A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Associations between antipsychotics and the risk of incident cardiovascular diseases in individuals with schizophrenia: a nested case-control study.

BACKGROUND: The association between antipsychotics and cardiovascular diseases (CVDs) remains significant yet unestablished, especially in Chinese populations. OBJECTIVE: To investigate the risk of CVDs associated with antipsychotics among Chinese individuals with schizophrenia. METHODS: We conducted a nested case-control study on individuals diagnosed with schizophrenia in Shandong, China. The case group included individuals diagnosed with incident CVDs between 2012 and 2020. Each case was randomly matched with up to three controls. We used weighted logistic regression models to assess the risk of CVDs associated with antipsychotics and restricted cubic spline analysis to explore the dose-response relationship. FINDINGS: In total, 2493 cases and 7478 matched controls were included in the analysis. Compared with non-users, any antipsychotics use was associated with higher risk of any CVDs (weighted OR=1.54, 95% CI 1.32 to 1.79), with the risk mainly driven by ischaemic heart diseases (weighted OR=2.26, 95% CI 1.71 to 2.99). Treatments with haloperidol, aripiprazole, quetiapine, olanzapine, risperidone, sulpiride and chlorpromazine were associated with increased risk of CVDs. A non-linear dose-response relationship between dosage of antipsychotics and risk of CVDs was observed, with a sharp increase in risk in the beginning and then flattening out with higher doses. CONCLUSIONS: Use of antipsychotics was associated with increased risk of incident CVDs among individuals with schizophrenia, and the risk varied substantially among different antipsychotics and specific CVDs. CLINICAL IMPLICATIONS: Clinicians should consider the cardiovascular risk of antipsychotics and choose the appropriate type and dose of drugs in the treatment of schizophrenia.

Study on the Application Value of CT Thin-Layer Scan Data Assisted 3D Printing Technology in Hip and Knee Replacement.

To better study hip and knee replacement, 50 eligible hip and knee patients from March 2020 to April 2021 were selected. A 1 : 1 scale solid model was printed with CT thin-layer scanning data assisted by 3D printing technology to evaluate the ankle function of patients six months after surgery. The results showed that the 3D rapid prototyping time of the 1 : 1 fracture model in 50 patients was 3-4 hours. The operation time was 70-90 min, and the average operation time was 80 min. The actual application in operation was consistent with that in the simulation of the 3D printing model, after surgery, and there was no infection of incision soft tissue or loss of reduction in all 50 patients. CT thin-layer scan data aided 3D printing technology can help clinical hip and knee replacement simulation and planning, improving surgery's accuracy and safety.

Prediction of risk of suicide death among lung cancer patients after the cancer diagnosis.

BACKGROUND: Patients diagnosed with lung cancer have a higher suicide rate than the general population and other cancer patients. The aim of this study was to develop and validate a prediction model for the individual risk for suicide after the diagnosis of lung cancer. METHODS: Patients diagnosed with lung cancer between 2007 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training and validation cohorts. Cox proportional hazard models were used to identify relevant predictors and construct prediction models. Additionally, graphic visualization methods were used to predict the risk for suicide within 5 years after the diagnosis of lung cancer. We used bootstrapping for the internal validation, Harrell's C-index for the discrimination, and a calibration plot for the calibration of the proposed model. RESULTS: We obtained complete information on 112372 patients diagnosed with lung cancer from the SEER cohort. Multivariate Cox regression identified sex, race, marital status, tumour grade, surgery, radiation, and chemotherapy as significant predictors for suicide. A nomogram and a risk matrix were developed to visualize the risk for suicide within 5 years after lung cancer diagnosis. The bootstrapped and validated C-indices of the nomogram were 0.77 and 0.78, respectively. The calibration plot indicated good agreement between the prediction and actual observation. CONCLUSIONS: The proposed model demonstrated good discrimination and calibration performance for predicting the risk for suicide within 5 years after lung cancer diagnosis. Reliable and feasible risk assessment tools can be promising for preventing unnecessary suicides among lung cancer patients.

Familial liability to asthma and ADHD: A Swedish national register-based study.

