Impact of cesarean section on metabolic syndrome components in offspring rats.

INTRODUCTION: Epidemiological evidence suggests an association between CS and offspring metabolic syndrome (MetS), but whether a causal relationship exists is unknown. METHODS: In this study, timed-mated Wistar rat dams were randomly assigned to cesarean section (CS), vaginal delivery (VD), and surrogate groups. The offspring from both CS and VD groups were reared by surrogate dams until weaning, and weaned male offspring from both groups were randomly assigned to receive normal diet (ND) or high-fat/high-fructose diet (HFF) ad libitum for 39 weeks. RESULTS: By the end of study, CS-ND offspring gained 17.8% more weight than VD-ND offspring, while CS-HFF offspring gained 36.4% more weight than VD-HFF offspring. Compared with VD-ND offspring, CS-ND offspring tended to have increased triglycerides (0.27 mmol/l, 95% CI, 0.05 to 0.50), total cholesterol (0.30 mmol/l, -0.08 to 0.68), and fasting plasma glucose (FPG) (0.30 mmol/l, -0.01 to 0.60); more pronounced differences were observed between CS-HFF and VD-HFF offspring in these indicators (triglyceride, 0.66 mmol/l, 0.35 to 0.97; total cholesterol, 0.46 mmol/l, 0.13 to 0.79; and FPG, 0.55 mmol/l, 0.13 to 0.98). CONCLUSIONS: CS offspring were more prone to adverse metabolic profile and HFF might exacerbate this condition, indicating the association between CS and MetS is likely to be causal. IMPACT: Whether the observed associations between CS and MetS in non-randomized human studies are causally relevant remains undetermined. Compared with vaginally born offspring rats, CS born offspring gained more body weight and tended to have compromised lipid profiles and abnormal insulin sensitivity, suggesting a causal relationship between CS and MetS that may be further amplified by a high-fat/high-fructose diet. Due to the high prevalence of CS births globally, greater clinical consideration must be given to the potential adverse effects of CS, and whether these risks should be made known to patients in clinical practice merits evaluation.

Development of PI3Kγ selective inhibitors: the strategies and application.

The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.

Novel imidazo[1,2,4] triazole derivatives: Synthesis, fluorescence, bioactivity for SHP1.

The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) is a convergent node for oncogenic cell-signaling cascades. Consequently, SHP1 represents a potential target for drug development in cancer treatment. The development of efficient methods for rapidly tracing and modulating the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of the related disease. Thus, we designed and synthesized a series of imidazo[1,2,4] triazole derivatives containing salicylic acid to explore novel scaffolds with inhibitory activities and good fluorescence properties for SHP1. The photophysical properties and inhibitory activities of these imidazo[1,2,4] triazole derivatives (5a-5y) against SHP1PTP were thoroughly studied from the theoretical simulation and experimental application aspects. The representative compound 5p exhibited remarkable fluorescence response (P: 0.002) with fluorescence quantum yield (QY) of 0.37 and inhibitory rate of 85.21 ± 5.17% against SHP1PTP at the concentration of 100 µM. Furthermore, compound 5p showed obvious aggregation caused quenching (ACQ) effect and had high selectivity for Fe3+ ions, good anti-interference and relatively low detection limit (5.55 µM). Finally, the cellular imaging test of compound 5p also exhibited good biocompatibility and certain potential biological imaging application. This study provides a potential way to develop molecules with fluorescent properties and bioactivities for SHP1.

Association of caesarean delivery with offspring health outcomes in full-cohort versus sibling-comparison studies: a comparative meta-analysis and simulation study.

