Search Results (2,042)

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups. Full article

Background: Immune checkpoint inhibitors (ICIs) have demonstrated significantly improved clinical efficacy in a minority of patients with advanced melanoma, whereas non-responders potentially suffer from severe side effects and delays in other treatment options. Predicting the response to anti-PD1 treatment in melanoma remains a challenge because the current FDA-approved gold standard, the nonsynonymous tumor mutation burden (nsTMB), offers limited accuracy. Methods: In this study, we developed a multi-omics-based machine learning model that integrates genomic and transcriptomic biomarkers to predict the response to anti-PD1 treatment in patients with advanced melanoma. We employed least absolute shrinkage and selection operator (LASSO) regression with 49 biomarkers extracted from tumor–normal whole-exome and RNA sequencing as input features. The performance of the multi-omics AI model was thoroughly compared to that of nsTMB alone and to models that use only genomic or transcriptomic biomarkers. Results: We used publicly available DNA and RNA-seq datasets of melanoma patients for the training and validation of our model, forming a meta-cohort of 449 patients for which the outcome was recorded as a RECIST score. The model substantially improved the prediction of anti-PD1 outcomes compared to nsTMB alone, with an ROC AUC of 0.7 in the training set and an ROC AUC of 0.64 in the test set. Using SHAP values, we demonstrated the explainability of the model’s predictions on a per-sample basis. Conclusions: We demonstrated that models using only RNA-seq or multi-omics biomarkers outperformed nsTMB in predicting the response of melanoma patients to ICI. Furthermore, our machine learning approach improves clinical usability by providing explanations of its predictions on a per-patient basis. Our findings underscore the utility of multi-omics data for selecting patients for treatment with anti-PD1 drugs. However, to train clinical-grade AI models for routine applications, prospective studies collecting larger melanoma cohorts with consistent application of exome and RNA sequencing are required. Full article

Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is characterized by its targeting of MET. Therefore, cabozantinib can be used as a late-line therapy for TKI-resistant RCC. According to data from The Cancer Genome Atlas (TCGA), heat shock transcription factor 4 (HSF4) expression is higher in RCC tissues than in normal renal tissues. HSF4 binds to the MET promoter in colorectal carcinoma to enhance MET expression and promote tumor progression. However, the functional role of HSF4 in RCC is unclear. We performed loss-of-function assays of HSF4, and our results showed that HSF4 knockdown in RCC cells significantly decreased cell functions. Moreover, MET expression was decreased in HSF4-knockdown cells but elevated in sunitinib-resistant RCC cells. The combination of cabozantinib and HSF4 knockdown reduced cell proliferation in sunitinib-resistant cells more than each monotherapy alone. Furthermore, HSF4 knockdown combined with an ICI showed synergistic suppression of tumor growth in vivo. Overall, our strategy involving HSF4 knockdown may enhance the efficacy of existing therapies, such as cabozantinib and ICIs. Full article

Mesothelioma is a highly malignant condition arising from the pleura and peritoneum that is closely related to asbestos exposure. The prognosis for this condition has traditionally been poor due to the difficulty physicians have faced in diagnosing and treating this disease, even in its early phase. Fortunately, recent advances in both the molecular understanding of the development of this disease and innovative and novel treatment modalities have accelerated the discovery of new ways to treat mesothelioma. In this review, we first summarize the mechanism of mesothelioma pathophysiology and then relate it to emerging treatment modalities. These include immunotherapy or immune checkpoint inhibitors (ICIs), molecular targeted therapies, and cell-based therapies (such as CAR-T cells or dendritic cells). The scientific basis for the utilization of these treatment modalities, alongside the current clinical evidence for each option, will be explored in detail later on. The hope is that this review can elucidate how these emerging therapeutic options work clinically to help accelerate further developments in novel mesothelioma treatment modalities. Full article

