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Drug-induced interstitial lung disease (DILD) is the most common pulmonary adverse event of anticancer drugs. In recent years, the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents. Due to the diverse clinical manifestations and the lack of specific diagnostic criteria, DILD is difficult to diagnose and may even become fatal if not treated properly. Herein, a multidisciplinary group of experts from oncology, respiratory, imaging, pharmacology, pathology, and radiology departments in China has reached the “expert consensus on the diagnosis and treatment of anticancer DILD” after several rounds of a comprehensive investigation. This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening, diagnosis, and treatment of anticancer DILD. This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

To build and validate a multi-parametric MRI (mpMRI)-based radiomics nomogram for early prediction of treatment response to neoadjuvant chemotherapy (NAC) in locally advanced gastric cancer.Baseline MRI were retrospectively enrolled from 141 patients with gastric adenocarcinoma who received NAC followed by radical gastrectomy. According to pathologic response of tumor regression grading (TRG), patients were labeled as responders (TRG = 0 + 1) and non-responders (TRG = 2 + 3) and further divided into a training (n = 85) and validation dataset (n = 56). Radiomics score (Radscore) were built from T2WI, ADC, and venous phase of dynamic-contrasted-enhanced MR imaging. Clinical information, laboratory indicators, MRI parameters, and follow-up data were also recorded. According to multivariable regression analysis, an mpMRI radiomics nomogram was built and its predictive ability was evaluated by ROC analysis. Decision curve analysis was applied to evaluate the clinical usefulness. Kaplan-Meier survival curves based on the nomogram were used to estimate the progression-free survival (PFS) and overall survival (OS) in the validation dataset.Both single sequence-based Radscores and mpMRI radiomics nomogram were associated with pathologic response (p0.001). The nomogram achieved the highest diagnostic ability with area under ROC curve of 0.844 (95% CI, 0.749-0.914) and 0.820 (95% CI, 0.695-0.910) in the training and validation datasets. The hazard ratio of the nomogram for PFS and OS prediction was 2.597 (95% CI: 1.046-6.451, log-rank p = 0.023) and 2.570 (95% CI: 1.166-5.666, log-rank p = 0.011).The mpMRI-based radiomics nomogram showed preferable performance in predicting pathologic response to NAC in LAGC.• This study investigated the value of multi-parametric MRI-based radiomics in predicting pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer. • The nomogram incorporating T2WI Radscore, ADC Radscore, and DCE Radscore as well as Borrmann classification outperformed the single sequence-based Radscore. • The nomogram also exhibited a promising prognostic ability for patient survival and enriched radiomics studies in gastric cancer.

Double tract reconstruction (DTR) is the main digestive tract reconstruction method after proximal gastrectomy (PG). Single tract jejunal interposition (STJI) derived from the double tract reconstruction is also increasingly used in clinical practice. However, there is still a great controversy as to which of the two reconstruction methods can achieve better results. In this study, we systematically reviewed studies on DTR and STJI after PG and performed a meta-analysis. We searched PubMed, Embase, and Cochrane Library databases for clinical studies comparing DTR and STJI after PG to December 2021 without language restriction. Review Manager (version5.4) software was used to perform meta-analysis on operative outcomes, postoperative complications and nutritional outcomes. The protocol for this meta-analysis was registered with PROSPERO (CRD42022301455). Five randomized controlled trials involving 453 patients were included in the meta-analysis. There were no significant differences between DTR and STJI in terms of intraoperative blood loss, postoperative hospital stay, incidence of reflux esophagitis, anastomotic complications and total complications. The operation time of STJI group was longer than that of DTR group [WMD - 0.79; 95% CI (- 1.55, - 0.03)] [heterogeneity: χ

Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5-10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched subtype in patients with HR+/HER2+ breast cancer.First of all, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n = 141) and METABRIC (n = 104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. From this, we constructed a novel marker termed rH/E, which was calculated as ERBB2 expression quantity/(ESR1 expression quantity + 1). Secondly, we performed multiplex immunofluorescence (mIF) to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). When using mIF, rH/E was adjusted to prH/E, which was calculated as HER2-positive cells%/(ER-positive cells + 1)%.All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal B subtype was the most common, followed by the HER2-enriched and luminal A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, prH/E showed a significant prognostic association in the CAMS cohort.This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+ breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

