Positive Development Patterns in Left-Behind Adolescents: Do Resilience and Making Sense of Adversity Have Beneficial Effects?

Purpose: Despite increased attention to the positive development of left-behind adolescents, research findings remain inconclusive. Utilizing latent profile analysis, we identified various positive development profiles among the left-behind adolescents and explored the association between resilience and positive development profiles, alongside the mediating role of making sense of adversity. Methods: A multi-stage cluster sampling procedure was employed, randomly selecting four provinces-Zhejiang, Guangdong, Henan, and Jiangxi-from the central and coastal regions. The sample comprised 718 left-behind adolescents recruited from primary and junior high schools across grades 4, 5, 7, and 8. Three scales were utilized, and analyses included latent profile analysis and mediation analysis. Results: Three latent subgroups of positive development among left-behind adolescents were identified: low, moderate, and high. Those with higher resilience and positive perceptions of adversity tended to belong to the high group rather than the low (ß = -0.45, p < 0.001; ß = -0.09, p < 0.001) or moderate group (ß = -0.23, p < 0.001; ß = -0.04, p < 0.05). Left-behind adolescents with higher negative perceptions of adversity tended to belong to the high group rather than the moderate group (ß = -0.07, p < 0.01). Mediation analysis revealed that resilience facilitated the development of positive appraisals of adversity, subsequently increasing the likelihood of being categorized into the high (95% CI of -0.09 to -0.03) or moderate group (95% CI of -0.05 to -0.01) rather than the low group. Conclusion: These findings hold significant implications for intervention formulation. Educators should focus on strengthening resilience and fostering positive perceptions of adversity among the low group. For the moderate group, maintaining moderate negative perceptions of adversity may stimulate the intrinsic potential for positive development more effectively.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Effects of cooking with solid fuel on hearing loss in Chinese adults-Based on two cohort studies.

The association between cooking fuel and hearing loss still needs more research to clarify, and two longitudinal cohort studies were explored to find if solid fuel use for cooking affected hearing in Chinese adults. The data from Chinese Health and Retirement Longitudinal Survey (CHARLS) and Chinese Longitudinal Healthy Longevity Survey (CLHLS) were analyzed. Participants (older than 18) without hearing loss at baseline and follow-up visits were included, which were divided into clean fuel and solid fuel groups. Hearing loss rate was from follow-up visits (both in year 2011) until the recent one (year 2018 in CHARLS and 2019 in CLHLS). Cox regressions were applied to examine the associations with adjustment for potential confounders. Fixed-effect meta-analysis was used to pool the results. A total of 9049 participants (average age 8.34 ± 9.12 [mean ± SD] years; 4247 [46.93%] males) were included in CHARLS cohort study and 2265 participants (average age, 78.75 ± 9.23 [mean ± SD] years; 1148 [49.32%] males) in CLHLS cohort study. There were 1518 (16.78%) participants in CHARLS cohort and 451 (19.91%) participants in CLHLS cohort who developed hearing loss. The group of using solid fuel for cooking had a higher risk of hearing loss (CHARLS: HR, 1.16; 95% CI 1.03-1.30; CLHLS: HR, 1.43; 95% CI 1.11-1.84) compared with the one of using clean fuel. Pooled hazard ratio showed the incidence of hearing loss in the solid fuel users was 1.17 (1.03, 1.29) times higher than that of clean fuel users. Hearing loss was associated with solid fuel use and older people were at higher risk. It is advised to replace solid fuel by clean fuel that may promote health equity.

Rapid Sample Pretreatment Facilitating SERS Detection of Trace Weak Organic Acids/Bases in Complex Matrices.

