Search

Abstract Immune checkpoint inhibitors (ICI) have emerged as a promising therapeutic option for melanoma, which demonstrating improved clinical outcomes in melanoma patients regardless of specific genetic mutations. However, the identification of reliable biomarkers for predicting immunotherapy response and prognosis remains a challenge. In this study, we performed genetic profiling of the melanoma patients with different subtypes and evaluated the efficacy of ICI treatment. A total of 221 melanoma patients were included in our cohort, consisting primarily of acral lentiginous melanoma (ALM), cutaneous malignant melanoma (CMM), and mucosal malignant melanoma (MMM). Genetic analysis revealed BRAF mutations was predominant in CMM and NRAS mutations was prevalent in ALM. Copy number variants (CNVs) and structural variants (SV) were also detected, with CCND1 and CDK4 being the most affected genes in CNV and BRAF, ALK and RAF1 being the druggable targets in SV. Furthermore, NRAS mutations were associated with a poor prognosis in ALM, while TERT mutations were linked to unfavorable outcomes in CMM after receiving PD-1 therapy. Additionally, ALK expression exhibited improved outcomes in both ALM and CMM subtypes. Our study provides a comprehensive genomic and pathological profiling of Chinese melanoma patients, shedding light on the molecular landscape of the disease. Furthermore, numbers of gene mutations and ALK expression were identified as prognostic indicators. These findings contribute to the understanding of melanoma genetics in the Chinese population and have implications for personalized treatment approaches.

BACKGROUND: One-lung ventilation (OLV) is frequently applied during video-assisted thoracoscopic surgery (VATS) airway management to collapse and isolate the nondependent lung (NL). OLV can give rise to hypoxemia as a result of the pulmonary shunting produced. Our study aimed to assess the influence of continuous positive airway pressure (CPAP) combined with small-tidal-volume ventilation on improving arterial oxygenation and decreasing pulmonary shunt rate (QS/QT) without compromising surgical field exposure during OLV. METHODS: Forty-eight patients undergoing scheduled VATS lobectomy were enrolled in this research and allocated into three groups at random: C group (conventional ventilation, no NL ventilation intervention was performed), LP group (NL was ventilated with lower CPAP [2 cmH2O] and a 40–60 mL tidal volume [TV]), and HP group (NL was ventilated with higher CPAP [5 cmH2O] and a 60–80 mL TV). Record the blood gas analysis data and calculate the QS/QT at the following time: at the beginning of the OLV (T0), 30 min after OLV (T1), and 60 min after OLV (T2). Surgeons blinded to ventilation techniques were invited to evaluate the surgical fields. RESULTS: The demography data of the three groups were consistent with the surgical data. At T1, PaO2 in the HP group was substantially higher compared to the C group (P < 0.05), while there was no significant difference in the LP group (P > 0.05). At T1-T2, PaCO2 in the LP and HP groups was significantly less than that in the C group (P < 0.05). At T1, the QS/QT values of groups C, LP, and HP were 29.54 ± 6.89%, 22.66 ± 2.08%, and 19.64 ± 5.76%, respectively, and the QS/QT values in the LP and HP groups markedly reduced (P < 0.01). The surgical field’s evaluation by the surgeon among the three groups was not notable (P > 0.05). CONCLUSION: CPAP combined with small-tidal-volume ventilation effectively improved arterial oxygenation and reduced QS/QT and PaCO2 without compromising surgical field exposure during OLV. Among them, 5 cmH2O CPAP + 60–80 ml TV ventilation had a better effect on improving oxygenation.

The dynamic temperature data of a transformer can be utilized to accurately assess its load capability and operational longevity. This paper presents a study on the temperature rise characteristics of hot-spots in dry-type transformer windings and develops a extrapolative computational model based on various load rates, utilizing the results of transformer temperature rise tests. Firstly, the dynamic temperature rise characteristics of B-phase low-voltage (LV) winding and high-voltage (HV) winding hot-spot, along with its correlation calculation model with varying load rates, were determined based on the results of temperature rise tests. Subsequently, an extrapolative computational model for the temperature rise of the winding hot-spot, utilizing a three-section continuous load application approach, was proposed employing the lumped parameter method. The validity of this model was confirmed through verification. Lastly, a temperature rise test was conducted on another dry-type transformer to validate the universality of the model. Finally, a different dry-type transformer is chosen, and a temperature rise test is conducted to confirm the general applicability of the model. The results indicate that the calculation model for the hot-spot temperature rise of the winding under three consecutive loads is associated with the dynamic temperature rise pattern of the hot-spot of the winding between the temperature rise test with a small load rate and the temperature rise test with a large load rate. The maximum deviation between the hot-spot temperature rise test of the winding of SCB14-800/10-NX2 transformer and the results of the steady-state temperature rise value calculation is only 1.3 K, with a maximum error of the time constant value of the temperature rise being only 0.05 h. Similarly, the maximum deviation of the steady-state temperature rise value obtained from the hot-spot temperature rise test and the extrapolative computation of SCB-1250kVA/10 kV transformer winding is only 2.03 K, with a maximum error of the temperature rise time constant value being only 0.09 h. The extrapolative computational model proposed in this study conducts the temperature rise test under a small load rate instead of a large load rate, addressing the industry challenge of the challenging implementation of transformer on-site temperature rise tests and high power loss. This approach enhances inspection efficiency.