Background: Studies have reported significant associations between asthma and attention-deficit/hyperactivity disorder (ADHD), but whether the association is due to shared etiology such as shared genetic risk factors remains unclear. We aimed to investigate patterns of familial co-aggregation of asthma and ADHD and also to quantify the relative contribution of genetic and environmental influences. Methods: Through Swedish register linkages, we obtained a cohort of 927,956 individuals born 1992-2001 and identified monozygotic twins (MZ), dizygotic twins (DZ), full- and half-siblings, and full- and half-cousins. Clinical diagnosis of asthma and ADHD were identified from the Swedish national registers. We used logistic regressions to investigate the within-individual association and familial co-aggregation between asthma and ADHD. We then used bivariate twin modeling to quantify the genetic and environmental correlations and their contributions to the familial liability. Results: Individuals with asthma had significantly higher risk of ADHD (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.47-1.54). Relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma; in familial co-aggregation analysis, the association was strongest in MZ twins (OR, 1.67; 95% CI, 0.99-2.84) and attenuated with degree of genetic relatedness. In the twin modeling, the phenotypic and genetic correlations between asthma and ADHD estimated from the ACE model were 0.09 (95% CI, 0.05-0.14) and 0.12 (95% CI, 0.02-0.21), respectively. The bivariate heritability was 0.88 (95% CI, 0.30-1.46). Estimates for contributions from shared and non-shared environment factors were not statistically significant. Conclusions: Asthma and ADHD co-aggregate in families primarily due to shared genetic risk factors. Within-individual and family history of either disorder should prompt clinical assessment of the other condition. Future studies should further investigate genetic variants underlying the co-occurrence of ADHD and asthma.

Associations between sleep problems and ADHD symptoms among adolescents: findings from the Shandong Adolescent Behavior and Health Cohort (SABHC).

STUDY OBJECTIVES: Sleep problems and symptoms of attention-deficit hyperactivity disorder (ADHD) in adolescence are common. Little is known about the prospective the prospective associations between sleep and subsequent ADHD symptoms in adolescents. This study examined the prospective associations between sleep problems and subsequent ADHD symptoms in a large sample of adolescents. METHODS: Participants included 7072 adolescents from the Shandong Adolescent Behavior and Health Cohort (SABHC) study in Shandong, China. Participants were initially assessed in November-December of 2015 and were reassessed 1-year later in 2016. Sleep duration, sleep problems, and psychosocial information were collected using a structured questionnaire. ADHD symptoms were measured by the Achenbach Child Behavior Checklist-Youth Self-Report. RESULTS: At baseline, 7.6% participants had clinically relevant ADHD symptoms, which were highly comorbid with sleep problems including insomnia symptoms, poor sleep quality, symptoms of restless legs syndrome (RLS), frequent snoring, and short sleep duration. Of the 6531 participants without clinically relevant ADHD symptoms at baseline, 4.5% reported clinically relevant ADHD symptoms at 1-year follow-up. After adolescent and family covariates were adjusted for, insomnia (OR = 2.09, 95% CI = 1.45-3.02), RLS (OR = 1.47, 95% CI = 1.02-2.11), and frequent snoring (OR = 2.30, 95% CI = 1.36-3.90) were all significantly associated with subsequent ADHD symptoms. CONCLUSION: ADHD symptoms and sleep problems are highly comorbid. Insomnia, RLS and frequent snoring appear to be significant predictors of subsequent ADHD symptoms. Our study highlights the importance of assessing and managing sleep problems for prevention and clinical treatment of ADHD symptoms in adolescence.

Mobile Phone Passive Positioning through the Detection of Uplink Signals for Search and Rescue.

To satisfy the service requirements of high accuracy and efficient life detection and location for search and rescue (SAR) missions after a disaster, we developed a passive positioning method to locate mobile phones by capturing the random access preamble, which can be applied to fourth-generation (4G) and even fifth-generation (5G) communication systems. We analyzed the characteristics of the random access procedure of a communication system and established a way to detect mobile phones by combining the time-difference-of-arrival (TDOA) estimation to determine the location. Then, we performed an experiment and a simulation of preamble sequence acquisition, and the results proved that the method is feasible and has high detection accuracy in high-noise conditions.

Association of Psychiatric Comorbidity With the Risk of Premature Death Among Children and Adults With Attention-Deficit/Hyperactivity Disorder.

