YaHS: yet another Hi-C scaffolding tool.

SUMMARY: We present YaHS, a user-friendly command-line tool for the construction of chromosome-scale scaffolds from Hi-C data. It can be run with a single-line command, requires minimal input from users (an assembly file and an alignment file) which is compatible with similar tools and provides assembly results in multiple formats, thereby enabling rapid, robust and scalable construction of high-quality genome assemblies with high accuracy and contiguity. AVAILABILITY AND IMPLEMENTATION: YaHS is implemented in C and licensed under the MIT License. The source code, documentation and tutorial are available at https://github.com/sanger-tol/yahs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Interaction Effects between the Main Components of Protein-Rich Biomass during Microwave-Assisted Pyrolysis.

The interaction effects between the main components (proteins (P), carbohydrates (C), and lipids (L)) of protein-rich biomass during microwave-assisted pyrolysis were investigated in depth with an exploration of individual pyrolysis and copyrolysis (PC, PL, and CL) of model compounds. The average heating rate of P was higher than those of C and L, and the interactions in all copyrolysis groups reduced the max instant heating rate. The synergistic extent (S) of PC and PL for bio-oil yield was 16.78 and 18.24%, respectively, indicating that the interactions promoted the production of bio-oil. Besides, all of the copyrolysis groups exhibited a synergistic effect on biochar production (S = 19.43-28.24%), while inhibiting the gas generation, with S ranging from -20.17 to -6.09%. Regarding the gaseous products, apart from H2, P, C, and L primarily generated CO2, CO, and CH4, respectively. Regarding bio-oil composition, the interactions occurring within PC, PL, and CL exhibited a significantly synergistic effect (S = 47.81-412.96%) on the formation of N-heterocyclics/amides, amides/nitriles, and acids/esters, respectively. Finally, the favorable applicability of the proposed interaction effects was verified with microalgae. This study offers valuable insights for understanding the microwave-assisted pyrolysis of protein-rich biomass, laying the groundwork for further research and process optimization.

Adpressins A-G: Oligophenalenone Dimers from Talaromyces adpressus.

Nine new oligophenalenone dimers, adpressins A-G (1-9), together with nine known compounds (10-18), were isolated from the fungus Talaromyces adpressus. Their chemical structures were determined on the basis of spectroscopic and mass spectral analyses. Their relative and absolute configurations were identified by 1H and 13C NMR calculations followed by DP4+ analyses, electronic circular dichroism (ECD) calculations, and ECD spectra comparison with related compounds. Compound 1 is the first example of a duclauxin derivative featuring an unusual 6/6/6/5/6/6/6 ring system, while compounds 6 and 7 contained a novel pyrrolidine ring. Compounds 5, 9, and 18 exhibited moderate inhibition against LPS-induced B lymphocyte proliferation with IC50 values ranging from 1.6 to 8.6 µM. Additionally, compounds 9 and 18 exhibited moderate inhibition against Con A-induced T lymphocyte proliferation with IC50 values of 9.3 and 2.6 µM, respectively.

New diarylcyclopentenone enantiomers and biphenyl derivatives from the fungus Talaromyces adpressus.

Ten new compounds, including three pairs of diarylcyclopentenone enantiomers (±) talaromycesins A-C (1-3) and four biphenyl derivatives talaromycesins D-G (4-7), along with four known compounds (8-11), were isolated from the fungus Talaromyces adpressus. Their structures were determined by analyses of extensive NMR spectroscopic and HRESIMS data, and their absolute configurations were elucidated by the dimolybdenum tetraacetate [Mo2(AcO)4]-induced ECD spectra, X-ray crystallographic studies, and ECD calculations. These new compounds were evaluated for their immunosuppressive activities for the first time, and compound 7 probably exerted liver-protective and anti-inflammatory effects on Con A-induced AIH by decreasing the levels of inflammatory cytokines, modulating immune homeostasis, and decreasing hepatocyte apoptosis, which may become a potential drug for the treatment of autoimmune diseases.

Associations between particulate matter exposure during pregnancy and executive function of toddlers in a prospective cohort study.

