Precise regulation of the activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development but is frequently disrupted in cancer. Among the polycomb group (PCGF) family members, which are key components of polycomb repressive complex 1 (PRC1), PCGF1 emerged as the factor most strongly associated with poor prognosis in non-small cell lung cancer (NSCLC) based on analyses of The Cancer Genome Atlas (TCGA) cohort. In lung cancer cells, PCGF1 upregulation enhanced the deposition of H2AK119ub and H3K27me3 at chromatin. These depositions inhibit the cytokine-cytokine receptor interaction pathway, especially CCL5, CXCL10, CD40, and FAS. Single-cell RNA sequencing further indicated that PCGF1 acts as a negative regulator of natural killer (NK) cell effector function. When NK cell-derived cytokines attempted to activate the cytokine-cytokine receptor interaction pathway in tumor cells, this repressive chromatin state attenuated pathway activation. Consequently, reduced expression of these genes weakened NK cell recruitment and cytotoxic responses. Collectively, this study uncovers a previously unrecognized mechanism by which PCGF1-driven disruption of bivalent promoter balance silences immune signaling cascades, enabling tumor cells to evade NK cell-mediated immunity in NSCLC. These findings highlight bivalent chromatin as a critical regulatory node in tumor immune escape and establish PCGF1 as a promising epigenetic target for immunotherapeutic intervention.PCGF1 promotes immune evasion in NSCLC by suppressing cytokine-cytokine receptor interaction pathway. Upregulation of PCGF1 in NSCLC cells enhances the deposition of the repressive histone modifications H2AK119ub and H3K27me3 while reducing the enrichment of the transcriptionally active histone modification H3K4me3 at target chromatin regions, thereby suppressing cytokine-cytokine receptor interaction pathway. This epigenetic repression reduces the expression of immune-related genes, including CCL5, CXCL10, CD40, and FAS. Consequently, tumor-cell responses to NK cell-derived cytokines are attenuated, leading to impaired NK cell recruitment and cytotoxicity. The schematic diagram was created using BioRender.

Background:While immune checkpoint inhibitors (ICIs) in combination with chemotherapy have improved outcomes for patients with extensive-stage small cell lung cancer (ES-SCLC), elderly patients (≥70 years) are often underrepresented in clinical trials, and real-world evidence on their efficacy and safety remains scarce. We conducted a real-world study to supplement data on using serplulimab [a programmed cell death protein 1 (PD-1) inhibitor] with chemotherapy as first-line treatment for elderly (≥70 years) ES-SCLC patients. Methods:We gathered data on ES-SCLC patients aged 70 and above treated with first-line serplulimab, focusing on progression-free survival (PFS) as the primary endpoint. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Kaplan-Meier survival curves were used for PFS and OS, and Cox proportional hazards models and accelerated failure time (AFT) models were used for the subgroup analyses. The baseline and post-4-cycle neutrophil-to-lymphocyte ratio (NLR) levels were also collected as exploratory endpoints. Results:Forty-three ES-SCLC patients with a median age of 73 years were included. Median PFS was 7.0 months [95% confidence interval (CI): 6.1-12.5]. Subgroup analysis indicated a significantly higher risk of disease progression in female patients (P=0.04) and those who had brain radiotherapy (P<0.001). OS rate was 94.7% (95% CI: 87.9-100.0%) at 6 months and 65.8% (95% CI: 50.0-86.5%) at 1 year. The ORR was 65.12% (95% CI: 49.07-78.99%), and the DCR was 97.67% (95% CI: 87.71-99.94%). AEs occurred in 19 patients (44.19%), mostly grade 1-2 (14 patients, 32.56%), with grade ≥3 AEs in 11.63% (5 patients). There was no significant difference in NLR levels before and after patient treatment. Conclusions:This study showed that combining serplulimab with chemotherapy improved survival and reduced toxicity in elderly ES-SCLC patients. Additionally, NLR may not be suitable as a biomarker for the elderly ES-SCLC population.

