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Radiofrequency ablation (RFA) promotes tumor antigen-specific T cell responses and enhances the effect of immunotherapy in preclinical settings. Here we report that the existence of remnant tumor masses due to incomplete RFA (iRFA) is associated with earlier new metastases and poor survival in patients with colorectal cancer liver metastases (CRCLM). Using mouse models, we demonstrate that iRFA promotes tumor progression and hinders the efficacy of anti-PD-1 therapy. Immune analysis reveals that iRFA induces sustained local inflammation with predominant myeloid suppressor cells, which inhibit T cell function in tumors. Mechanistically, tumor cell-derived CCL2 is critical for the accumulation of monocytes and tumor-associated macrophages (TAMs). The crosstalk between TAMs and tumor cells enhances the CCL2 production by tumor cells. Furthermore, we find that administration of a CCR2 antagonist or the loss of CCL2 expression in tumor cells enhances the antitumor activity of PD-1 blockade, providing a salvage alternative for residual tumors after iRFA. Radiofrequency ablation is used to treat metastatic colorectal cancer. In this study, the authors show that incomplete ablation of tumours results in metastases and show in mouse models that the chemokine CCL2 recruits myeloid cells to the partially ablated tumours, which can block T cell function.

To evaluate the benefits and risks of hepatic artery infusion (HAI) gemcitabine and floxuridine (FUDR) in patients with nasopharyngeal carcinoma liver metastases. HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 16 patients with unresectable nasopharyngeal carcinoma liver metastases. HAI gemcitabine and FUDR in combination with radiotherapy and systemic chemotherapy were delivered. Disease control rate (DCR) of intrahepatic lesions is 100%, objective response rate (ORR) of intrahepatic lesions is 87.5%, including 4 patients (25%) with complete response (CR), 10 patients (62.5%) with partial response (PR) and 2 patients (12.5%) with stable disease (SD). The median overall survival (mOS) was 30 months. There was no significant difference between patients with < 9 intrahepatic lesions and patients with ≥ 9 intrahepatic lesions (31 months vs. 24 months, P = 0.562). Patients without extrahepatic metastases has longer survival than patients with extrahepatic metastases (31 months vs. 17 months, P = 0.005). In all 72 cycles of HAI, the main grade 3/4 toxicities related to HAI include: leukopenia occur in 8 cycles (11.1%), thrombocytopenia in 5 cycles (6.9%), AST/ALT elevation in 12 cycles (16.7). Catheter related complications occurred in 2 patients (12.5%). HAI gemcitabine and FUDR is effective to improve DCR of intrahepatic lesions and prolong mOS for patients with nasopharyngeal carcinoma liver metastases, and is associated with a relative low rate of toxicity.

Objective: The prognosis of large hepatocellular carcinoma (HCC) is still unfavorable due to limited and challenging treatment. CalliSpheres® microsphere-transarterial chemoembolization (CSM-TACE) is an effective therapy for general HCC but not frequently applied for large HCC. Hence, this study aimed to investigate the efficacy and safety of CSM-TACE in large HCC patients. Materials and Methods: This prospective study analyzed 100 large HCC (tumor size >5 cm) patients receiving CSM-TACE. Treatment response, survival, change in liver function indexes, and adverse events were recorded. Result: The best complete response, partial response, stable disease, and progressive disease rates were 2.0%, 31.3%, 65.7%, and 1.0%, respectively, leading to the best objective response rate (ORR) of 33.3% and disease control rate of 99.9%. Multivariate analysis showed that intrahepatic metastasis was independently related to poor ORR (odd ratio = 0.366, P = 0.023). The 1- and 2-year progression-free survival (PFS) rates were 88.9% and 80.6%, with a mean [95% confidence interval (CI)] PFS of 21.6 (20.4-22.9) months. The 1- and 2-year overall survival (OS) rates were 99.0% and 99.0%, with a mean (95% CI) OS of 23.8 (23.3-24.2) months. Total bilirubin (P < 0.001), alanine transaminase (P < 0.001), aspartate transaminase (P < 0.001), and α-fetoprotein (P = 0.045) were abnormal in a short-term period then stably recovered from 1 month ± 15 days after drug-eluting bead-TACE to 24 months ± 15 days. During hospitalization and postdischarge, tolerable abdominal pain and decreased appetite were common adverse events. Conclusions: CSM-TACE shows favorable treatment response and survival with acceptable tolerance among large HCC patients, indicating that it may promote the management of these patients.

PurposePyrrolidine alkaloids-related hepatic sinusoidal obstruction syndrome (PA-HSOS) is associated with a high mortality rate without standardized therapy. The efficacy of transjugular intrahepatic portosystemic shunts (TIPS) remains controversial. The study aimed to explore the risk factors influencing the clinical response in patients with PA-HSOS related to Gynurasegetum (GS) to assess the disease prognosis at an early stage and to evaluate the efficacy of TIPS in these patients. MethodsThis study retrospectively enrolled patients diagnosed with PA-HSOS between January 2014 and June 2021 with a clear history of exposure to GS. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors influencing the clinical response in patients with PA-HSOS. Propensity score matched (PSM) was performed to compensate for differences in baseline characteristics between patients with and without TIPS. The primary outcome was the clinical response defined as the disappearance of ascites with normal total bilirubin levels and/or a reduction of elevated transaminase levels < 50% within 2 weeks.ResultsA total of 67 patients were identified in our cohort with a clinical response rate of 58.2%. Of these, thirteen patients were assigned to the TIPS group and 54 to the conservative treatment group. Logistic regression analysis revealed that TIPS treatment (P = 0.047), serum globulin levels (P = 0.043), and prothrombin time (P = 0.001) were independent factors influencing clinical response. After PSM, there was a higher long-term survival rate of patients (92.3% vs. 51.3%, P = 0.021) and a shorter hospital stay (P = 0.043), but a high trend in hospital costs (P = 0.070) in the TIPS group. The 6-month survival probability in patients undergoing TIPS therapy was more than ninefold higher than in patients without receiving that treatment [hazard ratio (95% CI) = 9.304 (4.250, 13.262), P < 0.05].ConclusionsTIPS therapy may be an effective treatment option for patients with GS-related PA-HSOS.

