Melittin promotes the proliferation of Schwann cells in hyperglycemic environment by up­regulating the Crabp2/Wnt/ß­catenin signaling pathway.

The present study aimed to explore the effect of melittin (MLT) on the growth of Schwann cells (SCs) in high glucose conditions and to understand the mechanisms involved. The goal was to provide a theoretical basis for using MLT in the treatment of diabetic peripheral neuropathy (DPN). The CCK­8 assay was used to measure cell activity at different concentrations of glucose and MLT. Flow cytometry was employed to analyze the effect of MLT on cell cycle phases and apoptosis in SCs under high glucose conditions. To identify differentially expressed proteins, 4D label­free quantitative proteomics with liquid chromatography­mass spectrometry was used, followed by biological analysis to explore potential mechanisms. PCR, western blotting and immunofluorescence were conducted to confirm these mechanisms. Melittin (0.2 µg/ml) increased the proliferation of SCs in a high glucose environment. Flow cytometry showed that after MLT treatment, the proportion of cells in the G2/M+S phase increased and the combined ratio of early and late apoptosis decreased under high glucose conditions. Proteomics identified 1,784 proteins with significant changes in expression; 725 were upregulated, and 1,059 were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the differentially expressed proteins were mainly involved in metabolic pathways and neurodegenerative disease pathways. PCR, western blotting and immunofluorescence confirmed the increase in Crabp2, Wnt3a, C­Jun, CDK4, CyclinD1 and proliferating cell nuclear antigen. In high glucose conditions, MLT protects SCs from glucose toxicity by upregulating the Crabp2/Wnt/ß­catenin signaling pathway, potentially providing a new treatment for DPN.

Differences in prescribing patterns of opioid dependence drugs among patients with primary alcohol use problems and opioid use disorders within New York State by social determinant factors, 2005-2018.

BACKGROUND: The increase in alcohol use problems and opioid use disorder (OUD) highlights the need for research on effective medication treatments for patients with dual diagnoses. OBJECTIVES: This study analyzed trends and social disparities in prescribing OUD medications for patients who initially had alcohol use problems and later received their first OUD diagnosis. METHODS: This study utilized merged data from the New York State Office of Addiction Services and Supports and the Medicaid to analyze individuals aged 18 and older who initially had primary alcohol use problems and later had OUD for the first time between 2005 and 2018. It examined the rates of new buprenorphine and naltrexone prescriptions across various demographic and socioeconomic groups. RESULTS: Among 27,029 clients, the average rate of new buprenorphine was 64.23 per 1,000 clients (95% CI [61.30, 67.15]), with upward trends. The 18-35 age group had the highest buprenorphine utilization (111.48 per 1,000 clients), and highest increase rates compared to other age groups. The White non-Hispanic group had the highest rates of buprenorphine (119.23 per 1000 clients) and showed larger increase over time compared to other race/ethnicity groups. Disabled patients showed slower increasing rates of buprenorphine compared to other groups. Upward trends were observed in naltrexone. All observed differences were statistically significant (P<0.05). CONCLUSIONS: Trends showed increased use of OUD medications, with varying rates of buprenorphine utilization across different ages, races, and employment statuses. Despite this, the rates of receiving new buprenorphine remained low, suggesting a need for innovative methods to expand access to treatments.

Combined detection of SHOX2 and PTGER4 methylation with serum marker CYFRA21-1 for improved diagnosis of malignant pleural mesothelioma.