BACKGROUND: Exposure to particulate matter (PM) has been found to be associated with impaired cognitive function. However, limited evidence is available on the relationship between PM exposure in the prenatal period and toddler executive function (EF), and the potential influence of breastfeeding. METHODS: The study included 1106 mother-toddler pairs recruited between 2015 and 2019. We assessed mothers' PM1, PM2.5, and PM10 prenatal exposure with a satellite-based dataset at a 1 × 1 km spatial resolution and assigned to participants based on residential addresses. Toddler EF was measured using the Behavior Rating Inventory of Executive Function for Preschoolers (BRIEF-P) questionnaire, higher BRIEF-P scores indicated poorer EF in toddlers. We determined the associations of PM exposure during pregnancy with BRIEF-P scores using multiple linear regression models. RESULTS: In the first trimester, a 10 µg/m3 increase of PM was associated with 1.49 (95% confidence interval [CI]: 0.14-2.83; PM1), 0.68 (95% CI: 0.10-1.26; PM2.5), and 0.63 (95% CI: 0.07-1.20; PM10) elevated toddler global executive composite index scores, respectively. In the stratified analysis, a 10 µg/m3 increase in first trimester PM1 exposure was related to 0.54 (95% CI: 0.19-0.89) higher inhibition scores in toddlers who received complementary breastfeeding for less than six months and -0.15 (95% CI: 0.81-0.51) higher inhibition scores in toddlers who received complementary breastfeeding for six months or more (P for interaction: 0.046). Additionally, a 10 µg/m3 increment in first trimester PM1 exposure was related to 0.36 (95% CI: 0.13-0.59) higher emotional control scores in toddlers who received breastfeeding for less than 12 months and -0.54 (95% CI: 1.25-0.18) higher inhibition scores in toddlers who received breastfeeding for no less than 12 months (P for interaction: 0.043). CONCLUSIONS: PM exposure during the first trimester, especially PM1, has been linked to lower toddler EF performance in toddlers; feeding with breast milk may be a potential protective measure.

Social isolation, loneliness, and motoric cognitive risk syndrome among older adults in China: A longitudinal study.

OBJECTIVES: This study aimed to investigate the associations between social isolation, loneliness, and motoric cognitive risk syndrome (MCR) among older adults in China. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study in the 2011 and 2015 waves. Social isolation and loneliness were measured by an index and an item, and MCR was defined as subjective cognitive complaints and slow gait. Multivariable logistic regression analyses were performed to examine the associations between social isolation, loneliness, and MCR by gender. RESULTS: Of 3251 eligible participants, the incidence of MCR was 10.03%. Social isolation and loneliness were not significantly associated with incident MCR in men. Loneliness was positively associated with incident MCR in women (OR: 1.45, 95% CI: 1.05, 2.01), while social isolation was not. CONCLUSIONS: Loneliness is associated with incident MCR among female older adults in China. More attention is advised to be paid to loneliness among female older adults, to hold promise for the prevention and reduction of MCR.

Fractional carbon dioxide vaginal laser treatment of stress urinary incontinence: Remodeling of vaginal tissues and improving pelvic floor structures.

OBJECTIVE: To demonstrate remodeling of vaginal biomechanical and physiological properties using vaginal fractional carbon dioxide (CO2 ) laser treatment of stress urinary incontinence (SUI). MATERIALS AND METHODS: The study cohort included 26 patients with SUI between October 2019 and November 2020. Patients were treated with two sessions of FemTouch vaginal fractional CO2 laser with a one-month interval. Three subjective assessments were administered to all patients: female sexual function index (FSFI), vaginal health index score (VHIS), and international consultation on incontinence questionnaire-short form (ICIQ-SF). Vaginal tissue biopsies were taken from 6 patients before treatment and one-month after the final treatment. Vaginal tactile imaging (VTI) measurements, ultrasonography, and magnetic resonance imaging (MRI) scans were performed before treatment and 10-12-months after treatment in 10, 9, and 6 patients, respectively. RESULTS: The average age of the cohort was 39.5 ± 12.0 years. The overall scores for FSFI, VHIS, and ICIQ-SF significantly improved in patients after each treatment sessions as compared with baseline scores. VTI showed significantly increased pressure resistance of both the anterior and posterior vaginal walls after treatment. Ultrasonography showed significant decreases in bladder neck mobility and urethrovesical angle during the Valsalva maneuver after treatment. MRI scans showed significant decreases in the length of the vaginal anterior wall after treatment. Histological examination confirmed that the laser treatment led to a thicker stratified squamous epithelium layer as compared to the baseline. CONCLUSIONS: Our results demonstrated that vaginal fractional CO2 laser treatment can restore vaginal biomechanical and physiological properties by increasing vaginal tightening and improving pelvic floor structures.