Background The mutual compensatory relationship between the upper cervical sagittal alignment and the lower cervical sagittal alignment has been repeatedly reported. However, the evaluation of the upper cervical sagittal parameters are varied in previous studies. This retrospective study was performed to compare three methods for measuring the upper cervical sagittal parameters. Methods A total of 263 individuals with standing neutral lateral cervical radiographs were included in this study. The Frankfort horizontal line (FHL), foramen magnum line (FML), and McGregor line (ML) were separately used as the reference lines for measuring the C0-1 angle and C0-2 angle. Intraclass correlation (ICC) values were used to compare the consistency and repeatability of the three methods. Pearson’s correlation analysis was used to analyze the correlation between the sagittal parameters of the upper and lower cervical spine. Results The interobserver and intraobserver ICC values obtained from using the ML to measure the C0-1 angle and C0-2 angle were both higher than those obtained from using the FML or FHL. The C0-1 angle and C0-2 angle measured by the three methods were negatively correlated with the C2-7 angle. The upper sagittal parameters measured by the FHL were the most correlated with the C2-7 angle. The correlation between the C0-1 angle measured by the three methods and the C0-2 angle measured with the FHL or ML and the C2-7 angle increased with aging. Conclusion Use of the ML to measure the C0-1 angle and C0-2 angle has higher reliability. Use of the FHL to measure the sagittal alignment of the upper cervical spine is more suitable for evaluating the compensation mechanism between the upper and the lower cervical spine.

Background Prior drought stress may change plants response patterns and subsequently increase their tolerance to the same condition, which can be referred to as “drought memory” and proved essential for plants well-being. However, the mechanism of transcriptional drought memory in psammophytes remains unclear. Agriophyllum squarrosum, a pioneer species on mobile dunes, is widely spread in Northern China’s vast desert areas with outstanding ability of water use efficiency. Here we conducted dehydration-rehydration treatment on A. squarrosum semi-arid land ecotype AEX and arid land ecotype WW to dissect the drought memory mechanism of A. squarrosum, and to determine the discrepancy in drought memory of two contrasting ecotypes that had long adapted to water heterogeneity. Result Physiological traits monitoring unveiled the stronger ability and longer duration in drought memory of WW than that of AEX. A total of 1,642 and 1,339 drought memory genes (DMGs) were identified in ecotype AEX and WW, respectively. Furthermore, shared DMGs among A. squarrosum and the previously studied species depicted that drought memory commonalities in higher plants embraced pathways like primary and secondary metabolisms; while drought memory characteristics in A. squarrosum were mainly related to response to heat, high light intensity, hydrogen peroxide, and dehydration, which might be due to local adaptation to desert circumstances. Heat shock proteins (HSPs) occupied the center of the protein-protein interaction (PPI) network in drought memory transcription factors (TF), thus playing a key regulatory role in A. squarrosum drought memory. Co-expression analysis of drought memory TFs and DMGs uncovered a novel regulating module, whereby pairs of TFs might function as molecular switches in regulating DMG transforming between high and low expression levels, thus promoting drought memory reset. Conclusion Based on the co-expression analysis, protein-protein interaction prediction, and drought memory metabolic network construction, a novel regulatory module of transcriptional drought memory in A. squarrosum was hypothesized here, whereby recurrent drought signal is activated by primary TF switches, then amplified by secondary amplifiers, and thus regulates downstream complicated metabolic networks. The present research provided valuable molecular resources on plants’ stress-resistance basis and shed light on drought memory in A. squarrosum.