Fast and efficient sample pretreatment is the prerequisite for realizing surface-enhanced Raman spectroscopy (SERS) detection of trace targets in complex matrices, which is still a big issue for the practical application of SERS. Recently, we have proposed a highly performed liquid-liquid extraction (LLE)-back extraction (BE) for weak acids/bases extraction in drinking water and beverage samples. However, the performance efficiency decreased drastically on facing matrices like food and biological blood. Based on the total interaction energies among target, interferent, and extractant molecules, solid-phase extraction (SPE) with a higher selectivity was introduced in advance of LLE-BE, which enabled the sensitive (µg L-1 level) and rapid (within 10 min) SERS detection of both koumine (a weak base) and celastrol (a weak acid) in different food and biological samples. Further, the high SERS sensitivity was determined unmanned by Vis-CAD (a machine learning algorithm), instead of the highly demanded expert recognition. The generality of SPE-LLE-BE for various weak acids/bases (2 < pKa < 12), accompanied by the high efficiency, easy operation, and low cost, offers SERS as a powerful on-site and efficient inspection tool in food safety and forensics.

3D printing of Ceffe-infused scaffolds for tailored nipple-like cartilage development.

The reconstruction of a stable, nipple-shaped cartilage graft that precisely matches the natural nipple in shape and size on the contralateral side is a clinical challenge. While 3D printing technology can efficiently and accurately manufacture customized complex structures, it faces limitations due to inadequate blood supply, which hampers the stability of nipple-shaped cartilage grafts produced using this technology. To address this issue, we employed a biodegradable biomaterial, Poly(lactic-co-glycolic acid) (PLGA), loaded with Cell-Free Fat Extract (Ceffe). Ceffe has demonstrated the ability to promote angiogenesis and cell proliferation, making it an ideal bio-ink for bioprinting precise nipple-shaped cartilage grafts. We utilized the Ceffe/PLGA scaffold to create a porous structure with a precise nipple shape. This scaffold exhibited favorable porosity and pore size, ensuring stable shape maintenance and satisfactory biomechanical properties. Importantly, it could release Ceffe in a sustained manner. Our in vitro results confirmed the scaffold's good biocompatibility and its ability to promote angiogenesis, as evidenced by supporting chondrocyte proliferation and endothelial cell migration and tube formation. Furthermore, after 8 weeks of in vivo culture, the Ceffe/PLGA scaffold seeded with chondrocytes regenerated into a cartilage support structure with a precise nipple shape. Compared to the pure PLGA group, the Ceffe/PLGA scaffold showed remarkable vascular formation, highlighting the beneficial effects of Ceffe. These findings suggest that our designed Ceffe/PLGA scaffold with a nipple shape represents a promising strategy for precise nipple-shaped cartilage regeneration, laying a foundation for subsequent nipple reconstruction.

The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer.

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.

Intrarenal pressure detection during flexible ureteroscopy with fiber optic pressure sensor system in porcine model.

To validate the feasibility of a fiber-optic pressure sensor-based pressure measurement device for monitoring intrarenal pressure and to analyze the effects of ureteral acess sheath (UAS) type, surgical location, perfusion flow rate, and measurement location on intrarenal pressure (IRP). The measurement deviations and response times to transient pressure changes were compared between a fiber-optic pressure sensing device and a urodynamic device IRP in an in vitro porcine kidney and in a water tank. Finally, pressure measurements were performed in anesthetized female pigs using fiber-optic pressure sensing device with different UAS, different perfusion flow rates, and different surgical positions at different renal calyces and ureteropelvic junctions (UPJ). According to our operation, the result is fiber optic pressure sensing devices are highly accurate and sensitive. Under the same conditions, IRP varied among different renal calyces and UPJ (P < 0.05). IRP was lowest at 50 ml/min and highest at 150 ml/min (P < 0.05). Surgical position had a significant effect on IRP (P < 0.05). 12/14 Fr UAS had a lower IRP than 11/13 Fr UAS. Therefore fiber optic pressure sensing devices are more advantageous for IRP measurements. In ureteroscopy, the type of ureteral sheath, the surgical position, the perfusion flow rate, and the location of the measurement all affect the intrarenal pressure value.

