Enhanced electrochemical nitrate reduction on copper nitride with moderate intermediates adsorption.

Nitrate in surface and underground water caused systematic risk to the ecological environment. The electrochemically reduction of nitrate into ammonia (NO3RR), offering a sustainable route for nitrate containing wastewater treatment and ammonia fertilizer conversion. Exploration of catalyst with improved catalytic activity with lower energy barriers is still challenging. Here, we report a copper nitride (Cu3N) catalyst with moderate *NOx and *H2O intermediates adsorptions showed enhanced NO3RR performance. Density functional theory calculations reveals that the unique electronic structure of Cu3N provides efficient active sites for NO3RR, thus enabled balanced adsorption of *NO3 and *H2O (ΔE descriptor), sufficient active hydrogen, and moderate intermediate (*NO3 â†’ HNO3, *NH2→*NH3) adsorption energy. Notably, the in-situ analysis technology revealed potential-driven reconstruction and rehabilitation of Cu3N, forming possible nitrogen vacancy, thus implied for better mechanism understanding. The NO3RR activity of Cu3N surpasses that of most recent catalysts and demonstrates superior stability and implies the application for NH4+ fertilizer recovery, which maintaining an NH3 Faradaic efficiency of 93.1 % and high yield rate of 2.9 mg cm2h-1 at -0.6 V versus RHE. These findings broaden the application scenarios of Cu3N catalyst for ammonia synthesis and provide strategy on improving NO3RR performance.

Copper-based electro-catalytic nitrate reduction to ammonia from water: Mechanism, preparation, and research directions.

Global water bodies are increasingly imperiled by nitrate pollution, primarily originating from industrial waste, agricultural runoffs, and urban sewage. This escalating environmental crisis challenges traditional water treatment paradigms and necessitates innovative solutions. Electro-catalysis, especially utilizing copper-based catalysts, known for their efficiency, cost-effectiveness, and eco-friendliness, offer a promising avenue for the electro-catalytic reduction of nitrate to ammonia. In this review, we systematically consolidate current research on diverse copper-based catalysts, including pure Cu, Cu alloys, oxides, single-atom entities, and composites. Furthermore, we assess their catalytic performance, operational mechanisms, and future research directions to find effective, long-term solutions to water purification and ammonia synthesis. Electro-catalysis technology shows the potential in mitigating nitrate pollution and has strategic importance in sustainable environmental management. As to the application, challenges regarding complexity of the real water, the scale-up of the commerical catalysts, and the efficient collection of produced NH3 are still exist. Following reseraches of catalyst specially on long term stability and in situ mechanisms are proposed.

Design, synthesis and evaluation of a myricetin and nobiletin hybrid compound for alleviating hyperuricemia based on metabolomics and gut microbiota.

Hyperuricemia (HUA) is the fourth most common basic metabolic disease that can cause damage to multiple organs throughout the body. In this study, a hybrid compound consisting of myricetin and nobiletin was synthesized and its biological activity was evaluated. We named the hybrid compound MNH, and its structure was confirmed by spectroscopy. This study used serum metabolomics profiling with LC/MS and 16S rRNA gene sequencing analysis to explore the anti-HUA efficacy of MNH on a yeast paste-induced mouse model. The results showed that serum uric acid (UA), creatinine (CRE) and urea nitrogen (BUN) levels were significantly decreased after the intervention of MNH. The efficacy of MNH in lowering UA was somewhat greater than that of myricetin and nobiletin. In addition, MNH could repair the renal histopathological damage. Moreover, serum metabolomics demonstrated that MNH regulated the metabolic pathways involved in glycerophospholipid metabolism, arachidonic acid metabolism and alanine etc. Furthermore, MNH supplementation restored the composition of gut microbiota with remarkable reductions in Lactobacillus and Limosilactobacillus and significant elevations in norank_f_Muribaculaceae and Bacteroides at the genus level. Taken together, these results indicated that MNH might represent a protective effect against HUA via modulating gut microbiota and metabolomics.

BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression.

Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to combine JQ1 with 240 antitumor drugs from the Food and Drug Administration (FDA)-approved drug library and found that sunitinib synergizes with BET inhibitors in melanoma cells. We further demonstrated that BET inhibitors synergize with sunitinib in melanoma by inducing apoptosis and cell cycle arrest. Mechanistically, BET inhibitors sensitize melanoma cells to sunitinib by inhibiting GDF15 expression. Strikingly, GDF15 is transcriptionally regulated directly by BRD4 or indirectly by the BRD4/IL6/STAT3 axis. Xenograft assays revealed that the combination of BET inhibitors with sunitinib causes melanoma suppression in vivo. Altogether, these findings suggest that BET inhibitor-mediated GDF15 inhibition plays a critical role in enhancing sunitinib sensitivity in melanoma, indicating that BET inhibitors synergize with sunitinib in melanoma.

Numerical study of transient indoor airflow and virus-laden droplet dispersion: Impact of interactive human movement.

Human movement affects indoor airflow and the airborne transmission of respiratory infectious diseases, which has attracted scholars. However, the interactive airflow between moving and stationary people has yet to be studied in detail. This study used the numerical method validated by experimental data to explore the transient indoor airflow and virus-laden droplet dispersion in scenes with interactive human movement. Human-shaped numerical models and the dynamic mesh method were adopted to realize human movement in scenes with different lateral distances (0.2-1.2 m) between a moving person and stationary (standing/sitting) persons. The interactive human movement obviously impacts other persons' respiratory airflow, and the lateral fusion ranged about 0.6 m. The interactive human movement strengthens the indoor airflow convection, and some exhaled virus-laden droplets were carried into wake flow and enhanced long-range airborne transmission. The impact of interactive human movement on sitting patients' exhalation airflow seems more evident than on standing patients. The impact might last over 2 min after movement stopped, and people in the affected area might be at a higher exposure. The results can provide a reference for epidemic control in indoor environments.

A numerical tool for assessing human thermal safety and thermal comfort in cold-weather activities.

This paper describes a newly developed software tool to evaluate human thermal safety and thermal comfort in cold-weather activities aimed at guiding users to arrange activity plans and select appropriate clothing ensembles. The software inputs include conditions of activity, environment, human body, and clothing ensemble. It outputs physiological temperatures, cold injury risks, thermal sensations, and thermal comforts in intuitive ways like cloud maps and curves. The software tool is characterized by (1) integration of a thermoregulatory model that predicts human thermophysiological responses under exercise conditions in cold environments, (2) the functions of clothing ensemble database and individual parameter database, (3) the human centric outputs that directly reflect human physiological and mental status, and (4) the user-friendly operation interface and output interface, as well as a wide applicability. The software is validated with human test studies covering ambient temperatures from - 30.6 to 5 °C, clothing ensembles from 1.34 to 3.20 clo, and activity intensities from 2 to 9 Mets. The average prediction RMSEs of core temperature, mean skin temperature, thermal sensation, and thermal comfort are 0.16 °C, 0.45 °C, 0.58, and 1.41, respectively. The software is an advanced expansion to current standards and guidance of cold exposure assessment and a meaningful tool for the fields of occupational health care, cold protection, and environmental ergonomics.

Graphitic carbon nitride-based photocatalysts in the applications of environmental catalysis.

Semiconductor photocatalytic technology has shown great prospects in converting solar energy into chemical energy to mitigate energy crisis and solve environmental pollution problems. The key issue is the development of high-efficiency photocatalysts. Various strategies in the state-of-the-art advancements, such as heterostructure construction, heteroatom doping, metal/single atom loading, and defect engineering, have been presented for the graphitic carbon nitride (g-C3N4)-based nanocomposite catalysts to design their surface chemical environments and internal electronic structures to make them more suitable for different photocatalytic applications. In this review, nanoarchitecture design, synthesis methods, photochemical properties, potential photocatalytic applications, and related reaction mechanisms of the modified high-efficiency carbon nitride-based photocatalysts were briefly summarized. The superior photocatalytic performance was identified to be associated with the enhanced visible-light response, fast photoinduced electron-hole separation, efficient charge migration, and increased unsaturated active sites. Moreover, the further advance of the visible-light harvesting and solar-to-energy conversions are proposed.

