Fertility-sparing surgery in children and adolescents with borderline ovarian tumors: a retrospective study.

OBJECTIVE: To describe the characteristics of children and adolescents with borderline ovarian tumors (BOTs) and evaluate the efficacy and safety of fertility-sparing surgery (FSS) in these patients. METHODS: Patients with BOTs younger than 20 years who underwent FSS were included in this study. RESULTS: A total of 34 patients were included, with a median patient age of 17 (range, 3-19) years; 97.1% (33/34) of cases occurred after menarche. Of the patients, 82.4% had mucinous borderline tumors (MBOTs), 14.7% had serous borderline tumors (SBOTs), and 2.9% had seromucinous borderline tumor (SMBOT). The median tumor size was 20.4 (range, 8-40)cm. All patients were at International Federation of Gynecology and Obstetrics stage I and all underwent FSS: cystectomy (unilateral ovarian cystectomy, UC, 14/34, 41.2% and bilateral ovarian cystectomy, BC, 1/34, 2.9%), unilateral salpingo-oophorectomy (USO; 18/34; 52.9%), or USO + contralateral ovarian cystectomy (1/34; 2.9%). The median follow-up time was 65 (range, 10-148) months. Recurrence was experienced by 10 of the 34 patients (29.4%). One patient with SBOT experienced progression to low-grade serous carcinoma after the third relapse. Two patients had a total of four pregnancies, resulting in three live births. The recurrence rate of UC was significantly higher in MBOTs than in USO (p = 0.005). The 5-year disease-free survival rate was 67.1%, and the 5-year overall survival rate was 100%. CONCLUSIONS: Fertility-sparing surgery is feasible and safe for children and adolescents with BOTs. For patients with MBOTs, USO is recommended to lower the risk of recurrence.

Predictors of mortality in patients with isolated gastrointestinal perforation.

Gastrointestinal (GI) perforation is common in the emergency department and has a high mortality rate. The present study aimed to identify risk factors for mortality in patients with GI perforation. The objective was to assess and prognosticate the surgical outcomes of patients, aiming to ascertain the efficacy of the procedure for individual patients. A retrospective cohort study of patients with GI perforation who underwent surgery in a public tertiary hospital in China from January 2012 to June 2022 was performed. Demographics, clinical characteristics, laboratory and imaging results, and outcomes were collected from electronic medical records. The primary outcome measure was in-hospital mortality, and patients were divided into survivor and non-survivor groups based on this measure. Univariate and multivariable logistic regression analyses were performed to obtain independent factors associated with mortality. A total of 529 patients with GI perforation were eligible for inclusion. The in-hospital mortality rate after emergency surgery was 10.59%. The median age of the patients was 60 years (interquartile range, 44-72 years). Multivariable logistic regression analysis indicated that age, shock on admission, elevated serum creatinine (sCr) and white blood cell (WBC) count <3.5x109 or >20x109 cells/l were predictors of in-hospital mortality. In conclusion, advanced age, shock on admission, elevated sCr levels and significantly abnormal WBC count are associated with higher in-hospital mortality following emergency laparotomy.

Pulmonary resection of residual lesions of pulmonary metastasis from gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the prognosis and recurrence in patients with residual lesions of pulmonary metastasis from gestational trophoblastic neoplasia after initial treatment, and to explore the clinical significance of pulmonary resection. METHODS: A retrospective analysis was performed on 606 patients with residual lesions from pulmonary metastasis after receiving standardized chemotherapy as initial treatment in Peking Union Medical College Hospital from January 2002 to December 2018. Patients were divided into surgery (51 patients) and non-surgery (555 patients) groups. The prognosis of these patients was compared. Risk factors affecting recurrence were analyzed to explore the effect of pulmonary resection. RESULTS: Among low risk patients, complete remission rate was 100% and recurrence rate was <1% in both groups. Among high risk patients, complete remission and recurrence rates were 93.5% and 10.3% in the surgery group and 94.7% and 14.3% in the non-surgery group, respectively. There was no significant difference in prognostic features between the two groups (all p>0.05). No significant difference was found in recurrence rates based on recurrence risk factors (≥3.2 cm residual lung lesions, prognosis score ≥9.0, and drug resistance) between the two groups (all p>0.05). CONCLUSION: After standardized chemotherapy, pulmonary resection was not necessary for initially treated stage III gestational trophoblastic neoplasia patients whose blood ß human chorionic gonadotropin levels normalized and residual lung lesions remained stable. These patients should be closely monitored during follow-up, regardless of the size of the residual lung lesions or high/low risk score, especially within a year after complete remission.

