Exploring the environmental risks and seasonal variations of potentially toxic elements (PTEs) in fine road dust in resource-based cities based on Monte Carlo simulation, geo-detector and random forest model.

The environmental pollution caused by mineral exploitation and energy consumption poses a serious threat to ecological security and human health, particularly in resource-based cities. To address this issue, a comprehensive investigation was conducted on potentially toxic elements (PTEs) in road dust from different seasons to assess the environmental risks and influencing factors faced by Datong City. Multivariate statistical analysis and absolute principal component score were employed for source identification and quantitative allocation. The geo-accumulation index and improved Nemerow index were utilized to evaluate the pollution levels of PTEs. Monte Carlo simulation was employed to assess the ecological-health risks associated with PTEs content and source orientation. Furthermore, geo-detector and random forest analysis were conducted to examine the key environmental variables and driving factors contributing to the spatiotemporal variation in PTEs content. In all PTEs, Cd, Hg, and Zn exhibited higher levels of content, with an average content/background value of 3.65 to 4.91, 2.53 to 3.34, and 2.15 to 2.89 times, respectively. Seasonal disparities were evident in PTEs contents, with average levels generally showing a pattern of spring (winter) > summer (autumn). PTEs in fine road dust (FRD) were primarily influenced by traffic, natural factors, coal-related industrial activities, and metallurgical activities, contributing 14.9-33.9 %, 41.4-47.5 %, 4.4-8.3 %, and 14.2-29.4 % to the total contents, respectively. The overall pollution and ecological risk of PTEs were categorized as moderate and high, respectively, with the winter season exhibiting the most severe conditions, primarily driven by Hg emissions from coal-related industries. Non-carcinogenic risk of PTEs for adults was within the safe limit, yet children still faced a probability of 4.1 %-16.4 % of unacceptable risks, particularly in summer. Carcinogenic risks were evident across all demographics, with children at the highest risk, mainly due to Cr and smelting industrial sources. Geo-detector and random forest model indicated that spatial disparities in prioritized control elements (Cr and Hg) were primarily influenced by particulate matter (PM10) and anthropogenic activities (industrial and socio-economic factors); variations in particulate matter (PM10 and PM2.5) and meteorological factors (wind speed and precipitation) were the primary controllers of seasonal disparities of Cr and Hg.

The FGF6 amplification mutation plays an important role in the progression and treatment of malignant meningioma.

Meningioma is a benign tumor with slow growth and long course. However, patients with recurrent malignant meningioma still face a lack of effective treatment. Here, we report a rare case of primary mediastinal malignant meningioma with lung and bone metastases, who benefited from the treatment of apatinib (≥33 months) and anlotinib (until the publication date). Retrospective molecular analysis revealed the frequent amplification of FGF6 in primary and metastatic lesions. Then we constructed the FGF6 over-expressed IOMM-LEE and CH157MN malignant meningioma cell lines, and in vitro and vivo experiments showed that overexpression of FGF6 can promote the proliferation, migration and invasion of malignant meningioma cells. Based on the Western analysis, we revealed that FGF6 can promote the phosphorylation of FGFR, AKT, and ERK1/2, which can be inhibited by anlotinib. Together, we were the first to verify that overexpression of FGF6 promotes the progression of malignant meningiomas by activating FGFR/AKT/ERK1/2 pathway and pointed out that anlotinib may effectively inhibit the disease progression of patients with FGF6 amplification.

Analysis of clinical features and prognostic factors in Takayasu arteritis involving pulmonary hypertension: A retrospective study.

