Impact of veliparib, paclitaxel dosing regimen, and germline BRCA status on the primary treatment of serous ovarian cancer - an ancillary data analysis of the VELIA trial.

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status. METHODS: Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status. RESULTS: 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups. CONCLUSIONS: DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

Genome-Wide Identification of MYB Transcription Factors and Screening of Members Involved in Stress Response in Actinidia.

MYB transcription factors (TFs) play an active role in plant responses to abiotic stresses, but they have not been systematically studied in kiwifruit (Actinidia chinensis). In this study, 181 AcMYB TFs were identified from the kiwifruit genome, unevenly distributed on 29 chromosomes. The high proportion (97.53%) of segmental duplication events (Ka/Ks values less than 1) indicated that AcMYB TFs underwent strong purification selection during evolution. According to the conservative structure, 91 AcR2R3-MYB TFs could be divided into 34 subgroups. A combination of transcriptomic data under drought and high temperature from four AcMYB TFs (AcMYB2, AcMYB60, AcMYB61 and AcMYB102) was screened out in response to stress and involvement in the phenylpropanoid pathway. They were highly correlated with the expression of genes related to lignin biosynthesis. qRT-PCR analysis showed that they were highly correlated with the expression of genes related to lignin biosynthesis in different tissues or under stress, which was consistent with the results of lignin fluorescence detection. The above results laid a foundation for further clarifying the role of MYB in stress.

Identification of Hub Genes in High-Grade Serous Ovarian Cancer Using Weighted Gene Co-Expression Network Analysis.

BACKGROUND High-grade serous ovarian cancer (HGSOC) is the most malignant gynecologic tumor. This study reveals biomarkers related to HGSOC incidence and progression using the bioinformatics method. MATERIAL AND METHODS Five gene expression profiles were downloaded from GEO. Differentially-expressed genes (DEGs) in HGSOC and normal ovarian tissue samples were screened using limma and the function of DEGs was annotated by KEGG and GO analysis using clusterProfiler. A co-expression network utilizing the WGCNA package was established to define several hub genes from the key module. Furthermore, survival analysis was performed, followed by expression validation with datasets from TCGA and GTEx. Finally, we used single-gene GSEA to detect the function of prognostic hub genes. RESULTS Out of the 1874 DEGs detected from 114 HGSOC versus 49 normal tissue samples, 956 were upregulated and 919 were downregulated. The functional annotation indicated that upregulated DEGs were mostly enriched in cell cycle, whereas the downregulated DEGs were enriched in the MAPK or Ras signaling pathway. Two modules significantly associated with HGSOC were excavated through WGCNA. After survival analysis and expression validation of hub genes, we found that 2 upregulated genes (MAD2L1 and PKD2) and 3 downregulated genes (DOCK5, FANCD2 and TBRG1) were positively correlated with HGSOC prognosis. GSEA for single-hub genes revealed that MAD2L1 and PKD2 were associated with proliferation, while DOCK5, FANCD2, and TBRG1 were associated with immune response. CONCLUSIONS We found that FANCD2, PKD2, TBRG1, and DOCK5 had prognostic value and could be used as potential biomarkers for HGSOC treatment.

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression.

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

Race influences survival in glioblastoma patients with KPS ≥ 80 and associates with genetic markers of retinoic acid metabolism.