BACKGROUND: Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect estimates from the latter being more likely directed towards the null value. We hypothesized that the seemingly conservative results obtained from the sibling-comparison design might be attributed to inadequate adjustment for non-shared confounders between siblings, particularly maternal age at delivery. METHODS: A systematic review and meta-analysis was first conducted. PubMed, Embase, and the Web of Science were searched from database inception to April 6, 2022. Included studies (1) examined the association of caesarean delivery, whether elective or emergency, with offspring health outcomes; (2) simultaneously conducted full-cohort and sibling-comparison analyses; and (3) reported adjusted effect estimates with 95% confidence intervals (95% CIs). No language restrictions were applied. Data were extracted by 2 reviewers independently. Three-level meta-analytic models were used to calculate the pooled odds ratios (ORs) and 95% CIs for caesarean versus vaginal delivery on multiple offspring health outcomes separately for full-cohort and sibling-comparison designs. Subgroup analyses were performed based on the method of adjustment for maternal age at delivery. A simulation study was then conducted. The simulated datasets were generated with some key parameters derived from the meta-analysis. RESULTS: Eighteen studies involving 21,854,828 individuals were included. The outcomes assessed included mental and behavioral disorders; endocrine, nutritional and metabolic diseases; asthma; cardiorespiratory fitness; and multiple sclerosis. The overall pooled OR for estimates from the full-cohort design was 1.14 (95% CI: 1.11 to 1.17), higher than that for estimates from the sibling-comparison design (OR = 1.08; 95% CI: 1.02 to 1.14). Stratified analyses showed that estimates from the sibling-comparison design varied considerably across studies using different methods to adjust for maternal age at delivery in multivariate analyses, while those from the full-cohort design were rather stable: in studies that did not adjust maternal age at delivery, the pooled OR of full-cohort vs. sibling-comparison design was 1.10 (95% CI: 0.99 to 1.22) vs. 1.06 (95% CI: 0.85 to 1.31), in studies adjusting it as a categorical variable, 1.15 (95% CI: 1.11 to 1.19) vs. 1.07 (95% CI: 1.00 to 1.15), and in studies adjusting it as a continuous variable, 1.12 (95% CI: 1.05 to 1.19) vs. 1.12 (95% CI: 0.98 to 1.29). The severe underestimation bias related to the inadequate adjustment of maternal age at delivery in sibling-comparison analyses was fully replicated in the simulation study. CONCLUSIONS: Sibling-comparison analyses may underestimate the association of caesarean delivery with multiple offspring health outcomes due to inadequate adjustment of non-shared confounders, such as maternal age at delivery. Thus, we should be cautious when interpreting the seemingly conservative results of sibling-comparison analyses in delivery-related studies.

Photophysical Exploration of Alectinib and Rilpivirine: Insights from Theory and Experiment.

Due to the excellent characteristics of fluorescence-based imaging, such as non-invasive detection of biomarkers in vitro and in vivo with high sensitivity, good spatio-temporal resolution and fast response times, it has shown significant prospects in various applications. Compounds with both biological activities and fluorescent properties have the potential for integrated diagnosis and treatment application. Alectinib and Rilpivirine are two excellent drugs on sale that represent a clinically approved targeted therapy for ALK-rearranged NSCLC and have exhibited more favorable safety and tolerance profiles in Phase III clinical trials, ECHO and THRIVE, respectively. The optical properties of these two drugs, Alectinib and Rilpivirine, were deeply explored, firstly through the simulation of molecular structures, electrostatic potential, OPA/TPA and emission spectral properties and experiments on UV-vis spectra, fluorescence and cell imaging. It was found that Alectinib exhibited 7.8% of fluorescence quantum yield at the 450 nm excited wavelength, due to a larger electronic transition dipole moment (8.41 Debye), bigger charge transition quantity (0.682 e) and smaller reorganization energy (2821.6 cm-1). The stronger UV-vis spectra of Rilpivirine were due to a larger electron-hole overlap index (Sr: 0.733) and were also seen in CDD plots. Furthermore, Alectinib possessed obvious active two-photon absorption properties (δmaxTPA* ϕ = 201.75 GM), which have potential TPA imaging applications in bio-systems. Lastly, Alectinib and Rilpivirine displayed green fluorescence in HeLa cells, suggesting the potential ability for biological imaging. Investigation using theoretical and experimental methods is certainly encouraged, given the particular significance of developing integrated diagnosis and treatment.

Exploring the mechanism of the PTP1B inhibitors by molecular dynamics and experimental study.