Introduction Idiopathic pulmonary fibrosis (IPF) represents a significant unmet medical need, with two existing therapies showing limited effect on disease progression and overall survival. Matrix metalloproteinase 7 (MMP7) is involved in epithelial-mesenchymal transition, fibrocyte migration, and fibroblast proliferation. Increased plasma MMP7 levels are highly predictive of all-cause mortality and transplant-free survival in IPF patients. In preclinical studies, inhibition of MMP7 demonstrated anti-fibrotic effect and therefore is a promising approach to IPF treatment. In an endeavor to develop a MMP7-specific inhibitor, we employed siRNA technology with the aim to generate a highly potent new molecular entity with long duration of action and better safety profile that is suitable for targeted lung delivery. Methods GenSciP117, a lung-targeted siRNA directed to MMP7 mRNA, was generated using high throughput screening and GenSci's internal chemical-oligonucleotide conjugate (COC) technology platform. In vitro knockdown of MMP7 was assessed by cellular transfection of chemically modified siRNAs. In vivo silencing effect was characterized in MMP7-humanized mice. Anti-fibrotic efficacy was examined in TGF-β1 treated cells in vitro and in bleomycin-induced IPF model in mice. Results GenSciP117 lead siRNA molecules displayed potent MMP7 mRNA and protein knockdown activity in vitro and in vivo. Moreover, Lead siRNA molecules inhibited TGF-β1 induced mRNA expression of COL1A1. Furthermore, these siRNAs reduced lung hydroxyproline content to basal level in the bleomycin-induced mouse model of IPF. Conclusions 1. GenSciP117 has demonstrated encouraging anti-fibrotic effect both in vitro and in vivo through efficient silencing of MMP7 mRNA. 2. Differentiated mechanism of action supports the potential of GenSciP117 as either a monotherapy or an add-on to standard of care to offer better efficacy for the treatment of IPF. These results warrant further evaluation of GenSciP117 in IND-enabling studies.

Lung cancer is still one of the most common malignant tumors in the world. With the increase of its incidence and the development of medical technology, the overall survival of lung cancer patients has significantly extended compared to before. The incidence of brain and meningeal metastases from lung cancer has also been rising year by year, but patients with brain and meningeal metastases from lung cancer have a poor prognosis and a very high mortality rate, and the diagnosis is mainly based on computed tomography (CT), magnetic resonance imaging (MRI) and other imaging examinations. However, the imaging features are diverse and the specificity is low, which makes it easy to be misdiagnosed and missed. Therefore, accurately identifying brain and meningeal metastases and timely targeted treatment is crucial for improving patient prognosis. This paper analyzed the diagnosis and treatment of a case of lung cancer with no obvious recurrence and metastasis in nearly 7-year long-term follow-up after radical lung cancer surgery, but the patient with abnormal behavior, impaired consciousness and epilepsy in the past 5 months, and multiple punctate calcifications in the brain found by head CT and MRI. This paper consider that the patient's mental and behavioral symptoms were caused by brain and meningeal metastasis of lung cancer after excluding infectious disease and ineffective treatment of autoimmune encephalitis, and further pathological biopsy and genetic detection confirmed the diagnosis of metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) L858R gene mutation, and the patient's symptoms were significantly improved after targeted therapy by Osimertinib. This paper also searched the relevant literatures of brain calcifications in databases such as China National Knowledge Infrastructure (CNKI), Wanfang, UpToDate, PubMed, etc., and found that intracerebral calcifications exist in a variety of diseases, including infectious, genetic and neurodegenerative diseases, vascular diseases, metabolic diseases and tumors. However, brain calcification in brain and meningeal metastases are often underestimated, and the consequent risk is misdiagnosis and delayed treatment. Therefore, brain and meningeal metastases manifested as brain calcification should not be ignored in patients with a history of previous tumors.