PURPOSE: To study whether the clinical outcome and molecular biology of gliomas in African-American patients fundamentally differ from those occurring in Whites. METHODS: The clinical information and molecular profiles (including gene expression array, non-silent somatic mutation, DNA methylation and protein expression) were downloaded from The Cancer genome atlas (TCGA). Electronic medical records were abstracted from Northwestern Medicine Enterprise Data Warehouse (NMEDW) for analysis as well. Grade II-IV Glioma patients were all included. RESULTS: 931 Whites and 64 African-American glioma patients from TCGA were analyzed. African-American with Karnofsky performance score (KPS) ≥ 80 have significantly lower risk of death than similar white Grade IV Glioblastoma (GBM) patients [HR (95% CI) = 0.47 (0.23, 0.98), P = 0.0444, C-index = 0.68]. Therefore, we further compared gene expression profiles between African-American GBM patients and Whites with KPS ≥ 80. Extrapolation of genes significantly associated with increased African-American patient survival revealed a set of 13 genes with a possible role in this association, including elevated expression of genes previously identified as increased in African-American breast and colon cancer patients (e.g. CRYBB2). Furthermore, gene set enrichment analysis revealed retinoic acid (RA) metabolism as a pathway significantly upregulated in African-American GBM patients who survive longer than Whites (Z-score = - 2.10, Adjusted P-value = 0.0449). CONCLUSIONS: African Americans have prolonged survival with glioma which is influenced only by initial KPS score. Genes previously associated with both racial disparities in cancer and pathways associated with RA metabolism may play an important role in glioma etiology. In the future exploration of these genes and pathways may inform novel therapies for this incurable disease.

Adoptive Transfer of IL13Rα2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma.

In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28.ζ) or truncated signaling domain (IL13Rα2-CAR.Δ) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Rα2-CAR.CD28.ζ T cells' specificity toward IL13Rα2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Rα2-CAR.CD28.ζ T cells significantly extended the survival of IL13Rα2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Rα2-negative and IL13Rα2-positive tumors. IL13Rα2-CAR.CD28.ζ T cells proliferated, produced cytokines (IFNγ, TNF-α), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4+ and CD8+ T cells and CD8α+ dendritic cells and a decrease in Ly6G+ myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13Rα2-CAR T cells as an efficacious therapeutic strategy for MG.

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations.

BACKGROUND AND PURPOSE: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. METHODS: Two heterozygous murine models, Ccm1+/-Msh2-/- and Ccm2+/-Trp53-/-, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity. RESULTS: Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/- mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/- mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/- mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/- mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/- mice alone, and Fasudil benefit seemed limited to males. CONCLUSIONS: ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.

Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1 deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches.

Topical medication instillation techniques for glaucoma.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness worldwide and the second most common cause of blindness after cataracts. The primary treatment for glaucoma aims to lower intraocular pressure (IOP) with the use of topical medicines. Topical medication instillation techniques, such as eyelid closure and nasolacrimal occlusion when instilling drops, have been proposed as potential methods to increase ocular absorption and decrease systemic absorption of the drops. OBJECTIVES: To investigate the effectiveness of topical medication instillation techniques compared with usual care or another method of instillation of topical medication in the management of glaucoma or ocular hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 12), MEDLINE Ovid (1946 to 8 December 2016), Embase Ovid (1947 to 8 December 2016), PubMed (1948 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), International Pharmaceutical Abstracts Database (1970 to 8 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 13 May 2013), ClinicalTrials.gov (www.clinicaltrials.gov) (searched 8 December 2016) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) (searched 8 December 2016). We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized controlled trials which had compared any topical medication instillation technique with usual care or a different method of instillation of topical medication. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records from the searches for eligibility, assessed the risk of bias, and extracted data. We followed methods recommended by Cochrane. MAIN RESULTS: We identified two trials (122 eyes of 61 participants) that had evaluated a topical medication instillation technique. We also identified two ongoing trials. Both included trials used a within-person design and administered prostaglandin monotherapy for glaucoma or ocular hypertension. Because the trials evaluated different instillation techniques and assessed different outcomes, we performed no meta-analysis.One trial, conducted in the US, evaluated the effect of eyelid closure (one and three minutes) versus no eyelid closure on lowering IOP. At one to two weeks' follow-up, reduction in IOP was similar in the eyelid closure group and the no eyelid closure group (mean difference (MD) -0.33 mmHg, 95% confidence interval (CI) -0.8 to 1.5; 51 participants; moderate-certainty evidence).The second trial, conducted in Italy, evaluated the effect of using an absorbent cloth to wipe excess fluid after instillation (fluid removal) versus not using an absorbent cloth (no removal) on reducing dermatologic adverse events. At four months' follow-up, eyelashes were shorter among eyes in the fluid removal group compared with the no fluid removal group (MD -1.70 mm, 95% CI -3.46 to 0.06; 10 participants; low-certainty evidence). Fewer eyes showed skin hyperpigmentation in the eyelid region towards the nose in the fluid removal group compared with the no removal group (RR 0.07, 95% CI 0.01 to 0.84; 10 participants; low-certainty evidence); however, the difference was uncertain in the eyelid region towards the temples (RR 0.44, 95% CI 0.07 to 2.66; 10 participants; low-certainty evidence). The effect hypertrichosis (excessive hair growth) was uncertain between groups (RR 1.00, 95% CI 0.17 to 5.98; 10 participants; low-certainty evidence).Neither trial reported other outcomes specified for this review, including the proportion of participants with IOP less than 21 mmHg; participant-reported outcomes related to the ease, convenience, and comfort of instillation techniques; physiologic measurements of systemic absorption; escalation of therapy; mean change in visual fields; optic nerve progression; mean change in best-corrected visual acuity; proportion in whom glaucoma developed; quality of life outcomes; or cost-effectiveness outcomes. Neither trial reported data at follow-up times of more than four months. AUTHORS' CONCLUSIONS: Evidence to evaluate the effectiveness of topical medication instillation techniques for treatment of glaucoma is lacking. It is unclear what, if any, effects instillation techniques have on topical medical therapy for glaucoma.