Background and Objectives: The prevalence of and risk factors for immune checkpoint inhibitor-associated diarrhea and colitis (IMDC) in the Chinese population are unclear. This study aimed to estimate IMDC incidence and identify potential risk factors. Materials and Methods: We reviewed the electronic medical records from Beijing Friendship Hospital (2015–2022) to identify the patients treated with immune checkpoint inhibitors. The primary outcome was IMDC occurrence. The demographics, cancer type, baseline labs, and concurrent medications were analyzed. The univariable and multivariable analyses validated the associated factors. Results: Among 1186 patients (median follow-up: 217 days), the IMDC incidence was 4.6%, with colitis at 0.67%. Digestive system tumors increased the IMDC risk (OR 2.79, 95% CI 1.42–5.75, p = 0.004), while platinum agents decreased it (OR 0.41, 95% CI 0.21–0.78, p = 0.008). PPIs, antibiotics, NSAIDs, and glucocorticoids showed no significant association. Colitis was the third most common irAE, leading to ICI discontinuation (15.6%). Conclusions: IMDC prevalence is 4.6% in the Chinese population, the third most frequent irAE causing ICI discontinuation. Digestive tumors and platinum agents are risk and protective factors, respectively, while other medications show no significant impact. Full article

Background: Approximately 25–30% of non-small-cell lung cancer (NSCLC) patients are diagnosed when the disease is still resectable, although the risk of recurrence is significant. Recently, approaches based on targeted agents or immune checkpoint inhibitors (ICIs) have modified the management of such patients. However, some questions remain unanswered. Objectives: Our aim is to assess the current evidence on approaches involving targeted agents and ICIs in resectable NSCLC, to provide an up-to-date overview of the subject, and to identify areas of current debate, Methods: We analyzed randomized trials on ICIs and targeted therapies in early-stage NSCLC, published or presented at international oncology meetings throughout the last 5 years. Results: Osimertinib and alectinib have shown robust results in the adjuvant setting for molecularly identified patient subgroups, while ICIs have achieved robust data in the neoadjuvant/perioperative setting, with less consistent data on the pure adjuvant approach. Circulating tumor DNA levels may offer a possible biomarker for therapeutic decisions, albeit more prospective data are needed. Conclusions: Targeted agents and ICIs are revolutionizing early-stage NSCLC, similarly to what was observed in advanced disease. Prospective studies designed to compare neoadjuvant, adjuvant, and perioperative approaches and to assess the role of circulating biomarkers are warranted. Full article

This paper examines the energy efficiency of smart electric vehicles equipped with regenerative braking systems under challenging weather conditions. While Advanced Driver Assistance Systems (ADAS) are primarily designed to enhance driving safety, they often overlook energy efficiency. This study proposes a Weather-Adaptive Regenerative Braking Strategy (WARBS) system, which leverages onboard sensors and data processing capabilities to enhance the energy efficiency of regenerative braking across diverse weather conditions while minimizing unnecessary alerts. To achieve this, we develop driving style recognition models that integrate road conditions, such as weather and road friction, with different driving styles. Next, we propose an adaptive deceleration plan that aims to maximize the conversion of kinetic energy into electrical energy for the vehicle’s battery under varying weather conditions, considering vehicle dynamics and speed constraints. Given that the potential for energy recovery through regenerative braking is diminished on icy and snowy roads compared to dry ones, our approach introduces a driving context recognition system to facilitate effective speed planning. Both simulation and experimental validation indicate that this approach can significantly enhance overall energy efficiency. Full article

The rapid growth of automotive intelligence and automation technology has made it difficult for traditional in-vehicle servo systems to satisfy the demands of modern intelligent systems when facing complex problems such as external disturbances, nonlinearity, and parameter uncertainty. To improve the anti-interference ability and control accuracy of the system, this study proposes a joint control method of electronic mechanical braking control combined with the anti-lock braking system. This method has developed a new type of actuator in the electronic mechanical brake control system and introduced a particle swarm optimization algorithm to optimize the parameters of the self-disturbance rejection control system. At the same time, it combines an adaptive inversion algorithm to optimize the anti-lock braking system. The results indicated that the speed variation of the developed actuator and the actual signal completely stopped at 1.9 s. During speed control and deceleration, the actuator could respond quickly and accurately to control commands as expected. On an asphalt pavement, the maximum slip rate error of the optimized control method was 0.0428, while the original control method was 0.0492. The optimized method reduced the maximum error by about 12.9%. On icy and snowy roads, the maximum error of the optimization method was 0.0632, significantly lower than the original method’s 0.1266. The optimization method could significantly reduce slip rate fluctuations under extreme road conditions. The proposed method can significantly improve the control performance of the vehicle-mounted servo platform, reduce the sensitivity of the system to external disturbances, and has high practical value. Full article

Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers. Approximately 20% of patients with NSCLC are diagnosed with stage IIIA–IIIB disease, for which the optimal treatment remains unclear. Meta-analyses reveal that neoadjuvant/perioperative ICI–chemotherapy significantly improves pathological complete response (pCR), overall survival (OS), major pathological response (MPR), and R0 rate compared to standard neoadjuvant chemotherapy. Resectability is achieved when R0 resection can be performed after surgery. Radiographic downstaging often does not correspond to surgical downstaging. In fact, intra-operative fibrosis due to chemo-immunotherapy (synonymous with ICI–chemotherapy) can create adhesions and consequent difficult planes for dissection. Thus, pneumonectomy cannot be avoided. Even the suspicion of N2 after neoadjuvant treatment is considered a limitation of upfront surgery because of the risk of pneumonectomy. The aim of this review is to explore the literature on the technical strategies for surgical excision of NSCLC after chemo-immunotherapy, addressing even the most challenging scenarios. Full article

The combination of chemotherapeutic agents with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, its success is often limited by insufficient immune priming in certain tumors, including pediatric malignancies. In this report, we explore clinical trials currently investigating the use of immunogenic cell death (ICD)-inducing chemotherapies in combination with ICIs for both adult and pediatric cancers. Given the limited clinical data available for pediatric tumors, we focused on recent preclinical studies evaluating the efficacy of these combinations in neuroblastoma (NB). Finally, to address this gap, we propose an innovative strategy to assess the impact of ICD-inducing chemotherapies on antitumor immune responses in NB. Using tumor spheroids derived from a transgenic NB mouse model, we validated our previous in vivo findings concerning how anthracyclines, specifically mitoxantrone and doxorubicin, significantly enhance MHC class I surface expression, stimulate IFNγ and granzyme B production by CD8⁺ T cells and NK cells, and promote immune cell recruitment. Importantly, these anthracyclines also upregulated PD-L1 expression on NB spheroids. This screening platform yielded results similar to in vivo findings, demonstrating that mitoxantrone and doxorubicin are the most potent immunomodulatory agents for NB. These data suggest that the creation of libraries of ICD inducers to be tested on tumor spheroids could reduce the number of combinations to be tested in vivo, in line with the principles of the 3Rs. Furthermore, these results highlight the potential of chemo-immunotherapy regimens to counteract the immunosuppressive tumor microenvironment in NB, paving the way for improved therapeutic strategies in pediatric cancers. They provide compelling evidence to support further clinical investigations of these combinations to enhance outcomes for children with malignancies. Full article

Background/Objectives: Fungal pathogens are increasingly developing concerning resistance against the currently available antifungal drugs, which creates a constant demand for new antifungal agents. Methods: Here, we report the synthesis of C3,N4-substituted triazole derivatives containing a N4-(2-((4-methoxybenzyl)thio)phenyl) group. By selectively removing the 4-methoxybenzyl group, we were able to access the free thiol analogs which, under oxidative conditions, undergo a cyclization reaction yielding a C5-substituted benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. We were able to show a broad functional group tolerance for the preparation of the triazole derivatives, as well as the tricyclic heteroarenes prepared thereof. Mechanistic investigations suggest that the oxidative cyclization reaction proceeds via an ionic pathway involving a disulfide intermediate. Isolation of the disulfide intermediate and resubjecting it to the reaction conditions shows that the presence of acid significantly increases its rate of conversion to the corresponding benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. Antifungal testing of both the novel triazoles and the benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles was carried out with Candida albicans (SC5314) and a clinical strain of Trichosporon asahii (OK01). Results: Most of the novel sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles showed activity against Candida albicans (SC5314) and the emerging pathogen Trichosporon asahii (OK01). Conclusions: A series of new sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles were synthesized. Antifungal testing revealed modest activity against Candida albicans (SC5314) and Trichosporon asahii (OK01). Full article