Importance: A previous register-based study reported elevated all-cause mortality in attention-deficit/hyperactivity disorder (ADHD), but cause-specific risks and the potential associations of psychiatric comorbidities remain unknown. Objectives: To investigate the all-cause and cause-specific mortality risks in ADHD and to explore the potential role of psychiatric comorbidities. Design, Setting, and Participants: This prospective cohort study used Swedish national registers to identify 2 675 615 individuals born in Sweden from January 1, 1983, through December 31, 2009, as the study population, among whom 86 670 individuals (3.2%) received a diagnosis of ADHD during follow-up. Follow-up was completed December 31, 2013, and data were analyzed from October 2018 through March 2019. Exposures: Attention-deficit/hyperactivity disorder identified by first clinical diagnosis or first prescription of ADHD medications as recorded in Swedish registers. Clinical diagnosis of psychiatric comorbidity was available in the National Patient Register. Main Outcomes and Measures: All-cause and cause-specific mortalities and hazard ratios (HRs) using Cox proportional hazards regression models. Results: In the overall cohort of 2 675 615 individuals, 1 374 790 (51.4%) were male (57 919 with an ADHD diagnosis) and 1 300 825 (48.6%) were female (28 751 with an ADHD diagnosis). Mean (SD) age at study entry was 6.4 (5.6) years. During follow-up, 424 individuals with ADHD and 6231 without ADHD died, resulting in mortality rates of 11.57 and 2.16 per 10 000 person-years, respectively. The association was stronger in adulthood (HR, 4.64; 95% CI, 4.11-5.25) compared with childhood (HR, 1.41; 95% CI, 0.97-2.04) and increased substantially with the number of psychiatric comorbidities with ADHD (HR for individuals with only ADHD, 1.41 [95% CI, 1.01-1.97]; HR for those with ≥4 comorbidities, 25.22 [95% CI, 19.60-32.46]). In adulthood, when adjusting for early-onset psychiatric comorbidity, the association between ADHD and risk of death due to natural causes was attenuated substantially and was no longer statistically significant (HR, 1.32; 95% CI, 0.94-1.85). When adjusting for later-onset psychiatric disorders, the association was attenuated to statistical nonsignificance for death due to suicide (HR, 1.13; 95% CI, 0.88-1.45) but remained statistically significant for death caused by unintentional injury (HR, 2.14; 95% CI, 1.71-2.68) or other external causes (HR, 1.75; 95% CI, 1.23-2.48). Conclusions and Relevance: Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD. In adulthood, early-onset psychiatric comorbidity contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbidity mainly influenced death due to unnatural causes, including suicide and unintentional injury. These findings suggest that health care professionals should closely monitor specific psychiatric comorbidities in individuals with ADHD to identify high-risk groups for prevention efforts.

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.

Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study.

BACKGROUND: Several studies have assessed the possible association between attention deficit hyperactivity disorder (ADHD) and asthma. However, existing evidence is inconclusive as to whether this association remains after controlling for possible important confounders. To fill this knowledge gap, we did a systematic review and meta-analysis, followed by a population-based study. METHODS: For the systematic review and meta-analysis, we searched PubMed, PsycINFO, Embase, Embase Classic, Ovid MEDLINE, and Web of Knowledge databases up to Oct 31, 2017, for observational studies allowing estimation of the association between asthma and ADHD. No restrictions to date, language, or article type were applied. Unpublished data were collected from authors of the identified studies. We extracted unadjusted and adjusted odds ratios (ORs) from the identified studies and calculated ORs when they were not reported. We assessed study quality using the Newcastle-Ottawa Scale and study heterogeneity using I2 statistics. A random-effects model was used to calculate pooled ORs. The systematic review is registered with PROSPERO (CRD42017073368). To address the fact that the ORs obtained in the meta-analysis were adjusted for confounders that inevitably varied across studies, we did a population-based study of individuals in multiple national registers in Sweden. We calculated an unadjusted OR and an OR that was simultaneously adjusted for all confounders identified in a directed acyclic graph based on the studies of asthma and ADHD identified in our systematic review. FINDINGS: We identified 2649 potentially eligible citations, from which we obtained 49 datasets including a total of 210 363 participants with ADHD and 3 115 168 without. The pooled unadjusted OR was 1·66 (95% CI 1·22-2·26; I2 =99·47) and the pooled adjusted OR was 1·53 (1·41-1·65; I2 =50·76), indicating a significant association between asthma and ADHD. Possible lack of representativeness of the study population was detected with the Newcastle-Ottawa Scale in 42 of 49 datasets. In the population-based study, we included 1 575 377 individuals born between Jan 1, 1992, and Dec 31, 2006, of whom 259 253 (16·5%) had asthma and 57 957 (3·7%) had ADHD. Asthma was significantly associated with ADHD (OR 1·60, 95% CI 1·57-1·63) in the crude model adjusting for sex and year of birth, and this association remained significant after simultaneous adjustment for all covariates (1·45, 1·41-1·48). INTERPRETATION: The combined results of the meta-analysis and the population-based study support a significant association between asthma and ADHD, which remained even after simultaneously controlling for several possible confounders in the population-based study. Awareness of this association might help to reduce delay in the diagnosis of both ADHD and asthma. FUNDING: Swedish Research Council and Shire International GmbH.