Analysis of appendicitis management during COVID-19 pandemic: A study of Chinese adult cohorts.

Background: Healthcare seeking behavior has been widely impacted due to the restricted movements of individuals during the Coronavirus disease-19 (COVID-19) pandemic. This study aims to perform risk stratification in patients requiring timely intervention during the recovery periods. Methods: Operation notes of acute appendicitis (AA) patients within a hospital were analyzed during three six-month periods (23 January-23 July in 2019, 2020, and 2021, respectively). Patient data were collected retrospectively including demographics, pre-emergency status, perioperative information, postoperative outcomes, and follow-up results. Results: 321 patients were included in this study, with 111, 86, and 124 patients in 2019, 2020, and 2021 groups, respectively. The median age of patients decreased by 4 years in 2020 as compared to that in 2019. The proportion of pre-hospitalization symptoms duration of more than 48 h in the 2020 group was higher (36.05% in 2020 vs. 22.52% in 2019). Length of hospital stay (LOS) in 2020 was shorter than it was during the same period in 2019 (4.77 vs. 5.64) and LOS in 2021 was shorter than in 2019 (4.13 vs. 5.64). Compared to the lockdown period, the proportion of patients with recurrent AA was higher in the post-lockdown period (15.1% vs. 27.4%). The median age was 34 years (vaccinated) vs. 37 years (unvaccinated). Logistic regression suggests that elevated C-reactive protein (CRP) (OR = 1.018, CI = 1.010-1.028), white cell count (WBC) (OR = 1.207, CI = 1.079-1.350), female (OR = 2.958, CI = 1.286-6.802), recurrent (OR = 3.865, CI = 1.149-12.997), and fecalith (OR = 2.308, CI = 1.007-5.289) were associated with complicated appendicitis (CA). Conclusion: The lockdown measures during the COVID-19 epidemic are shown to be correlated with a reduction in the proportion of AA patients who underwent surgery, particularly in older adults. Risk factors for CA include elevated CRP, WBC, female, recurrent, and fecalith.

Management and Predictors of Treatment Failure in Patients with Chemo-Resistant/Relapsed Gestational Trophoblastic Neoplasia with Lung Metastasis.

The aim of the study was to assess the effectiveness of a combined treatment modality of salvage chemotherapy and pulmonary resection in chemo-resistant/relapsed gestational trophoblastic neoplasia (GTN) with lung metastasis and identify predictors of treatment failure. Data of patients with chemo-resistant/relapsed GTN with lung metastasis who received salvage chemotherapy combined with pulmonary resection were retrospectively analyzed. Among 134 included patients, the number of preoperative chemotherapy regimens ranged from 2−8 (median, 3), and courses ranged from 4−37 (median, 14). Pulmonary lobectomies, segmentectomies, wedge resections, and lobectomies plus wedge resections were performed in 84, 5, 35, and 10 patients, respectively. After completion of treatment, 130 (97.0%) patients achieved complete remission. In the entire cohort, the 5-year overall survival (OS) rate was 87.6%. OS rates were similar between stage III and stage IV disease cohorts (89.4% vs. 75.0%, p = 0.137). Preoperative ß-human chorionic gonadotropin (ß-hCG) levels > 10 IU/L (p = 0.027) and number of preoperative chemotherapy regimens > 3 (p = 0.018) were predictors of treatment failure. The combined treatment modality of salvage chemotherapy and pulmonary resection is effective in patients with chemo-resistant/relapsed GTN with lung metastasis, improving their prognoses. Patients with preoperative serum ß-hCG >10 IU/L and those with >3 chemotherapy regimens preoperatively may not benefit from this multidisciplinary treatment.