Protein tyrosine phosphatase 1B (PTP1B) has proven to be an attractive target for the treatment of cancer, diabetes and other diseases. Although many PTP1B inhibitors with various scaffolds have been developed, there is still a lack of PTP1B inhibitor with high specificity and acceptable pharmacological properties. Therefore, it is urgent to develop more methods to explore complex action mode of PTP1B and ligands for designing ideal PTP1B modulators. In this work, we developed a potential molecular dynamics (MD) analytic mode to analyze the mechanism of active compounds 6a and 6e against PTP1B from different perspectives, including the stable ability, interactions and binding site of ligand and protein, the binding energy, relative movement between residues and changes in protein internal interactions. The simulated results demonstrated that compound 6a bound more stably to the active pocket of PTP1B than 6e due to its smaller molecular volume (326 Å3), matched electronegativity, and enhanced the positive correlation motion of residues, especially for WPD loop and P loop. Lastly, compound 6a as a competitive inhibitor for PTP1B was verified by enzyme kinetic assay. This work successfully studied the mechanism of compound 6a against PTP1B from various aspects, enriched the analysis of interaction mode between PTP1B and inhibitors. In summary, we hope that this work could provide more theoretical information for designing and developing more novel and ideal PTP1B inhibitors in the future.

Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway.

Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.

Design, Synthesis and Evaluation of Fluorescent Properties of Benzothiazole Derivatives.

Fluorescence imaging is conducive to establish a bridge between molecular biology and clinical medicine, and provides new tools for disease process research, early diagnosis, and efficacy evaluation, because of the advantages of rapid imaging and nondestructive detection. Herein, a series of fluorescent molecules with thiadiazole, or thiazole, or benzothiazole cores were designed and synthesized to develop more excellent fluorescent molecules in bio-imaging. According to theoretical and experimental methods, we found that benzothiazole derivative 14 B with conjugate expansion by (4-aminophenyl) ethynyl group was the most excellent fluorescent molecule among all the investigated compounds and exhibited low cytotoxicity and strong blue and green fluorescence by confocal cell imaging.

Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3Kα inhibitors via virtual screening and docking-based structure optimization.

Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a PI3Kα inhibitor hit via virtual screening strategy. Additional similarity search and molecular docking based structural modification yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited remarkably improved PI3Kα inhibitory activity with IC50 value of 0.24 µM and moderate to good isoform selectivity over other class I PI3K isoforms. In addition, 49b significantly inhibited the proliferation of Kasumi-1 and T47D cells with IC50 value of 1.64 and 1.82 µM, respectively. Further PK study demonstrated that it has favorable pharmacokinetic profiles (AUC0-t = 3294.05 ng·h/mL at 5.0 mg/kg PO, F = 91.8%). All these data indicated that compound 49b was a promising PI3Kα inhibitor with beneficial drug-like properties and merited further development.

Serum hsCRP in early pregnancy and preterm delivery in twin gestations: a prospective cohort study.

BACKGROUND: Systemic inflammation during pregnancy may be associated with preterm delivery (PTD), but data for twin gestations are lacking. The aim of this study was to examine the association of serum high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, in early pregnancy of twin gestations with risk of PTD, including spontaneous (sPTD) and medical-induced preterm delivery (mPTD). METHODS: A prospective cohort study involved 618 twin gestations was conducted in a tertiary hospital in Beijing, from 2017 to 2020. Serum samples collected in early pregnancy were analyzed for hsCRP using particle-enhanced immunoturbidimetric method. Unadjusted and adjusted geometric means (GM) of hsCRP were estimated using linear regression, and compared between PTD before 37 weeks of gestation and term delivery at 37 or more weeks of gestation using Mann-Whitney rank sum test. The association between hsCRP tertiles and PTDs was estimated using logistic regression, and further converted overestimated odds ratios into relative risks (RR). RESULTS: A total of 302 (48.87%) women were classified as PTD, with 166 sPTD and 136 mPTD. The adjusted GM of serum hsCRP was higher in PTDs (2.13 mg/L, 95% confidence interval [CI] 2.09 -2.16) compared to term deliveries (1.84 mg/L, 95% CI 1.80 -1.88) (P < 0.001). Compared with the lowest tertile of hsCRP, the highest tertile was associated with increased risk of PTD (adjusted relative risks [ARR] 1.42; 95% CI: 1.08-1.78). Among twin pregnancies, the adjusted association between high values of serum hsCRP in early pregnancy and preterm delivery was only observed in the subgroup of spontaneous preterm deliveries (ARR 1.49, 95%CI:1.08-1.93). CONCLUSIONS: Elevated hsCRP in early pregnancy was associated with increased risk of PTD, particular the risk of sPTD in twin gestations.