Effects of athletic walking on the physical endurance of athletes / Efeitos da marcha atlética sobre a resistência física dos atletas / Efectos de la marcha deportiva en la resistencia física de los atletas

ABSTRACT Introduction Athletic walking is a physical endurance test. This sport has a long competition time and a high load intensity. The long-term continuous movement of muscles is the most prominent characteristic of this sport. Strength and endurance are essential physical factors that determine the performance of the runners who do it. Physical endurance is an essential indicator to evaluate the level of physical training in athletic walking. Objective This study aims to analyze the effect of endurance training on the physical fitness and competition performance of athletic walkers. Methods This work selects four athletes as the research object. The athletes undergo one month of resistance training. The athletes recorded their physiological and biochemical indicators before and after resistance training. Then, the mathematical statistics method was used to analyze their physiological and biochemical indicators. Results Hemoglobin levels in the last three weeks of resistance training were significantly higher than in the first week (P<0.01). During endurance training, the athletes' morning blood urea peak appeared in the first test after going to high altitude (P<0.05). Conclusion Endurance training can improve the fitness of athletic walkers. Resistance training effectively stimulates the blood system of athletes for at least two weeks. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução A marcha atlética é uma prova de resistência física. Este esporte tem um longo tempo de competição e uma alta intensidade de carga. O movimento contínuo dos músculos a longo prazo é a característica mais proeminente deste esporte. Força e resistência são fatores físicos essenciais que determinam o desempenho dos corredores que a praticam. A resistência física é um indicador essencial para avaliar o nível de treinamento físico na marcha atlética. Objetivo Este estudo tem como objetivo analisar o efeito do treinamento de resistência sobre a aptidão física e o desempenho em competição dos praticantes de marcha atlética. Métodos Este trabalho seleciona quatro atletas como o objeto de pesquisa. Os esportistas passam por um mês de treinamento de resistência. Os atletas registraram seus indicadores fisiológicos e bioquímicos antes e depois do treinamento de resistência. Em seguida, foi utilizado o método de estatística matemática para analisar seus indicadores fisiológicos e bioquímicos. Resultados Os níveis de hemoglobina nas últimas três semanas de treinamento de resistência foram significativamente maiores do que os da primeira semana (P<0,01). Durante o treinamento de resistência, o pico da ureia sanguínea matinal dos atletas apareceu no primeiro teste depois de ter ido para altitude alta (P<0,05). Conclusão O treinamento de resistência pode melhorar a aptidão física dos praticantes de marcha atlética. O treinamento de resistência estimula efetivamente o sistema sanguíneo dos esportistas por pelo menos duas semanas. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción La marcha atlética es una prueba de resistencia física. Este deporte tiene un largo tiempo de competición y una alta intensidad de carga. El movimiento continuo y prolongado de los músculos es la característica más destacada de este deporte. La fuerza y la resistencia son factores físicos esenciales que determinan el rendimiento de los corredores que la practican. La resistencia física es un indicador esencial para evaluar el nivel de entrenamiento físico en la marcha atlética. Objetivo Este estudio pretende analizar el efecto del entrenamiento de resistencia sobre la aptitud física y el rendimiento en competición de los practicantes de marcha atlética. Métodos Este trabajo selecciona a cuatro atletas como objeto de investigación. Los atletas realizaron un mes de entrenamiento de resistencia. Los atletas registraron sus indicadores fisiológicos y bioquímicos antes y después del entrenamiento de resistencia. A continuación, se utilizó el método de estadística matemática para analizar sus indicadores fisiológicos y bioquímicos. Resultados Los niveles de hemoglobina en las últimas tres semanas de entrenamiento de resistencia fueron significativamente más altos que los de la primera semana (P<0,01). Durante el entrenamiento de resistencia, el pico de urea en sangre matinal de los atletas apareció en la primera prueba después de ir a la altitud (P<0,05). Conclusión El entrenamiento de resistencia puede mejorar la condición física de los caminantes atléticos. El entrenamiento de resistencia estimula eficazmente el sistema sanguíneo de los deportistas durante al menos dos semanas. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

The traditional chinese medicine monomer Ailanthone improves the therapeutic efficacy of anti-PD-L1 in melanoma cells by targeting c-Jun.