e16004 Background: Chemotherapy and PD-1 inhibitor have shown significant clinical benefits in first-line treatment of metastatic gastric and esophagogastric junction adenocarcinoma. The prospective, open-lable, single-arm, single-center clinical trial was designed to assess efficacy and safety of Toripalimab plus docetaxel, oxaliplatin and capecitabine. Methods: Eligible criteria were treatment histopathologically confirmed stage IV(AJCC8) and ECOG 0-2, HER2 negative, regardless of CPS expression of untreated metastatic gastric and esophagogastric junction adenocarcinoma. Patients were given with Docetaxel (75mg/m2, iv,d1), Oxaliplatin(130mg/m2, iv,d1), Capecitabine (750mg/m2 bid, po,d1-d14) combined with Toripalimab (240mg, iv,d4), every 3 weeks. Dexamethasone 4.5mg, q12h, po. started at the night before docetaxel administrated for 3 days. Tumor response was assessed every 2/4 cycles by radiologic imaging. After 4 cycles, MDT was employed to determine subsequent treatment plan. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. The secondary endpoints were progression-free survival and overall survival. Results: 30 patients were enrolled up to 6/1/2025. The median follow-up was 11.7month (range 1.1-61.4). The median age was 57 years (range 32-78), male was 53.3%.The proportion of ECOG 1 patients accounted for 60%, ECOG 2 for 23.3%. A total of 22 patients completed 4 cycles treatment, and 26 patients were eligible for efficacy assessment. Confirmed ORRs were 73.1% (95% CI: 53.9,86.3) and DCR were 96.2% (95%CI: 81.1, 99.3). 57.7% of patients had a disease response depth greater than 50%. Median PFS was 8.5 month (95% CI: 6.76-10.19), the 6-month and 12-month PFS rate was 72.4% and 29.0%, respectively. Median OS was 11.03 month (95% CI: 9.45,12.63) , the 6-month and 12-month OS rate was 80.0% and 43.3%, respectively. The OS of patients completed 4 cycles could reach 18 monthsThe overall incidence of adverse events is 86.7%, Gr ≥3 AEs were seen in 46.7% of patients, Gr 5 AEs were not observed. The most common treated-related AEs were Diarrhea (26.7%) and Platelet count decreased (26.7%). The most common immune-related AEs were Rash (10%). Conclusions: These results showed favorable tumor response, higher ORR, DCR, tumor response depth. The possible reasons were the use of immunotherapy on the 4 th day and the combination with docetaxel. Compared to other GC immunotherapy-related studies, there was no advantage in OS for all patients, while PFS and completed 4 cycles patients' OS were superior to others. The safety of Toripalimab plus docetaxel, oxaliplatin and capecitabine was consistent with each agents known safety profile; no new safety signals were identified. Clinical trial information: ChiCTR2000030877 .

Background:The incidence of meningeal metastasis in lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations is rising annually. Refractory meningeal metastasis following EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance presents a significant clinical challenge, lacking effective treatments and often leading to fatal outcomes. This study aims to evaluate the antitumor efficacy and safety of intrathecal pemetrexed in patients with EGFR-TKI-resistant meningeal metastasis. Methods:From November 1, 2020 to November 1, 2022, a total of 10 patients were enrolled. All underwent next-generation sequencing (NGS) and carcino-embryonic antigen (CEA) testing of cerebrospinal fluid (CSF). These patients had previously experienced symptomatic and supportive treatment, EGFR-TKI resistance, systemic intravenous chemotherapy, and bevacizumab therapy. Intrathecal pemetrexed was administered at doses of 20 or 40 mg once weekly and was well-tolerated. Results:The disease control rate (DCR) was 88.8% (8/9), with 10% (1/10) showing negative CSF cytology. Quality of life (QoL) scores improved, and CSF CEA levels decreased. The median progression-free survival (PFS) was 5 months, and the median overall survival (OS) was 8.15 months. Adverse events occurred in 90% of patients, with nausea, vomiting, and myelosuppression being the most common. Grade 3 or higher adverse events were observed in 40% (4/10) of patients, primarily myelosuppression, which improved with systemic treatment. No treatment-related deaths occurred. Conclusions:This study suggests that intrathecal pemetrexed can be a viable salvage treatment for refractory meningeal metastasis in EGFR-TKI-resistant lung adenocarcinoma.

