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Abstract Background Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer characterized by driver mutations detected in a substantial proportion of the cases. Tyrosine kinase inhibitors (TKIs) are standard care for the patients with these mutations. In this study, we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro. Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was performed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital (HNCH cohort). The mutational landscape of HNCH patients was compared with TCGA patients. Logistic regression analysis was used to determine the factors associated with presence of these mutations. Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs. Results A total of 574 single nucleotide variants (SNVs), 270 indels, 88 amplifications, and 87 rearrangements were identified in this study, with EGFR and KRAS being the most frequently mutated genes. Females, mostly life-long non-smokers, had significantly higher EGFR mutation rates than males. Males, primarily smokers, more frequently had KRAS mutations. HNCH patients in general had a higher mutation count than TCGA patients (1.09 vs 0.93 mutations per patient (m/p)), in consistent with its higher proportion of patients with advanced disease. Rare EGFR compound mutations identified in this study, including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873, conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo. Conclusion This NGS-based 8-gene test efficiently identified over 70% of Chinese treatment-naive LUAD patients who are targetable for TKIs. Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.

Abstract Background RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7G tRNA modifications in breast cancer (BC) remain largely obscure. Methods The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of m7G tRNA modification and mRNA translation efficiency in BC, m7G-methylated tRNA immunoprecipitation sequencing (m7G tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms. Results The tRNA m7G methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased m7G levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with m7G. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. Conclusion Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA m7G modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.

ABSTRACT Esophageal cancer (EC) is a multifaceted disease. Our understanding of the involvement of esophageal microbiota in its pathogenesis and progression is limited, which is due to the lack of proper endoscopic sampling methods. Hereby, we conducted a comparative analysis of paired samples obtained through endoscopic brushing and cytosponge, aiming at assessing the feasibility of using cytosponge as a minimally invasive sampling way for studying esophageal microbiota. Our findings suggest that cytosponge sampling yielded significantly superior community richness and diversity compared to endoscopic brushing in both controls (non-cancerous) and EC individuals. The analysis of beta-diversity revealed distinct microbial community pattern in the genus diversity between the two sampling methods, underscoring the importance of selecting appropriate sampling methods to effectively characterize the esophageal microbiota. Specifically, Lactococcus and Serratia showed higher abundance in the samples collected by endoscopic brushing, while Alloprevotella and Leptotrichia were more enriched in the samples collected by cytosponge. These differences in dominant microbes were associated with metabolic pathways that particularly were related to host inflammation, such as pyruvate and glucose metabolisms. Notably, the phylogenetic levels of the microbiota indicated varied explanatory power for different detection purposes. This study underscores the substantial impact of sampling method selection on the acquisition of esophageal microbiota associated with the EC development, encompassing considerations of both abundance and diversity. This highlights the significance of selecting an appropriate sampling method for investigating the esophageal microbial status and studying the micro-environment in EC-related individuals.IMPORTANCEThis study addresses a critical issue in esophageal cancer study by comparing two different sampling methods, endoscopic brushing and cytosponge, for investigating the esophageal microbiota. Our work highlights the suitability of the cytosponge technique as a minimally invasive sampling method for studying the esophageal microbiota and emphasizes the importance of selecting an appropriate sampling method to characterize the microbial community. Our findings have significant implications for advancing the understanding of the role of the esophageal microbiota in cancer development and will inform future research and clinical approaches in this field.

Esophageal cancer (EC) is an aggressive malignancy with a poor prognosis. Various factors, including dietary habits, and antacid and antibiotic use, have been shown to influence the esophageal microbiome. Conversely, enrichment and diversity of the esophageal microbiome can also impact its function. Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC, thus suggesting the potential contribution of the esophageal microbiome to EC development. Additionally, distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy, indicating the role of the esophageal microbiome in modulating treatment outcomes. In this review, we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases, with a focus on identifying microbial communities associated with EC pathogenesis and prognosis. Understanding the role of the microbiome in EC may aid in early detection and optimized treatment strategies, ultimately leading to better outcomes for patients.