BACKGROUND: Multiple takayasu arteritis (TA) is a chronic nonspecific large to medium vasculitis disease that mainly accumulates the aorta and its branches. Pulmonary vascular disease is often seen as stenosis and occlusion, and patients may show no moderate to severe pulmonary hypertension (PH). This study aims to summarize the clinical characteristics and analysis of prognostic factors in patients with PH caused by TA. METHODS: Patients diagnosed with aortitis involving the pulmonary artery by pulmonary arteriography or pulmonary artery and total aortic computed tomography arteriography (CTA). All patients underwent detailed clinical assessment, laboratory data collection, and analysis of imaging data. Patients were followed up and factors affecting the prognosis of the pulmonary arteries were analyzed. RESULTS: Most of the patients' complaints were chest tightness, shortness of breath, decreased activity tolerance, hemoptysis and chest pain. 56.90% of the patients were in at the time of admission. Echocardiographic estimation of pulmonary artery systolic pressure was 90.39 ±â€…22.87 mm Hg. In terms of laboratory tests, 39.66%% of the patients had elevated C-reactive protein and erythrocyte sedimentation rate, and amino-terminal natriuretic peptide precursor on admission. In terms of imaging, all patients had pulmonary artery involvement, which was combined with aortic involvement in 31.03%. Nuclide lung perfusion/ventilation imaging of the patients revealed multiple perfusion defects/absences in the segmental and subsegmental distribution of the lungs. Univariate Cox regression model analysis suggested that patients' WHO functional class at admission, age ≧ 51 years at the time of consultation, and amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL were factors affecting the prognosis. Further multifactorial Cox regression model analysis suggested amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL was an independent predictor of poor prognosis with a hazard ratio (HR) value of 5.248. CONCLUSION: Electrocardiogram and echocardiogram may suggest an increased right heart load; some patients have elevated serum inflammatory indexes. Characteristic imaging manifestations include widening of the main pulmonary artery, multiple pulmonary segmental and subsegmental stenoses.

CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be involved in the regulation of the PI3K/AKT pathway, but the underlying mechanisms are unclear. Therefore, this study aimed to identify protein-coding circRNAs and investigate their functions in ESCC. METHODS: Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. Thereafter, LC-MS/MS was used to identify circPDE5A-encoded novel protein PDE5A-500aa. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circPDE5A and PDE5A-500aa in ESCC. Lastly, circRNA-loaded nanoplatforms were constructed to investigate the therapeutic translation value of circPDE5A. RESULTS: We found that circPDE5A expression was down-regulated in ESCC cells and tissues and that it was negatively associated with advanced clinicopathological stages and poorer prognosis in ESCC. Functionally, circPDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding PDE5A-500aa, a key regulator of the PI3K/AKT signaling pathway in ESCC. Mechanistically, PDE5A-500aa interacted with PIK3IP1 and promoted USP14-mediated de-ubiquitination of the k48-linked polyubiquitin chain at its K198 residue, thereby attenuating the PI3K/AKT pathway in ESCC. In addition, Meo-PEG-S-S-PLGA-based reduction-responsive nanoplatforms loaded with circPDE5A and PDE5A-500aa plasmids were found to successfully inhibit the growth and metastasis of ESCC in vitro and in vivo. CONCLUSION: The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of ESCC by promoting USP14-mediated de-ubiquitination of PIK3IP1 and may serve as a potential target for the development of therapeutic agents.

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Hepatocellular Carcinoma Treated with Conventional Transcatheter Arterial Chemoembolization: A Propensity Score Matched Analysis.

PURPOSE: This study aims to evaluate the prognostic value of controlling nutritional status (CONUT) score in determining the prognosis of patients with hepatocellular carcinoma (HCC) treated with conventional transcatheter arterial chemoembolization (cTACE). METHODS: This study retrospectively analyzed 936 patients who underwent cTACE for HCC between January 2012 and December 2018, and divided them into two groups based on their CONUT score. To balance the bias in baseline characteristics, propensity score matched (PSM) analysis was conducted. The Kaplan-Meier method was used to establish a cumulative survival curve, and the log-rank test was employed to determine differences in overall survival (OS) and progression-free survival (PFS) among the CONUT score groups. Furthermore, the Cox proportional hazard model was employed to assess the correlation between CONUT score and OS and PFS, whereby hazard ratios (HRs) and 95% confidence intervals (95% CIs) were computed. RESULTS: Before PSM, the median OS for the low (≤ 3) and high (≥ 4) CONUT group (558 vs. 378 patients) was 21.7 and 15.6 months, respectively, and the median PFS was 5.7 and 5 months. Following PSM, both the low and high CONUT score groups comprised 142 patients. The low CONUT score group exhibited a significantly longer OS compared to the high CONUT score group, as determined by the log-rank test (median OS 22.2 vs. 17.0 months, P = 0.014). No significant association was observed between CONUT group and PFS (median PFS 6.4 vs. 4.7 months, log-rank test, P = 0.121). Cox proportional hazard regression analysis revealed that a CONUT score of ≥ 4 was an independent risk factor for OS in patients with HCC who underwent cTACE (HR = 1.361; 95% CI: 1.047-1.771; P = 0.022). These findings were consistent across most subgroup analyses. CONCLUSION: A high CONUT score has been found to be a prognostic factor for poorer OS in patients with HCC who underwent cTACE. LEVEL OF EVIDENCE: Level 3, Non-randomized controlled cohort.