Glioblastoma (GBM) remains a therapeutically intractable central nervous system malignancy with limited treatment options. Apatinib, a selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, shows emerging potential in recurrent or refractory glioblastoma, yet its impact on the cerebrospinal fluid (CSF) glycome remains unexplored. In this pioneering longitudinal study, we characterize the N-glycome dynamics in paired CSF specimens from GBM patients pre- and post-apatinib treatment using hydrophilic interaction-based ultra performance liquid chromatography (HILIC-UPLC)-fluorescence mass spectrometry-based glycan profiling. Our results highlight potential alterations in specific glycoforms, particularly an increase in GalNAcβ1-4GlcNAc (LacdiNAc or LDN), core fucosylation(a modification catalyzed by α1,6-fucosyltransferase (Fut8), which transfers L-fucose from GDP-fucose to the innermost GlcNAc residue), and bisecting glycans(a β1,4-linked GlcNAc attached to the core β-mannose residue), a decrease in sialylation and biantennary glycans among treatment responders. These shifts correlate with attenuated immunosuppressive signatures, suggesting enhanced immunomodulation that may contribute to apatinib's therapeutic efficacy. This work uncovers the remodeling of the CSF glycome driven by apatinib, providing a novel molecular lens for understanding its anti-angiogenic/immune-modulating mechanisms and proposing CSF N-glycans as dynamic biomarkers for treatment efficacy in GBM.

The diagnosis and prognosis of Primary Central Nervous System Lymphoma (PCNSL) present significant challenges. In this study, the potential use of machine learning algorithms in diagnosing and predicting the prognosis for PCNSL based on cerebrospinal fluid (CSF) N-glycomics was investigated. First, CSF samples obtained from a cohort of 60 PCNSL patients and 30 controls were analyzed by hydrophilic interaction-based ultra performance liquid chromatography (HILIC-UPLC)-fluorescence mass spectrometry. Subsequently, nine machine learning models were established to diagnose PCNSL based on the changes of CSF N-glycome, with the Random Forest algorithm proving to be the most effective, achieving an accuracy of 100% in the training set and 89.3% in the test set. Moreover, a COX proportional-hazard model and a nomogram incorporating CSF N-glycome (GP6 and GP27) along with clinical data (age) were crafted. This nomogram's discrimination capacity was considered satisfactory, as evidenced by a C-index of 0.804 (95% CI: 0.68, 0.927). The study reveals that machine learning models based on CSF N-glycome offer a valuable approach for diagnosing and prognosticating PCNSL, demonstrating high accuracy and sensitivity in both classification and survival analysis. These findings may offer new insights into the molecular mechanisms underlying PCNSL and contribute to the advancement of personalized medicine for patients with this disease.

BackgroundLung cancer stands as the second most prevalent malignant neoplasm worldwide. Addressing the underlying mechanisms propelling the progression of non-small cell lung cancer is of paramount importance. In this study, we have elucidated the pivotal role of PHF12 in this context.Materials and methodsWe harnessed clinical lung cancer tissue samples and non-small cell lung cancer cell lines to discern the expression pattern of PHF12. In vitro assays probing cell proliferation were conducted to substantiate the functional impact of PHF12. Furthermore, an in vivo Xenograft model was employed to dissect the role of PHF12. Employing ChIP assays and qRT-PCR, we delved into the intricate binding dynamics between PHF12 and HDAC1. Mechanistic insights into the PHF12-HDAC1 axis in lung cancer progression were pursued via RNA-seq and GSEA analyses.ResultsNotably, PHF12 exhibited a substantial upregulation within tumor tissue, concomitant with its correlation to HDAC1. The trilogy of cell proliferation assays, transwell assays, and the Xenograft model collectively underscored the promoting influence of PHF12 on lung cancer proliferation, both in vitro and in vivo. The ChIP assay unveiled the transcriptional regulatory role of PHF12 in governing HDAC1 expression. This correlation extended to both mRNA and protein levels. PHF12 promotes NSCLC progression through regulating HDCA1 expression. Intriguingly, the rescue of function within NSCLC cell lines post PHF12 knockdown was achievable through HDAC1 overexpression. Additionally, our findings unveiled the capacity of the PHF12-HDAC1 axis to activate the EGFR/AKT signaling pathway, thereby further corroborating its significance in lung cancer progression.ConclusionOur study identified PHF12 as an oncogenic role in lung cancer proliferation and migration for the first time. PHF12 transcriptionally regulate HDAC1 and activate EGFR/AKT signaling pathway in NSCLC progression. PHF12 may serve as an important target in lung cancer therapy.

