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Abstract Rice is highly sensitive to low temperatures, making cold stress a significant factor limiting its growth, especially during the bud bursting stage. To address this, an RIL population derived from a cross between cold-tolerant and cold-sensitive rice varieties was used to identify nine QTLs linked to cold tolerance under temperatures of 4 ℃, 5 °C, and 6 ℃ using a high-density genetic map. One candidate gene, LOC_Os07g44410, was identified through gene function annotation, haplotype analysis, and qRT-PCR, with two main haplotypes (Hap1 and Hap2) showing distinct phenotypic differences. qRT-PCR analysis showed that the expression level of LOC_Os07g44410 in cold tolerant lines carrying Hap1 was significantly higher than that in cold sensitive lines carrying Hap2. Hap1, associated with greater cold tolerance, was predominant in japonica rice, while Hap2 related to cold sensitive was majority in indica rice. This study offers valuable genetic resources for further research on cold tolerance mechanisms and breeding applications at the bud bursting stage in rice.

【Objective】High-temperature and rainy weather lead to pre-harvest sprouting (PHS), severely impacting yield and quality traits of rice. Identification and screening of germplasm or genetic resources is a fundamental pathway for developing new varieties resistant to PHS and eliminating PHS damage.【Method】In the study, a set of chromosome segment substitution lines (CSSLs) derived from Dongxiang wild rice ('C35') as the donor parent and 'Nipponbare' ('NIP') as the recipient parent were used as the experimental materials, and then PHS resistance were evaluated and QTLs were mapped in 2021-2023, with an aim to screen PHS germplasm and identify major QTLs.【Result】Dongxiang wild rice 'C35' exhibited strong dormancy under different environments with a pre-harvest sprouting rate (PHSR) of 0.00%; 'Nipponbare' showed significant PHS with an average PHSR of 31.95%. The PHSR varied widely among CSSL populations, the phenotypic repeatability of PHSR was relatively high in different years, and ten lines from the CSSL populations with strong dormancy and resistance to PHS were screened. A total of 14 QTLs controlling the PHSR were detected, and four QTLs were repeatedly detected under different environments. These QTLs formed four QTL clusters (qPHSRC1, qPHSRC2, qPHSRC8 and qPHSRC9), among which qPHSRC2 and qPHSRC9 had higher LOD values, phenotypic contribution rate (%) and additive effect, and qPHSRC2 was a newly discovered major QTL cluster.【Conclusion】A batch of PHS resistant germplasms were screened and 14 QTLs were mapped, four QTL clusters were repeatedly identified, and a new major QTL cluster qPHSRC2 controlling the PHSR was discovered.

Abstract Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1, which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the “2 + 0” carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA.

ABSTRACT: Poultry behavior indicates their health, welfare, and production performance. Timely access to broilers’ behavioral information can improve their welfare and reduce disease spread. Most behaviors require a period of observation before they can be accurately judged. However, the existing approaches for multi-object behavior recognition were mostly developed based on a single-frame image and ignored the temporal features in videos, which led to misrecognition. This study proposed an end-to-end method for recognizing multiple simultaneous behavioral events of cage-free broilers in videos by Broiler Behavior Recognition System (BBRS) based on spatiotemporal feature learning. The BBRS consisted of 3 main components: the improved YOLOv8s detector, the Bytetrack tracker, and the 3D-ResNet50-TSAM model. The basic network YOLOv8s was improved with MPDIoU to identify multiple broilers in the same frame of videos. The Bytetrack tracker was used to track each identified broiler and acquire its image sequence of 32 continuous frames as input for the 3D-ResNet50-TSAM model. To accurately recognize behavior of each tracked broiler, the 3D-ResNet50-TSAM model integrated a temporal-spatial attention module for learning the spatiotemporal features from its image sequence and enhancing inference ability in the case of its image sequence less than 32 continuous frames due to its tracker ID switching. Each component of BBRS was trained and tested with the rearing density of 7 to 8 birds/m2. The results demonstrated that the mAP@0.5 of the improved YOLOv8s detector was 99.50%. The Bytetrack tracker achieved a mean MOTA of 93.89% at different levels of occlusion. The Accuracy, Precision, Recall, and F1score of the 3D-ResNet50-TSAM model were 97.84, 97.72, 97.65, and 97.68%, respectively. The BBRS showed satisfactory inference ability with an Accuracy of 93.98% when 26 continuous frames of the tracked broiler were received by the 3D-ResNet50-TSAM model. This study provides an efficient tool for automatically and accurately recognizing behaviors of cage-free multi-broilers in videos. The code will be released on GitHub (https://github.com/CoderYLH/BBRS) as soon as the study is published.