Single dose GLP toxicity and biodistribution study of a conditionally replicative adenovirus vector, CRAd-S-pk7, administered by intracerebral injection to Syrian hamsters.

BACKGROUND: CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma. METHODS: This IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.5 × 10(7), 2.5 × 10(8), or 2.5 × 10(9) viral particles (vp)/animal (each n = 60) on day 1. The animals were closely monitored for toxicology evaluation, assessment of viral distribution, and immunogenicity of CRAd-S-pk7. RESULTS: Changes in hematology, clinical chemistry, and coagulation parameters were minor and transient, and consistent with the inflammatory changes observed microscopically. These changes were considered to be of little toxicological significance. The vector remained localized primarily in the brain and to some degree in the tissues at the incision site. Low levels of vector DNA were detected in other tissues in a few animals suggesting systemic circulation of the virus. Viral DNA was detected in brains of hamsters for up to 62 days. However, microscopic changes and virus-related toxicity to the central nervous system were considered minor and decreased in incidence and severity over time. Such changes are not uncommon in studies using adenoviral vectors. CONCLUSION: This study provides safety and toxicology data justifying a clinical trial of CRAd-S-pk7 loaded in FDA-approved HB1.F3.CD neural stem cell carriers administered at the tumor resection bed in humans with recurrent malignant glioma.

Mutant IDH1 and thrombosis in gliomas.

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

Cell-Penetrating Peptide-Modified Gold Nanoparticles for the Delivery of Doxorubicin to Brain Metastatic Breast Cancer.

As therapies continue to increase the lifespan of patients with breast cancer, the incidence of brain metastases has steadily increased, affecting a significant number of patients with metastatic disease. However, a major barrier toward treating these lesions is the inability of therapeutics to penetrate into the central nervous system and accumulate within intracranial tumor sites. In this study, we designed a cell-penetrating gold nanoparticle platform to increase drug delivery to brain metastatic breast cancer cells. TAT peptide-modified gold nanoparticles carrying doxorubicin led to improved cytotoxicity toward two brain metastatic breast cancer cell lines with a decrease in the IC50 of at least 80% compared to free drug. Intravenous administration of these particles led to extensive accumulation of particles throughout diffuse intracranial metastatic microsatellites with cleaved caspase-3 activity corresponding to tumor foci. Furthermore, intratumoral administration of these particles improved survival in an intracranial MDA-MB-231-Br xenograft mouse model. Our results demonstrate the promising application of gold nanoparticles for improving drug delivery in the context of brain metastatic breast cancer.

Abdominal obesity and its association with health-related quality of life in adults: a population-based study in five Chinese cities.