BACKGROUND:Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group.METHODS:We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers.RESULTS:Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months).CONCLUSION:The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Central nervous system metastasis of malignant tumors includes parenchymal metastasis and leptomeneneal metastasis. The optimal treatment of patients with central nervous system metastases involves a multidisciplinary approach, including supportive care, local treatments such as surgery, stereotactic radiation therapy and whole brain radiotherapy, and systemic therapy. In this paper, the choice of drugs, the selection of radiotherapy, the diagnosis of meningeal metastasis and Ventriculoperitoneal shunts were reviewed.

Background:Driver gene-positive non-small cell lung cancer (NSCLC) patients are prone to develop leptomeningeal metastasis (LM), leading to an extremely high mortality. The objective of this study was to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) treatments for patients with NSCLC and LM harboring targetable mutations. Methods:We retrospectively collected records of patients with NSCLC harboring targetable mutations and prescribed ICIs following the diagnosis of LM at Huashan Hospital, Fudan University. In addition, we reviewed relevant literature and enrolled patients who met the inclusion criteria. Clinical characteristics were statistically analyzed, and the Kaplan-Meier method and log-rank test were employed to assess the median progression-free survival (mPFS) and median overall survival (mOS). Results:A total of 37 patients with NSCLC harboring targetable mutations who received ICIs after LM diagnosis were included. The median age of the enrolled patients was 54 years (range, 33-70 years), and 62.2% were female. Following ICI administration, the intracranial objective response rate (iORR) and intracranial disease control rate (iDCR) for all enrolled patients were 18.9% and 62.2%, respectively. The mPFS of all patients was 2.5 months [95% confidence interval (CI): 2.166-2.834 months] and the mOS was 5.8 months (95% CI: 5.087-6.513 months). Both univariate and multivariate analyses revealed a significant increase in mOS or individuals who had previously undergone cranial radiation therapy compared to those who had not. Furthermore, different histology molecular types were found to be potentially associated with survival time. Conclusions:Some patients with NSCLC harboring targetable gene mutations following LM diagnosis may benefit from ICI treatment with relatively good tolerance. However, further screening of the most suitable patient populations for ICIs is required.

The incidence of meningeal metastasis in lung adenocarcinoma with EGFR mutation is increasing annually. Refractory meningeal metastasis following EGFR-TKI resistance has no effective treatment and a lethal complication of tumors. The purpose of this study was to evaluate the potential antitumor efficacy and safety of intrathecal pemetrexed in patients with EGFR-TKI resistance refractory meningeal metastasis. From November 1, 2020 to November 1 2022, a total of 10 patients were enrolled in the study, and all patients underwent NGS and CEA testing of cerebrospinal fluid. The patients had entered the stage of symptomatic and supportive treatment before intrathecal pemetrexed, experienced EGFR-TKI resistance, systemic intravenous chemotherapy and bevacizumab treatment previously. Intrathecal pemetrexed was well-effective and tolerated, occurring at the 20mg or 40mg once a week dose. The disease control rate of intrathecal injection was 88.8% (8/9); 10% (1/10) had negative cerebrospinal fluid cytology; concurrently, the quality of life (QoL)score improved, and cerebrospinal fluid CEA decreased. The median PFS of intrathecal injection was five months, and the median OS was 8.15 months. Ninety percent of patients experienced adverse events of varying degrees, with nausea, vomiting, and myelosuppression being the most common. The incidence of grade three or higher adverse events was 40% (4/10), primarily myelosuppression, which improved after systemic treatment; no treatment-related deaths occurred.This study suggests intrathecal pemetrexed can be used for salvage treatment of refractory meningeal metastatic in EGFR-TKI resistant lung adenocarcinoma.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients.METHODS: We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment ap-proaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. RESULTS: The median OSLM was 16.0 months and the 3 -year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was signifi-cantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P = 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P = 0.024). Better Eastern Cooperative Oncology Group perfor-mance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS.CONCLUSIONS: The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