Effectiveness of craniotomy and long-term survival in 35 patients with gestational trophoblastic neoplasia with brain metastases: a clinical retrospective analysis.

OBJECTIVE: To investigate the clinical characteristics, treatments, and prognostic factors among patients with gestational trophoblastic neoplasia (GTN) exhibiting brain metastases who underwent craniotomy. METHODS: Thirty-five patients with GTN who had brain metastases and subsequently underwent craniotomies between January 1990 and December 2018 at Peking Union Medical College Hospital were identified using the GTN database. Their clinical manifestations, treatments, outcomes, and prognostic factors were retrospectively analyzed. RESULTS: All 35 patients underwent decompressive craniotomy, hematoma removal, and metastatic tumor resection combined with multiagent chemotherapy. Eighty percent (28/35) achieved complete remission, 11.4% (4/35) achieved partial remission, and 8.6% (3/35) had progressive disease. Not counting 2 patients who were lost to follow-up, 81.8% of the patients (27/33) were alive after a median follow-up of 72 months. The 5-year overall survival rate was 80.4%. Univariate analysis revealed that a history of chemotherapy failure (p=0.020) and a >1-week interval between craniotomy and chemotherapy commencement (p=0.027) were adverse risk factors for survival. Multivariate analysis showed that previous chemotherapy failure remained an independent risk factor for poor survival (odds ratio=11.50; 95% confidence interval=1.55-85.15; p=0.017). CONCLUSION: Decompressive craniotomy is a life-saving option if metastatic hemorrhage and intracranial hypertension produce a risk of cerebral hernia in patients with GTN who have brain metastases. Higher survival rates and improved prognoses can be achieved through perioperative multidisciplinary cooperation and timely standard postoperative chemotherapy.

Microglial Activation of GLP-1R Signaling in Neuropathic Pain Promotes Gene Expression Adaption Involved in Inflammatory Responses.

Background: Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes and molecular signaling underlie the sensitization of nociceptive pathways. We previously found that the activation of microglial glucagon-like peptide 1 receptor (GLP-1R) could potently relieve formalin-, bone cancer-, peripheral nerve injury-, and diabetes-induced pain hypersensitivity. So far, little is known about how the gene profile changes upon the activation of GLP-1R signaling in the pathophysiology of neuropathic pain. Methods: Spinal nerve ligation (SNL) was performed to induce neuropathic pain in rats. Mechanical allodynia was assessed using von Frey filaments. The expression of IL-10, ß-endorphin, and µ-opioid receptor (MOR) was examined by real-time quantitative polymerase chain reaction (qPCR) and whole-cell recording. Measurements of cellular excitability of the substantia gelatinosa (SG) neurons by whole-cell recording were carried out. R packages of differential gene expression analysis based on the negative binomial distribution (DESeq2) and weighted correlation network analysis (WGCNA) were used to analyze differential gene expression and the correlated modules among GLP-1R clusters in neuropathic pain. Results: The GLP-1R agonist, exenatide, has an antiallodynic effect on neuropathic pain, which could be reversed by intrathecal injections of the microglial inhibitor minocycline. Furthermore, differential gene expression analysis (WGCNA) indicated that intrathecal injections of exenatide could reverse the abnormal expression of 591 genes in the spinal dorsal horn induced by nerve injury. WGCNA revealed 58 modules with a close relationship between the microglial GLP-1R pathway and features of nerve injuries, including pain, ligation, paw withdrawal latency (PWL), and anxiety. The brown module was identified as the highest correlated module, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that inflammatory responses were most correlated with PWL. To further unravel the changes of hyperalgesia-related neuronal electrophysiological activity mediated by microglia GLP-1 receptors, whole-cell recording identified that MOR agonism stimulated a robust outward current in the sham groups compared with the spinal nerve ligation (SNL) groups. This inhibitory effect on the SNL group was more sensitive than that of the sham group after bath application of ß-endorphin. Conclusions: Our results further confirmed that the GLP-1R pathway is involved in alleviating pain hypersensitivity mediated by spinal microglia activation, and inflammatory responses were the most correlated pathway associated with PWL changes in response to exenatide treatment. We found that the identification of gene regulation in response to GLP-1R activation is an effective strategy for identifying new therapeutic targets for neuropathic pain. Investigation for the activation of spinal microglial GLP-1R which might ameliorate inflammatory responses through gene expression and structural changes is providing a potential biomarker in pain management.