Abstract Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFβ1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFβ1 suppression. Overall, TGFβ1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.

Abstract Drought is a major abiotic stress affecting crop yields. Mapping quantitative trait loci (QTLs) and mining genes for drought tolerance in rice are important for identifying gene functions and targets for molecular breeding. Here, we performed linkage analysis of drought tolerance using a recombinant inbred line population derived from Jileng 1 (drought sensitive) and Milyang 23 (drought tolerant). An ultra-high-density genetic map, previously constructed by our research team using genotype data from whole-genome sequencing, was used in combination with phenotypic data for rice grown under drought stress conditions in the field in 2017–2019. Thirty-nine QTLs related to leaf rolling index and leaf withering degree were identified, and QTLs were found on all chromosomes except chromosomes 6, 10, and 11. qLWD4-1 was detected after 32 days and 46 days of drought stress in 2017 and explained 7.07–8.19% of the phenotypic variation. Two loci, qLRI2-2 and qLWD4-2, were identified after 29, 42, and 57 days of drought stress in 2018. These loci explained 10.59–17.04% and 5.14–5.71% of the phenotypic variation, respectively. There were 281 genes within the QTL interval. Through gene functional annotation and expression analysis, two candidate genes, Os04g0574600 and OsCHR731, were found. Quantitative reverse transcription PCR analysis showed that the expression levels of these genes were significantly higher under drought stress than under normal conditions, indicating positive regulation. Notably, Os04g0574600 was a newly discovered drought tolerance gene. Haplotype analysis showed that the RIL population carried two haplotypes (Hap1 and Hap2) of both genes. Lines carrying Hap2 exhibited significantly or extremely stronger drought tolerance than those carrying Hap1, indicating that Hap2 is an excellent haplotype. Among rice germplasm resources, there were two and three haplotypes of Os04g0574600 and OsCHR731, respectively. A high proportion of local rice resources in Sichuan, Yunnan, Anhui, Guangdong and Fujian provinces had Hap of both genes. In wild rice, 50% of accessions contained Hap1 of Os04g0574600 and 50% carried Hap4; 13.51%, 59.46% and 27.03% of wild rice accessions contained Hap1, Hap2, and Hap3, respectively. Hap2 of Os04g0574600 was found in more indica rice resources than in japonica rice. Therefore, Hap2 has more potential for utilization in future drought tolerance breeding of japonica rice.

Abstract Background The role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma. Methods A cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization. Results Our study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout. Conclusions Our findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF. Graphical abstract

Pain highly impacts the quality of life of patients. Morphine is used for pain treatment; however, its side effects, especially morphine tolerance, limit its use in the clinic. The problem of morphine tolerance has plagued health workers and patients for years. Unfortunately, the exact mechanism of morphine tolerance has not been fully clarified. The mechanisms of morphine tolerance that are currently being studied may include μ-opioid receptor (MOR) desensitization and internalization, mitogen-activated protein kinase (MAPK) pathway activation and crosstalk, the effects of microglia and the increase in inflammatory factors. Morphine tolerance can be alleviated by improving the pathophysiological changes that lead to morphine tolerance. Previous studies have shown that a cannabinoid type 2 (CB2) receptor agonist could attenuate morphine tolerance in a variety of animal models. Many studies have shown an interaction between the cannabinoid system and the opioid system. The CB2 receptor may modulate the effect of morphine through a pathway that is common to the MOR, since both receptors are G protein-coupled receptors (GPCRs). This study introduces the potential mechanism of morphine tolerance and the effect of CB2 receptor agonists on reducing morphine tolerance, which can provide new ideas for researchers studying morphine and provide beneficial effects for patients suffering from morphine tolerance.