BACKGROUND: C-Jun, a critical component of AP-1, exerts essential functions in various tumors, including melanoma, and is believed to be a druggable target for cancer therapy. Unfortunately, no effective c-Jun inhibitors are currently approved for clinical use. The advent of immune checkpoint inhibitor (ICI) has brought a paradigm shift in melanoma therapy, but more than half of patients fail to exhibit clinical responses. The exploration of new combination therapies has become the current pursuit of melanoma treatment strategy. This study aims to screen out Chinese herbal monomers that can target c-Jun, explore the combined effect of c-Jun inhibitor and ICI, and further clarify the related molecular mechanism.  METHODS: We adopted a combinatorial screening strategy, including molecular docking, ligand-based online approaches and consensus quantitative structure-activity relationship (QSAR) model, to filter out c-Jun inhibitors from a traditional Chinese medicine (TCM) library. A mouse melanoma model was used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Multicolor flow cytometry was employed to assess the tumor microenvironment (TME). Multiple in vitro assays were performed to verify down-streaming signaling pathway. CD4 + T-cell differentiation assay was applied to investigate Treg differentiation in vitro. RESULTS: Ailanthone (AIL) was screened out as a c-Jun inhibitor, and inhibited melanoma cell growth by directly targeting c-Jun and promoting its degradation. Surprisingly, AIL also facilitated the therapeutic efficacy of anti-programmed death ligand-1 (PD-L1) in melanoma cells by reducing the infiltration of Tregs in TME. Additionally, AIL treatment inhibited c-Jun-induced PD-L1 expression and secretion. As a consequence, Treg differentiation was attenuated after treatment with AIL through the c-Jun/PD-L1 axis. CONCLUSION: Our findings identified AIL as a novel c-Jun inhibitor, and revealed its previously unrecognized anti-melanoma effects and the vital role in regulating TME by Treg suppression, which provides a novel combination therapeutic strategy of c-Jun inhibition by AIL with ICI. AIL down-regulates c-Jun by reducing its stability, and inhibits the function of Tregs via AIL-c-Jun-PD-L1 pathway, ultimately suppressing melanoma progression and enhancing the efficacy of anti-PD-L1.

Modelling and experimental study of thermo-physiological responses of human exercising in cold environments.

A numerical human thermo-physiological model is developed with the consideration of characteristics of exercising people in cold environments. The developed model is characterized by: 1) the concept of net exercise efficiency which is used to correct the calculation of metabolic heat production by excluding mechanical energy; 2) the effects of low temperature on basal metabolic rate and basal blood flow rate; 3) the integration with a multi-layer clothing model to calculate the heat and moisture transfer through the clothing system, which takes into account the air gaps between the clothing layers to reflect the ventilation and air penetration effect from the ambient wind. Human subject experiment is conducted in a climate chamber to validate the proposed model. The human subject experiment is also carried out in a cold environment (-5 °C) combined with different air velocity conditions (still air, 2 m/s), taking into account the activities of different intensities (standing statically, 2 km/h walking and 7 km/h running). Thermo-physiological parameters including the core temperature, 8-point local skin temperatures and the clothing layer temperatures, are measured during the experiment. Comparison between the predicted and experimental results gives the root mean squared error (RMSE) of core temperature and mean skin temperature of 0.06-0.10 °C and 0.17-0.27 °C, respectively. RMSE values for local skin and clothing layer temperatures are no higher than 1.5 °C and most within 0.8 °C. The model is also validated with published data under various ambient temperature and activity intensity conditions. The proposed model is shown to be capable of predict the thermo-physiological responses of people exposed and exercising in cold environments.

Targeting Ferroptosis by Ubiquitin System Enzymes: A Potential Therapeutic Strategy in Cancer.