Tumor treatment has undergone revolutionary changes with the development of immunotherapy, especially immune checkpoint inhibitors. Because not all patients respond positively to immune therapeutic agents, and severe immune-related adverse events (irAEs) are frequently observed, the development of the biomarkers evaluating the response of a patient is key for the application of immunotherapy in a wider range. Recently, various multi-omics features measured by high-throughput technologies, such as tumor mutation burden (TMB), gene expression profiles, and DNA methylation profiles, have been proved to be sensitive and accurate predictors of the response to immunotherapy. A large number of predictive models based on these features, utilizing traditional machine learning or deep learning frameworks, have also been proposed. In this review, we aim to cover recent advances in predicting tumor immunotherapy response using multi-omics features. These include new measurements, research cohorts, data sources, and predictive models. Key findings emphasize the importance of TMB, neoantigens, MSI, and mutational signatures in predicting ICI responses. The integration of bulk and single-cell RNA sequencing has enhanced our understanding of the tumor immune microenvironment and enabled the identification of predictive biomarkers like PD-L1 and IFN-γ signatures. Public datasets and machine learning models have also improved predictive tools. However, challenges remain, such as the need for large and diverse clinical datasets, standardization of multi-omics data, and model interpretability. Future research will require collaboration among researchers, clinicians, and data scientists to address these issues and enhance cancer immunotherapy precision. Full article

Objective: To evaluate the differences in overall survival (OS) and progression-free survival (PFS) between men and women with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) in second-line and later treatments. Methods: A retrospective, single-center observational study was conducted on patients with advanced NSCLC treated with ICIs (nivolumab, pembrolizumab, and atezolizumab) from January 2015 to December 2019 (with follow-up until December 2021). Demographic, clinical, and treatment-related variables were collected. OSand PFSwere analyzed using the Kaplan–Meier method and compared between genders using the log-rank test.A multivariate Cox regression analysis was performed to adjust for confounders. Results: A total of 189 patients were included, and 47 (25%) were women. The most common histology was adenocarcinoma (61%). Women began treatment at a younger age (59.8 vs. 66 years, p < 0.001) and had higher rates of active smoking (46.8% vs. 38%, p = 0.001). The median OS was similar between men (9.5 months, 95% CI: 7.1–11.8) and women (9.2 months, 95% CI: 3.3–15.2; p = 0.382) while PFS was significantly higher in males (3.2 months, 95% CI: 2.5–4.0) than in females (2.1 months; 95% CI = 1.6–2.5) (p = 0.002).Women had higher rates of tumor cachexia (BMI < 20).Worse PFS was observed for women both in the <20 kg/m² (median PFS: 1.8 vs. 2.7 months, p = 0.016) and 20–24.9 kg/m² groups (median PFS: 2.2 vs. 3.3 months, p = 0.077), while in patients with a BMI >= 25 kg/m², median OS was higher in women than in men (14.7 months vs. 10.1 months). Women had also a significantly worse PFS than men among those with a cumulative tobacco consumption of <30 packs-year (median PFS: 2.2 vs. 3.2, p = 0.038. In the multivariate analysis, the male sex was significantly associated with a better PFS(HR = 0.59; p = 0.009), without significant differences between sexes in OS (HR = 0.90; p = 0.618). Among the other variables analyzed, only an ECOG >= 2 was significantly associated with both worse OS (HR = 3.53; 95% CI = 1.93–6.47) and PFS (HR = 2.19; 95% CI = 1.23–3.89). Women who discontinued due to toxicity (n = 7) had a median OS of 41.4 months (95% CI: 14.7–68.1) after discontinuation, whereas men (n = 15) had a median OS of 8.8 months (95% CI: 6.9–10.8), (p = 0.045). Conclusions: Sex-based differences were observed in the ICI outcomes. Women had worse PFS, particularly with lower BMI and lower tobacco exposure, despite similar OS between sexes. Women discontinued ICIs due to toxicity earlier but showed longer OS after discontinuation. Poor ECOG status was linked to worse outcomes across all the patients. Full article

The treatment landscape of pancreatic ductal adenocarcinoma (PDAC) has seen slow progress, with immune-checkpoint inhibitors (ICIs) failing to replicate the success observed in other malignancies. The immune-suppressive tumor microenvironment (TME) in PDAC represents a significant barrier, limiting the activation of an effective antitumor immune response following ICI administration. Radiation therapy (RT), with its immunomodulatory effects, has emerged as a promising partner for ICIs. This review discusses the recent efforts evaluating the combination of ICIs and RT in advanced PDAC. While the combination therapy has demonstrated an acceptable safety profile, the reported clinical efficacy remains modest, particularly for patients with refractory metastatic PDAC. The ongoing phase III trial (JCOG1908E) will clarify whether the combination of ICI and RT improves overall survival in chemo-naïve patients with locally advanced PDAC. Full article