Functional knee phenotypes appear to be more suitable for the Chinese OA population compared with CPAK classification: A study based on 3D CT reconstruction models.

PURPOSE: The aim of this study was to investigate the distribution of coronal plane alignment of the knee (CPAK) classification and functional knee phenotypes in a Chinese osteoarthritis (OA) population and to compare different lower limb alignment targets according to the distribution characteristics to find suitable total knee arthroplasty (TKA) bone cut strategies for the Chinese OA patients. METHODS: The computed tomography (CT) images were retrospectively collected and the three-dimensional (3D) models were reconstructed from 434 Chinese OA patients, including 93 males and 341 females, with a mean age of 66.4 ± 9.3 years. Femoral mechanical angle (FMA), tibial mechanical angle (TMA) and mechanical hip-knee-ankle angle (mHKA) were measured on the 3D models. Arithmetic hip-knee-ankle angle (aHKA) was calculated using FMA plus TMA, and joint line obliquity was calculated as 180 + TMA-FMA. The CPAK according to MacDessi and the functional knee phenotypes according to Hirschmann were performed. In addition, the suitable TKA bone cut strategies were explored according to the phenotypes and based on the characteristics of different alignment targets, such as mechanical alignment, anatomic alignment (AA), kinematic alignment, restricted KA (rKA) and adjusted MA (aMA). Statistical differences were determined using the independent-samples t-test or the two independent-samples Wilcoxon test, with p < 0.05 considered statistically significant. RESULTS: The Chinese OA population showed a varus alignment tendency (mHKA = 172.1° ± 7.2°), to which the TMA was a major contributor (TMA = 84.7° ± 4.4° vs. FMA = 91.3° ± 3.2°). The mHKA was on average 3.9° more varus than the aHKA. A total of 140 functional knee phenotypes were found and 45.6% were concentrated in VARFMA3°-NEUFMA0° to VARTMA3°-NEUTMA0°. More than 70% of patients had different FMA and TMA phenotypes. There were 92.9% of CPAK distributed in types I to IV, with type I accounting for 53.9%. The FMA phenotypes were less changed if the aMA and rKA were chosen, and the TMA phenotypes were less changed if the AA and rKA were chosen. CONCLUSION: Compared with the CPAK, the functional knee phenotypes were more suitable for the Chinese OA population with a wide distribution and a varus tendency, and it seemed more appropriate to choose aMA and rKA as TKA alignment targets for resection. LEVEL OF EVIDENCE: Level Ⅲ.

Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.

Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.

Single-cell RNA sequencing reveals the MIF-ACKR3 receptor-ligand interaction between iCAFs and tumor cells in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the gastrointestinal tract with a high morbidity and mortality rate. The heterogeneity of ESCC poses challenges in treatment and contributes to the poor prognosis of patients. Therefore, it is crucial to gain a better understanding of the tumor microenvironment (TME) heterogeneity and identify novel therapeutic targets. METHODS: To solve this problem, we performed a single-cell RNA sequencing (scRNA-seq) analysis of ESCC samples obtained from the GEO database. RESULTS: A total of 31,283 single cells were categorized into nine cell types, which included four non-immune cells (epithelial cells, endothelial cells, fibroblasts, schwann cells) and five immune cells (T cells, macrophages, mast cells, neutrophils, B cells). Our study revealed the presence of immunosuppressive tumor microenvironments in ESCC. We have also identified not only inflammatory cancer-associated fibroblast (iCAFs) and myofibroblastic cancer-associated fibroblasts (myCAFs) but also a subset of antigen presenting cancer-associated fibroblasts (apCAFs) which express high levels of HLA class II molecules in ESCC. Furthermore, our analysis of cell communication showed up-regulation of MIF-ACKR3 interaction between iCAFs and tumor cells in tumors compared to normal tissues. Finally, it was demonstrated that macrophage migration inhibitory factor (MIF) facilitates tumor cell migration and invasion through interacting with ACKR3 in vitro. CONCLUSIONS: This study exposes the features of the tumor microenvironment of ESCC via scRNA-seq and examines the dynamics of various cellular subpopulations, thus facilitating the identification of future therapeutic targets for ESCC.

