Key platelet genes play important roles in predicting the prognosis of sepsis.

Sepsis is a life-threatening organ malfunction induced by an imbalanced immunological reaction to infection in the host. Many studies have utilized traditional RNA sequencing (RNA-seq) data to identify important biological targets to predict sepsis prognosis. However, alterations in core cells and functional status cannot be effectively detected in sepsis patients. The goal of this study was to identify key cells through single-cell RNA-seq (scRNA-seq), and combine bulk RNA-seq data and multiple algorithm analysis to construct a stable prognostic model for sepsis. The scRNA-seq and bulk RNA-seq data from sepsis patients were collected from the Gene Expression Omnibus (GEO) database. The R package "Seurat" was used to process the scRNA-seq data. Cell communication was investigated using the R package "CellChat". The pseudo-time of the cells was calculated using the R package "monocle". The R package "limma" was used to identify differentially expressed genes (DEGs) between the sepsis group and the control group. Weighted gene correlation network analysis (WGCNA) was used to identify critical modules. Eight kinds of machine learning and 90 algorithm combinations were used to construct the prognostic model for sepsis. Quantitative real-time PCR (qRT‒PCR) was performed to determine the expression of key genes in the cecal ligation and puncture (CLP)-induced sepsis mouse model. The immunological status and related properties of DEGs were then investigated in the high- and low-risk groups delineated by the model. By combining the scRNA-seq data from nine samples, 13 clusters and 9 cell types were identified. CellChat analysis revealed that the number and strength of interactions between platelets and a variety of cells increased. We identified key platelet genes from the scRNA-seq data and combined these genes and the results of differential analysis and WGCNA of the bulk RNA-seq data. After univariate Cox regression analysis, we calculated the Cindex of the model constructed by the combination of 90 algorithms, and we finally determined the "CoxBoost + Lasso" combination. Multivariate Cox regression was used to construct the final prognostic model. The qRT-PCR results revealed significant differences in five key prognostic genes between the CLP and sham groups. The data was classified into high- and low-risk groups based on the model score. The high-risk group had a poorer survival rate and less immune infiltration. We identified the importance of platelets in sepsis patients through scRNA-seq, and established prognostic models with key genes that were identified via scRNA-seq combined with bulk RNA-seq analysis. The results of this model were closely associated with patient survival rates and immunological status and this model is useful for the prognostic management of sepsis.

Wide-based oblique anastomosis reduces urethral stricture rate following the transverse preputial island flap procedure.

Background: The transverse preputial island flap (TPIF) procedure remains one of the classic single-stage procedures for severe hypospadias repairs. The incidence of postoperative complications remained high. This study aims to describe a modified urethral anastomosis technique during the TPIF procedure for severe hypospadias repairs and report its outcomes. Methods: Data were collected retrospectively from consecutive patients who underwent the TPIF procedure by the same pediatric urologist between January 2018 and June 2023. Collected information included age at surgery, operative details, and outcomes at follow-up. Wide-based oblique anastomosis (WOA) technique was used as a modified urethral anastomosis in all cases. In brief, the dorsal edge of anastomosis was breadthwise anchored to the corpus cavernosum with 4-5 stitches, forming a spade-shaped anastomotic surface. Results: A total of 72 patients were included in the study. The location of the corpus spongiosum division was penile in 27 patients (37.5%) and proximal in 45 patients (62.5%). The median glans width was 13 mm (range, 6-30 mm). The median ventral curvature after degloving was 45° (range, 30-150°). At a median follow-up of 4.1 years, complications occurred in 15 patients (20.8%), including nine cases of fistula, seven cases of urethral diverticulum and two cases of meatal stenosis. No cases of urethral stricture (US), urethral dehiscence, or ventral curvature occurred. Subsequent reoperations for diverticulum repairs showed that the dorsal side of the anastomosis was extensively fixed to the corpus cavernosum, forming a wide-based, spacious lumen. Conclusions: WOA technique is straightforward and effective, especially in the prevention of postoperative US.

A molecular mechanism underlies grass carp (Ctenopharyngodon idella) TARBP2 regulating PKR-mediated cell apoptosis.