Knowledge, attitude, and practice regarding postoperative delirium among cardiac surgery nurses: A cross-sectional multi-centre study.

AIMS AND OBJECTIVES: To examine knowledge, attitude, and practice regarding postoperative delirium and the relationships among cardiac surgery nurses in China. BACKGROUND: Postoperative delirium is a prevalent and devastating complication following cardiac surgery. Nurses play a part in multi-disciplinary collaboration for preventing and managing postoperative delirium, of whom knowledge, attitude, and practice are essential. DESIGN: A cross-sectional multi-centre study. METHODS: Nurses from cardiac surgery wards and intensive care units of five tertiary hospitals in Wuhan, Hubei Province, China were enrolled. Data were gathered online using a self-administered questionnaire. Student's t-test, or analysis of variance, or non-parametric tests were performed to compare differences across groups. Bootstrapping mediation analysis was conducted to examine the relationship between knowledge, attitude, and practice. The STROBE checklist was used for the reporting of this study. RESULTS: Of 429 nurses, a moderate level of knowledge and high levels of attitude and practice regarding postoperative delirium were revealed. Nurses with higher education, higher academic title, 5-10 years of practice in nursing and cardiac surgery nursing exhibited increased knowledge. With advanced age, practice in a specialised hospital, and training experience, nurses reported a better degree of practice. Attitude played a full mediating effect in the relationship between knowledge and practice, accounting for 81.82% of the total effects. CONCLUSIONS: Knowledge, attitude, and practice regarding postoperative delirium are promising among Chinese cardiac surgery nurses, with knowledge of screening tools and perioperative nonpharmacological interventions and practice of screening in need of enhancement. Attitudes act as an intermediary between knowledge and practice regarding postoperative delirium. RELEVANCE TO CLINICAL PRACTICE: Innovative and stratified in-service education is warranted to address knowledge enhancement. Meanwhile, organisations are suggested to make efforts to foster nurses' positive attitudes, particularly in creating a favourable culture and developing institutional protocols for postoperative delirium management to improve practice. NO PATIENT OR PUBLIC CONTRIBUTION: This study is focused on cardiac surgery nurses' knowledge, attitude, and practice regarding postoperative delirium, and the research questions and design are from clinical nursing practice, literature review, and expert panel review, in which the patient or public is temporarily not involved.

[Postoperative Delirium in Patients on Cardiopulmonary Bypass for Cardiovascular Surgeries: Incidence and Influencing Factors].