Highly-dispersed 2D NiFeP/CoP heterojunction trifunctional catalyst for efficient electrolysis of water and urea.

The electrocatalytic production of "green hydrogen", such as through the electrolysis of water or urea has been vigorously advocated to alleviate the energy crisis. However, their electrode reactions including oxygen evolution reaction (OER), urea oxidation reaction (UOR), and hydrogen evolution reaction (HER) all suffer from sluggish kinetics, which urgently need catalysts to accelerate the processes. Herein, we design and prepare an OER/UOR/HER trifunctional catalyst by transforming the homemade CoO nanorod into a two-dimensional (2D) ultrathin heterojunction nickel-iron-cobalt hybrid phosphides nanosheet (NiFeP/CoP) via a hydrothermal-phosphorization method. Consequently, a strong electronic interaction was found among the Ni2P/FeP4/CoP heterogeneous interfaces, which regulates the electronic structure. Besides the high mass transfer property of 2D nanosheet, Ni2P/FeP4/CoP displays improved OER/UOR/HER performance. At 10 mA cm-2, the OER overpotential reaches 274 mV in 1.0 M KOH, and the potential of UOR is only 1.389 V in 1.0 M KOH and 0.33 M urea. More strikingly, the two-electrode systems for electrolysis water and urea-assisted electrolysis water assembled by NiFeP/CoP could maintain long-term stability for 35 h and 12 h, respectively. This work may help to pave the way for upcoming research horizons of multifunctional electrocatalysts.

The enigmatic interplay of immune cells and abnormal spermatozoa through Mendelian randomization.

PURPOSE: Abnormal spermatozoa significantly impact reproductive health, affecting fertility rates, potentially prolonging conception time, and increasing the risk of miscarriages. This study employs Mendelian randomization to explore their potential link with immune cells, aiming to reveal their potential causal association and wider implications for reproductive health. METHODS: We conducted forward and reverse Mendelian randomization analyses to explore the potential causal connection between 731 immune cell signatures and abnormal spermatozoa. Using publicly available genetic data, we investigated various immune signatures such as median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP). Robustness was ensured through comprehensive sensitivity analyses assessing consistency, heterogeneity, and potential horizontal pleiotropy. The MR study produced a statistically significant p-value of .0000684, Bonferroni-corrected for the 731 exposures. RESULTS: The Mendelian randomization analysis revealed strong indications of a reciprocal relationship between immune cell pathways and sperm integrity. When examining immune cell exposure, a potential causal link with abnormal sperm was observed in 35 different types of immune cells. Conversely, the reverse Mendelian randomization results indicated that abnormal sperm might causally affect 39 types of immune cells. These outcomes suggest a potential mutual influence between alterations in immune cell functionality and the quality of spermatozoa. CONCLUSION: This study highlights the close link between immune responses and sperm development, suggesting implications for reproductive health and immune therapies. Further research may offer crucial insights into male fertility and immune disorders.

Plant-based dietary patterns and risk of esophageal cancer: A prospective cohort study spanning 17 years.

Objective: Plant-based diets have multiple health benefits for cancers; however, little is known about the association between plant-based dietary patterns and esophageal cancer (EC).This study presents an investigation of the prospective associations among three predefined indices of plant-based dietary patterns and the risk of EC. Methods: We performed endoscopic screening for 15,709 participants aged 40-69 years from two high-risk areas of China from January 2005 to December 2009 and followed the cohort until December 31, 2022. The overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI), were calculated using survey responses to assess dietary patterns. We applied Cox proportional hazard regression to estimate the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) of EC across 3 plant-based diet indices and further stratified the analysis by subgroups. Results: The final study sample included 15,184 participants in the cohort. During a follow-up of 219,365 person-years, 176 patients with EC were identified. When the highest quartile was compared with the lowest quartile, the pooled multivariable-adjusted HR of EC was 0.50 (95% CI, 0.32-0.77) for hPDI. In addition, the HR per 10-point increase in the hPDI score was 0.42 (95% CI, 0.27-0.66) for ECs. Conversely, uPDI was positively associated with the risk of EC, and the HR was 1.80 (95% CI, 1.16-2.82). The HR per 10-point increase in the uPDI score was 1.90 (95% CI, 1.26-2.88) for ECs. The associations between these scores and the risk of EC were consistent in most subgroups. These results remained robust in sensitivity analyses. Conclusions: A healthy plant-based dietary pattern was associated with a reduced risk of EC. Emphasizing the healthiness and quality of plant-based diets may be important for preventing the development of EC.