Interferon-inducible double-stranded RNA-dependent protein kinase (PKR) is one of the key antiviral arms in the innate immune system. The activated PKR performs its antiviral function by inhibiting protein translation and inducing apoptosis. In our previous study, we identified grass carp TARBP2 as an inhibitor of PKR activity, thereby suppressing cell apoptosis. This study aimed to explore the effects of grass carp TARBP2 on PKR activity and cell apoptosis. Grass carp TARBP2 comprises two N-terminal dsRBDs and a C-terminal C4 domain. Subcellular localization analysis conducted in CIK cells revealed that TARBP2-FL (full-length TARBP2), TARBP2-Δ1 (lack of the first dsRBD), and TARBP2-Δ2 (lack of the second dsRBD) are predominantly located in the cytoplasm, while TARBP2-Δ3 (lack of the two dsRBDs) is distributed both in the nucleus and cytoplasm. Colocalization and immunoprecipitation assays confirmed the interaction of TARBP2-FL, TARBP2-Δ1, and TARBP2-Δ2 with PKR, while TARBP2-Δ3 showed no binding. Furthermore, our findings suggested that the inhibitory effect of TARBP2-Δ1 or TARBP2-Δ2 on the PKR-eIF2α pathway is depressed compared to TARBP2-FL. In cell apoptosis assays, it was observed that TARBP2-FL inhibits PKR-mediated cell apoptosis. TARBP2-Δ1 or TARBP2-Δ2 exhibits decreased inhibition to PKR-mediated cell apoptosis, whereas TARBP2-Δ3 nearly completely loses this inhibitory effect. These findings highlight the critical importance of two dsRBDs of TARBP2 in interaction with PKR, as well as in the inhibition of PKR activity, resulting in the suppression of cell apoptosis triggered by prolonged PKR activation.

PD-1 Inhibitors Combined with Chemotherapy versus Re-irradiation/chemoradiotherapy for Unresectable Locally Recurrent T3-4 Nasopharyngeal Carcinoma: A Retrospective Study.

Objective: To evaluate the efficacy, toxicity, and long-term outcomes of PD1 inhibitors plus chemotherapy versus re-irradiation/chemoradiotherapy in patients with unresectable locally recurrent T3-4 nasopharyngeal carcinoma (NPC). Methods: A retrospective analysis was conducted on 42 patients with recurrent nasopharyngeal cancer (NPC) after receiving immunochemotherapy or re-irradiation between February 2018 and May 2022 in Zhejiang Cancer Hospital. Overall survival (OS), progression-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were determined using the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression. Results: With a median follow-up duration of 28.7 months (ranging from 7.2 to 63.9 months), the 3-year OS rate was 23.3% in the re-irradiotherapy (RI) group (N = 24) and 59.6% in the immunochemotherapy (IC) group (N = 18) (p = 0.042). The 3-year PFS, LRFS, and DMFS rates were not significantly different between the two groups (PFS: 45.3% vs. 62.6%, P = 0.482; LRFS: 54.4% vs. 62.6%, P =0.891; DMFS: 89.8% vs. 100.0%, P = 0.489). The univariate analysis revealed that regimen (HR: 0.354, 95% CI: 0.130-0.962, P = 0.042) was significantly correlated with OS. Multivariate analysis also showed that treatment regimen (HR: 0.329, 95% CI: 0.12-0.970, P =0.044) was the only significant prognostic factor associated with OS. The most common late toxicities in the RI group were xerostomia, deafness, and nasopharyngeal necrosis. Of these, nasopharyngeal necrosis was present in 16 patients (66.7%) and in 10 patients (41.7%) at a grade 3 or above. Nasopharyngeal necrosis is the main cause of death in the RI group. In contrast, in the IC group, grade 3 or higher immune-related adverse events or late adverse events were not observed. Conclusions: For unresectable locally recurrent NPC, re-irradiation is an effective treatment; nevertheless, the survival obtains are usually surpassed by serious late complications. For these individuals, chemotherapy in addition to an anti-PD-1 checkpoint inhibitor may be a helpful course of treatment.

Ureteropelvic Junction Obstruction Caused by Crossing Vessels in Infants and Young Children.