Objective: To investigate the incidence and influencing factors of postoperative delirium (POD) and subsyndromal delirium (SSD) in patients connected to cardiopulmonary bypass during cardiovascular surgeries. Methods: We collected the general data and the data for the perioperative hematological, physiological, and biochemical indicators and the surgical and therapeutic conditions of patients connected to cardiopulmonary bypass during the course of cardiovascular surgeries conducted at a tertiary-care hospital in Hubei province between May 2022 and September 2022. The outcome indicators, including the incidence of POD and SSD, were assessed with the Nursing Delirium Screening Scale (Nu-DESC). Multinomial logistic regression was performed to analyze the influencing factors of patients with different statuses of POD and SSD. Results: Among the 202 patients, the incidence of SSD, SSD progressing to POD, and no POD or SSD (ND) progressing to POD were 13.4%, 6.4%, and 34.2%, respectively. Regression analysis showed that, with ND patients as the controls, the influencing factors for SSD were preoperative blood glucose (odds ratio [ OR]=0.38, 95% confidence interval [ CI]: 0.19-0.76), intraoperative platelet transfusion ( OR=0.37, 95% CI: 0.15-0.92), intraoperative etomidate ( OR=0.93, 95% CI: 0.87-0.98), and postoperative total bilirubin level ( OR=1.04, 95% CI: 1.01-1.07). For the progression of SSD to POD, the influencing factors were age ( OR=1.09, 95% CI: 1.01-1.17), ASA classification of IV and above ( OR=10.72, 95% CI: 1.85-62.08), intraoperative dexmedetomidine ( OR=1.01, 95% CI: 1.003-1.02), and the duration of mechanical ventilation ( OR=1.04, 95% CI: 1.01-1.07). For the progression of ND to POD, the influencing factors were age ( OR=1.06, 95% CI: 1.02-1.10), middle or high school education ( OR=0.35, 95% CI: 0.15-0.83), and the duration of mechanical ventilation ( OR=1.04, 95% CI: 1.01-1.07). Conclusion: Age, education, ASA classification, preoperative blood glucose, intraoperative platelet transfusion, intraoperative etomidate, intraoperative dexmedetomidine, postoperative total bilirubin, and the duration of mechanical ventilation are influencing factors for different statuses of POD and SSD among patients connected to cardiopulmonary bypass when they are undergoing cardiovascular surgeries. The influencing factors vary across groups of patients with different statuses of POD and SSD. Therefore, we should accurately assess the risk factors of patients with different statuses of POD and SSD and carry out corresponding interventions, thereby preventing or reducing the occurrence of POD and SSD, and ultimately promoting enhanced recovery after surgery.

Characteristics of Crosslinking Polymers Play Major Roles in Improving the Stability and Catalytic Properties of Immobilized Thermomyces lanuginosus Lipase.

This study aimed to improve the stability and catalytic properties of Thermomyces lanuginosus lipase (TLL) adsorbed on a hydrophobic support. At the optimized conditions (pH 5 and 25 °C without any additions), the Sips isotherm model effectively fitted the equilibrium adsorption data, indicating a monolayer and the homogenous distribution of immobilized lipase molecules. To preserve the high specific activity of adsorbed lipase, the immobilized lipase (IL) with a moderate loading amount (approximately 40% surface coverage) was selected. Polyethylenimine (PEI) and chitosan (CS) were successfully applied as bridging units to in situ crosslink the immobilized lipase molecules in IL. At the low polymer concentration (0.5%, w/w) and with 1 h incubation, insignificant changes in average pore size were detected. Short-chain PEI and CS (MW ≤ 2 kDa) efficiently improved the lipase stability, i.e., the lipase loss decreased from 40% to <2%. Notably, CS performed much better than PEI in maintaining lipase activity. IL crosslinked with CS-2 kDa showed a two- to three-fold higher rate when hydrolyzing p-nitrophenyl butyrate and a two-fold increase in the catalytic efficiency in the esterification of hexanoic acid with butanol. These in situ crosslinking strategies offer good potential for modulating the catalytic properties of TLL for a specific reaction.

Analysis of time-series gene expression data to explore mechanisms of isoniazid-induced liver toxicity.

Isoniazid (INH) is a first-line anti-tuberculosis drug which can cause idiosyncratic liver injury, while the underlying mechanisms need to be further elucidated. In this study, we explored the time series gene expression profiling of a hepatocyte cell line under isoniazid treatment. Through cluster analysis and enrichment analysis of differentially expressed genes, we revealed a total of 6 gene clusters and a series of pathways related to hepatotoxicity, and 13 key candidate genes were identified according to the protein-protein interaction (PPI) network analysis and maSigPro analysis. These findings lay a foundation for understanding the mechanisms of isoniazid -induced liver toxicity and provide new target genes for the monitoring and treatment of INH-induced hepatotoxicity in the future.

First meiotic anaphase requires Cep55-dependent inhibitory cyclin-dependent kinase 1 phosphorylation.