BACKGROUND: This study aimed to investigate the prevalence of abdominal obesity and its association with the health-related quality of life (HRQOL) in a randomly selected Chinese sample. METHODS: A population-based sample of 3,600 residents aged 18-80 years was selected randomly from 5 Chinese cities. Demographic information, and waist and hip circumference measurements were obtained. The Mandarin version of the Short Form 36 Health Survey questionnaire (SF-36) was used to assess the HRQOL. Waist circumference (WC) and waist-to-hip ratio (WHR) were used as measures of abdominal obesity, and the prevalence of abdominal obesity and its association with HRQOL were analysed. RESULTS: Among the 3,184 participants included in the analysis, the prevalence of abdominal obesity was about 45% in both women and men as evaluated by WC, and about 40% in women and 33% in men as evaluated by WHR. The prevalence varied by city, region, age, marital status, education level, family income, smoking, and the presence of chronic diseases. Both WC and WHR increased with age, and men had larger WC and WHR than women in most age groups. In women, abdominal obesity, as determined by both WC and WHR, was associated with meaningful impairments in 4 physical health scales and 2 mental health scales. In men, abdominal obesity, as determined by WC, was associated with 1 physical health scale and 1 mental health scale, and it was associated with 2 physical health scales based on WHR. CONCLUSIONS: Physical health, but not mental health, was more vulnerable to impairment with abdominal obesity, and the impairments varied between genders. Public health agencies should emphasize that abdominal obesity impairs physical health.

Electrosurgical enucleation versus bipolar transurethral resection for prostates larger than 70 ml: a prospective, randomized trial with 5-year followup.

PURPOSE: We compared the perioperative and postoperative characteristics of prostate PlasmaKinetic™ enucleation and bipolar transurethral resection for large volume benign prostatic hyperplasia. MATERIALS AND METHODS: In this prospective, randomized, controlled trial 80 patients with benign prostatic hyperplasia and a prostate of larger than 70 ml were randomly assigned to prostate bipolar transurethral resection or PlasmaKinetic enucleation. Operative time, resected adenoma weight, changes in hemoglobin, catheterization time and postoperative hospital stay were recorded and compared. Patients were followed 1, 6, 12, 24, 36, 48 and 60 months after surgery. RESULTS: Greater resected prostate weight (mean ± SD 64.2 ± 19.0 vs 50.6 ± 20.0 gm, p = 0.03), less blood loss (mean 0.87 ± 0.42 vs 1.74 ± 0.63 gm, p <0.01), and shorter catheterization time (mean 35.5 ± 5.8 vs 60.1 ± 5.8 hours, p <0.01) and postoperative hospital stay (mean 3 vs 4 days, [corrected] p <0.01) were recorded in the enucleation group than in the resection group. The postoperative improvement in International Prostate Symptom Score, quality of life, maximal flow rate and post-void residual urine volume was similar in the 2 groups at 1, 6, 12 and 24 months but significantly better in the enucleation group at 36, 48 and 60 months. During the 5-year followup no patient in the enucleation group but 2 in the resection group experienced recurrence. CONCLUSIONS: For large volume benign prostatic hyperplasia PlasmaKinetic enucleation of the prostate is associated with less blood loss, shorter hospital stay and catheterization time than bipolar transurethral resection of the prostate. Moreover, PlasmaKinetic enucleation seems to be superior at long-term followup with fewer reoperations necessary.

The relationship between self-rated health and objective health status: a population-based study.

BACKGROUND: Self-rated health (SRH), a subjective assessment of health status, is extensively used in the public health field. However, whether SRH can reflect the objective health status is still debatable. We aim to reveal the relationship between SRH and objective health status in the general population. METHODS: We assessed the relationship between SRH and objective health status by examining the prevalence of diseases, laboratory parameters, and some health-related factors in different SRH groups. Data were collected from 18,000 residents randomly sampled from the general population in five cities of China (3,600 in each city). SRH was assessed by a single-item health measure with five options: "very good," "good," "fair," "bad," and "very bad." The differences in prevalence of diseases, laboratory parameters, and health-related factors between the "healthy" (very good plus good), "relatively healthy" (fair), and "unhealthy" (bad plus very bad) groups were examined. The odds ratios (ORs) referenced by the healthy group were calculated using logistic regression analysis. RESULTS: The prevalence of all diseases was associated with poorer SRH. The tendency was more prominent in cardio-cerebral vascular diseases, visual impairment, and mental illnesses with larger ORs. Residents with abnormalities in laboratory parameters tended to have poorer SRH, with ORs ranging from 1.62 (for triglyceride) to 3.48 (for hemoglobin among men) in a comparison of the unhealthy and healthy groups. Most of the health-related factors regarded as risks were associated with poorer SRH. Among them, life and work pressure, poor spiritual status, and poor quality of interpersonal relationships were the most significant factors. CONCLUSIONS: SRH is consistent with objective health status and can serve as a global measure of health status in the general population.