Abstract Breast cancer (BC) is one of the most frequent cancer-related deaths in women worldwide. Studies have shown the potential impact of circRNAs in multiple human tumorigeneses. Research on the vital signaling pathways and therapeutic targets of circRNAs is indispensable. Here, we aimed to investigate the clinical implications and underlying mechanisms of circ_0042881 in BC. RT-qPCR validated circ_0042881 was notably elevated in BC tissues and plasma, and closely associated with BC clinicopathological features. Functionally, circ_0042881 significantly accelerated the proliferation, migration, and invasion of BC cells in vitro and tumor growth and metastasis in vivo. Mechanistically, circ_0042881 promoted BC progression by sponging miR-217 to relieve its inhibition effect in son of sevenless 1 (SOS1), which further activated RAS protein and initiated downstream signaling cascades, including MEK/ERK pathway and PI3K/AKT pathway. We also demonstrated that treatment of BAY-293, an inhibitor of SOS1 and RAS interaction, attenuated BC progression induced by circ_0042881 overexpression. Furthermore, Eukaryotic initiation factor 4A-III (EIF4A3) could facilitate circ_0042881 circularization. Altogether, we proposed a novel signaling network in which circ_0042881, induced by EIF4A3, influences the process of BC tumorigenesis and metastasis by miR-217/SOS1 axis.

Abstract Aerobic glycolysis has been considered as a hallmark of colorectal cancer (CRC). However, the potential functional regulators of glycolysis in CRC remains to be elucidated. In the current study, we found that Regenerating islet-derived protein 1-alpha (REG1α) was significantly increased in both CRC tissues and serum, and positively associated with CRC patients’ lymph node metastasis, advanced tumor stage, and unfavorable prognosis. Ectopic expression of REG1α contributed to various tumorigenic properties, including cell proliferation, cell cycle, migration, invasion, and glycolysis. In contrast, REG1α deficiency in CRC cells attenuated malignant properties and glucose metabolism. Mechanically, REG1α promoted CRC proliferation and metastasis via β-catenin/MYC axis-mediated glycolysis upregulation. Moreover, the malignant behaviors governed by REG1α could be effectively abolished by silencing of Wnt/β-catenin/MYC axis or glycolysis process using specific inhibitors. Besides, REG1α expression was mediated by METTL3 in an m6A-dependent manner. Overall, our work defines a novel regulatory model of the METTL3/REG1α/β-catenin/MYC axis in CRC, which indicates that REG1α could function as a novel biomarker and a potential therapeutic target for patients with CRC.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignancies with relatively high morbidity and mortality. Emerging evidence suggests circular RNAs (circRNAs) play critical roles in tumor cell malignancy. However, the biological function and clinical significance of many circRNAs in ESCC remain elusive. Methods The expression level and clinical implication of circRUNX1 in ESCC tissues were evaluated using qRT-PCR. In vitro and in vivo functional studies were conducted to investigate the underlying biological effects of circRUNX1 on ESCC cell growth and metastasis. Moreover, bioinformatics analysis, RNA sequencing (RNA-seq), RNA immunoprecipitation (RIP) assays, dual-luciferase reporter assays, and rescue experiments were performed to explore the relationships between circRUNX1, miR-449b-5p, Forkhead box protein P3 (FOXP3), and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Results CircRUNX1 was found to be significantly up-regulated in ESCC tissues and associated with TNM stage and differentiation grade. Functionally, circRUNX1 promoted ESCC cell proliferation and metastasis in vitro and in vivo. CircRUNX1 enhanced FOXP3 expression by competitively sponging miR-449b-5p. Notably, both miR-449b-5p mimics and FOXP3 knockdown restored the effects of circRUNX1 overexpression on cell proliferation and metastasis. Furthermore, IGF2BP2 binding to circRUNX1 prevented its degradation. Conclusions IGF2BP2 mediated circRUNX1 functions as an oncogenic factor to facilitate ESCC progression through the miR-449b-5p/FOXP3 axis, implying that circRUNX1 has the potential to be a promising diagnostic marker and therapeutic target for ESCC patients.