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review.

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.

Autophagy-mediated degradation of integumentary tapetum is critical for embryo pattern formation.

Autophagy modulates the degradation and recycling of intracellular materials and contributes to male gametophyte development and male fertility in plants. However, whether autophagy participates in seed development remains largely unknown. Here, we demonstrate that autophagy is crucial for timely programmed cell death (PCD) in the integumentary tapetum, the counterpart of anther tapetum, influencing embryo pattern formation and seed viability. Inhibition of autophagy resulted in delayed PCD of the integumentary tapetum and defects in embryo patterning. Cell-type-specific restoration of autophagic activities revealed that the integumentary tapetum plays a non-autonomous role in embryo patterning. Furthermore, high-throughput, comprehensive lipidomic analyzes uncovered an unexpected seed-developmental-stage-dependent role of autophagy in seed lipid metabolism: it contributes to triacylglycerol degradation before fertilization and to triacylglycerol biosynthesis after fertilization. This study highlights the critical role of autophagy in regulating timely integumentary tapetum PCD and reveals its significance in seed lipid metabolism and viability.

Reduced production of Ethyl Carbamate in wine by regulating the accumulation of arginine in Saccharomyces cerevisiae.

Ethyl carbamate (EC), a multisite carcinogenic compound, is naturally produced from urea and ethanol in alcoholic beverages. In order to reduce the content of EC in wine, the accumulation of arginine in Saccharomyces cerevisiae was regulated by genetic modifying genes involved in arginine transport and synthesis pathways to reduce the production of urea. Knockout of genes encoding arginine permease (Can1p) and amino acid permease (Gap1p) on the cell membrane as well as argininosuccinate synthase (Arg1) respectively resulted in a maximum reduction of 66.88% (9.40 µg/L) in EC, while overexpressing the gene encoding amino acid transporter (Vba2) reduced EC by 52.94% (24.13 µg/L). Simultaneously overexpressing Vba2 and deleting Arg1 showed the lowest EC production with a decrease of 68% (7.72 µg/L). The yield of total higher alcohols of the mutants all decreased compared with that of the original strain. Comprehensive consideration of flavor compound contents and sensory evaluation results indicated that mutant YG21 obtained by deleting two allele coding Gap1p performed best in must fermentation of Cabernet Sauvignon with the EC content low to 9.40 µg/L and the contents of total higher alcohols and esters of 245.61 mg/L and 41.71 mg/L respectively. This study has provided an effective strategy for reducing the EC in wine.