A Flexible Ensemble Learning Method for Survival Extrapolation.

OBJECTIVES: Survival extrapolation is an important statistical concept for estimating long-term survival from short-term clinical trial data. It is widely used in health technology assessment (HTA). Survival extrapolation is often performed by fitting one or two parametric models selected based on experience or selecting a model based on some goodness of fit statistics from a predefined collection of models. The main challenge in survival extrapolation is that the result is sensitive to model misspecification. In this study, we aim to propose a new approach that has a robust performance for survival extrapolation. METHODS: We propose a new method called Ensemble Learning for Survival Extrapolation (ELSE). Instead of selecting one best model from a predefined collection, ELSE builds an ensemble model based on a collection of models from the model library. Under this framework, we construct a point estimate of the long-term survival with a weighted average of the estimates of all candidate models and derive confidence intervals using nonparametric bootstrap. RESULTS: With our extensive numerical simulation studies, the proposed ELSE method shows better performance than the traditionally used model selection procedure based on Akaike Information Criterion (AIC). With a real data application to the Therapeutically Applicable Research to Generate Effective Treatment Wilms Tumor project (TARGET-WT) data, the ELSE method produces better survival extrapolation results in point estimate accuracy and confidence interval coverage. CONCLUSIONS: We developed an ensemble learning method for survival extrapolation (ELSE) which is robust for the underline data model and has good real data performance.

Improving the Segmentation Accuracy of Ovarian-Tumor Ultrasound Images Using Image Inpainting.

Diagnostic results can be radically influenced by the quality of 2D ovarian-tumor ultrasound images. However, clinically processed 2D ovarian-tumor ultrasound images contain many artificially recognized symbols, such as fingers, crosses, dashed lines, and letters which assist artificial intelligence (AI) in image recognition. These symbols are widely distributed within the lesion's boundary, which can also affect the useful feature-extraction-utilizing networks and thus decrease the accuracy of lesion classification and segmentation. Image inpainting techniques are used for noise and object elimination from images. To solve this problem, we observed the MMOTU dataset and built a 2D ovarian-tumor ultrasound image inpainting dataset by finely annotating the various symbols in the images. A novel framework called mask-guided generative adversarial network (MGGAN) is presented in this paper for 2D ovarian-tumor ultrasound images to remove various symbols from the images. The MGGAN performs to a high standard in corrupted regions by using an attention mechanism in the generator to pay more attention to valid information and ignore symbol information, making lesion boundaries more realistic. Moreover, fast Fourier convolutions (FFCs) and residual networks are used to increase the global field of perception; thus, our model can be applied to high-resolution ultrasound images. The greatest benefit of this algorithm is that it achieves pixel-level inpainting of distorted regions without clean images. Compared with other models, our model achieveed better results with only one stage in terms of objective and subjective evaluations. Our model obtained the best results for 256 × 256 and 512 × 512 resolutions. At a resolution of 256 × 256, our model achieved 0.9246 for SSIM, 22.66 for FID, and 0.07806 for LPIPS. At a resolution of 512 × 512, our model achieved 0.9208 for SSIM, 25.52 for FID, and 0.08300 for LPIPS. Our method can considerably improve the accuracy of computerized ovarian tumor diagnosis. The segmentation accuracy was improved from 71.51% to 76.06% for the Unet model and from 61.13% to 66.65% for the PSPnet model in clean images.