Prevalence and predictor for malignancy of contralateral thyroid nodules in patients with unilateral PTMC: a systematic review and meta-analysis.

BACKGROUND: The presence of clinically negative nodules on the contralateral lobe is common in patients with unilateral papillary thyroid microcarcinoma (PTMC). The appropriate operational strategies of contralateral thyroid nodules remain controversial. In this study, we analyzed clinical features that could be predictors for malignancy of contralateral thyroid nodules coexisting with diagnosed unilateral PTMC. METHODS: The literatures published from January 2000 to December 2019 were searched in PubMed, Cochrane Library, Embase, Web of Science, CNKI, and Wan Fang database. Odds ratio (OR) with 95% CI was used to describe categorical variables. Heterogeneity among studies was examined by the Q test and I2 test; potential publication bias was detected by Harbord test and 'trim and fill' method. RESULTS: In this meta-analysis, 2541 studies were searched and 8 studies were finally included. The results showed that the rate of carcinoma in contralateral nodules was 23% (OR = 0.23, 95% CI = 0.18-0.29). The pooled data indicated that contralateral malignancy was not associated with age, gender, primary lesion size, ipsilateral central lymph node metastasis and multifocality of contralateral lesion. The following variables have correlations with an increased risk of contralateral malignancy: multifocality of primary carcinomas (OR = 3.93, 95% CI = 2.70-5.73, P < 0.0001), capsular invasion (OR = 1.61, 95% CI = 1.10-2.36, P = 0.01), and Hashimoto's thyroiditis (OR = 1.57, 95% CI = 1.13-2.20, P = 0.008). CONCLUSIONS: Based on our meta-analysis, the rate at which contralateral malignancies are preoperatively misdiagnosed as benign is 23%. The risk factors for contralateral malignancy in unilateral PTMC patients with contralateral clinical negative nodules include multifocality of primary carcinomas, capsular invasion, and Hashimoto's thyroiditis.

Spatiotemporal 7q11.23 protein network analysis implicates the role of DNA repair pathway during human brain development.

Recurrent deletions and duplications of chromosome 7q11.23 copy number variants (CNVs) are associated with several psychiatric disorders. Although phenotypic abnormalities have been observed in patients, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Furthermore, the targeted human brain regions, developmental stages, protein networks, and signaling pathways, influenced by this CNV remain unclear. Previous works showed GTF2I involved in Williams-Beuren syndrome, but pathways affected by GTF2I are indistinct. We first constructed dynamic spatiotemporal networks of 7q11.23 genes by combining data from the brain developmental transcriptome with physical interactions of 7q11.23 proteins. Topological changes were observed in protein-protein interaction (PPI) networks throughout different stages of brain development. Early and late fetal periods of development in the cortex, striatum, hippocampus, and amygdale were observed as the vital periods and regions for 7q11.23 CNV proteins. CNV proteins and their partners are significantly enriched in DNA repair pathway. As a driver gene, GTF2I interacted with PRKDC and BRCA1 to involve in DNA repair pathway. The physical interaction between GTF2I with PRKDC was confirmed experimentally by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified that early and late fetal periods are crucial for 7q11.23 genes to affect brain development. Our results implicate that 7q11.23 CNV genes converge on the DNA repair pathway to contribute to the pathogenesis of psychiatric diseases.