A novel risk signature based on liquid-liquid phase separation-related genes reveals prognostic and tumour microenvironmental features in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma(ccRCC) is one of the most common malignancies. However, there are still many barriers to its underlying causes, early diagnostic techniques and therapeutic approaches. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA)- Kidney renal clear cell (KIRC) cohort differentially analysed liquid-liquid phase separation (LLPS)-related genes from the DrLLPS website. Univariate and multivariate Cox regression analyses and LASSO regression analyses were used to construct prognostic models. The E-MTAB-1980 cohort was used for external validation. Then, potential functions, immune infiltration analysis, and mutational landscapes were analysed for the high-risk and low-risk groups. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) experiments as well as single-cell analyses validated the genes key to the model. RESULTS: We screened 174 LLPS-related genes in ccRCC and constructed a risk signature consisting of five genes (CLIC5, MXD3, NUF2, PABPC1L, PLK1). The high-risk group was found to be associated with worse prognosis in different subgroups. A nomogram constructed by combining age and tumour stage had a strong predictive power for the prognosis of ccRCC patients. In addition, there were differences in pathway enrichment, immune cell infiltration, and mutational landscapes between the two groups. The results of qRT-PCR in renal cancer cell lines and renal cancer tissues were consistent with the biosignature prediction. Three single-cell data of GSE159115, GSE139555, and GSE121636 were analysed for differences in the presence of these five genes in different cells. CONCLUSIONS: We developed a risk signature constructed based on the five LLPS-related genes and can have a high ability to predict the prognosis of ccRCC patients, further providing a strong support for clinical decision-making.

The infection kinetics and transmission potential of two Guaico Culex viruses in Culex quinquefasciatus mosquitoes.

Guaico Culex virus (GCXV) is a newly identified segmented Jingmenvirus from Culex spp. mosquitoes in Central and South America. The genome of GCXV is composed of four or five single-stranded positive RNA segments. However, the infection kinetics and transmission capability of GCXV in mosquitoes remain unknown. In this study, we used reverse genetics to rescue two GCXVs (4S and 5S) that contained four and five RNA segments, respectively, in C6/36 â€‹cells. Further in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics, protein expression and viral titers. Importantly, GCXV RNAs were detected in the bodies, salivary glands, midguts and ovaries of Culex quinquefasciatus at 4-10 days after oral infection. In addition, two GCXVs can colonize Cx. quinquefasciatus eggs, resulting in positive rates of 15%-35% for the second gonotrophic cycle. In conclusion, our results demonstrated that GCXVs with four or five RNA segments can be detected in Cx. quinquefasciatus eggs during the first and second gonotrophic cycles after oral infection.

Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.

Incidence and Mortality of Cancers in Female Genital Organs - China, 2022.

Introduction: This study presented the incidence and mortality rates of cancers affecting the female genital organs in China, along with their trends spanning from 2010 to 2018. Methods: 700 population-based cancer registries provided relevant cancer incidence and mortality data for the year 2018. Among these, 106 registries had continuous monitoring data suitable for trend analysis from 2010 to 2018. We focused specifically on cancers affecting female genital organs (ICD10=C51-C54, C56) and projected their incidences and mortalities in China for 2022 based on data from 2018 and the trends observed from 2010 to 2018. Age-standardized incidence rate (ASIR) and mortality rate (ASMR) were calculated using Segi's world standard population. Results: In 2022, there were an estimated 296,300 new cases and 104,900 deaths from female cancers in China. ASIRs for vulva (C51), vagina (C52), cervix uteri (C53), corpus uteri (C54), and ovary (C56) were 0.32, 0.23, 13.83, 6.84, and 5.68 per 100,000 population. ASIRs for corpus uteri and ovary cancers were higher in urban areas. ASMRs for vulva, vagina, cervix, corpus uteri, and ovary cancers were 0.14, 0.08, 4.54, 1.05, and 2.64 per 100,000 population, respectively. ASMR for ovarian cancer was higher in urban areas. ASIRs and ASMRs for most female genital organ cancers increased from 2010 to 2018, although the rate of increase for vulvar and cervical cancers in rural areas has slowed recently. Conclusions: Tailored cancer prevention and control programs specific to each region are necessary to address the growing disease burden.

An Integrated Clinical and Computerized Tomography-Based Radiomic Feature Model to Separate Benign from Malignant Pleural Effusion.