BackgroundSenescence-accelerated mouse prone 8 (SAMP8) and age-matched SAMR1 mice are used to study the pathogenesis and therapeutics of Alzheimer’s disease (AD); however, the molecular mechanisms are not completely understood.ObjectiveThis study aimed to examine the effects of the 5-month administration of formononetin in SAMP8 mice and used RNA-seq to explore the molecular targets.MethodsSAMP8 mice were orally administered formononetin (0, 8, and 16 mg/kg) from 4 months of age, and age-matched SAMR1 mice were used as controls. Behavioral tests were performed in 9-month-old mice, followed by histopathologic analysis. Total RNA from the hippocampus was isolated and subjected to RNA-seq, RT-qPCR, and bioinformatics analysis.ResultsThe 9-month-old SAMP8 mice exhibited cognition deficits, evidenced by novel object recognition, open-field test, elevated plus maze, and passive avoidance. Nissl bodies in the cortex and hippocampus were decreased. Formononetin treatments ameliorated behavioral deficits and improved morphological changes, which were evidenced by Nissl and H&E staining. RNA-seq revealed distinct gene expression patterns between SAMP8 and SAMR1 mice. Differentially expressed genes in SAMP8 mice were attenuated or normalized by formononetin. Ingenuity pathway analysis (IPA) of canonical pathway and upstream regulators revealed increases in proinflammatory factors and immune dysfunction and decreases in NRF2 and SIRT-1 signaling pathways, leading to neuroinflammation. Formononetin treatment attenuated or reversed these molecular changes. The transcriptome of SAMP8 mice was correlated with transcriptomic profiles of other AD mouse models in the GEO database.ConclusionNeuroinflammation and decreased antioxidant and SIRT-1 signaling contributed to cognitive deficits in aged SAMP8 mice, which are potential therapeutic targets of formononetin in combination with other therapies.

This long-term study protocol aims to compare the clinical outcomes of patients with severe lower limb trauma undergoing orthoplastic and orthopedic surgeries, focusing on their physical and psychological status. Patients with lower limb injuries and open fractures have been recruited since October 2019 and will be followed up until October 2024. The patients will be divided into two groups: (1) Orthoplastic group, where single-stage debridement, fixation, and soft tissue repair will be performed, and (2) Orthopedic group, where soft tissue repair will be done in a delayed-stage. The follow-up period will be one year, during which clinical data, limb function recovery, psychological scores, and health-related quality of life (HRQOL) will be evaluated to assess postoperative recovery and clinical outcomes. Additional clinical data, such as socio-demographic information, baseline features, Enneking score, Visual Analogue Scale (VAS) score, two-point discrimination score, and blood test parameters will also be collected. The 36-Item Short Form Health Survey (SF-36) will be used to evaluate HRQOL, while the Post-traumatic Stress Disorder Checklist (PCL) will assess the severity of self-reported post-traumatic stress disorder. The results of this study will provide valuable insights into prognostically relevant targets and contribute to improving the management and outcomes of patients with lower limb injuries and open fractures, who often face challenges related to limb disability and potential amputation postoperatively, significantly impacting their psychological and physical well-being.

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of malignant liver tumor with poor prognosis. In this study, we investigated the expression of transforming growth factor beta regulator 4 (TBRG4) in HCC and its effects on the proliferation, invasion, and metastasis of HCC cells, and analyzed the possible molecular mechanisms. Method Downloading the expression and clinical information of HCC samples in the TCGA database, analyzing the expression differences of TBRG4 by bioinformatics methods, analyzing the clinical relevance and prognostic significance. Performing GO, KEGG and GSEA enrichment analysis on the TBRG4-related gene set in patient HCC tissues. Applying cell counting, scratch test and Transwell experiment to study the biological function of TBRG4 in HCC. Mitochondrial membrane potential, apoptosis and ROS levels were evaluated to assess cell iron death. Western blot, RT-PCR, laser confocal microscopy and co-immunoprecipitation were used to detect and analyze the downstream signaling pathways and interacting molecules of TBRG4. Results Bioinformatics analysis revealed that TBRG4 was abnormally highly expressed in HCC tumor tissues and was associated with poor prognosis and metastasis in HCC patients. GO and KEGG functional enrichment analysis showed that TBRG4 was related to oxidative stress and NADH dehydrogenase (ubiquinone) activity. GSEA enrichment analysis showed that TBRG4 was associated with Beta catenin independent wnt signaling and B cell receptor. Functional experiments confirmed that knocking down TBRG4 could inhibit the proliferation, migration, and invasion of HCC cells. Mechanistically, TBRG4 inhibited the function of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. In addition, interference with TBRG4 expression could reduce the mitochondrial membrane potential and accumulate ROS in HCC cells, leading to increased ferroptosis. Co-IP analysis showed that TBRG4 specifically bound to Beclin1. Conclusion TBRG4 is highly expressed in HCC tumor tissues and is associated with poor prognosis. It may regulate the proliferation, invasion, and metastasis of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. TBRG4 may interact with Beclin1 to regulate the ferroptosis of HCC cells.