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive gastrointestinal cancers with high incidence and mortality. Therefore, it is necessary to identify novel sensitive and specific biomarkers for ESCC detection and treatment. Circular RNAs (circRNAs) are a type of noncoding RNAs featured by their covalently closed circular structure. This special structure makes circRNAs more stable in mammalian cells, coupled with their great abundance and tissue specificity, suggesting circRNAs may present enormous potential to be explored as valuable prognostic and diagnostic biomarkers for tumor. Mounting studies verified the critical roles of circRNAs in regulating ESCC cells malignant behaviors. Here, we summarized the current progresses in a handful of aberrantly expressed circRNAs, and elucidated their biological function and clinical significance in ESCC, and introduced a series of databases for circRNA research. With the improved advancement in high-throughput sequencing and bioinformatics technique, new frontiers of circRNAs will pave the path for the development of precision treatment in ESCC.

Abstract Platinum-based chemotherapy was previously the first-choice treatment for lung cancer. The discovery of epidermal growth factor receptor (EGFR) gene mutations and the development of EGFR tyrosine kinase inhibitors (TKIs) marked the beginning of the targeted therapy era for non-small-cell lung cancer (NSCLC). Thirty percent of NSCLC patients carry EGFR gene mutations. For these advanced NSCLC patients, EGFR-TKIs are currently preferred for their superior activity and survival benefits over platinum-based chemotherapy. However, therapeutic efficacy is quite different in patients with EGFR exon 20 insertion (ex20ins) mutations versus common mutations. Patients with ex20ins mutations are insensitive to EGFR-TKIs and have poor prognosis. Some drugs targeting EGFR ex20ins mutations have been approved. Here, we systematically reviewed the recent clinical research of and treatments used for EGFR ex20ins mutations, summarized the latest data on emerging therapies, and discussed future prospects and treatments.

BackgroundWhile the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated.MethodsWe performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy.ResultsA high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy.ConclusionsOur data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC.

IntroductionTransformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event determines a rapid disease deterioration and needs specific treatment.Patient and methodWe report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified.ResultsEGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy number gain for Proto-Oncogene C-Myc (MYC) and a Phosphoinositide 3-Kinase Alpha (PIK3CA) p.E545K mutation were found in the transformed sample specifically. Strong TP53 staining and negative RB1 staining were observed in both LUAD and SCLC samples, but FISH only identified MYC amplification in SCLC tissue.ConclusionWe consider the combined presence of MYC amplification with mutations in TP53 and RB1 as drivers of SCLC transformation. Our results highlight the need to systematically evaluate TP53 and RB1 status in LUAD patients to offer a different therapeutic strategy.

PurposeThis study determined the efficacy of low-dose gemcitabine combined with programmed death-1 (PD-1) inhibitors for treating multiple malignancies, providing a cost-effective and safe treatment option.Study DesignThis study included 61 patients with advanced solid tumors treated with low-dose gemcitabine combined with PD-1 inhibitors at the Henan Cancer Hospital between January 2018 and February 2022. We retrospectively reviewed medical records to evaluate several clinical factors, including progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and objective response to treatment.ResultsSixty-one patients received treatment with low-dose gemcitabine combined with PD-1 inhibitors. The objective response rate (ORR) was 29.5% and the disease control rate (DCR) was 62.3%. The median PFS was 4.3 months (95% confidence interval, 2.3 to 6.3 months) and the median OS was 15.0 months (95% confidence interval, 8.8 to 21.2 months). Hematological toxicity, mainly leukopenia or thrombocytopenia, was the most common AE, with any-grade and grade 3/4 hematological toxicity reported in 60.7 and 13.1% of patients, respectively.ConclusionsLow-dose gemcitabine combined with PD-1 inhibitors may offer a novel treatment option for patients with advanced malignancies.