During mitosis, anaphase is triggered by anaphase-promoting complex (APC)-mediated destruction of securin and cyclin B1, which leads to inactivation of cyclin-dependent kinase 1 (Cdk1). By regulating APC activity, the mitotic spindle assembly checkpoint (SAC) therefore has robust control over anaphase timing to prevent chromosome mis-segregation. Mammalian oocytes are prone to aneuploidy, the reasons for which remain obscure. In mitosis, Cep55 is required post-anaphase for the final steps of cytokinesis. We found that Cep55-depleted mouse oocytes progress normally through early meiosis I, but that anaphase I fails as a result of persistent Cdk1 activity. Unexpectedly, Cdk1 inactivation was compromised following Cep55 depletion, despite on-time SAC silencing and intact APC-mediated proteolysis. We found that impaired Cdk1 inactivation was caused by inadequate inhibitory Cdk1 phosphorylation consequent upon failure to suppress Cdc25 phosphatase, identifying a proteolysis-independent step necessary for anaphase I. Thus, the SAC in oocytes does not exert exclusive control over anaphase I initiation, providing new insight into vulnerability to error.

Ultrasensitive Microfluidic Paper-Based Electrochemical/Visual Analytical Device via Signal Amplification of Pd@Hollow Zn/Co Core-Shell ZIF67/ZIF8 Nanoparticles for Prostate-Specific Antigen Detection.

An effective signal amplification strategy is essential to enhance the analytical performance of microfluidic paper-based analytical devices (µPADs) for tracing biomarkers. Here, a simple but efficient approach with superior electrocatalytic performance of Pd@hollow Zn/Co core-shell ZIF67/ZIF8 nanoparticles for regulating the efficacious signal amplification process was utilized to realize the detection of prostate-specific antigen (PSA). By rationally designing the core-shell structure of ZIF67/ZIF8 with hollow characteristics on the nanoscale and introducing the noble metal element Pd into the cavity, the diffusion limitation and porous confinement reduction of the obtained nanomaterials with uniform morphology and satisfactory chemical stability could be realized, which endowed it with better catalytic performance than solid metal-organic frameworks (MOFs) and ensured effective signal amplification of H2O2 reduction for achieving enhanced electrochemical signals. Moreover, with the assistance of signal probes, the remaining H2O2 could flow to the color area to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine to form a colored product by changing the spatial configuration of the µPAD, thus realizing the visual detection of PSA. On the basis of this novel analytical device, dual-mode ultrasensitive detection of PSA could be achieved with a lower limit of detection of 0.78 pg/mL (S/N = 3) and a wider linear range from 5 pg/mL to 50 ng/mL. This work provided the opportunity of introducing the noble metal element Pd into the cavity of the MOF hollow structure to improve its electrocatalytic efficiency and construct a high-performance µPAD for clinical detection of other biomarkers.

A methylation functional detection hepatic cell system validates correlation between DNA methylation and drug-induced liver injury.

Drug-induced liver injury (DILI) is a life-threatening, adverse reaction to certain drugs. The onset and extent of DILI can vary drastically in different patients using identical drugs. Association studies suggested that subtle differences in DNA methylation may help explain the individual differences in DILI. However, there are very few experimental methods to confirm such associations. In this study, we established a novel DNA methylation functional detection system in human hepatocytes, using CRISPR/dCas9 for targeted modification of DNA methylation, and set four parameters to indicate the liver injury by cell model. Using this system, we validated the association of hypermethylation of CYP2D6 and CYP2E1 with rifampin-induced DILI. Our results revealed that, following treatment of HepaRG cells with rifampin, the methylation levels of CYP2D6 and CYP2E1 were inversely proportional to cell viability and glutathione content, and directly proportional to caspase 3/7 activity. We expect that our methylation detection system will serve as a useful tool in validating correlations between DNA methylation and DILI in other in vitro systems. Our results establish a foundation for future investigations to better understand the mechanisms underlying DILI and may aid in advancing personalized DILI medicine.