Injuries prior and subsequent to index poisoning with medication among adolescents: a national study based on Norwegian patient registry.

BACKGROUND: Adolescents treated for self-poisoning with medication have a high prevalence of mental health problems and constitute a high-risk population for self-harm repetition. However, little is known about whether this population is also prone to injuries of other forms. METHODS: Data were extracted from the Norwegian Patient Registry to include all incidents of treated injuries in adolescents aged 10-19 years who were treated for self-poisoning with medication during 2008-2011. This longitudinal approach allowed for the inclusion of injuries of various forms both before and after the index poisoning with medication. Gender differences and associations of injuries with recorded deliberate self-harm or psychiatric comorbidity at index poisoning were analysed. Forms of injury and psychiatric illnesses were coded according to the ICD-10 system. RESULTS: 1497 adolescents treated for self-poisoning with medication were identified from the source database, including 1144 (76.4%) girls and 353 (23.6%) boys. For these 1497 adolescents a total of 2545 injury incidents were recorded in addition to the index poisoning incidents, consisting of 778 injury incidents taking place before the index poisoning and 1767 incidents taking place subsequently. Altogether 830 subjects (55.4%) had an injury treated either before or after the index poisoning. Injuries to the hand and wrist as well as injuries to the head, neck and throat were predominant in males. Females were more likely to repeat poisoning with medication, particularly those with psychiatric disorders. CONCLUSION: Adolescents treated for poisoning with medication represent a high-risk population prone to both prior and subsequent injuries of other forms, and should be assessed for suicidal intent and psychiatric illness.

Social Psychological Factors and Suicidal Intent Among Suicide Attempters in Rural China: A Path Analysis.

This study explores the effects of social psychological factors on suicidal intent among suicide attempters in rural China. Suicide attempters were identified by the county-level Centers for Disease Control and Prevention (CDCs) and interviewed by the research team. A path analysis was conducted with physical illness, social support, and negative life events as exogenous variables, and life satisfaction, depressive emotions, and suicidal intent as endogenous variables. Beginning with a saturation model, a best model was obtained after removing the paths that were not significant. In the final model, depressive emotions and life satisfaction were directly associated with suicidal intent, and the standardized effect estimates were 0.3007 (p < 0.001) and -0.1182 (p = 0.0368). Physical illness, social support, and negative life events did not directly affect suicidal intent but had indirect effect. Depressive emotions may be the most important and direct predictor of suicidal intent; physical illness, negative life events, and social support affect suicidal intent through life satisfaction and depressive emotions.

The COMT rs4680 polymorphism and suicide attempt in rural Shandong, China.

BACKGROUND: Suicide attempt is a major public health problem and are associated with genetic factors. This paired case-control study examined the association between the COMT gene rs4680 polymorphism and suicide attempts. METHODS: A case-control study of 369 (117 men, 31.7%; mean age=44.1±13.3 years) suicide attempters and an equal number of controls without a lifetime history of suicide attempt matched on sex, age, and residence was carried out in rural Shandong, Eastern China. Demographics and psychiatric history were obtained through face-to-face interviews. Blood samples were collected during interviews and the COMT gene rs4680 polymorphism was analyzed using the ligation detection reaction method. RESULTS: The G/G genotype was significantly more prevalent in female suicide attempters than their matched controls. Conditional logistic regression showed that the G/G genotype was significantly associated with an increased risk of suicide attempts only for women (odds ratio=2.3; 95% confidence interval: 1.2-4.2). CONCLUSION: The findings support an association between the COMT gene rs4680 polymorphism and suicide attempts only in women. Further research with larger samples is needed to explore the interactions of the COMT gene rs4680 polymorphism and sex and psychiatric disorders on suicide attempts.