Ferroptosis is a novel type of regulated cell death driven by the excessive accumulation of iron-dependent lipid peroxidation. Therapy-resistant tumor cells, particularly those in the mesenchymal-like state and prone to metastasis, are highly susceptible to ferroptosis, suggesting that induction of ferroptosis in tumor cells is a promising strategy for cancer therapy. Although ferroptosis is regulated at various levels, ubiquitination is key to post-translational regulation of ferroptotic cell death. E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are the most remarkable ubiquitin system enzymes, whose dysregulation accounts for the progression of multiple cancers. E3s are involved in the attachment of ubiquitin to substrates for their degradation, and this process is reversed by DUBs. Accumulating evidence has highlighted the important role of ubiquitin system enzymes in regulating the sensitivity of ferroptosis. Herein, we will portray the regulatory networks of ferroptosis mediated by E3s or DUBs and discuss opportunities and challenges for incorporating this regulation into cancer therapy.

The risk of developing second primary malignancies among colorectal cancer patients.

BACKGROUND: The increasing number of young colorectal cancer (CRC) survivors has led to ongoing concerns about the risk of secondary primary malignancies (SPMs). Here, we intended to comprehensively explore the pooled standardized incidence rates (SIRs) for total and site-specific SPMs in CRC survivors with different restriction to lag period. METHODS: Pubmed, Embase, Cochrane Library, and Web of science databases were searched to identify any studies reporting the SIRs of SPM following CRC until August 2021. Total and site-specific SIRs with different restriction to lag period were pooled using fixed/random effect models. RESULTS: A total of 42 full-text publications with more than 1, 524, 236 CRC survivors and 166, 210 SPM patients were included in the meta-analysis. Pooled data showed an increased SIRs for all SPMs in CRC survivors with different restriction to lag period (no restriction to lag period, SIR = 1.15, 95% CI = [1.08-1.23]; 1-year lag, 1.16 [1.10-1.23]; 5-year lag, 1.18 [1.09-1.28]; 10-year lag, 1.24 [1.11-1.39]). The conclusions were consistent for neoplasms of colorectum, corpus uteri, and small intestine with different restriction to lag period. However, limited evidence was presented for associations between CRC survivors and SPM for prostate, breast (female), ovarian, stomach, urinary bladder, kidney, thyroid, bone and soft tissue. CONCLUSION: CRC survivors are associated with an increased risk of SPMs, especially neoplasms of colorectum, corpus uteri, and small intestine. Further studies should explore the risks for these neoplasms in CRC survivors, thus providing the reference for future follow-up care.

Clinical characteristics and outcomes of patients with COVID-19 and psoriasis.

To summarize the clinical characteristics and explore the role of treatment types in outcomes among psoriasis patients with coronavirus disease 2019 (COVID-19). The principal summary measures were pooled prevalence and risk ratio (RR) with 95% confidential interval (CI). R statistic software was used for all the analysis. A total of 19 studies including 4073 psoriasis patients with COVID-19 were eligible for the meta-analysis. The overall hospitalization rate is about 20.2% (95% CI: 12.7%-28.7%), and changed to be 18.0% (95% CI: 9.9%-27.6%) or 14.1% (95% CI: 5.9%-24.6%) after systemic or biologic treatment. Moreover, the overall fatality rate is 1.5% (95% CI: 0.4%-3.0%), and turned to be 0.7% (95% CI: 0%-2.0%) or 0.5% (95% CI: 0%-2.2%) after systemic or biologic therapy. Notably, a lower hospitalization RR was found in patients receiving biologic therapy than those receiving other treatments (RR = 0.62, 95% CI: 0.42-0.94). The results were consistent after sensitivity analysis and trim-and-fill analysis. Systemic, especially biologic therapy could lessen the clinical severity in psoriasis patients with COVID-19. Our finding will help to guide current recommendations and provide a reference for clinical decision-making.

Identification of a Novel Tumor Inflammation Signature for Risk Stratification, Prognosis Prediction, and Immune Status in Colorectal Cancer.