Introduction: Dysregulation in lipid metabolism contributes to the occurrence and development of various cancers. The connection between changes in lipid metabolism and the development of intrahepatic cholangiocarcinoma remains uncertain. Our objective was to investigate the significance of blood lipid levels in patients with intrahepatic cholangiocarcinoma who have undergone surgery. Methods: Ninety-seven ICC patients who underwent surgery were retrospectively enrolled. After 92.2 months of follow-up, the Kaplan-Meier analysis and Cox proportional hazard model were used to calculate overall survival and recurrence-free survival. Results: The median age of this cohort was 56 years, and 79 (81.4 %) of them were male. Eighty-eight (90.7 %) patients presented with tumor recurrence and 73 (75.3 %) died. In multivariate analyses, high-density lipoprotein cholesterol level (

Abstract Magnetic flux ropes are ubiquitous in various space environments, including the solar corona, interplanetary solar wind, and planetary magnetospheres. When these flux ropes intertwine, magnetic reconnection may occur at the interface, forming disentangled new ropes. Some of these newly formed ropes contain reversed helicity along their axes, diverging from the traditional flux rope model. We introduce new observations and interpretations of these newly formed flux ropes from existing Hall Magnetohydrodynamics model results. We first examine the time‐varying local magnetic field direction at the impact interface to assess the likelihood of reconnection. Then we investigate the electric current system to describe the evolution of these structures, which potentially accelerate particles and heat the plasma. This study offers novel insights into the dynamics of space plasmas and suggests a potential solar wind heating source, calling for further synthetic observations.

Abstract Background Kupffer cells (KCs) originate from yolk-sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at a steady state and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adults remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. Methods We first traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models, respectively. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC-depletion in mice. Finally, we traced the fate of hematopoietic stem cells (HSCs) in an HSC-specific fate-mapping mouse model, in the context of chronic liver inflammation induced by repeated carbon tetrachloride treatment. Results By using fate-mapping mouse models, we found no evidence that repopulating KCs originate from preexisting KCs or MOs and found that in response to KC-depletion, HSCs proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Then, in the chronic liver inflammation context, we confirmed that repopulating KCs originated directly from HSCs. Conclusion Taken together, these findings provided in vivo fate-mapping evidence that repopulating KCs originate directly from HSCs, which presents a completely novel understanding of the cellular origin of repopulating KCs and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

Background & aimsThe effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC.MethodsUsing a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS.ResultsAmong the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC.ConclusionThis real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.

Abstract Aims Splenectomy combined with pericardial devascularization is one of the important methods to treat hypersplenism, gastrointestinal bleeding, and other complications caused by liver cirrhosis; however, it is accompanied by a high risk of portal vein thrombosis (PVT). This study aimed to explore the preventive and therapeutic effects of proximal splenic vein ligation (PSVL) with postoperative transcatheter anticoagulant therapy (TCAT) on PVT. Methods This study retrospectively selected 143 patients with liver cirrhosis and portal hypertension, who received splenectomy combined with pericardial devascularization from June 30, 2018 to June 30, 2021. According to computed tomography photography, within 1 week before the operation, the patients were divided into a prevention group (without preoperative PVT, n = 112) and a treatment group (preoperative PVT, n = 31). Then, each group was subdivided based on the treatment and prevention measures into PSVL + TCAT (n = 70) and systemic anticoagulant therapy (SAT) subgroups (n = 73). The preventive and therapeutic effects of PSVL followed by TCAT on PVT were analyzed. Results The operation time in the PSVL + TCAT subgroups was longer than that in the SAT subgroups (185 ± 76 min vs. 161 ± 55 min; p 0.50). There was no operative death, and all patients recovered uneventfully. In the prevention group, procedure‐related complications occurred in two patients in the PSVL + TCAT subgroup (3.7% [2/54]), including one patient with slight pancreatitis and one patient with chylous leakage, owing to mobilization of the pancreas. The PVT incidence in the prevention group was significantly different between the two subgroups at postoperative 7th day, 3rd month, and 6th month (PSVL + TCAT: 0%, 11.1%, and 5.6% vs. SAT: 39.7%, 31.0%, and 20.7%, respectively; all p

Abstract Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6–80.4, n = 40) and cohort 2 (34.3%; 95% CI, 17.0–51.8, n = 32). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 47 (65.3%) of 72 patients. Results of our predefined exploratory investigation of predictive biomarkers show: B cell markers are the most differentially expressed genes in the tumors of responders versus non-responders in cohort 1 and that tertiary lymphoid structure is associated with higher ORR; Angiogenesis gene expression signatures are strongly associated with ORR in cohort 2. Camrelizumab plus apatinib combination effectiveness is associated with high expression of PD-L1, VEGF Receptor 2 and B-cell-related genes signatures. Camrelizumab plus apatinib shows promising efficacy with a measurable safety profile in RM-NPC patients.