AIMS: To investigate the performance of a combined biomarker approach using the methylation status of the short stature homeobox 2 (SHOX2) and prostaglandin E2 receptor EP4 (PTGER4) genes, along with the serum levels of CYFRA21-1, for differential diganosis of malignant pleural mesothelioma (MPM) from benign reactive mesothelial hyperplasia (RMH). METHODS: We analysed 48 MPM tissue or pleural effusion cell block specimens and 42 cases with RMH. Real-time quantitative methylation-specific PCR was used to examine the methylation status of SHOX2, PTGER4, ras association domain family 1 isoform A, septin 9 gene and homeobox gene A9 genes. Additionally, we employed electrochemiluminescence immunoassay to measure nine serum tumour markers commonly used in pan-cancer screening tests. RESULTS: The receiver operating curve indicated that SHOX2, PTGER4 gene methylation and serum biomarker CYFRA21-1 exhibited good diagnostic performance in identifying MPM, with area under curves (AUCs) of 0.761, 0.904 and 0.847, respectively. The combination of SHOX2, PTGER4 methylation and CYFRA21-1 yielded an AUC value of 0.972. The diagnostic sensitivity and specificity of this panel in differentiating MPM from RMH were 91.3% (42/46) and 97.6% (41/42), respectively. Both tissue and cell block specimens can be used in the diagnostic process. Furthermore, elevated CYFRA21-1 levels were associated with poor prognosis (p<0.05). Hypermethylation level of PTGER4 may indicate an unfavourable prognosis of MPM, but the difference was not statistically significant. CONCLUSIONS: The combined detection of SHOX2 and PTGER4 methylation alongside serum CYFRA21-1 level significantly enhances the diagnosis of MPM. Additionally, CYFRA21-1 can serve as a prognostic indicator for MPM.

The Belt and Road Initiative's impact on tourism and heritage along the Silk Roads: A systematic literature review and future research agenda.

This is a systematic review of the literature on the Belt and Road Initiative (BRI) and its impact on tourism and heritage in participating countries along the Silk Roads. China launched the BRI in 2013 with the aim of promoting global trade and stimulating economic growth through the development of infrastructure and cultural cooperation. This review examines studies for the period from 2013 to 2023, focusing on key themes such as tourist flows, destination development, urban renewal, heritage preservation, and cultural route revival. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating 56 relevant documents that cover both tourism and heritage domains. The findings highlight substantial potential for the development of new tourism products and destinations, improved urban renewal, and the preservation of cultural heritage, provided that integrated policies, public-private collaboration, and equitable community participation frameworks are implemented with attention to ecological limits. However, the review also identifies significant challenges, including financial imbalances, uneven access to benefits, social disruption, cultural commodification, and environmental degradation. Addressing these issues requires careful, context-specific planning. The study concludes with a proposal for a future research agenda that includes exploring underrepresented regions, developing sustainable tourism models, and fostering interdisciplinary research to ensure a balanced approach to economic development and heritage preservation. This review's findings provide valuable insight for policymakers, tourism officials, and cultural heritage managers, guiding the development of policies that balance economic growth with the preservation of cultural and natural heritage sites. This research contributes to the academic discourse by elucidating the complex interplay between the BRI and the Silk Roads' tourism and heritage, offering a pathway for sustainable and inclusive growth.

Impact of frailty on mortality, hospitalization, cardiovascular events, and complications in patients with diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Several studies have focused on the impact of frailty on the health outcomes of individuals with diabetes mellitus (DM). This meta-analysis aims to systematically synthesize the existing evidence on frailty and its association with mortality, hospitalizations, cardiovascular diseases, and diabetic complications in DM. METHODS: A comprehensive search in PubMed, Embase, and SCOPUS was carried out to identify relevant studies assessing the impact of frailty on mortality, hospitalizations, complications, and cardiovascular events in individuals with DM. The quality of the included studies was evaluated using the New Castle Ottawa Scale. RESULTS: From the 22 studies included, our meta-analysis revealed significant associations between frailty and adverse outcomes in individuals with DM. The pooled hazard ratios for mortality and frailty showed a substantial effect size of 1.84 (95% CI 1.46-2.31). Similarly, the odds ratio for hospitalization and frailty demonstrated a significant risk with an effect size of 1.63 (95% CI 1.50-1.78). In addition, frailty was associated with an increased risk of developing diabetic nephropathy (HR, 3.17; 95% CI 1.16-8.68) and diabetic retinopathy (HR, 1.94; 95% CI 0.80-4.71). CONCLUSION: Our results show a consistent link between frailty and increased mortality, heightened hospitalization rates, and higher risks of cardiovascular disease, diabetic nephropathy, and diabetic retinopathy for patients with DM. PROSPERO Registration Number: CRD42023485166.

Conserved DNA sequence analysis reveals the phylogeography and evolutionary events of Akebia trifoliata in the region across the eastern edge of the Tibetan Plateau and subtropical China.