Background Sepsis is an abnormal immune response after infection, wherein the lung is the most susceptible organ to fail, leading to acute lung injury. To overcome the limitations of current therapeutic strategies and develop more specific treatment, the inflammatory process, in which T cell-derived extracellular vesicles (EVs) play a central role, should be explored deeply. Methods Liquid chromatography–tandem mass spectrometry was performed for serum EV protein profiling. The serum diacylglycerol kinase kappa (DGKK) and endotoxin contents of patients with sepsis-induced lung injury were measured. Apoptosis, oxidative stress, and inflammation in A549 cells, bronchoalveolar lavage fluid, and lung tissues of mice were measured by flow cytometry, biochemical analysis, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. Results DGKK, the key regulator of the diacylglycerol (DAG)/protein kinase C (PKC) pathway, exhibited elevated expression in serum EVs of patients with sepsis-induced lung injury and showed strong correlation with sepsis severity and disease progression. DGKK was expressed in CD4+ T cells under regulation of the NF-κB pathway and delivered by EVs to target cells, including alveolar epithelial cells. EVs produced by CD4+ T lymphocytes exerted toxic effects on A549 cells to induce apoptotic cell death, oxidative cell damage, and inflammation. In mice with sepsis induced by cecal ligation and puncture, EVs derived from CD4+ T cells also promoted tissue damage, oxidative stress, and inflammation in the lungs. These toxic effects of T cell-derived EVs were attenuated by the inhibition of PKC and NOX4, the downstream effectors of DGKK and DAG. Conclusions This approach established the mechanism that T-cell-derived EVs carrying DGKK triggered alveolar epithelial cell apoptosis, oxidative stress, inflammation, and tissue damage in sepsis-induced lung injury through the DAG/PKC/NOX4 pathway. Thus, T-cell-derived EVs and the elevated distribution of DGKK should be further investigated to develop therapeutic strategies for sepsis-induced lung injury.

Background Breast cancer (BC) metastasis is the leading cause of poor prognosis and therapeutic failure. However, the mechanisms underlying cancer metastasis are far from clear. Methods We screened candidate genes related to metastasis through genome-wide CRISPR screening and high-throughput sequencing of patients with metastatic BC, followed by a panel of metastatic model assays. The effects of tetratricopeptide repeat domain 17 (TTC17) on migration, invasion, and colony formation ability together with the responses to anticancer drugs were investigated in vitro and in vivo. The mechanism mediated by TTC17 was determined by RNA sequencing, Western blotting, immunohistochemistry, and immunofluorescence. The clinical significance of TTC17 was evaluated using BC tissue samples combined with clinicopathological data. Results We identified the loss of TTC17 as a metastasis driver in BC, and its expression was negatively correlated with malignancy and positively correlated with patient prognosis. TTC17 loss in BC cells promoted their migration, invasion, and colony formation capacity in vitro and lung metastasis in vivo. Conversely, overexpressing TTC17 suppressed these aggressive phenotypes. Mechanistically, TTC17 knockdown in BC cells resulted in the activation of the RAP1/CDC42 pathway along with a disordered cytoskeleton in BC cells, and pharmacological blockade of CDC42 abolished the potentiation of motility and invasiveness caused by TTC17 silencing. Research on BC specimens demonstrated reduced TTC17 and increased CDC42 in metastatic tumors and lymph nodes, and low TTC17 expression was linked to more aggressive clinicopathologic characteristics. Through screening the anticancer drug library, the CDC42 inhibitor rapamycin and the microtubule-stabilizing drug paclitaxel showed stronger inhibition of TTC17-silenced BC cells, which was confirmed by more favorable efficacy in BC patients and tumor-bearing mice receiving rapamycin or paclitaxel in the TTC17Low arm. Conclusions TTC17 loss is a novel factor promoting BC metastasis, that enhances migration and invasion by activating RAP1/CDC42 signaling and sensitizes BC to rapamycin and paclitaxel, which may improve stratified treatment strategies under the concept of molecular phenotyping-based precision therapy of BC.