Genetic associations of docetaxel-based chemotherapy-induced myelosuppression in Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single-nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual-patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population. Until now, few researches on myelosuppression included Chinese Han patients. In this study, we conducted a systematic study of potential biomarkers for docetaxel-induced myelosuppression in Han Chinese patients. METHODS: We examined 61 SNPs in 36 genes that code for drug transporters, metabolism enzymes, nuclear receptors and DNA repair pathway in 110 Chinese Han patients receiving docetaxel-based chemotherapy. Genotyping was conducted using the Sequenom MassARRAY system. Significant SNPs were identified by logistic regression, and gene-gene interactions were investigated by generalized multifactor dimensionality reduction (GMDR) analysis. RESULTS AND DISCUSSION: Our results revealed that 11 SNPs in nine genes (SLC15A1, SLCO1A2, CYP2D6, FMO3, UGT1A1, NAT2, SULT2A1, PXR and HNF4α) were associated with docetaxel-induced myelosuppression. GMDR analyses suggested that a 3-locus model: SLC15A1 rs2297322-PXR rs3732359-FMO3 rs2266782 was an appropriate predictive model of docetaxel-induced myelosuppression (P = .017, Testing Bal.Acc = 0.653, CV Consistency = 10/10). WHAT IS NEW AND CONCLUSION: Our findings suggest multiple novel predictive biomarkers of docetaxel-induced myelosuppression: SLC15A1 rs2297322, PXR rs3732359 and FMO3 rs2266782. These discoveries should help in advancing future personalized therapy of docetaxel-based chemotherapy specific to Chinese Han patients.

Modelling of self-management in schizophrenia: The role of neurocognition, self-efficacy and motivation.

AIMS AND OBJECTIVES: This study aimed to address the interrelationships among neurocognition, self-efficacy, motivation and self-management in individuals with schizophrenia. BACKGROUND: Self-management performance of individuals with schizophrenia is relatively poor. The effect of neurocognitive impairment on self-management in schizophrenia remains inconsistent, which may be attributed to the neglect of possible mediating factors. Little attention has been given to the role of motivation and self-efficacy for linking neurocognition to self-management. DESIGN: A cross-sectional study. METHODS: Three hundred and twenty patients were recruited with convenience sampling in this study. Patients' neurocognitive function, self-efficacy, motivation and self-management behaviours were measured. Pearson or Spearman correlation analysis and path analysis were performed to examine the interrelationships. This study followed STROBE checklist for cross-sectional studies (see Appendix S1). RESULTS: The final model, with good fit indices, revealed that (1) neurocognition, self-efficacy and motivation were directly associated with self-management, (2) self-efficacy and motivation partly mediated the impact of neurocognition on self-management and (3) motivation additionally mediated the association of self-efficacy and self-management. CONCLUSIONS: Our study extends the current findings, indicating that self-efficacy and motivation may act as mediators in the relationship between neurocognition and self-management in schizophrenia. RELEVANCE TO CLINICAL PRACTICE: Mental health professionals should pay attention to interventions targeting both cognitive and psychosocial components to enhance self-management in individuals with schizophrenia.

Simulating the dynamics of targeted capture sequencing with CapSim.

Motivation: Targeted sequencing using capture probes has become increasingly popular in clinical applications due to its scalability and cost-effectiveness. The approach also allows for higher sequencing coverage of the targeted regions resulting in better analysis statistical power. However, because of the dynamics of the hybridization process, it is difficult to evaluate the efficiency of the probe design prior to the experiments which are time consuming and costly. Results: We developed CapSim, a software package for simulation of targeted sequencing. Given a genome sequence and a set of probes, CapSim simulates the fragmentation, the dynamics of probe hybridization and the sequencing of the captured fragments on Illumina and PacBio sequencing platforms. The simulated data can be used for evaluating the performance of the analysis pipeline, as well as the efficiency of the probe design. Parameters of the various stages in the sequencing process can also be evaluated in order to optimize the experiments. Availability and implementation: CapSim is publicly available under BSD license at https://github.com/Devika1/capsim. Contact: l.coin@imb.uq.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.

Isomeric Pyrenodithiophenediones and Their Derivatives: Synthesis, Reactivity, and Device Performance.