The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development.

Abstract Background NRG1 fusions are rare oncogenic drivers in solid tumors, and the incidence of NRG1 fusions in non-small cell lung cancer (NSCLC) was 0.26%. It is essential to explore potential therapeutic strategies and efficacy predictors for NRG1 fusion-positive cancers. Case presentation We report an advanced lung adenocarcinoma patient harboring a novel NPTN-NRG1 fusion identified by RNA-based next-generation sequencing (NGS), which was not detected by DNA-based NGS at initial diagnosis. Transcriptomics data of the tissue biopsy showed NRG1α isoform accounted for 30% of total NRG1 reads, and NRG1β isoform was undetectable. The patient received afatinib as fourth-line treatment and received a progression-free survival (PFS) of 14 months. Conclusions This report supports afatinib can provide potential benefit for NRG1 fusion patients, and RNA-based NGS is an accurate and cost-effective strategy for fusion detection and isoform identification.

Abstract Low back pain (LBP) is the world’s leading cause of years lived with disability. Digital exercise-based interventions have shown great potential in the management of musculoskeletal conditions, promoting access and easing the economic burden. However, evidence of their effectiveness for chronic LBP (CLBP) management compared to in-person physiotherapy has yet to be unequivocally established. This randomized controlled trial (RCT) aims to compare the clinical outcomes of patients with CLBP following a digital intervention versus evidence-based in-person physiotherapy. Our results demonstrate that patient satisfaction and adherence were high and similar between groups, although a significantly lower dropout rate is observed in the digital group (11/70, 15.7% versus 24/70, 34.3% in the conventional group; P = 0.019). Both groups experience significant improvements in disability (primary outcome), with no differences between groups in change from baseline (median difference: −0.55, 95% CI: −2.42 to 5.81, P = 0.412) or program-end scores (−1.05, 95% CI: −4.14 to 6.37; P = 0.671). Likewise, no significant differences between groups are found for secondary outcomes (namely pain, anxiety, depression, and overall productivity impairment). This RCT demonstrates that a remote digital intervention for CLBP can promote the same levels of recovery as evidence-based in-person physiotherapy, being a potential avenue to ease the burden of CLBP.

In this paper, a prediction model of the inner ring runout of angular contact ball bearings is established according to the geometric and kinematic relationships of the bearing, considering factors such as the roundness error of the inner and outer grooves, the dimensional error of the balls, and the change of the contact angle between the balls and the grooves. The correctness of the model is verified through experiments. The effects of the order and amplitude of the roundness error of the inner groove and the order and amplitude of the roundness error of the outer groove on the inner ring runout are analyzed. The coupling effect of the roundness error of the inner and outer grooves on the inner ring runout is further analyzed. The results show that the inner ring runout changes periodically with a change to the roundness error order of the grooves, which increases with an increase in the roundness error amplitude. Under the coupling of the roundness error of the inner and outer grooves, the magnification of the inner ring runout increases as a whole. When there are specific relationships between the roundness error orders of the grooves and the number of balls, the magnification of the axial or radial runout changes significantly.