The discovery of monolayer superconductors bears consequences for both fundamental physics and device applications. Currently, the growth of superconducting monolayers can only occur under ultrahigh vacuum and on specific lattice-matched or dangling bond-free substrates, to minimize environment- and substrate-induced disorders/defects. Such severe growth requirements limit the exploration of novel two-dimensional superconductivity and related nanodevices. Here we demonstrate the experimental realization of superconductivity in a chemical vapour deposition grown monolayer material—NbSe 2 . Atomic-resolution scanning transmission electron microscope imaging reveals the atomic structure of the intrinsic point defects and grain boundaries in monolayer NbSe 2 , and confirms the low defect concentration in our high-quality film, which is the key to two-dimensional superconductivity. By using monolayer chemical vapour deposited graphene as a protective capping layer, thickness-dependent superconducting properties are observed in as-grown NbSe 2 with a transition temperature increasing from 1.0 K in monolayer to 4.56 K in 10-layer. Two-dimensional superconductors will likely have applications not only in devices, but also in the study of fundamental physics. Here, Wang et al. demonstrate the CVD growth of superconducting NbSe2 on a variety of substrates, making these novel materials increasingly accessible.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

Background Dyslipidemia is a common comorbidity in patients with cancer, yet the impact of abnormal lipid levels on tumor prognosis remains contentious. This study was conducted to synthesize the current evidence regarding the prognostic utility of blood lipid levels, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), in predicting overall survival (OS) and disease-free survival (DFS) in cancer patients. Methods A comprehensive literature search was performed across electronic databases to assess the associations between blood lipid levels and OS or DFS in cancer patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to analyze the data. The research protocol was previously submitted to the International Prospective Register of Systematic Reviews (PROSPERO): CRD42023458597. Results Our study represents the largest and most extensive evaluation of the prognostic significance of blood lipid levels in cancer to date. It includes a meta-analysis of 156 eligible studies involving 85,173 cancer patients. The findings revealed a significant association between elevated levels of HDL-C, TC, and ApoA1 and improved OS and DFS in cancer patients. In contrast, no significant relationships were identified between LDL-C, TG, and ApoB levels and the OS or DFS of cancer patients. Conclusion Blood lipids, particularly HDL-C, TC, and ApoA1, emerge as accessible and cost-effective biomarkers that may aid in assessing survival outcomes in cancer patients and potentially inform clinical decision-making.

Background This case highlights the diagnostic challenges of atrial flutter with concealed atrial activity on surface electrocardiograms, emphasizing the necessity of invasive electrophysiological study to avoid unnecessary pacemaker implantation in patients with structural heart disease—a scenario rarely documented in current literature. Case presentation A 60-year-old ​Chinese woman with rheumatic mitral stenosis and prior maze procedure presented with fatigue and bradycardia (heart rate, 47 beats per minute). Surface electrocardiograms (including modified Lewis leads) revealed no discernible P waves, while echocardiography demonstrated atrial mechanical silence. Electrophysiological study identified cavotricuspid isthmus-dependent atrial flutter with extensive right atrial low-voltage zones (voltage < 0.5 mV), explaining the absent surface atrial activity. Radiofrequency ablation achieved bidirectional isthmus block, restoring sinus rhythm (heart rate, 59 beats per minute) without pacemaker requirement. Conclusion In patients with bradycardia and electromechanical atrial dissociation, electrophysiological study proves indispensable for detecting atrial flutter obscured by severe fibrosis. This approach prevents inappropriate pacemaker implantation while restoring physiological rhythm, establishing a paradigm for managing complex arrhythmias in structural heart disease.

Background Osimertinib is a standard treatment for first- or second-line therapy in patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR). However, options are limited for patients with acquired EGFR T790M mutations resistant to first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of combining osimertinib with anlotinib in this patient population and explored circulating tumor DNA (ctDNA) as a biomarker of treatment outcomes. Methods In this prospective, single-arm, phase II trial, 31 patients with advanced NSCLC resistant to prior first- or second-generation EGFR-TKIs therapy received osimertinib (80 mg daily) and anlotinib (12 mg daily on days 1–14 of each 21-day cycle). Efficacy endpoints included progression-free survival (PFS) and overall survival (OS). ctDNA was analyzed using next-generation sequencing (NGS) to monitor mutation status and treatment response. Results The median PFS was 16.2 months (95% confidence interval [CI] 9.8–23.6, 90% CI 14.2–20.9), and the median OS was 31.4 months (95% CI 27.3–not reached). The objective response rate (ORR) was 45.2% (95% CI 30.6–66.6%), with a disease control rate (DCR) of 96.8% (95% CI 86.3–100.0%). ctDNA analysis showed that activating EGFR mutation clearance after two treatment cycles correlated with significantly longer PFS and OS. The regimen was well-tolerated, with no grade 4 or higher adverse events observed. Conclusions Osimertinib combined with anlotinib demonstrates promising long-term efficacy and manageable safety in EGFR T790M-positive NSCLC. Clearance of ctDNA, particularly of EGFR mutations, could serve as a valuable predictive biomarker, supporting the implementation of personalized treatment strategies. Trial registration ClinicalTrials.gov, NCT04029350.

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.