BACKGROUND: The eastern edge of the Qinghai‒Tibet Plateau (QTP) and subtropical China have various regions where plant species originate and thrive, but these regions have been the focus of very few integrative studies. Here, we elucidated the phylogeographic structure of a continuous and widespread Akebia trifoliata population across these two regions. RESULTS: Sixty-one populations consisting of 391 genotypes were examined to assess population diversity and structure via network distribution analysis, maximum likelihood phylogenetic tree reconstruction, divergence time estimation, demographic history inference, and ancestral area reconstruction of both conserved internal transcribed spacer (ITS) and chloroplast (rps16) DNA sequences. The results showed that the ITS region was more variable than the rps16 region and could be suitable for studying intraspecific phylogeography. The A. trifoliata population displayed high genetic diversity, genetic differentiation and obvious phylogeographical structure, possibly originating on the eastern QTP, expanding during the last glacial-interglacial cycle, diverging in the early Pleistocene and middle Pleistocene, and extensively migrating thereafter. The migration route from west to east along rivers could be largely responsible for the long-distance dispersal of this species, while three main refuges (Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) with multiple ice shelters facilitated its wide distribution. CONCLUSIONS: Our results suggested that the from west to east long migration accompanying with the minor short reciprocal migration in the south-north direction, and the three main refuges (the Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) contributed to the extant geographical distribution of A. trifoliata. In addition, this finding also strongly reduced the discrepancy between glacial contraction and postglacial expansion and the in situ survival hypothesis by simultaneously considering the existence of many similar climate-related ecological niches and migration influences.

Unveiling the negative association of Faecalibacterium prausnitzii with ischemic stroke severity, impaired prognosis and pro-inflammatory markers.

Background: The correlation between acute ischemic stroke (AIS) and gut microbiota has opened a promising avenue for improving stroke prognosis through the utilization of specific gut bacterial species. This study aimed to identify gut bacterial species in AIS patients and their correlation with stroke severity, 3-month prognosis, and inflammatory markers. Methods: We enrolled 59 AIS patients (from June 2021 to July 2022) and 31 age-matched controls with similar cerebrovascular risk profiles but no stroke history. Fecal samples were analyzed using 16 S rDNA V3-V4 sequencing to assess α and ß diversity and identify significant microbiota differences. AIS cases were categorized based on the National Institute of Health Stroke Scale (NIHSS) scores and 3-month modified Rankin Scale (mRS) scores. Subgroup analyses were performed, and correlation analysis was used to examine associations between flora abundance, inflammatory markers and stroke outcome. Results: Significant differences in ß-diversity were observed between case and control groups (P < 0.01). Bacteroides dominated AIS samples, while Clostridia, Lachnospirales, Lachnospiraceae, Ruminococcaceae, Faecalibacterium, and Faecalibacterium prausnitzii were prominent in controls. Faecalibacterium and Faecalibacterium prausnitzii were significantly reduced in non-minor stroke and 3-month poor prognosis groups compared to controls, while this difference was less pronounced in patients with minor stroke and 3-month good prognosis. Both Faecalibacterium and Faecalibacterium prausnitzii were negatively correlated with the NIHSS score on admission (r = -0.48, -0.48, P < 0.01) and 3-month mRS score (r = -0.48, -0.44, P < 0.01). Additionally, they showed negative correlations with pro-inflammatory factors and positive correlations with anti-inflammatory factors (both P < 0.01). Conclusions: Faecalibacterium prausnitzii is negatively associated with stroke severity, impaired prognosis, and pro-inflammatory markers, highlighting its potential application in AIS treatments.

Fluoride promotes the secretion of inflammatory factors in microglia through NLRP3/Caspase-1/GSDMD pathway.

It is widespread of endemic fluorosis in China, and the exposure of excessive fluoride will cause nervous system disease and activate microglia. However, the mechanism of the damage is not clear. It is well-known that NLRP3/Caspase-1/GSDMD pathway, a classic pyroptosis pathway, is widely involved in the occurrence and development of nervous system-related diseases, infectious diseases, and atherosclerotic diseases. This research aimed to explore the molecular mechanism of sodium fluoride on inflammation and pyroptosis in BV2 microglia based on the NLRP3/Caspase-1/GSDMD signaling pathway. BV2 microglia was treated with sodium fluoride at the dose of 0.25, 1, and 2 mmol/L for 24, 48, and 72 h, respectively. Cell viability, cell morphology, lactate dehydrogenase content, and related proteins and genes were examined to investigate if sodium fluoride caused damage to BV2 microglia through the pyroptosis pathway. Dithiolam (5 µmol/L), a pyroptosis inhibitor, was added for further verification. NaF could induced BV2 cells injury in a dose-dependent fashion through disrupting the integrity of cell membranes and increasing IL-1ß via upregulating NLRP3, Caspase-1, and its downstream protein GSDMD. Disulfiram could improve these changes caused by NaF. In conclusion, our results suggested that NLRP3/Caspase-1/GSDMD-mediated classical pyroptosis pathway was involved in fluoride-induced BV2 microglia damage.