IntroductionPhysical fitness has been widely recognized as a powerful marker of health in children and adolescents, and it negatively affected by the COVID-19 pandemic. The construction of world-class universities and first-class disciplines, known as the “Double First-Class” Initiative (DFC), is a major commitment made by the Chinese government to adapt to changes in the educational environment, both domestically and internationally, in order to promote the development and practice of international higher education. The aim of the study was to look deep into the regional differences of physical fitness and overweight and obesity prevalence among college students before and after the COVID-19 pandemic since the DFC.MethodsThe original physical fitness parameters of students from 10 DFC universities and colleges in Central South China were downloaded from the official website of Chinese National Student Physical Fitness Database (CNSPFD) and then divided into 3 groups based on the pandemic periods: pre-pandemic (2019), the first year after pandemic outbreak (2020), and the second year after pandemic outbreak (2021). All the data were stored in Excel 2010, analyzed by SPSS 17.0, and plotted with ArcGIS 10.4.ResultsThe total “fail” percentage (from 9.19% in 2019 to 12.94% in 2021) and the prevalence of overweight and obesity in boys (from 22.53 to 29.25% in 2021) exhibited a continuous increase year by year, and among all the physical fitness indicators the score of strength in boys and endurance quality in all individuals were the lowest in overweight and obesity groups. Students with ‘fail’ rate developed from northern and northeastern province to southern areas from 2019 to 2021. For grade 2019th, overweight and obesity students who also failed the test had covered nationwide and the most affected areas including northeast, east, as well as central north in senior year. The distribution of overall fitness assessments in Hubei province was in accordance with the national data, and the overall scoring growths in both class of 2021st and 2022nd were measured with a negative increase (p

Laser directed energy deposition (L-DED) allows the production of multi-materials and functionally graded material (FGM) parts. But for commercialisation, process and quality monitoring of parts is required. For the first time, a novel monitoring method for chemical composition and process regimes of FGMs is proposed using a cost-effective acoustic emission (AE) (microphone) and optical emission spectroscopy (OES) sensors. Four chemical compositions (100%Ti, 58%Ti42%Nb, 37%Ti63%Nb, and 100% Nb) and two process parameters (475 W – 1'400 mm/min and 175 W – 2'000 mm/min) were selected, leading to four regimes/quality (conduction mode, partial, minor, medium, and severe lack of fusion pores). The signals were classified using seven mainstream artificial intelligence algorithms. The main conclusions are twofold. First, microphones are unsuitable candidates for monitoring the laser-material interaction during L-DED. The acoustic waves generated by the laser-material interaction are shielded by high gas flow surrounding it and so are either highly disturbed or does not reach the microphone. Conversely, OES are suitable candidates as the classification accuracies are higher than 90% for most category and machine learning algorithms, even after drastic feature reduction. Considering the wide range of chemical composition and quality, our proposed methods using OES have high industrialised potentials for them during L-DED FGM.

The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates. However, chemotherapy in practice has only had limited success in inducing long-term survival or cure of cancers when used either alone or in combination with immunotherapy. We think that this is because the importance of dose, schedule, and tumor model dependence of chemotherapy-activated anti-tumor immunity is under-appreciated. Here, we review immune modulation function of representative chemotherapy agents and propose a model of immunogenic chemotherapy-induced long-lasting responses that rely on synergetic interaction between killing tumor cells and inducing anti-tumor immunity. We comb through several chemotherapy treatment schedules, and identify the needs for chemotherapy dose and schedule optimization and combination therapy with immunotherapy when chemotherapy dosage or immune responsiveness is too low. We further review tumor cell intrinsic factors that affect the optimal chemotherapy dose and schedule. Lastly, we review the biomarkers indicating responsiveness to chemotherapy and/or immunotherapy treatments. A deep understanding of how chemotherapy activates anti-tumor immunity and how to monitor its responsiveness can lead to the development of more effective chemotherapy or chemo-immunotherapy, thereby improving the efficacy of cancer treatment.