BACKGROUND: To analyze the clinical characteristics of ureteropelvic junction obstruction (UPJO) caused by crossing vessels (CV) in infants and young children. METHODS: A retrospective analysis was performed on children with UPJO who underwent primary surgery. Patients were classified into laparoscopic pyeloplasty (LP) and open pyeloplasty (OP) groups and classified as ≤3 or >3 (years old) groups. Children with CV-caused UPJO were identified. RESULTS: A total of 747 patients were included. Ninety cases of CV were identified. The CV discovery rate was higher in the LP group (78/457, 17.1%) than in the OP group (12/290, 4.1%) (P < 0.001). In the ≤3 group, the CV discovery rate in the LP group (27/144, 18.8%) was higher than that in the OP group (11/274, 4.0%) (P < 0.001). In the LP group, there was no significant difference between ≤3 (27/144, 18.8%) and >3 (51/313, 16.3%) groups in the CV discovery rate. The rate in children with UPJO was not significantly different at any age (P > 0.05). Progressive aggravation of hydronephrosis (21/27, 77.8%) and symptomatic hydronephrosis (44/51, 86.3%) were the main surgical indications in the ≤3 and > 3 groups, respectively. There were no preoperatively confirmed cases of CV in the ≤3 group. In the OP group, five patients underwent reoperation, three of whom were due to failure to detect CV during the initial operation. CONCLUSIONS: The CV distribution is similar in children with UPJO across all ages; CV in infants and young children are not rare. LP should be considered as CV are prone to being missed during OP. LEVELS OF EVIDENCE: III.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

Endoscopic combined intrarenal surgery composed of micro-perc and retrograde intrarenal surgery in the treatment of complex kidney stones in children.

OBJECTIVE: This research aims to explore the efficiency and safety of endoscopic combined intrarenal surgery (Micro-ECIRS) composed of micro-percutaneous nephrolithotomy (Micro-perc) and retrograde intrarenal surgery (RIRS) in the Galdakao-modified supine Valdivia (GMSV) position for a single session for the treatment of complex nephrolithiasis in children. MATERIALS AND METHODS: This study retrospectively reviewed patients aged < 18 years who underwent Micro-ECIRS in the GMSV position for renal stones larger than 2 cm under ultrasound guidance between August 2020 to May 2022 at our institution. RESULTS: A total of 13 patients (8 males and 5 females) received Micro-ECIRS for renal stones under ultrasound guidancewhile adopting the GMSV position. The average stone size was 2.7 cm (range: 2.1-3.7 cm). Among them, 6 patients had left kidney stones, 5 patients had right kidney stones, and 2 patients had bilateral kidney stones. The mean operative time was 70.5 min (range: 54-93 min). The mean hospital stay was 6.4 days (range: 4-9 days). The mean hemoglobin decrease was 8.2 g/L (range: 5.1-12.4 g/L). The total number of kidneys that had complete stone clearance was 8 kidneys at 48 h postoperatively, 11 kidneys at 2 weeks postoperatively, and 14 kidneys at 1 month postoperatively. CONCLUSION: Our results demonstrate that Micro-ECIRS while patients are in the GMSV position is a safe and effective method for the treatment of complex children nephrolithiasis. However, all children made three hospital visits and received anesthesia three times. Further research is needed to confirm these findings.

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM: To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS: SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS: We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION: High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

A novel corporoplasty technique with a urethral plate flap in hypospadias repair.

OBJECTIVES: To report a novel corporoplasty technique with a urethral plate flap in hypospadias repair and evaluate its safety and efficacy for ventral lengthening. METHODS: Data were retrospectively collected from consecutive patients with hypospadias who underwent urethral plate flap corporoplasty between July 2021 and March 2022. All patients underwent hypospadias repair using the Duckett technique. The corporoplasty procedure involved the following key steps: the half-spongiosum of the urethral plate was harvested as a flap (with a pedicle attached to the corpus cavernosum); a transverse incision of the tunica albuginea was made adjacent to the pedicle; and the flap was patched onto the corporal defect. RESULTS: The study included 10 patients, with a median age of 20 months. The initial meatal location was penile in two patients, penoscrotal in four patients, and scrotal in four patients. The median ventral curvature was 45° after degloving and urethral plate transection. The median ventral lengthening distance proportional to penis length was 0.21. During the median follow-up of 13.8 months, complications occurred in three cases, including two cases of fistula and one case of urethral stricture with secondary diverticulum. No cases of recurrent ventral curvature, meatal stenosis, or urethral dehiscence were noted. Postoperative ultrasonography showed a good continuation of the tunica albuginea and integrity of the stratum spongiosum at the corporoplasty site. CONCLUSIONS: Urethral plate flap corporoplasty is a simple and effective ventral lengthening procedure. The novel corporoplasty technique allows for anatomical and architectural repair of corporal disproportion.