Combination of Palbociclib and Endocrine Therapy in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With or Without Brain Metastases.

OBJECTIVE: This real-world study aimed to investigate the efficacy and safety of palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the real world in a Chinese population. METHODS: The clinical data of consecutively enrolled patients from the Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, and the University of Hong Kong - Shenzhen Hospital were collected. Progression-free survival curves were generated using log-rank tests with the Kaplan-Meier method. Univariate and multivariate logistic regression analyses were performed to identify the factors affecting progression-free survival. RESULTS: In total, 118 patients were enrolled, including 6 patients with brain metastases. At the last follow-up date, the median progression-free survival was 16.8 months (95% confidence interval, 11.1-22.5), with the 6-month and 12-month progression-free survival rates of 77.1% and 57.6%, respectively. The disease control rate and the intracranial disease control rate were 82.2% and 50%, respectively. A longer progression-free survival was observed for patients with the following characteristics: treatment-naive; without hepatic metastasis; sensitive to previous endocrine therapy and harboring fewer metastatic sites. The multivariate logistic regression analysis demonstrated that treatment lines and exposure to palliative chemotherapy were independent influencing factors of progression-free survival. CONCLUSIONS: Palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer was effective and well-tolerated, even in patients with brain metastases. More benefits were observed in frontline therapy, chemotherapy-naive, and endocrine therapy-sensitive patients with fewer metastatic sites.

Genome-Wide Analysis of the Polygalacturonase Gene Family Sheds Light on the Characteristics, Evolutionary History, and Putative Function of Akebia trifoliata.

Polygalacturonase (PG) is one of the largest families of hydrolytic enzymes in plants. It is involved in the breakdown of pectin in the plant cell wall and even contributes to peel cracks. Here, we characterize PGs and outline their expression profiles using the available reference genome and transcriptome of Akebia trifoliata. The average length and exon number of the 47 identified AktPGs, unevenly assigned on 14 chromosomes and two unassembled contigs, were 5399 bp and 7, respectively. The phylogenetic tree of 191 PGs, including 47, 57, 51, and 36 from A. trifoliata, Durio zibethinus, Actinidia chinensis, and Vitis vinifera, respectively, showed that AktPGs were distributed in all groups except group G and that 10 AktPGs in group E were older, while the remaining 37 AktPGs were younger. Evolutionarily, all AktPGs generally experienced whole-genome duplication (WGD)/segmental repeats and purifying selection. Additionally, the origin of conserved domain III was possibly associated with a histidine residue (H) substitute in motif 8. The results of both the phylogenetic tree and expression profiling indicated that five AktPGs, especially AktPG25, could be associated with the cracking process. Detailed information and data on the PG family are beneficial for further study of the postharvest biology of A. trifoliata.

Breast cancer metastases to the thyroid and stomach: A case report.

The most common sites of metastasis for breast cancer are the soft tissues, bones, lungs, liver and brain; however, metastases to the gastrointestinal tract and thyroid gland from breast cancer rarely occur. The present study describes the case of a 30-year-old woman who developed gastric and thyroid metastases 5 years after her initial diagnosis of invasive ductal breast carcinoma. The initial pathological diagnosis when receiving modified radical mastectomy was invasive ductal carcinoma, and further immunohistochemical examination revealed the cancer to be estrogen receptor (-), progesterone receptor (-), human epidermal growth factor receptor 2 (HER2; ++) and Ki-67 (70%). Genetic testing indicated the HER2 amplification mutation, whereas BRCA1/2 testing was negative. A total of 21 months after surgery, during regular follow-up, the patient was revealed to have developed an enlarged lymph node in the left side of the neck and the first recurrence was confirmed. Approximately 5 years after surgery, the patient gradually developed multi-site metastasis, and developed metastases to the thyroid gland and stomach confirmed by pathology and imaging. Combined chemotherapy and targeted therapy were administered and exhibited good efficacy; however, the patient subsequently died due to heart failure. This case report describes the occurrence of gastric and thyroid metastases from breast cancer, and highlights the importance of distinguishing between metastatic and primary tumors. Distinguishing between a metastatic and primary tumor is crucial as treatment protocols vary significantly for these two types of tumors. For patients with a history of breast cancer it should first be considered whether they have metastasis of the primary disease or discomfort caused by treatment; however, the possibility of a second primary tumor cannot be ignored. If the patient has symptoms such as loss of appetite, nausea, vomiting, stomach pain and stomach discomfort, a gastroscopy should be performed in a timely manner.