INTRODUCTION: Distinguishing between malignant pleural effusion (MPE) and benign pleural effusion (BPE) poses a challenge in clinical practice. We aimed to construct and validate a combined model integrating radiomic features and clinical factors using computerized tomography (CT) images to differentiate between MPE and BPE. METHODS: A retrospective inclusion of 315 patients with pleural effusion (PE) was conducted in this study (training cohort: n = 220; test cohort: n = 95). Radiomic features were extracted from CT images, and the dimensionality reduction and selection processes were carried out to obtain the optimal radiomic features. Logistic regression (LR), support vector machine (SVM), and random forest were employed to construct radiomic models. LR analyses were utilized to identify independent clinical risk factors to develop a clinical model. The combined model was created by integrating the optimal radiomic features with the independent clinical predictive factors. The discriminative ability of each model was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS: Out of the total 1,834 radiomic features extracted, 15 optimal radiomic features explicitly related to MPE were picked to develop the radiomic model. Among the radiomic models, the SVM model demonstrated the highest predictive performance [area under the curve (AUC), training cohort: 0.876, test cohort: 0.774]. Six clinically independent predictive factors, including age, effusion laterality, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase (NSE), were selected for constructing the clinical model. The combined model (AUC: 0.932, 0.870) exhibited superior discriminative performance in the training and test cohorts compared to the clinical model (AUC: 0.850, 0.820) and the radiomic model (AUC: 0.876, 0.774). The calibration curves and DCA further confirmed the practicality of the combined model. CONCLUSION: This study presented the development and validation of a combined model for distinguishing MPE and BPE. The combined model was a powerful tool for assisting in the clinical diagnosis of PE patients.

DNA-methylome-derived epigenetic fingerprint as an immunophenotype indicator of durable clinical immunotherapeutic benefits in head and neck squamous cell carcinoma.

BACKGROUND: Cancer immunotherapy provides durable response and improves survival in a subset of head and neck squamous cell carcinoma (HNSC) patients, which may due to discriminative tumor microenvironment (TME). Epigenetic regulations play critical roles in HNSC tumorigenesis, progression, and activation of functional immune cells. This study aims to identify an epigenetic signature as an immunophenotype indicator of durable clinical immunotherapeutic benefits in HNSC patients. METHODS: Unsupervised consensus clustering approach was applied to distinguish immunophenotypes based on five immune signatures in The Cancer Genome Atlas (TCGA) HNSC cohort. Two immunophenotypes (immune 'Hot' and immune 'Cold') that had different TME features, diverse prognosis, and distinct DNA methylation patterns were recognized. Immunophenotype-related methylated signatures (IPMS) were identified by the least absolute shrinkage and selector operation algorithm. Additionally, the IPMS score by deconvolution algorithm was constructed as an immunophenotype classifier to predict clinical outcomes and immunotherapeutic response. RESULTS: The 'Hot' HNSC immunophenotype had higher immunoactivity and better overall survival (p = 0.00055) compared to the 'Cold' tumors. The immunophenotypes had distinct DNA methylation patterns, which was closely associated with HNSC tumorigenesis and functional immune cell infiltration. 311 immunophenotype-related methylated CpG sites (IRMCs) was identified from TCGA-HNSC dataset. IPMS score model achieved a strong clinical predictive performance for classifying immunophenotypes. The area under the curve value (AUC) of the IPMS score model reached 85.9% and 89.8% in TCGA train and test datasets, respectively, and robustness was verified in five HNSC validation datasets. It was also validated as an immunophenotype classifier for predicting durable clinical benefits (DCB) in lung cancer patients who received anti-PD-1/PD-L1 immunotherapy (p = 0.017) and TCGA-SKCM patients who received distinct immunotherapy (p = 0.033). CONCLUSIONS: This study systematically analyzed DNA methylation patterns in distinct immunophenotypes to identify IPMS with clinical prognostic potential for personalized epigenetic anticancer approaches in HNSC patients. The IPMS score model may serve as a reliable epigenome prognostic tool for clinical immunophenotyping to guide immunotherapeutic strategies in HNSC.

The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.