Background: Inflammation and immune cell dysfunction have been widely known as an essential role in the tumorigenesis of colorectal cancer (CRC). Yet, the role of tumor inflammation signature (TIS) associated with CRC prognosis, immune infiltration, and drug resistance remained unknown. Method: The transcriptome sequencing data, as well as clinical data of CRC from the public dataset, were acquired for further investigation. Inflammation-related gene expression patterns were obtained and analyzed. Bioinformatics methods were used to build a prognostic TIS, and its prediction accuracy was verified by using ROC curve analyses. The independent prognostic factors in CRC were identified through multivariable Cox regression analysis. In addition, the specific features of the immunological landscape between low- and high-risk CRC cohorts were analyzed. Results: We firstly screened the differentially expressed inflammation-related genes in CRC and constructed a prognostic TIS. We further classified CRC patients into high or low TIS score groups based on the optimal cutoff of prognostic TIS, and patients with high-risk scores had shorter overall survival (OS) than those in the low-risk cohort. The diagnostic accuracy of TIS was evaluated and confirmed with ROC analysis. The result of the univariate and multivariate analysis found that TIS was directly and independently linked to OS of CRC. Otherwise, an optimal nomogram model based on TIS exhibited a better prognostic accuracy in OS. Finally, the immunological status and immune cell infiltration were observed different in the two-risk cohorts. Conclusion: In summary, the risk model of the TIS in CRC was found to be useful for predicting patient prognosis and guiding individual treatment. This risk signature could also serve as potential biomarkers and immunotherapeutic targets and indicate immunotherapy response for patients with CRC.

Monolithic 6 × 6 transmitter-router with simultaneous sub-nanosecond port and wavelength switching.

A monolithic 6 × 6 transmitter-router with both port and wavelength switching at sub-nanosecond speed is proposed and experimentally demonstrated. Based on an intra-cavity cyclic echelle diffraction grating router (EDGR) and semiconductor optical amplifier (SOA) arrays, each selectable output port can realize a selected multi-wavelength laser (MWL) output. The measurement results show that all 36 input-output combinations have a single-mode emission spectrum with a sidemode suppression ratio (SMSR) over 30 dB. Simultaneous switching of six laser wavelengths is achieved together with the switching of the output port by a single electrode selection. The switching time is less than 1 ns. It can offer a cost-effective solution to multi-wavelength multi-port optical transmitter-routers for fast distributed optical switching in datacenters and high-performance computers (HPCs).

Melanoma survivors are at increased risk for second primary keratinocyte carcinoma.

BACKGROUND: Recent large cohorts have reported that melanoma survivors are at risk of developing second keratinocyte carcinoma (KC). However, the detailed proportion and risk are still unknown. We aimed to comprehensively analyze the risk of developing keratinocyte carcinoma after primary melanoma. METHODS: We conducted systematic literature research in PubMed, Embase, Web of Science, and Cochrane Library published prior to September 13, 2021. Proportion and standardized incidence ratios (SIR) with its corresponding 95% confidence interval (CI) were pooled for assessing the risk. RESULTS: A total of 15 studies encompassing 168,286 patients were included in our analysis. The pooled proportions of melanoma survivors that developed a subsequent basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and KC were 4.11% (95% CI, 1.32-6.90), 2.54% (95% CI, 1.78-3.31), and 5.45% (95% CI, 3.06-7.84), respectively. The risks of developing a second BCC, SCC, and KC in melanoma survivors were 5.3-fold (SIR 5.30; 95% CI, 4.87-5.77), 2.6-fold (SIR 2.58; 95% CI, 1.33-5.04), and 6.2-fold (SIR 6.17; 95% CI, 3.66-10.39) increased in comparison with the general population. Both fixed effects and random effects models were applied in conducting meta-analysis and reached a consistent conclusion. CONCLUSIONS: Our results indicated melanoma survivors are at elevated risk of experiencing second primary BCC and SCC, which suggested the significance of surveillance for second primary KC and efforts for prevention in patients with a history of melanoma.

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers.

Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.

The Prognostic Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Melanoma Patients Receiving Immunotherapy.