The anti-tumor efficiency of low-dose apatinib-based chemotherapy in pretreated HER2-negative breast cancer with brain metastases.

BACKGROUND: More than half of the metastatic breast cancer patients with brain metastases (BCBM) are HER-2 negative, and the prognosis of HER2-negative BCBM is dismal. But few clinical trials have investigated systemic therapies for this subgroup of patients. METHODS: This real-world study included 58 HER2-negative BCBMs who received low-dose apatinib (250 mg daily) in combination with chemotherapy between 18 March 2017 and 31 December 2021. The objective response rate (ORR) of the central nervous system, clinical benefit rate (CBR), progression-free survival of central nervous system (CNS-PFS) and overall survival (OS) were analyzed. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for CNS-PFS and OS. RESULTS: At the cut-off date, the median follow-up time was 28.2 months. Of the 58 patients, 36 patients were HR+/HER2-, and 22 patients were TNBC. The CNS-ORR was 17.2% (95%CI 9.6% to 28.9%) and the CBR was 53.4% (95%CI 40.8% to 65.7%). The median duration of CNS-PFS for the entire cohort was 6.4 months, and the median OS was 10.7 months. The median CNS-PFS and OS were not affected by hormone receptor status, disease-free survival, the number of prior lines of therapy and local treatment. The most common grade 2-3 adverse events associated with low-dose apatinib were hypertension (20.6%), elevated bilirubin (10.4%), hypothyroidism (10.3%), and hand-foot skin reaction (10.3%). CONCLUSION: Apatinib-based chemotherapy demonstrates potential feasibility with acceptable tolerance for HER2-negative BCBM. Its clinical application in BCBM still needs further verification.

HER2-negative breast cancer patients with brain metastases (BCBM) face an extremely poor prognosis, and a lack of effective treatment options. Apatinib, as a small molecule anti-angiogenic TKI, might have special central nervous system activity. Apatinib-based chemotherapy exhibits good tolerance and gains a favorable survival for HER2-negative BCBM.

A single-arm phase II clinical trial of anlotinib combined with chemotherapy for the treatment of metastatic triple-negative breast cancer.

Background: Anlotinib is a novel oral small-molecule tyrosine kinase inhibitor (TKI), which can inhibit angiogenesis. The purpose of this study was to evaluate the efficacy and safety of anlotinib combined with chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Methods: This phase II clinical trial included 40 patients with metastatic TNBC who had previously received anthracycline and/or taxane treatment. All patients received anlotinib combined with chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. Results: During May 1, 2019 and April 30, 2022, there were 40 patients enrolled in this study. The median PFS and median OS were 8.8 months (95% confidence interval [CI] 6.5-11.1 months) and 19.0 months (95% CI, 12.1-25.9 months), respectively. The ORR, CBR and DCR were 40.0% (16/40), 85.0% (34/40) and 95.0% (38/40), respectively. Cox univariate and multivariate analyses demonstrated that having more than 3 metastatic sites (p = 0.001; p = 0.020) was an independent and meaningful unfavorable prognostic factor for PFS. 37.5% of patients had grade 3 to 4 treatment-related adverse events (TRAEs). The grade 3 to 4 TRAEs included neutropenia (22.5%), leukopenia (20.0%), secondary hypertension (10.0%), hand-foot syndrome (5.0%), vomiting (5.0%), proteinuria (5.0%) and thrombocytopenia (2.5%). None of the patients withdrew from the study or died due to TRAEs. Conclusion: In this single-arm study, the treatment of metastatic TNBC with anlotinib combined with chemotherapy showed certain efficacy, and its toxicity was acceptable.