Abstract Objective To investigate the safety and efficacy of chemoradiotherapy or radiotherapy combined with nimotuzumab in the treatment of unresectable oesophageal squamous cell carcinoma (ESCC) in elderly patients. Methods This study retrospectively analysed 54 cases of elderly patients (aged over 70 years) with unresectable ESCC in our centre between December 2016 and November 2019. The patients were treated with a radiation dose of 50–61.6 Gy (25–30 fractions) combined with nimotuzumab for targeted therapy with or without chemotherapy according to each patient’s condition. The patients were observed for quality of life, safety, side effects and survival before and after the treatment. Results Among the 54 patients, 26 were treated with nimotuzumab combined with chemoradiotherapy and 28 were treated with nimotuzumab combined with radiotherapy. Toxicities were mainly oesophagitis (≥ Grade 2, 38.9%), myelosuppression (≥ Grade 3, 24.1%) and hypoproteinaemia (any grade, 94.4%). The rates of complete response, partial response, disease stability and disease progression were 11.1% (6/54), 81.5% (44/54), 3.7% (2/54) and 3.7% (2/54), respectively, and the overall objective response rate was 92.6% (50/54). The median follow-up time was 35.1 months, and the 1- and 2-year overall survival (OS) and progression-free survival (PFS) rates were 61.1% (1 year OS) and 35.2% (2 year OS), 42.6% (1 year PFS) and 16.7% (2 year PFS), respectively. The median OS and PFS rates were 16.0 and 10.0 months, respectively. Conclusion Nimotuzumab combined with chemoradiotherapy or radiotherapy was well tolerated in elderly patients with unresectable ESCC. This combination can achieve a good treatment response and enhance survival.

BackgroundTumor microenvironment (TME) status is closely related to breast cancer (BC) prognosis and systemic therapeutic effects. However, to date studies have not considered the interactions of immune and stromal cells at the gene expression level in BC as a whole. Herein, we constructed a predictive model, for adjuvant decision-making, by mining TME molecular expression information related to BC patient prognosis and drug treatment sensitivity.MethodsClinical information and gene expression profiles were extracted from The Cancer Genome Atlas (TCGA), with patients divided into high- and low-score groups according to immune/stromal scores. TME-related prognostic genes were identified using Kaplan-Meier analysis, functional enrichment analysis, and protein-protein interaction (PPI) networks, and validated in the Gene Expression Omnibus (GEO) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to construct and verify a prognostic model based on TME-related genes. In addition, the patients’ response to chemotherapy and immunotherapy was assessed by survival outcome and immunohistochemistry (IPS). Immunohistochemistry (IHC) staining laid a solid foundation for exploring the value of novel therapeutic target genes.ResultsBy dividing patients into low- and high-risk groups, a significant distinction in overall survival was found (p < 0.05). The risk model was independent of multiple clinicopathological parameters and accurately predicted prognosis in BC patients (p < 0.05). The nomogram-integrated risk score had high prediction accuracy and applicability, when compared with simple clinicopathological features. As predicted by the risk model, regardless of the chemotherapy regimen, the survival advantage of the low-risk group was evident in those patients receiving chemotherapy (p < 0.05). However, in patients receiving anthracycline (A) therapy, outcomes were not significantly different when compared with those receiving no-A therapy (p = 0.24), suggesting these patients may omit from A-containing adjuvant chemotherapy. Our risk model also effectively predicted tumor mutation burden (TMB) and immunotherapy efficacy in BC patients (p < 0.05).ConclusionThe prognostic score model based on TME-related genes effectively predicted prognosis and chemotherapy effects in BC patients. The model provides a theoretical basis for novel driver-gene discover in BC and guides the decision-making for the adjuvant treatment of early breast cancer (eBC).

Abstract The protein Talin1 encoded by the TLN1 gene is a focal adhesion-related protein that binds to various cytoskeletal proteins and plays an important role in cell adhesion and movement. Recent studies have shown that it is overexpressed in prostate cancer, liver cancer, and oral squamous cell carcinoma, and is closely related to tumor progression and metastasis. This study integrated bioinformatics and functional analysis to reveal the prognosis and potential functions of TLN1 in AML. The results showed that the expression level of TLN1 was abnormally increased in AML and localized in the cell membrane and cytoplasm, and TLN1 is a significant prognostic indicator of overall survival (OS). Enrichment analysis of related genes showed that TLN1 is related to neutrophil mediated immunity, neutrophil activation and may regulate important signal pathways in hematological tumors including tyrosine kinase receptor, FLT3 and PIK3/AKT. The PPI network shows that TLN1 and MYH9 may be involved in the process of AML tumors together with PIP5K1C, ROCK1, S100A4, MY01A and WAC. Immune infiltration analysis explains that TLN1 is associated with multiple immune cells and may be an important immune marker in AML. Furthermore, molecular biology experiments confirmed that TLN1 is related to the proliferation, differentiation and cycle of AML cells. Silencing TLN1 can inhibit the proliferation of AML cells and promote differentiation through the Talin1/P-AKT/CREB signaling pathway.