Objective The purpose of this study was to evaluate the feasibility of a novel technique named spinal joints release (SJR) and observe its efficacy in treating rigid post-traumatic thoracolumbar kyphosis (RPTK). Methods RPTK patients who were treated by SJR with facet resection, limited laminotomy, clearance of the intervertebral space, and release of the anterior longitudinal ligament through the intervertebral foramen and disc of injury segment from August 2015 to August 2021 were reviewed. Intervertebral space release, internal fixation segment, operation time, and intraoperative blood loss were recorded. The intraoperative, postoperative, and final follow-up complications were observed. An improvement in the VAS score and ODI index was observed. Spinal cord functional recovery was evaluated by American Spinal Injury Association Impairment Scale (AIS). Improvement of local kyphosis (Cobb angle) was evaluated by radiography. Results Forty-three patients were successfully treated by the SJR surgical technique. Open-wedge anterior intervertebral disc space was performed in 31 cases, and repeated release and dissection of the anterior longitudinal ligament and callus were performed in 12 cases. There was no lateral annulus fibrosis release in 11 cases, the anterior half release of lateral annulus fibrosis in 27 cases, and complete release in five cases. There were five cases of screw placement failure in one or two side pedicles of the injured vertebrae due to excessive resection of the facets and improper pre-bending of the rod. Sagittal displacement occurred in four cases at the released segment due to the complete release of bilateral lateral annulus fibrosus. Autologous granular bone + Cage was implanted in 32 cases, and autologous granular bone was implanted in 11 cases. There were no serious complications. The average operation time was 224 ± 31 min, and intraoperative blood loss was 450 ± 225 mL. All the patients were followed up with an average of 26 ± 8.5 months. The VAS scores and ODI index improved significantly at the final follow-up. All of the 17 patients with incomplete spinal cord injury achieved more than one grade of neurological recovery at the final follow-up. An 87% correction rate of kyphosis was achieved and maintained, with the Cobb angle decreasing from 27.7° preoperatively to 5.4° at the final follow-up. Conclusion Posterior SJR surgery for patients with RPTK has the advantages of less trauma and less blood loss, and kyphosis correction is satisfactory.

Background Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients. Methods We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers. Results A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7–93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4–12.9 months) and median OS was 31.0 months (95% CI: 16.5–45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013). Conclusions The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC. Trial registration ClinicalTrials.gov. (NCT01937689, NCT02361112).

Contrast-enhanced ultrasound (CEUS) is advantageous for evaluating microcirculation, and has been applied to assess arthritis in previous studies. However, CEUS examinations have not been studied for hemophilia arthritis. Hemophilia arthritis is different from other arthritis, because it is induced by spontaneous joint bleeding. Hence, CEUS may have special value in evaluating hemophilia arthritis. The present study assessed the value of CEUS in evaluating synovial hypertrophy and predicting recurrent joint bleeding in severe hemophilia A patients.From August 2016 to January 2017, 81 severe hemophilia A patients, who were referred to our hospital for ultrasound joint assessment with conventional ultrasound, were enrolled. Among these 81 patients, 46 patients consented for CEUS examinations on the same day.Compared to color Doppler flow imaging (CDFI), four more joints presented with a blood flow signal under CEUS mode. In addition, the synovial hypertrophy measured by CEUS was thicker than that measured by conventional ultrasound. The ultrasound scores (including the total grey-scale ultrasound score, joint effusion/hemarthrosis, synovial hypertrophy, CDFI semi-quantitative score, and CEUS semi-quantitative score) were significantly higher in the joint bleeding group than in the no joint bleeding group (P0.05). Furthermore, these ultrasound scores were positively correlated with the joint bleeding frequency, and had the highest correlation with the CEUS score (r=0.620, P0.05).CEUS can more accurately assess the degree of synovial hypertrophy and vascularization, and diagnose synovitis, when compared to conventional ultrasound. In addition, CEUS appears to be essential for evaluating the possibility of recurrent joint bleeding, and providing more reliable evidence for individualized treatment.