Immunotherapy has revolutionized the treatment in metastatic melanoma, but alternative biomarkers that are economical, simple and reliable still need to be clarified. In this study, we aimed to comprehensively analyze the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) in melanoma patients with immunotherapy. We searched PubMed, Embase, and Cochrane Library until September 16, 2020. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled to investigate the association of baseline NLR with overall survival (OS) and progression-free survival (PFS). Sensitivity analysis, subgroup analyses, publication bias assessment, and the Duval and Tweedie trim-and-fill method were used to evaluate the stability of results. A total of 18 studies including 2054 patients were included in our analysis. Pooled data demonstrated that higher baseline NLR was associated with a poorer OS (HR=2.46, 95% CI=1.77, 3.43) and PFS (HR=2.38, 95% CI=1.95, 2.89) of melanoma patients receiving immunotherapy. Subgroup analysis according to immunotherapy type showed that the prognostic effects of baseline NLR existed in all the subtypes of immunotherapy, including anticytotoxic T lymphocyte-associated protein 4 therapy (OS HR=2.26, 95% CI=1.43, 3.59; PFS HR=2.68, 95% CI=1.79, 4.02), antiprogrammed cell death-1 therapy (OS HR=3.08, 95% CI=2.21, 4.27; PFS HR=2.01, 95% CI=1.64, 2.47), and combination therapy (OS HR=1.75, 95% CI=1.13, 2.72; PFS HR=3.13, 95% CI=1.63, 6.03). Conclusions were still consistent in subgroup analyses stratified by study year, region, study type, sample size, analysis of HR and cuttoff of baseline NLR. Altogether, baseline NLR is a promising prognostic biomarker for melanoma patients receiving immunotherapy.

A novel ribosomal protein S6 kinase 2 inhibitor attenuates the malignant phenotype of cutaneous malignant melanoma cells by inducing cell cycle arrest and apoptosis.

Malignant melanoma (MM) is a highly life-threatening tumor causing the majority of the cutaneous cancer-related deaths. Previously, ribosomal protein S6 kinase 2 (RSK2), the downstream effector of the MAPK pathway, represents a therapeutic target in melanoma. AE007 is discovered as a targeted RSK2 inhibitor, and subsequent results showed that AE007 inhibits RSK2 by directly binding to its protein kinase domain. AE007 causes cell cycle arrest and cellular apoptosis, thereby dramatically inhibiting proliferation, migration, and invasion of melanoma cells. Nevertheless, melanocytes and keratinocytes are not affected by this compound. In addition, suppression of RSK2 abrogates the inhibitory effect of AE007 on melanoma cell proliferation. AE007 treatment significantly inhibits the expression of Cyclin D1, Cyclin B1, CDK2, and Bcl-2, while raises the cleavage of PARP. Moreover, RNA sequencing results show that AE007 treatment can affect the genes expression profile, including the expression of cell cycle and DNA replication genes. In conclusion, AE007 is a promising melanoma therapeutic agent by targeting RSK2.

Nomogram based on autophagy related genes for predicting the survival in melanoma.

BACKGROUND: Autophagy, a highly conserved lysosomal degradation pathway, is associated with the prognosis of melanoma. However, prognostic prediction models based on autophagy related genes (ARGs) have never been recognized in melanoma. In the present study, we aimed to establish a novel nomogram to predict the prognosis of melanoma based on ARGs signature and clinical parameters. METHODS: Data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were extracted to identify the differentially expressed ARGs. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate analysis were used to select the prognostic ARGs. ARGs signature, age and stage were then enrolled to establish a nomogram to predict the survival probabilities of melanoma. The nomogram was evaluated by concordance index (C-index), receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was performed to assess the clinical benefits of the nomogram and TNM stage model. The nomogram was validated in GEO cohorts. RESULTS: Five prognostic ARGs were selected to construct ARGs signature model and validated in the GEO cohort. Kaplan-Meier survival analysis suggested that patients in high-risk group had significantly worse overall survival than those in low-risk group in TCGA cohort (P = 5.859 × 10-9) and GEO cohort (P = 3.075 × 10-9). We then established and validated a novel promising prognostic nomogram through combining ARGs signature and clinical parameters. The C-index of the nomogram was 0.717 in TCGA training cohort and 0.738 in GEO validation cohort. TCGA/GEO-based ROC curve and decision curve analysis (DCA) demonstrated that the nomogram was better than traditional TNM staging system for melanoma prognosis. CONCLUSION: We firstly developed and validated an ARGs signature based-nomogram for individualized prognosis prediction in melanoma patients, which could assist with decision making for clinicians.