Alternatively Splicing Interactomes Identify Novel Isoform-Specific Partners for NSD2.

Nuclear receptor SET domain protein (NSD2) plays a fundamental role in the pathogenesis of Wolf-Hirschhorn Syndrome (WHS) and is overexpressed in multiple human myelomas, but its protein-protein interaction (PPI) patterns, particularly at the isoform/exon levels, are poorly understood. We explored the subcellular localizations of four representative NSD2 transcripts with immunofluorescence microscopy. Next, we used label-free quantification to perform immunoprecipitation mass spectrometry (IP-MS) analyses of the transcripts. Using the interaction partners for each transcript detected in the IP-MS results, we identified 890 isoform-specific PPI partners (83% are novel). These PPI networks were further divided into four categories of the exon-specific interactome. In these exon-specific PPI partners, two genes, RPL10 and HSPA8, were successfully confirmed by co-immunoprecipitation and Western blotting. RPL10 primarily interacted with Isoforms 1, 3, and 5, and HSPA8 interacted with all four isoforms, respectively. Using our extended NSD2 protein interactions, we constructed an isoform-level PPI landscape for NSD2 to serve as reference interactome data for NSD2 spliceosome-level studies. Furthermore, the RNA splicing processes supported by these isoform partners shed light on the diverse roles NSD2 plays in WHS and myeloma development. We also validated the interactions using Western blotting, RPL10, and the three NSD2 (Isoform 1, 3, and 5). Our results expand gene-level NSD2 PPI networks and provide a basis for the treatment of NSD2-related developmental diseases.

Use of tobacco in schizophrenia: A double-edged sword.

OBJECTIVE: It has been identified that the smoking rate is higher in schizophrenic patients than general population. This study aimed to explore the association between schizophrenia and tobacco use, and provide rational recommendations for clinical care of schizophrenia. METHODS: We recruited 244 patients with schizophrenia and 225 healthy controls. Of schizophrenia patients, 54 patients were untreated with any antipsychotics over the previous 6 months or first-episode and drug-naïve. These patients (nonmedication subgroup) were followed up for 8 weeks. The associations between tobacco use and susceptibility to schizophrenia and psychotic symptoms were analyzed. RESULTS: Although there was no significant difference between schizophrenia patients and healthy controls in the entire sample, stratification analysis showed the rate of smoking was higher in male patients versus healthy controls and that male smokers exhibited higher odds ratios for schizophrenia than nonsmokers. Next, when we repeated analyses in first-episode patients and healthy controls, significant differences were not observed, indicating tobacco use is an outcome rather than a cause of schizophrenia. Furthermore, among nonmedication subgroup, smokers presented with more severe psychotic symptoms at baseline, and better improvement after medication than nonsmokers, suggesting patients with worse symptoms tend to smoke to relieve symptoms. CONCLUSION: This study supports the self-medication hypothesis. Nonetheless, considering the serious health hazard associated with tobacco use, we should encourage patients to stop smoking. Further investigations are warranted to determine the tobacco constituents that are beneficial or harmful to schizophrenia.

Characterization and evolution of gene clusters for terpenoid phytoalexin biosynthesis in tobacco.

MAIN CONCLUSION: The study performed genome-wide identification, characterization and evolution analysis of gene clusters for phytoalexin terpenoid biosynthesis in tobacco, and specifically illustrated ones for capsidiol, an efficient defensive specialized metabolite. Terpenoid phytoalexins play an important role in plant self-defense against pest and pathogen attack. Terpenoid biosynthesis involves terpene synthase and cytochrome P450, which always locate and function as cluster(s). In this study, we performed genome-wide investigation of metabolic gene clusters involved in terpenoid production in tobacco (Nicotiana tabacum). Due to the complexity of the tobacco genome, we modified a published prediction pipeline to reduce the influence of the large number of repeats and to improve the annotation of tobacco genes with respect to their metabolic functions. We identified 1181 metabolic gene clusters with 34 of them potentially being involved in terpenoid biosynthesis. Through integration with transcriptome and metabolic pathway annotation analyses, 3 of the 34 terpenoid biosynthesis-related gene clusters were determined to be high-confidence ones, with 2 involved in biosynthesis of capsidiol, a terpenoid recognized as 1 of the effective resistance compounds in the Nicotiana species. The capsidiol-related gene cluster was conserved in N. sylvestris, N. tomentosiformis and N. attenuate. Our findings demonstrate that phytoalexins in tobacco can arise from operon-like gene clusters, a genomic pattern characterized as being beneficial for rapid stress response, gene co-regulation, co-function and co-heredity.