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. OBJECTIVE: To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. DESIGN, SETTING, AND PARTICIPANTS: Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. RESULTS AND LIMITATIONS: Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p<0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p=0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p=0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. CONCLUSIONS: We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. PATIENT SUMMARY: In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.

Association of the HTR2A 102T/C polymorphism with attempted suicide: a meta-analysis.

An association between the serotonin 2A receptor (5-HT2A receptor) gene and suicidal behavior has been reported in many studies. However, no consistent conclusion has been reached. One potential reason for this is heterogeneity in the studies analyzed, which may have been caused by the selection of different types of cases and controls. In the present study, we pooled data from the previous published papers to clarify the association between HTR2A 102T/C and attempted suicide. All case-control studies written in English and published up until 20 November 2013 were selected. The history of suicide attempts and other relevant data were extracted. According to the findings of previous studies, the recessive model was used to evaluate the role of genotype in attempted suicide. We divided the patients into three groups on the basis of the history of suicide attempts and mental disorder. Genotype distribution of the suicide attempters was compared with normal controls and patients with mental disorder, respectively. There were no significant differences in 5-HT2A receptor 102T/C genotype distributions between those who attempted suicide and the normal controls, and the results were similar for the comparisons with mental disorder patient controls. When subgroup analysis of the types of mental disorder was carried out, all heterogeneity disappeared and effect sizes increased. A significant association was observed for the schizophrenia disorder subgroup (odds ratio=1.73; 95% confidence interval: 1.11-2.69). Our meta-analysis does not support the previously suggested association between HTR2A 102T/C and attempted suicide in the general population. However, in patients with schizophrenia, the C/C genotype of 5-HT2A receptor 102T/C may increase the risk of attempted suicide. The heterogeneity in relevant studies may have been caused by the characteristic variety of mixed mental disorders.

MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand.

The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation has not been defined. A distinct transcriptome enriched with cell cycle genes, e.g. UBE2C, has been associated with AR-Vs, which indicates the possibility of an altered transcriptional mechanism when compared to full-length wild-type AR (ARfl). Importantly, a recent study reported the critical role of p-MED1 in enhancing UBE2C expression through a locus looping pattern, which only occurs in CRPC but not in androgen-dependent prostate cancer (ADPC). To investigate the potential correlation between AR-V and MED1, in the present study we performed protein co-immunoprecipitation, chromatin immunoprecipitation, and cell proliferation assays and found that MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to ARv567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es. Our data indicate that p-MED1 serves as a key mediator in ARv567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC.

Completed suicide with violent and non-violent methods in rural Shandong, China: a psychological autopsy study.

BACKGROUND: This study aims to describe the specific characteristics of completed suicides by violent methods and non-violent methods in rural Chinese population, and to explore the related factors for corresponding methods. METHODS: Data of this study came from investigation of 199 completed suicide cases and their paired controls of rural areas in three different counties in Shandong, China, by interviewing one informant of each subject using the method of Psychological Autopsy (PA). RESULTS: There were 78 (39.2%) suicides with violent methods and 121 (60.8%) suicides with non-violent methods. Ingesting pesticides, as a non-violent method, appeared to be the most common suicide method (103, 51.8%). Hanging (73 cases, 36.7%) and drowning (5 cases, 2.5%) were the only violent methods observed. Storage of pesticides at home and higher suicide intent score were significantly associated with choice of violent methods while committing suicide. Risk factors related to suicide death included negative life events and hopelessness. CONCLUSIONS: Suicide with violent methods has different factors from suicide with non-violent methods. Suicide methods should be considered in suicide prevention and intervention strategies.

Androgen receptor splice variants determine taxane sensitivity in prostate cancer.

Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active androgen receptor splice variants that drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC); however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for androgen receptor nuclear translocation and activity. In this study, we used a set of androgen receptor deletion mutants to identify the microtubule-binding domain of the androgen receptor, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant androgen receptor splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or coprecipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumor xenografts displayed docetaxel resistance. Our results suggest that androgen receptor variants that accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of taxanes, suggesting a mechanistic rationale to customize treatments for patients with CRPC, which might improve outcomes.