Effects of vaginal seeding on gut microbiota, body mass index, and allergy risks in infants born through cesarean delivery: a randomized clinical trial.

BACKGROUND: Vaginal seeding-exposure of neonates to maternal vaginal fluids-has been proposed to improve the microbiota of infants born through cesarean delivery, but its impacts on the infants' subsequent health outcomes remain unclear. OBJECTIVE: This study aimed to examine the impacts of vaginal seeding on gut microbiota, growth, and allergy risks in infants born through cesarean delivery. STUDY DESIGN: This randomized controlled trial was conducted at Liuyang Maternal and Child Health Care Hospital in Hunan, China. We estimated that a minimum sample size of 106 was needed by assuming a standardized effect size of 0.6 for the primary outcomes, with a statistical power of 80%, a 2-sided type I error of 0.05, and an expected loss to follow-up rate of 15%. Finally, 120 singleton term pregnant women scheduled for cesarean delivery were enrolled from November 2018 to September 2019. Infant follow-up was completed in September 2021. The participants were randomized in a 1:1 ratio to the vaginal seeding group (n=60; infants were swabbed immediately after birth using gauze preincubated in maternal vagina) or the control group (n=60; routine standard care). The first set of primary outcomes was infant body mass index and body mass index z-scores at 6, 12, 18, and 24 months of age. The other primary outcome was the total allergy risk score at 18 months for 20 common allergens (each scored from 0-6 points). Characteristics of gut microbiota, overweight/obesity, and allergic diseases and symptoms were included as secondary outcomes. The main analyses were performed according to the modified intention-to-treat principle. RESULTS: Of 120 infants, 117 were included in the analyses. Infant body mass index and body mass index z-scores did not significantly differ between the 2 groups at any of the 4 time points, with the largest difference in point estimates occurring at 6 months: the mean (standard deviation) body mass index was 17.5 (1.4) kg/m2 and 17.8 (1.8) kg/m2 in the vaginal seeding and control groups, respectively (mean difference, -0.31 kg/m2 [95% confidence interval, -0.91 to 0.28]; P=.30), and body mass index z-score was 0.2 (1.0) and 0.4 (1.1), respectively (mean difference, -0.20 [95% confidence interval, -0.58 to 0.18]; P=.31). The median total allergy risk score was 1.5 (interquartile range, 0.0-4.0) in the vaginal seeding group and 2.0 (interquartile range, 1.0-3.0) in the control group (median difference, 0.00 [95% confidence interval, -1.00 to 1.00]; P=.48). For infants from the vaginal seeding group, the relative abundance of genera Lactobacillus and Bacteroides in the gut microbiota was slightly yet nonsignificantly elevated at birth and 6 months, and the risk of overweight/obesity was lower at 6 months (0/57 vs 6/59; relative risk, 0.03 [95% confidence interval, 0.00-0.57]; P=.03) though not at subsequent time points. Other secondary outcomes did not differ between groups. No adverse events related to the intervention were reported. CONCLUSION: For infants born through cesarean delivery, vaginal seeding has no significant impacts on the gut microbiota, growth, or allergy risks during the first 2 years of life.

Discovery of toxoflavin, a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition.