Regulation of Nicotine Biosynthesis by an Endogenous Target Mimicry of MicroRNA in Tobacco.

The interaction between noncoding endogenous target mimicry (eTM) and its corresponding microRNA (miRNA) is a newly discovered regulatory mechanism and plays pivotal roles in various biological processes in plants. Tobacco (Nicotiana tabacum) is a model plant for studying secondary metabolite alkaloids, of which nicotine accounts for approximately 90%. In this work, we identified four unique tobacco-specific miRNAs that were predicted to target key genes of the nicotine biosynthesis and catabolism pathways and an eTM, novel tobacco miRNA (nta)-eTMX27, for nta-miRX27 that targets QUINOLINATE PHOSPHORIBOSYLTRANSFERASE2 (QPT2) encoding a quinolinate phosphoribosyltransferase. The expression level of nta-miRX27 was significantly down-regulated, while that of QPT2 and nta-eTMX27 was significantly up-regulated after topping, and consequently, nicotine content increased in the topping-treated plants. The topping-induced down-regulation of nta-miRX27 and up-regulation of QPT2 were only observed in plants with a functional nta-eTMX27 but not in transgenic plants containing an RNA interference construct targeting nta-eTMX27. Our results demonstrated that enhanced nicotine biosynthesis in the topping-treated tobacco plants is achieved by nta-eTMX27-mediated inhibition of the expression and functions of nta-miRX27. To our knowledge, this is the first report about regulation of secondary metabolite biosynthesis by an miRNA-eTM regulatory module in plants.

Arabidopsis inositol pentakisphosphate 2-kinase, AtIPK1, is required for growth and modulates phosphate homeostasis at the transcriptional level.

Inositol hexakisphosphate (IP6 ) provides a phosphorous reservoir in plant seeds; in addition, along with its biosynthesis intermediates and derivatives, IP6 also plays important roles in diverse developmental and physiological processes. Disruption of the Arabidopsis inositol pentakisphosphate 2-kinase coding gene AtIPK1 was previously shown to reduce IP6 content in vegetative tissues and affect phosphate (Pi) sensing. Here we show that AtIPK1 is required for sustaining plant growth, as null mutants are non-viable. An incomplete loss-of-function mutant, atipk1-1, exhibited disturbed Pi homeostasis and overaccumulated Pi as a consequence of increased Pi uptake activity and root-to-shoot Pi translocation. The atipk1-1 mutants also showed a Pi deficiency-like root system architecture with reduced primary root and enhanced lateral root growth. Transcriptome analysis indicated that a subset of Pi starvation-responsive genes was transcriptionally perturbed in the atipk1-1 mutants and the expression of multiple genes involved in Pi uptake, allocation, and remobilization was increased. Genetic and transcriptional analyses suggest that disturbance of Pi homeostasis caused by atipk1 mutation involved components in addition to PHR1(-like) transcription factors. Notably, the transcriptional increase of a number of Pi starvation-responsive genes in the atipk1-1 mutants is correlated with the reduction of histone variant H2A.Z occupation in chromatin. The myo-inositol-1-phosphate synthase mutants, atmips1 and atmips2 with comparable reduction in vegetative IP6 to that in the atipk1-1 mutants did not overaccumulate Pi, suggesting that Pi homeostasis modulated by AtIPK1 is not solely attributable to IP6 level. This study reveals that AtIPK1 has important roles in growth and Pi homeostasis.