Docosahexaenoic acid supplementation in gestational diabetes mellitus and neonatal metabolic health biomarkers.

Background and objective: Gestational diabetes mellitus (GDM) "programs" an elevated risk of metabolic dysfunctional disorders in the offspring, and has been associated with elevated leptin and decreased adiponectin levels in cord blood. We sought to assess whether docosahexaenoic acid (DHA) supplementation in GDM affects neonatal metabolic health biomarkers especially leptin and adiponectin. Methods: In a randomized controlled trial, singleton pregnant women with de novo diagnosis of GDM at 24-28 weeks of gestation were randomized to dietary supplementation of 500 mg DHA per day (intervention, n = 30) until delivery or standard care (control, n = 38). The primary outcomes were cord blood leptin and total adiponectin concentrations. Secondary outcomes included high-molecular-weight (HMW) adiponectin and insulin-like growth factor-1 (IGF-1) concentrations in cord blood, maternal glycemic control post-intervention and birth weight (z score). In parallel, 38 euglycemic pregnant women were recruited for comparisons of cord blood biomarkers. Results: There were no significant differences in cord serum leptin, total and HMW adiponectin and IGF-1 concentrations between DHA supplementation and control groups (all p > 0.05). Maternal fasting and 2-h postprandial blood glucose levels at 12-16 weeks post-intervention were similar between the two groups. The newborns in the DHA group had higher birth weight z scores (p = 0.02). Cord blood total and HMW adiponectin concentrations were significantly lower in GDM vs. euglycemic pregnancies. Conclusion: Docosahexaenoic acid supplementation at 500 mg/day in GDM women did not affect neonatal metabolic biomarkers including leptin, adiponectin and IGF-1. The results are reassuring in light of the absence of influence on neonatal adipokines (leptin and adiponectin), and potential benefits to fetal growth and development. Clinical Trial Registration: Clinicaltrials.gov, NCT03569501.

Genome-Wide Identification of Superoxide Dismutase and Expression in Response to Fruit Development and Biological Stress in Akebia trifoliata: A Bioinformatics Study.

Akebia trifoliata is a newly domesticated perennial fruit tree, and the lack of molecular research on stress resistance seriously affects its genetic improvement and commercial value development. Superoxide dismutase (SOD) can effectively eliminate the accumulation of reactive oxygen species (ROS) during the rapid growth of plant organs under biotic and abiotic stresses, maintaining a steady state of physiological metabolism. In this study, 13 SODs consisting of two FeSODs (FSDs), four MnSODs (MSDs) and seven Cu/ZnSODs (CSDs) were identified in the A. trifoliata genome. Structurally, the phylogeny, intron-exon pattern and motif sequences within these three subfamilies show high conservation. Evolutionarily, segmental/wide genome duplication (WGD) and dispersed duplication form the current SOD profile of A. trifoliata. Weighted gene coexpression network analysis (WGCNA) revealed the metabolic pathways of nine (69.2%) SODs involved in fruit development, among which AktMSD4 regulates fruit development and AktCSD4 participates in the stress response. In addition, under the stress of multiple pathogens, six (46.6%) SODs were continuously upregulated in the rinds of resistant lines; of these, three SODs (AktMSD1, AktMSD2 and AktMSD3) were weakly or not expressed in susceptible lines. The results pave the way for theoretical research on SODs and afford the opportunity for genetic improvement of A. trifoliata.

Identification of Photoperiod- and Phytohormone-Responsive DNA-Binding One Zinc Finger (Dof) Transcription Factors in Akebia trifoliata via Genome-Wide Expression Analysis.