Objective: The aim of this study was to assess associations of PART1 rs27565 and DEFB1 rs11362 polymorphisms with the prevalence of dental caries in twelve-year-old children in Nandan County, Guangxi, China. Methods: A total of 1,061 children were included in this cross-sectional study and divided into two groups based on the Decayed, Missing and Filled teeth (DMFT) index: caries-free children (DMFT score = 0) and children with caries (DMFT score ≥ 1). Demographic characteristics, oral hygiene behaviour and dietary habits were collected through household records and questionnaires. Genomic DNA was extracted from buccal cells, and PART1 rs27565 and DEFB1 rs11362 polymorphisms were genotyped using a custom-designed 48-Plex single nucleotide polymorphism-scan kit. Results: Carriers of the PART1 rs27565 C allele (odds ratio [OR] = 1.338, 95% confidence interval (CI) = 1.015–1.764, P value = 0.039) and carriers of the DEFB1 rs11362 T allele (OR = 1.364, 95% CI = 1.056–1.762, P value = 0.017) had a higher risk of caries. Carriers of the PART1 rs27565 TC or CC genotype who ate sugary food more than once a week had a 1.6-fold higher risk of caries than TT carriers who ate sugary food at most once a week (OR = 1.579, 95% CI = 1.032–2.414, P value = 0.035). Carriers of the DEFB1 rs11362 CT or TT genotype who ate sugary food more than once a week had a 2.1-fold higher risk of caries than CC carriers who ate sugary food at most once a week (OR = 2.057, 95% CI = 1.438–2.940, P value Conclusion: PART1 rs27565 and DEFB1 rs11362 polymorphisms were associated with caries in 12-year-old children in Nandan County, Guangxi, China. Carriers of the PART1 rs27565 TC or CC genotype and the DEFB1 rs11362 CT or TT genotype who ate sugary food more than once a week had a high probability of having caries.

The semiarid regions are one of the core areas in the construction of ecological civilization in China. Previous studies have shown that afforestation was an effective way for the ecological restoration to prevent soil degradation in the semiarid regions of North China. Unfortunately, little is known about the genetic information of these afforested plant populations, resulting in the defective assessment of the population stability and conservation in the process of ecological restoration under climate change. In this study, using maternally and bi-parentally inherited markers, genetic diversity was estimated in 5 artificial and 12 natural populations of Caragana korshinskii. The significant genetic differentiation was found among the artificial populations, and it could not support their population persistence in the restoration ecosystems. Compared to the natural populations, the artificial populations harbored much lower genetic diversity in both nrITS and cpDNA, which indicated that mating might be greatly limited and unbalanced among the germplasms. Based on the ecological niche modeling analysis, we proposed that both the natural and artificial populations were at a great risk of facing the impact of climate change, although the artificial populations were afforested in the optimum areas. These results suggested that it was necessary to assess the genetic diversity of founder populations before afforestation, and to conduct genetic rejuvenation for the defective artificial forest. This study proposed a pragmatic approach to guide the sustainable afforestation and provided the molecular evaluation on the ecological restoration in the desert areas of North China.

Altered regulatory-associated protein of mTOR, complex 1 (RPTOR) methylation levels in peripheral blood was originally discovered as breast cancer (BC)-associated risk factor in Caucasians. To explore the relationship between RPTOR methylation and BC in the Chinese population, we conducted two independent case–control studies. Peripheral blood samples were collected from a total of 333 sporadic BC cases and 378 healthy female controls for the DNA extraction and bisulfite-specific PCR amplification. Mass spectrometry was applied to quantitatively measure the levels of methylation. The logistic regression, Spearman’s rank correlation, and Non-parametric tests were used for the statistical analyses. In our study, we found an association between BC and RPTOR_CpG_4 hypomethylation in the general population (per-10% of methylation, OR 1.29, P = 0.012), and a weak association between BC and RPTOR_CpG_8 hypomethylation in the women with older age (per-10% of methylation, OR 2.34, P = 0.006). We also identified age as a confounder for the change of RPTOR methylation patterns, especially at RPTOR_CpG_4, which represented differential methylation comparing age groups especially in the BC cases (age

It is well known that the intelligent hybridization of active materials and the controllable recombination of nanostructures can significantly improve the electrochemical performance of pseudocapacitor electrodes. In this work, a NiO/NiCo2O4 needle/sphere nanostructure was synthesized on the hydrochloric acid-activated Nickel foam by a simple hydrothermal method and measured the performance of it as an electrode material for supercapacitors. Field emission scanning electron microscope, transmission electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy were used to characterize the morphology and composition of the samples. The electrodes display a prominent specific capacitance (2447 F/g at the ampere density of 2 A/g) and remarkable cycling stability (85.2% capacity remained after 3000 cycles), owing to the unique needle/sphere composite architecture and the rational combination of active materials. The results demonstrate that the three-dimensional composite structure of NiO/NiCo2O4 nanomaterials provides a large specific surface area for the electrode, which promotes the penetration of electrolyte ions and the transmission of electrons. This novel structured material will be promising in the application of supercapacitor electrode materials.