Inositol-requiring enzyme 1α (IRE1α) is the most conserved endoplasmic reticulum (ER) stress sensor with two catalytic domains, kinase and RNase, in its cytosolic portion. IRE1α inhibitors have been used to improve existing clinical treatments against various cancers. In this study we identified toxoflavin (TXF) as a new-type potent small molecule IRE1α inhibitor. We used luciferase reporter systems to screen compounds that inhibited the IRE1α-XBP1s signaling pathway. As a result, TXF was found to be the most potent IRE1α RNase inhibitor with an IC50 value of 0.226 µM. Its inhibitory potencies on IRE1α kinase and RNase were confirmed in a series of cellular and in vitro biochemical assays. Kinetic analysis showed that TXF caused time- and reducing reagent-dependent irreversible inhibition on IRE1α, implying that ROS might participate in the inhibition process. ROS scavengers decreased the inhibition of IRE1α by TXF, confirming that ROS mediated the inhibition process. Mass spectrometry analysis revealed that the thiol groups of four conserved cysteine residues (CYS-605, CYS-630, CYS-715 and CYS-951) in IRE1α were oxidized to sulfonic groups by ROS. In molecular docking experiments we affirmed the binding of TXF with IRE1α, and predicted its binding site, suggesting that the structure of TXF itself participates in the inhibition of IRE1α. Interestingly, CYS-951 was just near the docked site. In addition, the RNase IC50 and ROS production in vitro induced by TXF and its derivatives were negative correlated (r = -0.872). In conclusion, this study discovers a new type of IRE1α inhibitor that targets a predicted new alternative site located in the junction between RNase domain and kinase domain, and oxidizes conserved cysteine residues of IRE1α active sites to inhibit IRE1α. TXF could be used as a small molecule tool to study IRE1α's role in ER stress.

[Clinical study of sinus tarsal approach combined with Herbert screw and minimally invasive calcaneal locking plate in the treatment of Sandersâ ¡ and â ¢ calcaneal fractures].

OBJECTIVE: To investigate the clinical effect of the tarsal sinus approach combined with Herbert screw and minimally invasive calcaneal locking plate compared with traditional lateral L-shaped incision approach combined with plate internal fixation in the treatment of SandersⅡ and Ⅲ calcaneal fractures. METHODS: Total of 110 patients with SandersⅡ and Ⅲ calcaneal fractures admitted from March 2018 to March 2020 were selected. There were 66 males and 44 females, ranging in age from 20 to 72 years old, with an average of (48.82±8.03) years old. There were 48 SandersⅡ patients and 62 Sanders Ⅲ patients, including 41 left calcaneal fractures and 69 right calcaneal fractures. According to the surgical approach, the patients were divided into the tarsal sinus approach group and the L-shaped incision approach group, 55 cases in each group. The L-shaped incision approach group was treated with traditional lateral L-shaped incision approach combined with internal fixation plate, while the sinus tarsal approach group was treated with tarsal sinus approach combined with Herbert screw and minimally invasive calcaneal locking plate. The operative time, intraoperative blood loss, length of hospital stay and time of fracture healing were recorded to evaluate the surgical effect. The B?hler angle, Gissane angle, calcaneal length and width of the patients before and after surgery were examined by X-ray and the surgical reduction was highly evaluated. Foot function recovery was evaluated by American Orthopedic Foot and Ankle Society (AOFAS) Maryland Scale, and postoperative complications were recorded. RESULTS: All patients were followed up to 12 months after surgery, the operation time and hospitalization time of patients in the sinus tarsal approach group were shorter than those in the L-shaped incision approach group (P<0.05), and the amount of intraoperative blood loss was lower than that in the L-shaped incision approach group(P<0.05). One year after surgery, B?hler angle, Gissane angle, calcaneus length and height were increased(P<0.05), calcaneus width was decreased (P<0.05). One year after the operation, the Maryland scores of the two groups were increased(P<0.05). During the follow-up period, the incidence of postoperative complications (incision infection, joint pain, soft tissue injury) in the sinus tarsalapproach group was lower than that in the L-shaped incision approach group(P<0.05). CONCLUSION: The traditional lateral L-shaped incision approach and the tarsal sinus approach are both good for the treatment of SandersⅡand Ⅲ calcaneal fractures, but the latter can shorten the surgical treatment time and reduce the incidence of complications.

Triazine-Based Covalent DNA-Encoded Libraries for Discovery of Covalent Inhibitors of Target Proteins.