Protocol for culturing and functionally manipulating planarian neoblasts using SiR-DNA-based flow cytometry.

Neoblasts are the only cells capable of proliferation in planarians. The traditional flow cytometry protocol using Hoechst inhibits the cell cycle. Here, we present a protocol for culturing and functionally manipulating planarian neoblasts using SiR-DNA-based flow cytometry. We describe steps for cell dissociation and staining, flow cytometry, and cell collection and culture. We then detail procedures for Nanoluciferase mRNA transfection. This protocol facilitates further investigations into the pluripotency and regeneration mechanisms within neoblasts. For complete details on the use and execution of this protocol, please refer to Lei et al.1.

Impact of preoperative transcatheter arterial chemoembolization (TACE) on postoperative long-term survival in patients with nonsmall hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The purpose of this propensity score matching (PSM) analysis was to compare the effects of preoperative transcatheter arterial chemoembolization (TACE) and non-TACE on the long-term survival of patients who undergo radical hepatectomy. METHODS: PSM analysis was performed for 387 patients with hepatocellular carcinoma (HCC) (single > 3 cm or multiple) who underwent radical resection of HCC at our centre from January 2011 to June 2018. The patients were allocated to a preoperative TACE group (n = 77) and a non-TACE group (n = 310). The main outcome measures were progression-free survival (PFS) and overall survival (OS) since the treatment date. RESULTS: After PSM, 67 patients were included in each of the TACE and non-TACE groups. The median PFS times in the preoperative TACE and non-TACE groups were 24.0 and 11.3 months, respectively (p = 0.0117). The median OS times in the preoperative TACE and non-TACE groups were 41.5 and 29.0 months, respectively (p = 0.0114). Multivariate Cox proportional hazard regression analysis revealed that preoperative TACE (hazard ratio, 1.733; 95% CI, 1.168-2.570) and tumour thrombosis (hazard ratio, 0.323; 95% CI, 0.141-0.742) were independent risk factors significantly associated with OS. CONCLUSIONS: Preoperative TACE is related to improving PFS and OS after resection of HCC. Preoperative TACE and tumour thrombus volume were also found to be independent risk factors associated with OS.

Nrf2/HO-1 signaling activation alleviates cigarette smoke-induced inflammation in chronic obstructive pulmonary disease by suppressing NLRP3-mediated pyroptosis.

BACKGROUND: This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD) and the potential molecular mechanism. METHODS: A COPD mouse model was established by cigarette smoke exposure and administered with either ML385 or dimethyl fumarate (DMF). Airway resistance of mice was detected. IL-1ß and IL-6 levels in mice alveolar lavage fluid were examined by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical of lung tissues were utilized to detect lung injury and NLRP3 expression. DMF was used to treat COPD cell model constructed by exposing normal human bronchial epithelial (NHBE) cells to cigarette smoke extract. NHBE cells were transfected by NLRP3-expression vectors. Expression of proteins was detected by Western blot. RESULTS: COPD mice showed the enhanced airway resistance, the inactivated Nrf2/HO-1 pathway and the overexpressed NLRP3, Caspase-1 and GSDMD-N proteins in lung tissues, and the increased IL-1ß and IL-6 levels in alveolar lavage fluid. ML385 treatment augmented these indicators and lung injury in COPD mice. However, DMF intervention attenuated these indicators and lung injury in COPD mice. Nrf2/HO-1 pathway inactivation and overexpression of NLRP3, Caspase-1 and GSDMD-N proteins were observed in COPD cells. DMF intervention activated Nrf2/HO-1 pathway and down-regulated NLRP3, Caspase-1 and GSDMD-N proteins in COPD cells. However, NLRP3 overexpression abolished the effect of DMF on COPD cells. CONCLUSION: Nrf2/HO-1 pathway activation may alleviate inflammation in COPD by suppressing the NLRP3-related pyroptosis. Activating the Nrf2/HO-1 pathway may be an effective method to treat COPD.