High expression of WTAP is related to poor prognosis in nasopharyngeal carcinoma.

Wilms' tumor 1-associated protein (WTAP), a component of the m6A methyltransferase complex, recruits the m6A methyltransferases METTL3 and METTL14 to the corresponding mRNA targets to participate in the formation of N6-methyladenosine. However, the molecular mechanism of WTAP in the tumorigenesis and progression of nasopharyngeal carcinoma (NPC) remains unclear. This study aimed to explore the prognostic value and biological function of WTAP in NPC. We assessed WTAP expression and its prognostic significance using microarray datasets from the Gene Expression Omnibus (GSE12452) database and 100 NPC tissues via bioinformatics analysis and immunohistochemistry (IHC), respectively. Moreover, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed. In addition, the correlation of WTAP expression with the expression of immune cell biomarkers was analyzed. The results showed that WTAP expression was significantly overexpressed in NPC tissues in GSE12452. The overexpression of WTAP was validated by the external datasets including NPC tissues (GSE150430) and NPC cell lines (GSE39826). GO analysis suggested enrichment in the nucleoplasm (cellular component) and cell cycle (biological process). The GSEA revealed that differentially expressed genes were enriched in E2F-targets, Myc_targets_v1, G2M checkpoint, Myc_targets_v2, and Interferon-alpha-response. In IHC analysis, WTAP was upregulated in NPC tissues, and high levels of WTAP expression were significantly correlated with the advanced T stage (p=0.047) and advanced N stage (p=0.018). Cox regression demonstrated that WTAP overexpression was an independent biomarker of poor prognosis for overall survival (hazard ratio [HR], 4.747; 95% confidence interval [CI], 1.671-13.482; p=0.003). In IHC analysis, the expression of WTAP was positively correlated with CD206 (biomarker for M2 macrophages) (p=0.018) but negatively correlated with CD8a (biomarker for cytotoxic T cells) (p=0.001). In conclusion, WTAP is a promising prognostic biomarker and may participate in the regulation of immune cell infiltration in NPC.

Single-center experience of micro-perc in the treatment of children with 1.0-2.0 cm sized kidney stones in the Galdakao-modified supine Valdivia position.

OBJECTIVE: We aimed to explore the applicability and safety of micro-percutaneous nephrolithotomy (micro-perc) in the treatment of children with kidney stones in the Galdakao-modified supine Valdivia (GMSV) position under the guidance of whole-course ultrasound. MATERIALS AND METHODS: Patients were aged < 18 years in the GMSV position who underwent micro-perc for kidney stones under ultrasound guidance between August 2020 and May 2022 at our institution were reviewed retrospectively. RESULTS: A total of 23 patients, 15 males and 8 females, received micro-perc. The average stone size was 1.6 cm (range 1.1-2.0 cm). Among them, 12 patients had left kidney stones, 10 patients had right kidney stones, and 1 patient had bilateral kidney stones. The mean operative time was 55.3 min (range 35-86 min). The mean hospital stay was 2.9 days (range 2-4 days). The mean hemoglobin decrease was 1.7 g/L (range 0.9-3.2 g/L). A total of 17 patients had complete stone clearance at 48 h postoperatively. A total of 22 patients had complete stone clearance at 2 weeks postoperatively. CONCLUSION: Our results demonstrate that micro-perc under ultrasound guidance is a safe and effective method for the treatment of children with kidney stones in the GMSV position. Further research is warranted to confirm these results.

Laparoscopic versus robot-assisted pyeloplasty in infants and young children.

