Predictors of survival in immunotherapy-based treatments in advanced melanoma: a meta-analysis.

The introduction of immunotherapy-based strategies has significantly improved the prognosis for melanoma patients. Nevertheless, some patients still have dismal outcomes, emphasizing the significance of survival predictive indicators in immunotherapy-based approaches. We systematically searched randomized controlled clinical trials investigating dual immunotherapy or chemoimmunotherapy versus placebo or mono-immunotherapy or chemotherapy alone in advanced melanoma patients. R version 4.3.0. was employed to perform all analyses. A comprehensive analysis was conducted on a total of 13,809 patients with advanced melanoma from 19 randomized clinical trials. Immunotherapy-based strategies (alone or in combination) could significantly lengthen the overall survival(OS) and recurrence-free survival (RFS) compared with corresponding controls. Mono-immunotherapy improved RFS and OS in PD-L1 positive patients, in stage AJCC IIIC, and with 4 or more positive lymph nodes, compared with chemotherapy. Combined immunotherapy statistically improved RFS and OS in those aged < 65, with an Eastern Cooperative Oncology Group (ECOG) status of 0, and LDH ≤ ULN at baseline compared with single treatment alone. Our findings indicated that certain clinicopathological and molecular features could assist in choosing appropriate melanoma patients for immune-based treatments.

Ubiquitin-specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling.

Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin-specific protease 22 (USP22) as a pro-oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin-specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial-mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration-approved drug library screening and identified topotecan as a clinically applicable USP22-targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3-induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22-targeting drug to limit melanoma metastasis.

Molecular and therapeutic landscape of ferroptosis in skin diseases.

ABSTRACT: Regulated cell death (RCD) is a critical physiological process essential in maintaining skin homeostasis. Among the various forms of RCD, ferroptosis stands out due to its distinct features of iron accumulation, lipid peroxidation, and involvement of various inhibitory antioxidant systems. In recent years, an expanding body of research has solidly linked ferroptosis to the emergence of skin disorders. Therefore, understanding the mechanisms underlying ferroptosis in skin diseases is crucial for advancing therapy and prevention strategies. This review commences with a succinct elucidation of the mechanisms that underpin ferroptosis, embarks on a thorough exploration of ferroptosis's role across a spectrum of skin conditions, encompassing melanoma, psoriasis, systemic lupus erythematosus (SLE), vitiligo, and dermatological ailments precipitated by ultraviolet (UV) exposure, and scrutinizes the potential therapeutic benefits of pharmacological interventions aimed at modulating ferroptosis for the amelioration of skin diseases.

Efficacy and safety of tebentafusp in patients with metastatic uveal melanoma: A systematic review and meta-analysis.

Patients with metastatic uveal melanoma (mUM) have a poor prognosis, and few appropriate medications are available. Tebentafusp is approved by the Food and Drug Administration for mUM recently. However, the real efficacy and safety of tebentafusp are still unclear. We searched PubMed, Embase, and Cochrane Library from inception to March 20, 2024. The research was reported based on the preferred reporting items for systematic reviews and meta-analysis guidelines. We used random effects models to aggregate data on the response rates and adverse events of tebentafusp therapy. Six studies met the inclusion criteria with a total sample of 589 participants. The pooled objective response rate was 0.08 (95% CI: 0.05-0.12), and pooled disease control rate was 0.51 (95% CI: 0.44-0.57). The overall incidence was 0.99 (95% CI: 0.95-1.00) for any grade adverse events, 0.50 (95% CI: 0.41-0.59) for grade 3-4 adverse events, and 0.01 (95% CI: 0-0.03) for discontinuation due to adverse events. Tebentafusp exhibits promising treatment outcomes for mUM patients. Although accompanied with a common occurrence of adverse events, which can typically be managed and controlled. Future research is necessary for substantiating these findings and refining guidelines for management of mUM.

Clinical characteristics and risk factors for ZF2001 fully vaccinated inpatients with COVID-19: A retrospective cohort study.

The ZF2001 vaccine has demonstrated high efficacy in preventing coronavirus disease 2019 (COVID-19). However, the clinical characteristics of breakthrough infections in vaccinated individuals and the risk factors for adverse outcomes in COVID-19 patients remain unclear. We conducted a retrospective single-center cohort study at Xiangya Hospital of Central South University, including 210 fully vaccinated COVID-19 inpatients from December 5, 2022, to January 31, 2023. Data on clinical characteristics, laboratory findings, disease severity, treatment, and prognosis were collected and analyzed. Our findings revealed that COVID-19 inpatients still experienced common symptoms at the onset of illness, but most laboratory findings were within the normal range, except for white blood cell count (WBC), lymphocyte count, and lactate dehydrogenase (LDH) levels. Following standard treatment, 95.7% of patients were discharged from the hospital. We identified seven variables significantly associated with a higher risk of adverse outcomes, including age over 65, elevated WBC count, reduced lymphocyte count, higher levels of blood urea nitrogen (BUN), LDH, troponin, D-dimer, and procalcitonin. This study supports the substantial clinical benefits of the ZF2001 vaccine for COVID-19 patients. Additionally, age over 65, elevated WBC count, reduced lymphocyte count, and higher blood levels of BUN, LDH, D-dimer, and procalcitonin may be used as predictive factors for disease progression in fully vaccinated COVID-19 inpatients.

Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP1R) agonists have been approved by Food and Drug Administration for management of obesity. However, the causal relationship of GLP1R agonists (GLP1RA) with cancers still unclear. METHODS: The available cis-eQTLs for drugs target genes (GLP1R) were used as proxies for exposure to GLP1RA. Mendelian randomizations (MR) were performed to reveal the association of genetically-proxied GLP1RA with 14 common types cancer from large-scale consortia. Type 2 diabetes was used as positive control, and the GWASs data including 80 154 cases and 853 816 controls. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, all the related randomized controlled trails (RCTs) on GLP1RA were systematically searched from PubMed, Embase, and the Cochrane Library to comprehensively synthesize the evidence to validate any possible association with cancers. RESULT: A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instrument. The association of genetically-proxied GLP1RA with significantly decreased type 2 diabetes risk [OR (95%)=0.82 (0.79-0.86), P <0.001], which ensuring the effectiveness of identified genetic instruments. The authors found favorable evidence to support the association of GLP1RA with reduced breast cancer and basal cell carcinoma risk [0.92 (0.88-0.96), P <0.001, 0.92 (0.85-0.99), P =0.029, respectively], and with increased colorectal cancer risk [1.12 (1.07-1.18), P <0.001]. In addition, there was no suggestive evidence to support the association of GLP1RA with ovarian cancer [0.99 (0.90-1.09), P =0.827], lung cancer [1.01 (0.93-1.10), P =0760], and thyroid cancer [0.83 (0.63-1.10), P =0.187]. Our findings were consistent with the meta-analysis. Finally, 80 RCTs were included in the systematic review, with a low incidence of different kinds of cancer. CONCLUSIONS: Our study suggests that GLP1RA may decrease the risk of breast cancer and basal cell carcinoma, but increase the risk of colorectal cancer. However, according to the systematic review of RCTs, the incidence of cancer in patients treated with GLP1RA is low. Larger sample sizes of RCTs with long-term follow-up are necessary to establish the incidence of cancers and evaluate the risk-benefit ratios.

Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors. Intriguingly, mesenchymal and dedifferentiated cancer cells, which are usually resistant to apoptosis and traditional therapies, are exquisitely vulnerable to ferroptosis, further underscoring its potential as a treatment approach for cancers, especially for refractory cancers. However, the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells. Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms, biological functions, regulatory pathways, and interactions with the tumor microenvironment. We also summarize the potential applications of ferroptosis induction in immunotherapy, radiotherapy, and systemic therapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis markers, the current challenges and future directions of ferroptosis in the treatment of cancer.

The prevalence, complications, and risk factors for infantile hemangioma: a systematic review and meta-analysis.

The epidemiological landscape of infantile hemangioma (IH) has been extensively explored through diverse data sources; however, a scarcity of systematically pooled and quantified evidence from comprehensive global studies persists. In this meta-analysis, we systematically review available literature to elucidate the prevalence, distribution of lesions, complications, and risk factors associated with IH. A meticulous search encompassing the Cochrane Library, PubMed, Embase, and Web of Science identified 3206 records, of which 55 studies met the inclusion criteria. We found that the overall prevalence of IH is 2.8% [95% confidence interval (CI): 1.5-4.4%] (31,274,396 infants), and IH was located more frequently in the head and neck with a prevalence of 47.4% (95% CI: 39.5-55.4%). The overall prevalence of complications of IH is 24.3% (95% CI: 18.6-30.5%), ulceration is 16.0% (95% CI: 10.4-21.2%), bleeding is 5.6% (95% CI: 3.3-8.5%), visual impairment is 5.6% (95% CI: 3.0-8.9%), infection is 2.8% (95% CI: 1.5-4.8%), subglottic obstruction is 1.5% (95% CI: 0.5-3.0%), respectively. Through 27 studies, we have evaluated 35 factors encompassing perinatal factors, socioeconomic factors, maternal complications, drug factors, and antepartum procedures, and identified 18 risk factors that increase the prevalence of IH. These findings can greatly assist clinicians and family members in effectively evaluating the risk of IH, and determining whether pregnant women should undergo intensified monitoring or preventive measures.