Background The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare. Methods To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis. Results We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts. Conclusions In summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

Background Paclitaxel/docetaxel after doxorubicin plus cyclophosphamide (ECT) is considered as an adjuvant chemotherapy and improves the survival of early triple-negative breast cancer (TNBC) patients. We aim to assess whether carboplatin plus taxanes (TP) is non-inferior to ECT in prolonging the survival time. Methods TNBC patients were randomized (1:1) to receive ECT (90 mg/m2 epirubicin + 600 mg/m2 cyclophosphamide followed by 75 mg/m2 docetaxel or 175 mg/m2 paclitaxel every 3 weeks, n = 154) or TP (75 mg/m2 docetaxel or 175 mg/m2 paclitaxel + carboplatin AUC 5 every 3 weeks, n = 154). These expression of SPARC, PD-L1, and BRCA were studied. Patients were followed up for disease-free survival (DFS), overall survival (OS), and safety. Results We recruited 308 TNBC patients (median follow-up of 97.6 months). The median DFS and OS were not reached; the 8-year DFS rate of ECT and TP arms was 78.4% and 81.7%, respectively, while the 8-year OS rate were 87.2% and 89.1%, respectively. In the SPARC (> 50%) subgroup analysis, the TP arm had longer DFS (P = 0.049) and a tendency with better OS (P = 0.06) than ECT arm. No significant differences were observed in the DFS and OS between the ECT arm and TP arm in TNBC with SPARC (≤ 50%), PD-L1 (-) PD-L1 (+), and BRCA mutation or BRCA wild (all P values > 0.05). Conclusion TP showed non-inferiority for DFS and OS compared with ECT in early TNBC. TP may be an effective alternative chemotherapy for TNBC patients whom the standard ECT regimen is not being used. Trail registration ClinicalTrials.gov identifier NCT01150513.

Oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are generally catalyzed by precious metals (Pt) and metal oxides (IrO2) which still have many shortages including expensive price, poor selectivity and undesirable stability. In this work, we report a Mn0-doped CoNx on N-doped porous carbon (Mn-CoNx/N-PC) composite from carbonizing metal-organic framework (MOF) derivative as the dual-functional catalyst to boost both the ORR and OER performances. Owing to the strong coordination effect between nitrogen and metal elements, the introduction of N can obviously improve the content of Co-N-C active sites for ORR. Meanwhile, the Mn-doping significantly regulates the electronic structure of the Co element and increases the content of Co0 which provide efficient OER active sites. Mn-CoNx/N-PC catalyst delivers super dual-functional activity with a half-wave potential of 0.85 V, better than the 20% Pt/C catalyst (0.82 V). When used in Zn-air batteries for testing, Mn-CoNx/N-PC electrocatalyst shows a high power density (145 mW·cm−2) and good cycle performance.

In clinical diagnosis, karyotyping is carried out to detect genetic disorders due to chromosomal aberrations. Accurate segmentation is crucial in this process that is mostly operated by experts. However, it is time-consuming and labor-intense to segment chromosomes and their overlapping regions. In this research, we look into the automatic segmentation of overlapping pairs of chromosomes. Different from standard semantic segmentation applications that mostly detect object regions or boundaries, this study attempts to predict not only non-overlapping regions but also the order of superposition and opaque regions of the underlying chromosomes. We propose a novel convolutional neural network called Compact Seg-UNet with enhanced deep feature learning capability and training efficacy. To address the issue of unrealistic images in use characterized by overlapping regions of higher color intensities, we propose a novel method to generate more realistic images with opaque overlapping regions. On the segmentation performance of overlapping chromosomes for this new dataset, our Compact Seg-UNet model achieves an average IOU score of 93.44% ± 0.26 which is significantly higher than the result of a simplified U-Net reported by literature by around 6.08%. The corresponding F1 score also increases from $$0.9262\pm 0.1188$$ to $$0.9596 \pm 0.0814$$ .