OBJECTIVE: To compare the characteristics of conventional laparoscopic pyeloplasty (LP) and robotic-assisted laparoscopic pyeloplasty (RALP) in infants and young children with ureteropelvic junction obstruction (UPJO). METHODS: We performed a retrospective study of patients (age: 0-36 months) who underwent dismembered pyeloplasty (Anderson-Hynes) with the fourth-generation RALP or traditional LP between April 2020 and December 2020. RESULTS: A total of 33 patients with UPJO were enrolled: 12 underwent RALP (9 left side; 3 right side) and 21 underwent LP (18 left side; 3 right side). In the RALP group, the median patient age was 17 months (range: 5-36 months). In the LP group, the median patient age was 9 months (range: 2-36 months) (P = 0.182). The mean operation times were 120.25 ± 37.54 min (RALP) and 156.10 ± 51.11 min (LP) (P = 0.042), and the mean lengths of hospital stay were 6.42 ± 1.62 days (RALP) and 8.19 ± 2.25 days (LP) (P = 0.023). Removal of the drainage tube was performed after 3.08 ± 0.69 days (RALP) and after 4.76 ± 1.81 days (LP) (P = 0.001). The postoperative pain showed no significant difference. The mean hospitalization costs were 61464.75 ± 2800.53 yuan (RALP) and 22169.52 ± 3442.15 yuan (LP) (P < 0.001). The mean follow-up time was 10-18 months. Significant improvements in the anteroposterior diameter and parenchymal thickness were observed after surgery. Conversion to laparotomy was not performed. No short-term complications occurred during postoperative hospitalization and follow-up. CONCLUSION: RALP has the advantages of less trauma and faster recovery. It can be safely and effectively performed in infants and young children, and its effectiveness is similar to that of traditional LP.

Health system preparedness in infectious diseases: perspective of Malaysia, a middle-income country, in the face of monkeypox outbreaks.

The World Health Organization declared monkeypox as a Public Health Emergency of International Concern on July 23, 2022. As of July 25th, 2022, there were 16,016 laboratory-confirmed cases reported worldwide with 5 deaths. Malaysia's Health Ministry has developed a five-point strategy to prepare for the impending threat of the infectious disease, encompassing early detection of monkeypox, consolidation of laboratory diagnostic facilities, case management and treatment, cluster management, and strengthening public awareness. Crisis and disaster preparedness within a nation's health system is paramount to preventing disease spread. Various strategies for developing resilience in the face of global infectious disease spread were discussed. The current disease preparedness and response framework and guidelines in Malaysia have established a health system that is proactive and responsive to any potential infectious disease outbreaks. Despite this, the future remains unpredictable, and ongoing fortification is required as events unfold.

Isotropic reconstruction for electron tomography with deep learning.

Cryogenic electron tomography (cryoET) allows visualization of cellular structures in situ. However, anisotropic resolution arising from the intrinsic "missing-wedge" problem has presented major challenges in visualization and interpretation of tomograms. Here, we have developed IsoNet, a deep learning-based software package that iteratively reconstructs the missing-wedge information and increases signal-to-noise ratio, using the knowledge learned from raw tomograms. Without the need for sub-tomogram averaging, IsoNet generates tomograms with significantly reduced resolution anisotropy. Applications of IsoNet to three representative types of cryoET data demonstrate greatly improved structural interpretability: resolving lattice defects in immature HIV particles, establishing architecture of the paraflagellar rod in Eukaryotic flagella, and identifying heptagon-containing clathrin cages inside a neuronal synapse of cultured cells. Therefore, by overcoming two fundamental limitations of cryoET, IsoNet enables functional interpretation of cellular tomograms without sub-tomogram averaging. Its application to high-resolution cellular tomograms should also help identify differently oriented complexes of the same kind for sub-tomogram averaging.

Digitalizing neuronal synapses with cryo-electron tomography and correlative microscopy.

Synapses are the structural and functional joints of neuronal circuits, and brain function is fundamentally based on synaptic quantal transmission and plasticity. Precise mapping of key components within individual synapses in different states can reveal the principles governing synapse formation, transmission, and plasticity and improving understanding of the mechanisms of synapse-related diseases. Cryo-electron tomography (cryo-ET) and correlative microscopy are increasingly powerful tools that can dissect the molecular sociology of intact cells, including neuronal synapses. In this study, we discuss current progress made in cryo-ET studies assessing neuronal synapses, especially sample preparation, molecule identification, and correlative approaches for synaptic dynamics and functions.

Association between Cervical Lymph Node Metastasis and the Incidence of Radiation-Induced Hypothyroidism in Nasopharyngeal Carcinoma.