Abstract BRAF and KRAS are two key oncogenes in the RAS/RAF/MEK/MAPK signaling pathway. Concomitant mutations in both KRAS and BRAF genes have been identified in non-small cell lung cancer (NSCLC). They lead to the proliferation, differentiation, and apoptosis of tumor cells by activating the RAS/RAF/MEK/ERK signaling pathway. To date, agents that target RAS/RAF/MEK/ERK signaling pathway have been investigated in NSCLC patients harboring BRAF mutations. BRAF and MEK inhibitors have gained approval for the treatment of patients with NSCLC. According to the reported findings, the combination of MEK inhibitors with chemotherapy, immune checkpoint inhibitors, epidermal growth factor receptor-tyrosine kinase inhibitors or BRAF inhibitors is highly significant for improving clinical efficacy and causing delay in the occurrence of drug resistance. This review summarized the existing experimental results and presented ongoing clinical studies as well. However, further researches need to be conducted to indicate how we can combine other drugs with MEK inhibitors to significantly increase therapeutic effects on patients with lung cancer.

Abstract Background Genotyping of structural variation is an important computational problem in next generation sequence data analysis. However, in cancer genomes, the copy number variant(CNV) often coexists with other types of structural variations which significantly reduces the accuracy of the existing genotype methods. The bias on sequencing coverage and variant allelic frequency can be observed on a CNV region, which leads to the genotyping approaches that misinterpret the heterozygote as a homozygote. Furthermore, other data signals such as split mapped read, abnormal read will also be misjudged because of the CNV. Therefore, genotyping the structural variations with CNV is a complicated computational problem which should consider multiple features and their interactions. Methods Here we proposed a computational method for genotyping indels in the CNV region, which introduced a machine learning framework to comprehensively incorporate a set of data features and their interactions. We extracted fifteen kinds of classification features as input and different from the traditional genotyping problem, here the structure of variant may fall into types of normal homozygote, homozygous variant, heterozygous variant without CNV, heterozygous variant with a CNV on the mutated haplotype, and heterozygous variant with a CNV on the wild haplotype. The Multiclass Relevance Vector Machine (M-RVM) was used as a machine learning framework combined with the distribution characteristics of the features. Results We applied the proposed method to both simulated and real data, and compared it with the existing popular softwares include Gindel, Facets, GATK, and also compared with other machine learning cores: Support Vector Machine, Lanrange-SVM with OVO multiple classification, Naïve Bayes and BP Neural Network. The results demonstrated that the proposed method outperforms others on accuracy, stability and efficiency. Conclusion This work shows that the genotyping of structural variations on the CNV region cannot be solved as a traditional genotyping problem. More features should be used to efficiently complete the five-category task. According to the result, the proposed method can be a practical algorithm to correct genotype structural variations with CNV on the next generation sequence data. The source codes have been uploaded at https://github.com/TrinaZ/Mixgenotype for academic usage only.

Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with “conflicting interpretations of its pathogenicity”. Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients’ family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.

Desmoid tumor is a rare disease, which is histologically characterized by local invasion, monoclonality, and fibroblast proliferation; and clinically characterized by a variable and often unpredictable course. The treatment of desmoid tumor is mainly surgical resection, but the recurrence rate is high. In recent years, a variety of treatment methods, including endocrine therapy, surgery, radiotherapy, chemotherapy, non-steroidal anti-inflammatory drugs, targeted drugs, interferon and more, have been used and achieved certain curative effects. In addition, in view of the inertia characteristics of desmoid tumor, observation is also a first-line scheme recommended by multiple guidelines. In the past, the research progress of targeted therapy for desmoid tumor is relatively slow and the curative effect is limited. Thus, targeted therapy is usually used as a remedial treatment after the failure of other conventional treatment methods. However, in recent years, with the rapid progress in the basic research of targeted therapy, some new targeted drugs are increasingly used for the clinical treatment of desmoid tumor and have achieved good results. Herein, we described a patient with aggressive fibromatosis in the abdominal cavity. Following a combined treatment using anlotinib and celecoxib, the patient achieved a partial response with mild toxicity. Simultaneously, the patient’s pain symptoms completely disappeared. This case indicates that the combination of anlotinib and NSAIDs could be an effective treatment for desmoid tumor.

Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.