Background CDK4/6 inhibitors combined with endocrine therapy has become the preferred treatment approach for patients with estrogen receptor-positive metastatic breast cancer. However, the predictive biomarkers and mechanisms of innate resistance to CDK4/6 inhibitors remain largely unknown. We sought to elucidate the molecular hallmarks and therapeutically actionable features of patients with resistance to CDK4/6 inhibitors. Methods A total of 36 patients received palbociclib and endocrine therapy were included in this study as the discovery cohort. Next-generation sequencing of circulating tumour DNA in these patients was performed to evaluate somatic alterations associated with innate resistance to palbociclib. Then the candidate biomarker was validated in another independent cohort of 104 patients and publicly available datasets. The resistance was verified in parental MCF-7 and T47D cells, as well as their derivatives with small interfering RNA transfection and lentivirus infection. The relevant mechanism was examined by RNA sequencing, chromatin immunoprecipitation and luciferase assay. Patient-derived organoid and patient-derived xenografts studies were utilized to evaluated the antitumor activity of rational combinations. Results In the discovery cohort, S6K1 amplification (3/35, 9%) was identified as an important reason for innate resistance to CDK4/6 inhibitors. In the independent cohort, S6K1 was overexpressed in 15/104 (14%) patients. In those who had received palbociclib treatment, patients with high-expressed S6K1 had significantly worse progression free survival than those with low S6K1 expression (hazard ratio = 3.0, P = 0.0072). Meta-analysis of public data revealed that patients with S6K1 amplification accounted for 12% of breast cancers. Breast cancer patients with high S6K1 expression had significantly worse relapse-free survival (hazard ratio = 1.31, P Conclusions S6K1 amplification is an important mechanism of innate resistance to palbociclib in breast cancers. Breast cancers with S6K1 amplification could be considered for combinations of CDK4/6 and S6K1 antagonists.

BackgroundThe role of trimethylamine-N-oxide (TMAO) in the development of diabetes remains controversial, and prospective data are few. We aimed to investigate the association between serum TMAO and incident type 2 diabetes in middle-aged and older adults.MethodsThis study was based on the Guangzhou Nutrition and Health Study (GNHS), a community-based prospective cohort study in China. A total of 2088 diabetes-free participants aged 40–75 years were included from 2008 to 2010. Incident type 2 diabetes was ascertained during follow-up visits. Baseline serum TMAO was measured by high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for diabetes across tertiles of serum TMAO were calculated using Cox proportional hazard models. Prospective associations of serum TMAO with changes in glycemic traits (fasting glucose, HbA1c, insulin, HOMA-IR) over time were estimated using linear mixed-effects models (LMEMs).ResultsWe ascertained 254 incident type 2 diabetes cases during a median follow-up of 8.9 years. The median (interquartile range) of serum TMAO was 1.54 (0.86–2.91) μmol/L. From the first to the third tertile of serum TMAO, the multivariable-adjusted HRs for diabetes were 1.00 (reference), 1.17 (95% CI: 0.84–1.61), and 1.42 (95% CI: 1.03–1.96) (P-trend = 0.031). LMEMs showed that the estimated yearly change in fasting glucose was 0.011 (0.001–0.022) mmol/L/y in the highest tertile of serum TMAO, compared with the lowest tertile (P-interaction = 0.044). Serum TMAO was not associated with longitudinal changes in HbA1c, insulin or HOMA-IR.ConclusionsOur findings suggested that higher serum TMAO was associated with a higher risk of type 2 diabetes and an increase in fasting glucose among middle-aged and older Chinese adults.Trial registration:NCT03179657.https://clinicaltrials.gov/ct2/show/NCT03179657?term=NCT03179657&draw=2&rank=1