Lactate dehydrogenase predicts disease progression outcome in COVID-19 patients treated with Azvudine.

Background: Azvudine has been approved in China for the treatment of COVID-19 patients. Previous studies have suggested a correlation between high levels of lactate dehydrogenase (LDH) and the severity of COVID-19. However, the impact of LDH levels in COVID-19 patients receiving Azvudine treatment remains unclear. Methods: In this retrospective cohort study, we analyzed the data of 351 hospitalized COVID-19 patients who were consecutively treated with Azvudine, with or without high LDH levels. The clinical features, treatment strategies and prognosis data were collected and analyzed. Results: Among the 351 hospitalized patients with COVID-19 treated with Azvudine (119 with high-LDH levels), the median age was 69 years (range 58-78), and 213 (60.7%) were male. Common symptoms included cough (86.0%), expectoration (73.5%), fever (69.8%), polypnea (47.6%) and poor appetite (46.4%). Patients with high LDH levels exhibited significantly elevated leucocyte and neutrophil counts, elevated level of myocardial enzymes, as well as higher levels of inflammatory markers such as interleukin-6, interleukin-10, procalcitonin, C reactive protein, ferritin, and prolonged erythrocyte sedimentation rate upon admission. COVID-19 patients with high-LDH levels had higher rates of corticosteroid therapy, non-invasive and invasive mechanical ventilation, worsened and death (2.5% vs. 0%). The Cox proportional hazard model demonstrated that high LDH levels (adjusted hazard ratio = 5.27; 95% confidence interval: 1.19, 14.50) were associated with a more unfavorable composite disease progression outcome among COVID-19 patients treated with Azvudine, after accounting for potential confounding variables. Conclusion: High-LDH levels predict a worse composite disease progression outcome in COVID-19 patients treated with Azvudine.

Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy.

The mystery about the mechanistic basis of disulfidptosis has recently been unraveled and shows promise as an effective treatment modality for triggering cancer cell death. However, the limited understanding of the role of disulfidptosis in tumor progression and drug sensitivity has hindered the development of disulfidptosis-targeted therapy and combinations with other therapeutic strategies. Here, we established a disulfidptosis signature model to estimate tumor disulfidptosis status in approximately 10,000 tumor samples across 33 cancer types and revealed its prognostic value. Then, we characterized disulfidptosis-associated molecular features and identified various types of molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-tumor drugs. We further showed the vast heterogeneity in disulfidptosis status among 760 cancer cell lines across 25 cancer types. We experimentally validated that disulfidptosis score-high cell lines are more susceptible to glucose starvation-induced disulfidptosis compared to their counterparts with low scores. Finally, we investigated the impact of disulfidptosis status on drug response and revealed that disulfidptosis induction may enhance sensitivity to anti-cancer drugs, but in some cases, it could also lead to drug resistance in cultured cells. Overall, our multi-omics analysis firstly elucidates a comprehensive profile of disulfidptosis-related molecular alterations, prognosis, and potential therapeutic therapies at a pan-cancer level. These findings may uncover opportunities to utilize multiple drug sensitivities induced by disulfidptosis, thereby offering practical implications for clinical cancer therapy.

Clinical characteristics, outcomes, and risk factors of SARS-CoV-2 breakthrough infections among 572 fully vaccinated (BBIBP-CorV) hospitalized patients.

Background: Breakthrough infections have been widely reported in vaccinated individuals. However, the clinical characteristics, outcomes, and risk factors of SARS-CoV-2 breakthrough infections among fully vaccinated (BBIBP-CorV) hospitalized patients have not yet been fully elucidated. Methods: In the single-center cohort study conducted at Xiangya Hospital of Central South University, we enrolled the hospitalized COVID-19 patients who had received full (2 doses) vaccination with the BBIBP-CorV vaccine between December 5, 2022, and January 31, 2023. We collected and analyzed information related to clinical characteristics, laboratory results, treatments, outcomes and prognostic data. Univariate and multivariable Cox regression were performed to assess the impact of clinical characteristics and laboratory results on the composite outcome (including the initiation of endotracheal intubation, non-invasive respiratory support, intensive care unit admission, and all-cause death). Results: A total of 572 COVID-19 hospitalized patients with fully vaccinated (BBIBP-CorV) were included. The median age of the patients was 66 years (IQR 53, 74). The most common symptoms included fever (347 [60.7 %]), dry cough (401 [70.1 %]), and expectoration (333 [58.2 %]). Among those with pre-existing chronic comorbidities, 44.2 % had hypertension and 20.5 % had diabetes. Laboratory tests revealed that the majority of patients (425/549 [77.4 %]) had normal white blood cell counts. Composite outcome occurred in 11.9 % of patients, with 96.7 % of patients discharged and 3.3 % of patients died. Multivariate Cox regression analyses suggested that the NLR >4 (adjusted HR, 5.50 [95%CI: 1.56-19.47]; P = 0.008), D-dimer >0.5 mg/ml (adjusted HR, 2.17 [95%CI: 1.03-4.59]; P = 0.042) and procalcitonin >0.1 ng/ml (adjusted HR, 3.22 [95%CI: 1.38-7.52]; P = 0.007) were independently associated with the composite outcome. Conclusion: Breakthrough infection after being fully vaccinated (BBIBP-CorV) is more likely to occur in older patients and patients with pre-existing chronic comorbidities. NLR >4, D-dimer >0.5 mg/ml and procalcitonin >0.1 ng/ml were independent risk factors for composite outcome.