Two isomeric pyrenodithiophenediones and their triisopropylsilyl(TIPS)-ethynyl-functionalized derivatives were synthesized and characterized. With treatment of excess lithium TIPS-acetylide, the isomeric diones could undergo Michael and carbonyl additions to form three derivatives with four, three, and two TIPS-ethynyl groups, respectively. The isomeric TIPS-ethynyl-functionalized derivatives show different physicochemical properties. The single-crystalline transistors based on TIPS-ethynyl-functionalized derivatives exhibit a promising p-type transport behavior, with hole mobilities up to 0.51 cm2 V-1 s-1.

Predictable Resistance and Overall Survival of Gemcitabine/Cisplatin by Platelet Activation Index in Non-Small Cell Lung Cancer.

BACKGROUND Gemcitabine/cisplatin (GP) resistance displays a negative role in treating advanced and metastatic non-small cell lung cancer (NSCLC). Several studies found that the association existed between platelets and cancer antigen 125 (CA125) with anticancer drugs. But the exact correlation between GP resistance and platelet activation index remains poorly understood. MATERIAL AND METHODS Pre-chemotherapy platelet activation index and CA125 were retrospectively evaluated in 169 advanced and metastatic NSCLC patients. All variables were screened by chi-square test and then evaluated by log-rank test. Survival curves were generated by Kaplan-Meier analysis. Univariate and multivariate survival analysis were performed by using Cox proportional hazards model. RESULTS The overall rate of GP resistance for NSCLC patients was 72.19%. Mean platelet volume (MPV) and plateletcrit (PCT) are negative predictors of GP resistance adenocarcinoma [Odds ratio (OR): 5.81, 95% confidence interval (CI): 1.082-31.195, P=0.004] and squamous cell carcinoma (PCT: R: 3.517, 95% CI: 1.087-11.387, P=0.036), respectively. But both were an independent factor associated with overall survival (OS). Moreover, only CA125 was a dependent factor associated with OS for squamous cell carcinoma [OS: hazard ratio (HR): 1.741, 95% CI: 1.002-3.024, P=0.049; GP resistance: OR: 4.862, 95% CI: 1.437-16.448, P=0.011]. CONCLUSIONS Platelet activation index will be a potential marker for predicting GP resistance. Besides, CA125 ≥16.9 could be used as a potential marker for predicting GP resistance and OS, which was more sensitive than CA125 ≥35 for squamous cell carcinoma.

Acute cell volume regulation by Janus kinase 2-mediated sodium/hydrogen exchange activation develops at the late one-cell stage in mouse preimplantation embryos.

Early preimplantation embryos are extremely sensitive to dysregulation of cell volume, which can lead to developmental arrest. It was previously shown that mouse embryos at the two-cell stage respond to a cell volume decrease by quickly activating Na+/H+ exchange via a signaling mechanism that involves the tyrosine kinase Janus kinase 2 (JAK2). However, it was not known whether this mechanism is active at the one-cell stage, when embryos are most sensitive to perturbed cell volume. Na+/H+ exchanger activity elicited by an induced cell volume decrease was significantly lower at the mid one-cell stage than at the late one-cell stage or during the two-cell stage. This activity could be completely blocked by the broad specificity tyrosine kinase inhibitor genistein at either stage, but only at the two-cell stage was there a substantial component of activity that was sensitive to low concentrations of the JAK2-selective inhibitors TG101348 or ruxolitinib. Western blots to detect active JAK2 phosphorylated on tyrosine Y1007/8 revealed that JAK2 became substantially phosphorylated in response to a cell volume decrease at the mid two-cell, but not mid one-cell stage. Such cell volume decrease-induced JAK2 phosphorylation appeared by the late one-cell stage. At least in part this appears to be due to an increase in total JAK2 protein at the late one-cell stage. Furthermore, TG101348 impaired maintenance of cell volume at the two-cell, but not mid one-cell, stages. Thus, cell volume homeostasis requiring Na+/H+ exchange signaled by JAK2 first becomes prominent during mouse embryonic development at the late one-cell stage.