As a kind of plant-specific transcription factor (TF), DNA-Binding One Zinc Finger (Dof) is widely involved in the response to environmental change, and as an evolutionarily important perennial plant species, Akebia trifoliata is ideal for studying environmental adaptation. In this study, a total of 41 AktDofs were identified in the A. trifoliata genome. First, the characteristics, including the length, exon number, and chromosomal distribution of the AktDofs and the isoelectric point (PI), amino acid number, molecular weight (MW), and conserved motifs of their putative proteins, were reported. Second, we found that all AktDofs evolutionarily underwent strong purifying selection, and many (33, 80.5%) of them were generated by whole-genome duplication (WGD). Third, we outlined their expression profiles by the use of available transcriptomic data and RT-qPCR analysis. Finally, we identified four candidate genes (AktDof21, AktDof20, AktDof36, and AktDof17) and three other candidate genes (AktDof26, AktDof16, and AktDof12) that respond to long day (LD) and darkness, respectively, and that are closely associated with phytohormone-regulating pathways. Overall, this research is the first to identify and characterize the AktDofs family and is very helpful for further research on A. trifoliata adaptation to environmental factors, especially photoperiod changes.

Pyrotinib combined with trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer: a single-arm exploratory phase II trial.

PURPOSE: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC. METHODS: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety. RESULTS: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed. CONCLUSION: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

Large-Area Flexible Memory Arrays of Oriented Molecular Ferroelectric Single Crystals with Nearly Saturated Polarization.

Molecular ferroelectrics (MFs) have been proven to demonstrate excellent properties even comparable to those of inorganic counterparts usually with heavy metals. However, the validation of their device applications is still at the infant stage. The polycrystalline feature of conventionally obtained MF films, the patterning challenges for microelectronics and the brittleness of crystalline films significantly hinder their development for organic integrated circuits, as well as emerging flexible electronics. Here, a large-area flexible memory array is demonstrated of oriented molecular ferroelectric single crystals (MFSCs) with nearly saturated polarization. Highly-uniform MFSC arrays are  prepared on large-scale substrates including Si wafers and flexible substrates using an asymmetric-wetting and microgroove-assisted coating (AWMAC) strategy. Resultant flexible memory arrays exhibit excellent nonvolatile memory properties with a low-operating voltage of <5 V, i.e., nearly saturated ferroelectric polarization (6.5 µC cm-2 ), and long bending endurance (>103 ) under various bending radii. These results may open an avenue for scalable flexible MF electronics with high performance.

Expression Profiles of Microsatellites in Fruit Tissues of Akebia trifoliata and Development of Efficient EST-SSR Markers.

Akebia trifoliata, a member of the family Lardizabalaceae, has high exploitation potential for multiple economic purposes, so genetic improvements to meet requirements for commercial demand are needed. However, this progress is largely impeded by a lack of effective selection markers. In this study, we obtained 271.49 Gb of clean transcriptomic data from 12 samples (three tissues at four developmental stages) of A. trifoliata fruit. We identified 175,604, 194,370, and 207,906 SSRs from the de novo assembled 416,363, 463,756, and 491,680 unigene sequences obtained from the flesh, seed, and rind tissues, respectively. The profile and proportion of SSR motifs expressed in each fruit tissue and developmental stage were remarkably similar, but many trinucleotide repeats had differential expression levels among different tissues or at different developmental stages. In addition, we successfully designed 16,869 functional EST-SSR primers according to the annotated unigenes. Finally, 94 and 72 primer pairs out of 100 randomly selected primer pairs produced clear bands and polymorphic bands, respectively. These results were also used to elucidate the expression profiles of different tissues at various stages. Additionally, we provided a set of effective, polymorphic, and reliable EST-SSR markers sufficient for accelerating the discovery of metabolic and pathway-specific functional genes for genetic improvement and increased commercial productivity.

Acute-on-chronic liver failure following eribulin treatment for metastatic breast cancer: a case report.

The efficacy and tolerability of eribulin mesylate, a synthetic halichondrin B analog, in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes have been established. Acute-on-chronic liver failure (ACLF) is a clinical syndrome manifesting as acute and severe hepatic derangement resulting from varied insults in patients with established chronic liver disease or cirrhosis who did not previously receive eribulin. A middle-aged woman diagnosed with MBC and diffuse liver metastases who was pretreated with multi-line chemotherapy received eribulin as eighth-line chemotherapy and presented with hepatic encephalopathy, rapid bilirubin elevation, and significant coagulation dysfunction on day 4 in cycle 1. The patient was diagnosed with ACLF induced by eribulin. Therefore, ACLF may be a lethal and rare adverse event when patients with chronic liver metastases receive eribulin treatment, and clinicians' awareness should be increased for optimal prevention and prompt diagnosis and treatment.