the apoptosis and cell cycle distribution of A549 cells. Western blot was used to examine the expression of apoptotic protein.
 Results: BUF and DOX showed inhibitory effect on the A549 cells in a dose and time-dependent manner. Compared with BUF or DOX alone, combination of BUF (1, 20, 100 nmol/L) with DOX (1.0 µg/mL) could significantly increase the growth inhibition rate of A549 cells at 24, 36, 72 h, respectively (all P<0.05). BUF and DOX alone could induce apoptosis, and their combination could significantly increase the apoptosis ratio. In addition, BUF combined with DOX could block the cell stage of A549 cells, keep the cell stage stay in S stage and up-regulate the expression of caspase-3.
 Conclusion: BUF combined with DOX can significantly inhibit the proliferation of A549 cells, which might be related to the induction of apoptosis, cell cycle S phase arrest and caspase-3 up-regulation.

An efficient approach to large-scale genotype-phenotype association analyses.

Modern molecular biotechnology generates a great deal of intermediate information, such as transcriptional and metabolic products in bridging DNA and complex traits. In genome-wide linkage analysis and genome-wide association study, regression analysis for large-scale correlated phenotypes is applied to map genes for those by-products that are regarded as quantitative traits. For a single trait, least absolute shrinkage and selection operator with coordinate descent step can be employed to efficiently shrink sparse non-zero genetic effects of quantitative trait loci (QTLs). However, regression analyses in a trait-by-trait basis do not take account of the correlations among the analyzed traits. In this study, conditional phenotype of each trait is defined, given other traits. Large-scale genotype-phenotype association analyses are therefore transformed to separate genotype-conditional phenotype ones. Meanwhile, the correlation architecture between each trait and other traits can also be provided by shrinkage estimation for each conditional phenotype. Simulation demonstrates that the proposed conditional mapping method is generally identical to joint mapping method based on multivariate analysis in terms of statistical detection power and parameter estimation. Application of the method is provided to locate eQTL in yeast.

Characterisation of betatrophin concentrations in childhood and adolescent obesity and insulin resistance.

BACKGROUND AND OBJECTIVE: Betatrophin, a novel hormone, is correlated with insulin resistance and promotes pancreatic ß-cell growth in mice. The aim of this study was to determine circulating betatrophin levels in overweight or obese children and adolescents. METHODS: The following pairs of subjects were included: (i) normal-weight healthy (n = 27) and overweight or obese (n = 28); (ii) non-insulin-resistant overweight or obese (n = 25) and insulin-resistant obese (n = 15); (iii) normal-weight males (n = 18) and females (n = 20); (4) 5 to 8 yr olds (n = 20) and 8 to 14 yr olds (n = 18). Circulating betatrophin levels were measured using enzyme-linked immunosorbent assay (ELISA). In addition, clinical data were recorded and anthropometrical measurements were performed. RESULTS: Circulating betatrophin levels were increased significantly in obese children and adolescents with insulin resistance (365.77 ± 30.86 pg/mL) compared with overweight or obese subjects without insulin resistance (274.25 ± 26.52 pg/mL; p < 0.05). However, no differences in betatrophin levels were seen between lean and overweight or obese children (323.18 ± 25.91 vs. 348.27 ± 18.91 pg/mL, respectively; p > 0.05). In the normal-weight cohort, males had higher serum betatrophin level than did females, and subjects <8 yr old had lower serum betatrophin levels compared with those >8 yr. Surprisingly, betatrophin concentrations were correlated negatively with body mass index (BMI), but not with the BMI Z-score, in non-insulin-resistant children and adolescents. CONCLUSIONS: These results demonstrated that circulating betatrophin levels were increased in insulin-resistant obese children or adolescents and might act as a potential biomarker of insulin resistance in these populations. Furthermore, serum betatrophin concentrations might vary during the development of children and adolescents, as well as between genders.

Exploring the potential of thiophene derivatives as dual inhibitors of ß-tubulin and Wnt/ß-catenin pathways for gastrointestinal cancers in vitro.

Background: Gastrointestinal cancer poses a considerable global health risk, encompassing a heterogeneous spectrum of malignancies that afflict the gastrointestinal tract. It is significant to develop efficacious therapeutic agents, as they are indispensable for both the treatment and prevention of this formidable disease. Methods: In this study, we synthesized a novel thiophene derivative, designated as compound 1312. An assessment was performed to investigate its anti-proliferative activity in several cancer cell lines (GES-1, EC9706, SGC7901, and HT-29). Furthermore, we performed molecular biology techniques to investigate the inhibitory impact of compound 1312 on gastrointestinal cell lines SGC-7901 and HT-29. Results: Our findings reveal that compound 1312 exhibits significant efficacy in suppressing colony formation of cancer cells. Notably, it triggers cell cycle arrest at the G2/M phase in gastrointestinal cell lines SGC7901 and HT-29. Compound 1312 was confirmed to exert inhibitory effects on cell migration and invasion in SGC7901. Additionally, the compound elicits apoptotic cell death through the activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) and the caspase signaling cascade. Furthermore, in vitro experiments revealed that compound 1312 effectively suppresses both the ß-tubulin cytoskeletal network and the Wnt/ß-catenin signaling pathway. These multifaceted anti-cancer activities highlight the potential of compound 1312 as a promising therapeutic agent for the treatment of gastrointestinal malignancies. Conclusion: This study indicates the promising potential of compound 1312 as a prospective candidate agent for gastrointestinal cancer treatment. Further comprehensive investigations are needed to explore its therapeutic efficacy in greater detail.

Bronchopulmonary foregut malformation with severe hemoptysis in advanced age: a case report and literature review.

Bronchopulmonary foregut malformation (BPFM) is a rare developmental malformation disease due to embryonic defects, with an even rarer occurrence in adults. We report a diagnosed case in an adult patient, and notably, this is the first reported case of such advanced age. Additionally, she experienced coughing up approximately 1 liter of blood and partial lung tissue, accompanied by respiratory failure and shock. Following treatment with transcatheter arterial embolization, her condition improved, and she has remained stable during follow-up. We present a case report and conducted a systematic review on this particular case.

Zanubrutinib is effective in non-germinal-center B-cell-like diffuse large B-cell lymphoma with mutated CD79B, high TCL1A expression, or over- expressed MYC/BCL-2.

To evaluate the effects of gene mutations on Bruton tyrosine kinase inhibitor, zanubrutinib's effectiveness in patients with diffuse large B-cell lymphoma (DLBCL), we examined pooled data from four single-arm studies (BGB-3111-AU-003 [NCT02343120], BGB-3111-207 [NCT03145064], BGB-3111_GA101_Study_001 [NCT02569476], BGB-3111-213 [NCT03520920]; n = 121). Objective response rate (ORR) was higher, though not statistically significant, in patients with activated B-cell-like (ABC)- and unclassified DLBCL (42.9% [21/49]) versus those with germinal-center B-cell-like DLBCL (14.3% [1/7]; p = 0.15). Patients with CD79B mutations had better ORR (60%) versus patients with wild-type alleles (25.9%, p < 0.01). Higher TCL1A expression correlated with better zanubrutinib response (p = 0.03), longer progression-free survival (p = 0.01), and longer overall survival (p = 0.12). TCL1A expression was higher in ABC-DLBCL (p < 0.001) and MYD88/CD79B-mutated subtypes (p < 0.0001). Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.