Since ibrutinib was approved by the FDA as an effective monotherapy for chronic lymphocytic leukemia (CLL) and multilymphoma, more and more FDA-approved covalent drugs are coming back into the market. On this occasion, the resurgence of interest in covalent drugs calls for more hit discovery techniques. However, the limited numbers of covalent libraries prevent the development of this area. Herein, we report the design of covalent DNA-encoded library (DEL) and its selection method for the discovery of covalent inhibitors for target proteins. These triazine-based covalent DELs yielded potent compounds after covalent selection against target proteins, including Bruton's Tyrosine Kinase (BTK), Janus kinase 3 (JAK3), and peptidyl-prolyl cis/trans isomerase NIMA-interacting-1 (Pin1).

Gestational Diabetes Mellitus as an Effect Modifier of the Association of Gestational Weight Gain with Perinatal Outcomes: A Prospective Cohort Study in China.

The association of gestational weight gain (GWG) with perinatal outcomes seems to differ between women with and without gestational diabetes mellitus (GDM). Whether GDM is an effect-modifier of the association has not been verified. This study aimed to assess the modifying effect of GDM on the association of GWG with perinatal outcomes. Data on 12,128 pregnant women (3013 with GDM and 9115 without GDM) were extracted from a prospective, multicenter, cohort study in China. The associations of total and trimester-specific GWG rates (GWGR) with perinatal outcomes, including small size for gestational age, large size for gestational age (LGA), preterm birth, cesarean delivery, and gestational hypertension disorders, were assessed. The modifying effect of GDM on the association was assessed on both multiplicative and additive scales, as estimated by mixed-effects logistic regression. As a result, total GWGR was associated with all of the perinatal outcomes. GDM modified the association of total GWGR with LGA and cesarean delivery on both scales (all p < 0.05) but did not modify the association with other outcomes. The modifying effect was observed in the third trimester but not in the first or the second trimester. Therefore, maternal GWG is associated with perinatal outcomes, and GDM modifies the association with LGA and cesarean delivery in the third trimester.

Cesarean delivery on maternal request and common child health outcomes: A prospective cohort study in China.

Background: Cesarean delivery vs vaginal delivery was reported to increase the risks of childhood obesity, pneumonia, anemia, and neurobehavioral disorders, but few studies were able to deal with the confounding biases associated with medical conditions indicating cesareans. This prospective cohort study aims to investigate the associations of non-medically indicated cesarean delivery on maternal request (CDMR) with these child health outcomes. Methods: Among 17 748 liveborn infants whose mothers (primiparas) participated in a randomized controlled trial on micronutrient supplementation and pregnancy outcomes during 2006-2009 in 5 rural counties in Hebei Province, China, 6972 singletons born by full-term spontaneous vaginal delivery (SVD) and 3626 by CDMR were extracted for the assessments of obesity (weight-for-height z-score >3) and pneumonia (self-reported) at 1.5-5 years in 2011. Some children were further randomly selected from these two groups for the assessments of anemia (hemoglobin <110 g/L, 2341 SVD and 2417 CDMR) and neurobehavioral disorders (raw score of Child Behavior Checklist larger than the 90th percentile of the normative sample, 1257 SVD and 1060 CDMR). Results: Compared with SVD, CDMR was associated with increased risks of obesity (adjusted odds ratio (aOR) = 1.41, 95% confidence interval (CI) = 1.14-1.75, P = 0.002) and anemia (aOR = 1.65, 95% CI = 1.28-2.12, P < 0.001), but not with the risk of pneumonia (aOR = 1.16, 95% CI = 0.94-1.45, P = 0.17) or neurobehavioral disorders (aORs varied from 0.82 to 0.91, P > 0.05) in childhood. Conclusions: Cesarean delivery, independent of cesarean indications, is likely associated with childhood obesity and anemia, indicating a need to keep pregnant women informed, especially those seeking CDMR, a need to explore possible improvement on obstetric service, and even a need for main stakeholders to reach a compromise in making a cesarean decision. Trial registration: ClinicalTrials.gov: NCT00133744 and NCT01404416.

Two New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora.

Two new maytansinoids, N-methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3:  - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1:  - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1: and 4: also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1: and 2: significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma.

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.