BACKGROUND: It is controversial and unclear how N-stage would increase the risk of incidence of hypothyroidism (HT) for patients with nasopharyngeal carcinoma (NPC) after radiotherapy. Our study aimed to explore the correlation between cervical lymph node metastasis and the incidence of HT in NPC. MATERIALS AND METHODS: A total of 206 patients with NPC treated at the Cancer Hospital of University of Chinese Academy of Sciences, and their clinical information were retrospectively collected. A series of univariate logistic regression models were performed to explore the association of clinical and lymph node indices with the development of HT. Significant features in univariate analysis were then used to construct three prediction models, for HT prediction using multivariate logistic regression based on Bayesian information criterion. Prediction performance of those models was measured by area under the receiver operating characteristic curve (AUC) using 10-fold cross-validation. RESULTS: A total of 111 patients developed HT, and the incidence of HT in N 2-3 and N 0-1 patients was 58.82% and 44.29%, respectively. Compared to Model 1 (consisted of pretreatment TSH concentration, thyroid volume, and N-stage) whose AUCs were 0.801 and 0.766 in training and validation sets, with N-stage be replaced by shortest distance from thyroid, Model 2 achieved more stable AUCs of 0.824 and 0.801. While with numbers of positive lymph nodes in Level IIb additionally added, Model 3 improved its AUCs to 0.841 and 0.813. CONCLUSION: The shortest distance between the lymph nodes and thyroid gland and the number of lymph nodes in IIb are better predictors of radiation-induced HT than the N-stage.

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients.

Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone (AMH) gene or the anti-Müllerian hormone receptor type 2 (AMHR2) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as "pathogenic" or "likely pathogenic", and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

Research progress regarding programmed cell death 1/programmed cell death ligand 1 inhibitors combined with targeted therapy for treating hepatocellular carcinoma.

In recent years, a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma (HCC), including sorafenib, lenvatinib, and regorafenib. Immunotherapy is considered to be an effective treatment for advanced HCC. Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC. However, treating advanced HCC is still a great challenge, and the need for new treatments remains urgent. This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.

PAQR6 Upregulation Is Associated with AR Signaling and Unfavorite Prognosis in Prostate Cancers.

Progesterone-induced rapid non-genomic signaling events have been confirmed through several membrane progesterone receptors (mPR). Some mPRs were reported to correlate with cancer progression and patient prognosis. In this study, we conducted a comprehensive analysis of all progesterone receptor (PGR)-related genes in prostate cancer tissues and examined the correlations of their expression levels with disease progression and patient survival outcomes. We utilized multiple RNA-seq and cDNA microarray datasets to analyze gene expression profiles and performed logistics aggression and Kaplan-Meier survival analysis after stratifying patients based on tumor stages and Gleason scores. We also used NCBI GEO datasets to examine gene expression patterns in individual cell types of the prostate gland and to determine the androgen-induced alteration of gene expression. Spearman coefficient analysis was conducted to access the correlation of target gene expression with treatment responses and disease progression status. The classic PGR was mainly expressed in stromal cells and progestin and adipoQ receptor (PAQR) genes were the predominant genes in prostate epithelial cells. Progesterone receptor membrane component-1 (PGRMC1) was significantly higher than PGRMC2 in all prostate cell types. In prostate cancer tissues, PAQR6 expression was significantly upregulated, while all other genes were largely downregulated compared to normal prostate tissues. Although both PAQR6 upregulation and PAQR5 downregulation were significantly correlated with tumor pathological stages, only PAQR6 upregulation was associated with Gleason score, free-prostate-specific antigen (fPSA)/total-PSA (tPSA) ratio, and patient overall survival outcomes. In addition, PAQR6 upregulation and PGR/PGRMC1 downregulation were significantly associated with a quick relapse. Conversely, in neuroendocrinal prostate cancer (NEPC) tissues, PAQR6 expression was significantly lower, but PAQR7/8 expression was higher than castration-resistant prostate cancer (CRPC) tissues. PAQR8 expression was positively correlated with androgen receptor (AR) score and AR-V7 expression levels but inversely correlated with NEPC score in metastatic CRPC tumors. This study provides detailed expression profiles of membrane progesterone receptor genes in primary cancer, CRPC, and NEPC tissues. PAQR6 upregulation in primary cancer tissues is a novel prognostic biomarker for disease progression, overall, and progression-free survival in prostate cancers. PAQR8 expression in CRPC tissues is a biomarker for AR activation.