目的:分析1 例卵巢癌脑膜转移患者的临床表现、诊断、治疗经过,结合既往文献报道,探讨卵巢癌脑膜转移的治疗方案.方法:回顾性分析2021 年1 月我科收治的1 例BRCA2 突变的卵巢癌脑膜转移患者的临床资料,治疗方案为奥拉帕利/尼拉帕利,根据患者的神经系统症状、头颅磁共振及脑脊液细胞学评估临床疗效.结果:经治疗后,患者神经系统症状明显缓解,头颅磁共振提示小脑转移灶消失,脑膜强化减轻,脑脊液细胞学稳定,患者总生存时间为23 个月.结论:对于不能接受化疗的BRCA突变的卵巢癌脑膜转移,PARP抑制剂单药具有明显疗效.

Background Although numerous measures have been used to improve the outcome of lung cancer patients, lung cancer, as the second most common diagnosed cancer, is still the main cause of cancer death. It becomes increasingly urgent for us to deeply deplore the molecular mechanism of lung cancer and to discover the potential therapeutic targets. In our study, we are dedicated to discovering the role of MIB2 in lung cancer development. Methods The public databases were used to compare the expression level of MIB2 in cancer and non-cancer tissue. We analyzed the expression of MIB2 in lung cancer samples by performing Rt-PCR and western blot. We carried out CCK8 and clone assays to study the influence of MIB2 in lung cancer proliferation. The transwell assays and wound healing assays were implemented to study the function of MIB2 in metastasis and invasion. Proteins of cell cycle control pathways are detected to verify the potential mechanism of MIB2 in lung cancer progression. Results MIB2 is up regulated in lung cancer tissue compared to adjacent normal lung tissue according to both public databases and our clinical lung cancer samples. Knockdown of MIB2 inhibits proliferation, metastasis, and invasion of lung cancer cell lines. Cyclins and cyclin dependent kinases (CDK) including CDK2, CDK4, and cyclinB1 were down regulated in MIB2 knockdown cells. Conclusion Our results prove that MIB2 acts as a driver in NSCLC tumorigenesis by regulating cell cycle control pathways.

Lung cancer with Leptomeningeal metastasis has a poor prognosis, and for epidermal growth factor receptor(EGFR) mutation-positive patients with T790M negative after first-generation tyrosine kinase inhibitors resistance, guidelines recommend chemotherapy combined with anti-angiogenesis therapy. This article presented a female patient with EGFR L858R mutation and Iressa-resistant T790M negative leptomeningeal metastasis of lung cancer, who refused chemotherapy because of senior and could not tolerate the gastrointestinal reaction of chemotherapy. According to the multidisciplinary consultation and discussion opinions of the adiologist, neurosurgeon,radiotherapist and medical oncologist, the best curative effect of Osimertinib followed ventriculoperitoneal shunt was disease stability, and the overall survival time after diagnosis of leptomeningeal metastasis was more than 3 years.

BACKGROUND:As a small G protein of Ras family, Ras-like-without-CAAX-1 (RIT1) plays a critical role in various tumors. Our previous study has demonstrated the involvement of RIT1 in promoting malignant progression of hepatocellular carcinoma (HCC). However, its underlying mechanism remains unclear.METHODS:Gene set enrichment analysis (GSEA) was conducted in the TCGA LIHC cohort to investigate the underlying biological mechanism of RIT1. Live cell imaging, immunofluorescence (IF) and flow cytometry assays were used to verify biological function of RIT1 in HCC mitosis. Subcutaneous xenografting of human HCC cells in BALB/c nude mice was utilized to assess tumor proliferation in vivo. RNA-seq, co-immunoprecipitation (Co-IP), mass spectrometry analyses, western blot and IF assays were employed to elucidate the mechanisms by which RIT1 regulates mitosis and promotes proliferation in HCC.RESULTS:Our findings demonstrate that RIT1 plays a crucial role in regulating mitosis in HCC. Knockdown of RIT1 disrupts cell division, leading to G2/M phase arrest, mitotic catastrophe, and apoptosis in HCC cells. SMC3 is found to interact with RIT1 and knockdown of SMC3 attenuates the proliferative effects mediated by RIT1 both in vitro and in vivo. Mechanistically, RIT1 protects and maintains SMC3 acetylation by binding to SMC3 and PDS5 during mitosis, thereby promoting rapid cell division and proliferation in HCC. Notably, we have observed an upregulation of SMC3 expression in HCC tissues, which is associated with poor patient survival and promotion of HCC cell proliferation. Furthermore, there is a significant positive correlation between the expression levels of RIT1, SMC3, and PDS5. Importantly, HCC patients with high expression of both RIT1 and SMC3 exhibit worse prognosis compared to those with high RIT1 but low SMC3 expression.CONCLUSIONS:Our findings underscore the crucial role of RIT1 in regulating mitosis in HCC and further demonstrate its potential as a promising therapeutic target for HCC treatment.