Deep convolutional neural networks for multiple histologic types of ovarian tumors classification in ultrasound images.

Objective: This study aimed to evaluate and validate the performance of deep convolutional neural networks when discriminating different histologic types of ovarian tumor in ultrasound (US) images. Material and methods: Our retrospective study took 1142 US images from 328 patients from January 2019 to June 2021. Two tasks were proposed based on US images. Task 1 was to classify benign and high-grade serous carcinoma in original ovarian tumor US images, in which benign ovarian tumor was divided into six classes: mature cystic teratoma, endometriotic cyst, serous cystadenoma, granulosa-theca cell tumor, mucinous cystadenoma and simple cyst. The US images in task 2 were segmented. Deep convolutional neural networks (DCNN) were applied to classify different types of ovarian tumors in detail. We used transfer learning on six pre-trained DCNNs: VGG16, GoogleNet, ResNet34, ResNext50, DensNet121 and DensNet201. Several metrics were adopted to assess the model performance: accuracy, sensitivity, specificity, FI-score and the area under the receiver operating characteristic curve (AUC). Results: The DCNN performed better in labeled US images than in original US images. The best predictive performance came from the ResNext50 model. The model had an overall accuracy of 0.952 for in directly classifying the seven histologic types of ovarian tumors. It achieved a sensitivity of 90% and a specificity of 99.2% for high-grade serous carcinoma, and a sensitivity of over 90% and a specificity of over 95% in most benign pathological categories. Conclusion: DCNN is a promising technique for classifying different histologic types of ovarian tumors in US images, and provide valuable computer-aided information.

LmNaTx15, a novel scorpion toxin, enhances the activity of Nav channels and induces pain in mice.

Polypeptide toxins are major bioactive components found in venomous animals. Many polypeptide toxins can specifically act on targets, such as ion channels and voltage-gated sodium (Nav) channels, in the nervous, muscle, and cardiovascular systems of the recipient to increase defense and predation efficiency. In this study, a novel polypeptide toxin, LmNaTx15, was isolated from the venom of the scorpion Lychas mucronatus, and its activity was analyzed. LmNaTx15 slowed the fast inactivation of Nav1.2, Nav1.3, Nav1.4, Nav1.5, and Nav1.7 and inhibited the peak current of Nav1.5, but it did not affect Nav1.8. In addition, LmNaTx15 altered the voltage-dependent activation and inactivation of these Nav channel subtypes. Furthermore, like site 3 neurotoxins, LmNaTx15 induced pain in mice. These results show a novel scorpion toxin with a modulatory effect on specific Nav channel subtypes and pain induction in mice. Therefore, LmNaTx15 may be a key bioactive component for scorpion defense and predation. Besides, this study provides a basis for analyzing structure-function relationships of the scorpion toxins affecting Nav channel activity.

Methylation of AcGST1 Is Associated with Anthocyanin Accumulation in the Kiwifruit Outer Pericarp.

Most red-fleshed kiwifruit cultivars, such as Hongyang, only accumulate anthocyanins in the inner pericarp; the trait of full red flesh becomes the goal pursued by breeders. In this study, we identified a mutant "H-16" showing a red color in both the inner and outer pericarps, and the underlying mechanism was explored. Through transcriptome analysis, a key differentially expressed gene AcGST1 was screened out, which was positively correlated with anthocyanin accumulation in the outer pericarp. The result of McrBC-PCR and bisulfite sequencing revealed that the SG3 region (-292 to -597 bp) of AcGST1 promoter in "H-16" had a significantly lower CHH cytosine methylation level than that in Hongyang, accompanied by low expression of methyltransferase genes (MET1 and CMT2) and high expression of demethylase genes (ROS1 and DML1). Transient calli transformation confirmed that demethylase gene DML1 can activate transcription of AcGST1 to enhance its expression. Overexpression of AcGST1 enhanced the anthocyanin accumulation in the fruit flesh and leaves of the transgenic lines. These results suggested that a decrease in the methylation level of the AcGST1 promoter may contribute to accumulation of anthocyanin in the outer pericarp of "H-16".