Extended lymphadenectomy based on the TRIANGLE for pancreatic head cancer: a single-center experience.

BACKGROUND: This study was to compare the safety and efficacy of different lymphadenectomy methods in patients with pancreatic head cancer undergoing pancreaticoduodenectomy (PD). MATERIAL AND METHODS: A total of 150 patients were included in this study. Patients were divided into Group A (n = 79), Group B (n = 44), and Group C (n = 27) according to the different lymphadenectomy methods. The clinical endpoint was time to progression (TTP) and overall survival (OS). Postoperative complications of different lymphadenectomy methods were compared respectively. TTP and OS of the three groups were compared by Kaplan-Meier curves. RESULTS: There were no significant differences between the three groups in operative time (P = 0.300), death in the hospital (P = 0.253), postoperative hemorrhage (P = 0.863), postoperative pancreatic fistula (POPF) B/C (P = 0.306), bile leakage (P = 0.215), intestinal fistula (P = 0.177), lymphatic leakage (P = 0.267), delayed gastric emptying [(DGE) (P = 0.283)], ICU stay (P = 0.506), and postoperative hospital stay [(PHS) (P = 0.810)]. Median TTP in Groups B and C was significantly longer than in Group A (log-rank test, A vs B: P = 0.0005, A vs C: P = 0.0001). Median OS between the three groups has no statistical difference (P = 0.1546). CONCLUSIONS: Extended lymphadenectomy methods based on the TRIANGLE do not increase perioperative complications significantly and can effectively delay tumor progression in patients with pancreatic head cancer.

Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis.

Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM. SIGNIFICANCE: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.

Generation of two induced pluripotent stem cell lines from two sporadic amyotrophic lateral sclerosis patients.

Peripheral blood mononuclear cells were obtained from two patients diagnosed with amyotrophic lateral sclerosis (ALS), a 47-year-old female and a 45-year-old male. Induced pluripotent stem cells (iPSCs) were generated using a non-integrating SeV-based method, delivering the transcription factors OCT4, SOX2, c-MYC, and KLF4. These transgene-free iPSC lines exhibited typical pluripotent cell morphology, expressed pluripotency-associated markers, and had tri-lineage differentiation potential. Both iPSC lines were free of mycoplasma contamination and displayed normal karyotypes. The availability of these two cell lines provides a promising opportunity to use sporadic ALS models for investigating the intricate pathological mechanisms of ALS.

LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity.

High-fat diet (HFD)-induced obesity is a crucial risk factor for metabolic syndrome, mainly due to adipose tissue dysfunctions associated with it. However, the underlying mechanism remains unclear. This study has used genetic screening to identify an obesity-associated human lncRNA LINK-A as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo by establishing the HFD-induced obesity knock-in (KI) mouse model. Mechanistically, HFD LINK-A KI mice induce the infiltration of inflammatory factors, including IL-1ß and CXCL16, through the LINK-A/HB-EGF/HIF1α feedback loop axis in a self-amplified manner, thereby promoting the adipose tissue microenvironment remodeling and adaptive thermogenesis disorder, ultimately leading to obesity and insulin resistance. Notably, LINK-A expression is positively correlated with inflammatory factor expression in individuals who are overweight. Of note, targeting LINK-A via nucleic acid drug antisense oligonucleotides (ASO) attenuate HFD-induced obesity and metabolic syndrome, pointing out LINK-A as a valuable and effective therapeutic target for treating HFD-induced obesity. Briefly, the results reveale the roles of lncRNAs (such as LINK-A) in remodeling tissue inflammatory microenvironments to promote HFD-induced obesity.

Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review.