Objective:Focusing on the dynamic changes of B cells in the development and progression of lung adenocarcinoma, the role of B cells in the tumor microenvironment of lung adenocarcinoma was preliminarily elucidated by analyzing the single-cell data of lung adenocarcinoma.Methods:Single-cell data of lung adenocarcinoma were analyzed, raw read counts were normalized using the NormalizeData function, and cell-to-cell differences in gene expression were eliminated using the ScaleData function. Use "FindVariableFeatures" to calculate high-expression genes between groups. After cell clustering, SingleR-assisted cell class annotation was performed, 10 B-cell subclass cells were time-quasi-sequence analysis using monocle2, differences between genes in different states were calculated and heat maps were drawn, differentially expressed genes were enriched by GO pathway.Results:B cells are rarely distributed in normal lung tissue, and relatively more in tumor tissue. Among them, the number of memory B cells and plasma cells in the lung primary lesion increased significantly, in brain metastases, plasma cells were significant, and the differential genes in various tissues were enriched and analyzed, and it was found that immune B cells in the primary tumor of lung cancer produced a strong immune response to cancer cells, and when the tumor cells metastasized, the role of plasma cells in brain metastases was mainly to inhibit cell growth, ensure the stability of cells and tissues, and alleviate the damage of tumor cells invading other tissues to a certain extent.Conclusion:Based on single-cell analysis, the mechanism of action of B cells in the pathogenesis and brain metastasis of lung adenocarcinoma can be further understood, and the clinical application of immunity to lung adenocarcinoma brain metastasis can be further understood.

(1) Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been the first line therapy for EGFR-mutant lung adenocarcinoma (LAC) patients with brain metastases (BMs). However, the role and the optimal time of brain radiotherapy remains controversial. We aimed to investigate the role of upfront brain stereotactic radiotherapy (SRS) and the impact of deferral radiotherapy on patients’ clinical outcomes. (2) Methods: We retrospectively studied 53 EGFR-mutant LAC patients with limited synchronous BMs between 2014 and 2020 at our institute. The limited BMs was defined with one to four BM lesions, with a maximal size of ≤4 cm. Patients were categorized into two groups: upfront brain SRS (upfront RT) and upfront TKIs. The intracranial progression-free survival (iPFS), progression-free survival (PFS), and overall survival (OS) between groups were analyzed. (3) Results: The median iPFS (21.0 vs. 12.0 months, p = 0.002) and PFS (20.0 vs. 11.0 months, p = 0.004) of the upfront RT group was longer than that of the upfront TKI group. There were no significant differences in median OS (30.0 vs. 26.0 months, p = 0.552) between the two groups. The upfront RT group is less likely to suffer from intracranial progression of the original sites than that of upfront TKIs during the disease course (36.1% vs. 0.0%, p = 0.025). Multivariate analysis showed that the Karnofsky Performance Scale and the presence of synchronous meningeal metastases were associated with overall survival. (4) Conclusions: Compared with upfront TKI, the combination of upfront SRS with TKIs can improve the iPFS and PFS in EGFR-mutant LAC with synchronous BMs. The addition of upfront brain SRS was useful for the original intracranial metastatic lesions.