Many children with attention deficit hyperactivity disorder (ADHD) perform poorly in their academic studies. They also have difficulties in their social lives due to a lack of interpersonal skills and this often continues into adult life. Appropriate early therapies and medications can be very beneficial. In this paper, we introduce and demonstrate the benefits of a new type of treatment, namely, an eye-contact game which successfully exploits mixed reality technology. None of the patients in our experiment were older than ten years of age. They were able to pay attention and sustain interest in the treatment sessions over a span of six weeks. After participating in the treatment sessions with our game, the omission/commission errors which were evaluated in an attention test taken by the experimental group decreased significantly and appeared within the normal range. In addition to the improvement in error rates, the mean response time to an interactive metronome test significantly decreased. Importantly, our game allows patients to conduct this treatment by themselves at home without professional assistance. To the best of our knowledge, this study is one of the first studies to use a mixed reality head-mounted display to treat children with attention deficit hyperactivity disorder and to prove its potential as a treatment for clinically diagnosed children.

Predisposition of germline BRCA1/2 mutations (gBRCAMUT) increases the risk of breast and ovarian cancer in females, but the mutation prevalence and spectrum are highly ethnicity-specific with different recurrent mutations being reported in different populations. Hereby, we performed hybridization-based target sequencing of BRCA1/2 in 530 ovarian cancer patients from Henan, the central region of China, followed by haplotype analysis of six short tandem repeat (STR) markers in the patients with recurrent mutations to determine their founder effect. About 28.3% (150/530) of the OC patients in our cohort harbored gBRCAMUT; of the 151 mutations, 117 in BRCA1 and 34 in BRCA2, identified in this study, BRCA1:c.5470_5477del, c.981_982del, and c.4065_4068del are the top three mutants, recurrently detected in eight, seven, and six independent patients respectively. Haplotype analysis identified a region of 0.6 MB genomic length covering BRCA1 highly conserved across all eight carriers of BRCA1:c.5470_5477del, but not c.981_982del, suggesting a consequence of founder effect. Retrospective analysis in a subgroup of serous ovarian cancer patients revealed gBRCAMUT status was not associated with the progression-free survival (PFS); instead, an expression of Ki-67% ≥50% was associated with a shorter PFS (p = 0.041). In conclusion, patients with pathogenic or likely pathogenic gBRCAMUT account for 28.3% of the OC cases from Henan, and BRCA1:c.5470_5477del, the most frequently detected mutation in Henan patients, is a founder mutation in the population.

Background The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. Materials and Methods A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane’s Q test and index of heterogeneity (I2) indicated no obvious heterogeneity among studies. Results Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036). Conclusion MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings.

Demand Responsive Transit (DRT) responds to the dynamic users' requestswithout any fixed routes and timetables and determines the stop and the start according to the demands. This study explores the optimization of dynamic vehicle scheduling and real-time route planning in urban public transportation systems, with a focus on bus services. It addresses the limitations of current shared mobility routing algorithms, which are primarily designed for simpler, single origin/destination scenarios, and do not meet the complex demands of bus transit systems. The research introduces an route planning algorithm designed to dynamically accommodate passenger travel needs and enable real-time route modifications. Unlike traditional methods, this algorithm leverages a queue-based, multi-objective heuristic A* approach, offering a solution to the inflexibility and limited coverage of suburban bus routes. Also, this study conducts a comparative analysis of the proposed algorithm with solutions based on Genetic Algorithm (GA) and Ant Colony Optimization Algorithm (ACO), focusing on calculation time, route length, passenger waiting time, boarding time, and detour rate. The findings demonstrate that the proposed algorithmsignificantly enhances route planning speed, achieving an 80-100-fold increase in efficiency over existing models, thereby supporting the real-time demands of Demand-Responsive Transportation (DRT) systems. The study concludes that this algorithm not only optimizes route planning in bus transit but also presents a scalable solution for improving urban mobility. [ABSTRACT FROM AUTHOR]

Background: While the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated. Methods: We performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy. Results: A high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy. Conclusions: Our data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC. [ABSTRACT FROM AUTHOR]