Background: Lung cancer is the second most common form of malignant tumor and has the highest mortality rate worldwide. Among its subtypes, lung adenocarcinoma is the most prevalent. Leptomeningeal metastasis (LM) is rare and is characterized by a dismal prognosis, with overall survival periods typically spanning 4 to 6 weeks without treatment. However, in specific cases, survival can be extended to 4 to 6 months with appropriate therapy. The recent approval of third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, aumolertinib, and furmonertinib, has introduced promising treatment options for individuals with non-small cell lung cancer (NSCLC) who develop LM after developing resistance to first- and second-generation TKIs. These third-generation TKIs exhibit an enhanced ability to penetrate the blood-brain barrier (BBB), opening up new avenues for managing this challenging condition. Case summary: We report the case of a 48-year-old Chinese man diagnosed with advanced NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. Following a pulmonary lobectomy and postoperative adjuvant therapy with gefitinib, the patient was diagnosed with LM, which was confirmed by his neurologic symptoms, cerebrospinal fluid cytologic analysis, and cranial enhancement magnetic resonance imaging. Subsequently, he received oral treatment in the form of 160 mg of furmonertinib daily. After 5 days of furmonertinib therapy, the patient recovered from lethargy, with an obvious improvement in cognitive function. Follow-up visits revealed a 6-month survival period following the LM diagnosis. Patients with NSCLC and LM typically present with severe symptoms, and the efficacy of systemic treatment, intrathecal chemotherapy, and radiotherapy remains unsatisfactory. We hope that this specific case provide valuable insights into the management of patients with EGFR mutation-associated NSCLC with LM. Conclusion: Furmonertinib, a third-generation EGFR TKI with notable BBB penetration, shows promise in LM control and the rapid alleviation of intracranial symptoms. Further investigations into appropriate dosage and toxicity management are imperative.

CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection.

Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development.

Wrapping pancreaticojejunostomy using the ligamentum teres hepatis during laparoscopic pancreaticoduodenectomy: a propensity score matching analysis.

BACKGROUND AND OBJECTIVE: It is controversial whether wrapping around the pancreaticojejunostomy (PJ) could reduce the rate of postoperative pancreatic fistula (POPF), especially in laparoscopic pancreaticoduodenectomy (LPD). This study aims to summarize our single-center initial experience in wrapping around PJ using the ligamentum teres hepatis (LTH) and demonstrate the feasibility and safety of this method. METHODS: Patients who underwent LPD applying the procedure of wrapping around the PJ were identified. The cohort was compared to the cohort with standard non-wrapping PJ. A 1:1 propensity score matching (PSM) was performed to compare the early postoperative outcomes of the two cohorts. Risk factors for POPF were determined by using univariate and multivariate logistic regression analysis. RESULTS: Overall, 143 patients were analyzed (LPD without wrapping (n = 91) and LPD with wrapping (n = 52)). After 1:1 PSM, 48 patients in each cohort were selected for further analysis. Bile leakage, DGE, intra-abdominal infection, postoperative hospital stays, harvested lymph nodes, and R0 resection were comparable between the two cohorts. However, the wrapping cohort was associated with significantly less POPF B (1 vs 18, P = 0.003), POPF C (0 vs 8, P = 0.043), and Clavien-Dindo classification level III-V (5 vs 26, P = 0.010). No patients died due to the clinically relevant POPF in the two cohorts. No patients who underwent the LTH wrapping procedure developed complications directly related to the wrapping procedure. After PSM, whether wrapping was an independent risk factor for POPF (OR = 0.202; 95%CI:0.080-0.513; P = 0.001). CONCLUSIONS: Wrapping the LTH around the PJ technique for LPD was safe, efficient, and reproducible with favorable perioperative outcomes in selected patients. However, further validations using high-quality RCTs are still required to confirm the findings of this study.

RAD51 paralogs synergize with RAD51 to protect reversed forks from cellular nucleases.

Fork reversal is a conserved mechanism to prevent stalled replication forks from collapsing. Formation and protection of reversed forks are two crucial steps in ensuring fork integrity and stability. Five RAD51 paralogs, namely, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which share sequence and structural similarity to the recombinase RAD51, play poorly defined mechanistic roles in these processes. Here, using purified BCDX2 (RAD51BCD-XRCC2) and CX3 (RAD51C-XRCC3) complexes and in vitro reconstituted biochemical systems, we mechanistically dissect their functions in forming and protecting reversed forks. We show that both RAD51 paralog complexes lack fork reversal activities. Whereas CX3 exhibits modest fork protection activity, BCDX2 significantly synergizes with RAD51 to protect DNA against attack by the nucleases MRE11 and EXO1. DNA protection is contingent upon the ability of RAD51 to form a functional nucleoprotein filament on DNA. Collectively, our results provide evidence for a hitherto unknown function of RAD51 paralogs in synergizing with RAD51 nucleoprotein filament to prevent degradation of stressed replication forks.