Immunophenotyping characteristics and outcome of COVID-19 patients: peripheral blood CD8+T cell as a prognostic biomarker for patients with Nirmatrelvir.

Background: Nirmatrelvir has been authorized for the treatment of both hospitalized and non-hospitalized COVID-19 patients. However, the association between T lymphocyte subsets and the outcome of hospitalized COVID-19 patients treated with oral Nirmatrelvir has not been investigated. The objective of this study was to examine whether lymphocyte subsets could serve as biomarkers to assess the risk of mortality in COVID-19 patients undergoing Nirmatrelvir treatment, with the aim of enhancing medication management for COVID-19 patients. Methods: We conducted a retrospective cohort study at the Xiangya Hospital of Central South University in China between December 5, 2022 and January 31, 2023. The study reported demographic, clinical, T lymphocyte subsets, and inflammatory cytokine data of COVID-19 patients. We evaluated the associations of T lymphocyte subsets on admission with the composite outcome or death of patients using univariate and multivariable Cox regression analyses with hazards ratios (HRs) and 95% confidence intervals (CIs). Results: We identified 2118 hospitalized COVID-19 patients during the study period, and conducted a follow-up of up to 38 days. Of these, 131 patients received Nirmatrelvir, with 56 (42.7%) in the composite outcome group, and 75 (57.3%) in the non-composite outcome group. Additionally, 101 (77.1%) patients were discharged, while 30 (22.9%) died. Our results showed a significant decrease in the CD3+, CD4+, and CD8+ T cell counts of patients in the composite outcome group and mortality group compared to the non-composite outcome group and discharged group, respectively. Multivariate Cox regression analysis showed that the significant decrease in CD8+ T cell count in peripheral blood was independently associated with the composite outcome in COVID-19 patients treated with Nirmatrelvir, with an HR of 1.96 (95%CI: 1.01-3.80). The significant decrease in CD4+ and CD8+ T cell counts in peripheral blood increased the hazard of developing mortality, with HRs of 6.48 (95%CI: 1.47-28.63) and 3.75 (95%CI: 1.27-11.11), respectively. Conclusion: Our study revealed a significant positive correlation between a decrease in CD8+ T cell counts and progression and mortality of hospitalized COVID-19 patients treated with Nirmatrelvir. Lower counts (/µL) of CD8+ T cell (<201) were associated with a higher risk of in-hospital severity and death. Our findings may provide valuable references for physicians in optimizing the use of Nirmatrelvir.

Corrigendum to 'Oral Azvudine for hospitalised patients with COVID-19 and pre-existing conditions: a retrospective cohort study.' [EClinicalMedicine 59 (2023) 101981].

[This corrects the article DOI: 10.1016/j.eclinm.2023.101981.].

Serological response following COVID-19 vaccines in patients living with HIV: a dose-response meta-analysis.

To quantify the pooled rate and risk ratio of seroconversion following the uncomplete, complete, or booster dose of COVID-19 vaccines in patients living with HIV. PubMed, Embase and Cochrane library were searched for eligible studies to perform a systematic review and meta-analysis based on PRIMSA guidelines. The pooled rate and risk ratio of seroconversion were assessed using the Freeman-Tukey double arcsine method and Mantel-Haenszel approach, respectively. Random-effects model was preferentially used as the primary approach to pool results across studies. A total of 50 studies involving 7160 patients living with HIV were analyzed. We demonstrated that only 75.0% (56.4% to 89.9%) patients living with HIV achieved a seroconversion after uncomplete vaccination, which improved to 89.3% (84.2% to 93.5%) after complete vaccination, and 98.4% (94.8% to 100%) after booster vaccination. The seroconversion rates were significantly lower compared to controls at all the stages, while the risk ratios for uncomplete, complete, and booster vaccination were 0.87 (0.77 to 0.99), 0.95 (0.92 to 0.98), and 0.97 (0.94 to 0.99), respectively. We concluded that vaccine doses were associated with consistently improved rates and risk ratios of seroconversion in patients living with HIV, highlighting the significance of booster vaccination for patients living with HIV.