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.

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.

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.

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. Nonspecific 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 patient-derived xenograft 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.

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.

Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene.

The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF1R) expression. DNA methylation of CpG islands is an epigenetic mechanism associated with gene silencing. Recent studies have demonstrated that methylation occurs early in prostate carcinogenesis and, furthermore, may contribute to androgen independence. The methylation status of the AR and IGF1R genes was evaluated in a series of prostate cancer cell lines corresponding to early (benign) and advanced (metastatic) stages of the disease. Results of 5-Aza-2'-deoxycytidine (5-Aza) experiments, methylation-specific PCR, and sodium bisulfite-direct DNA sequencing revealed that the AR promoter is hypermethylated in metastatic M12, but not in benign P69, cells. On the other hand, no methylation was seen in the IGF1R promoter at any stage of the disease. We show, however, that 5-Aza treatment, which caused demethylation of the AR promoter, led to a significant increase in IGF1R mRNA levels, whereas addition of the AR inhibitor flutamide decreased the IGF1R mRNA levels to basal values measured prior to the 5-Aza treatment. Given that the IGF1R gene has been identified as a downstream target for AR action, our data is consistent with a model in which the AR gene undergoes methylation during progression of the disease, leading to dysregulation of AR targets, including the IGF1R gene, at advanced metastatic stages.

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.

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.

Tumor suppressor BRCA1 is expressed in prostate cancer and controls insulin-like growth factor I receptor (IGF-IR) gene transcription in an androgen receptor-dependent manner.

PURPOSE: The insulin-like growth factor (IGF) system plays an important role in prostate cancer. The BRCA1 gene encodes a transcription factor with tumor suppressor activity. The involvement of BRCA1 in prostate cancer, however, has not yet been elucidated. The purpose of the present study was to examine the functional correlations between BRCA1 and the IGF system in prostate cancer. EXPERIMENTAL DESIGN: An immunohistochemical analysis of BRCA1 was done on tissue microarrays comprising 203 primary prostate cancer specimens. In addition, BRCA1 levels were measured in prostate cancer xenografts and in cell lines representing early stages (P69 cells) and advanced stages (M12 cells) of the disease. The ability of BRCA1 to regulate IGF-I receptor (IGF-IR) expression was studied by coexpression experiments using a BRCA1 expression vector along with an IGF-IR promoter-luciferase reporter. RESULTS: We found significantly elevated BRCA1 levels in prostate cancer in comparison with histologically normal prostate tissue (P<0.001). In addition, an inverse correlation between BRCA1 and IGF-IR levels was observed in the androgen receptor (AR)-negative prostate cancer-derived P69 and M12 cell lines. Coexpression experiments in M12 cells revealed that BRCA1 was able to suppress IGF-IR promoter activity and endogenous IGF-IR levels. On the other hand, BRCA1 enhanced IGF-IR levels in LNCaP C4-2 cells expressing an endogenous AR. CONCLUSIONS: We provide evidence that BRCA1 differentially regulates IGF-IR expression in AR-positive and AR-negative prostate cancer cells. The mechanism of action of BRCA1 involves modulation of IGF-IR gene transcription. In addition, immunohistochemical data are consistent with a potential survival role of BRCA1 in prostate cancer.

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.

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.

Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells.

BACKGROUND: Because lung cancer is the leading cause of cancer-related death, new approaches for preventing and controlling the disease are needed. Chemoprevention approaches are both feasible and effective. We evaluated the potential of deguelin, a natural plant product, as a lung cancer chemopreventive agent and investigated its mechanism of action. METHODS: The effects of deguelin on proliferation and apoptosis of normal, premalignant, and malignant human bronchial epithelial (HBE) cells were assessed by using the MTT assay, a flow cytometry-based TUNEL assay, and western blot analyses. The effects of deguelin on the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses and with adenoviral vectors that expressed constitutively active Akt. RESULTS: Deguelin treatment in vitro at doses attainable in vivo inhibited the growth of and induced apoptosis of premalignant and malignant HBE cells but had minimal effects on normal HBE cells. Levels of phosphorylated Akt (pAkt) were higher in premalignant HBE cells than in normal HBE cells. In premalignant HBE cells, deguelin inhibited PI3K activity and reduced pAkt levels and activity but had mimimal effects on the MAPK pathway. Although overexpression of a constitutively active Akt in premalignant and malignant HBE cells had no effect on growth inhibition mediated by N-(4-hydroxyphenyl)retinamide (4-HPR), a novel chemopreventive retinoid, it blocked deguelin-induced growth arrest and apoptosis. CONCLUSIONS: The ability of deguelin to inhibit PI3K/Akt-mediated signaling pathways may contribute to the potency and specificity of this pro-apoptotic drug. Because both premalignant and malignant HBE cells are more sensitive to deguelin than normal HBE cells, deguelin may have potential as both a chemopreventive agent for early stages of lung carcinogenesis and a therapeutic agent against lung cancer.

Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence.

A cure for prostate cancer (CaP) will be possible only after a complete understanding of the mechanisms causing this disease to progress from androgen dependence to androgen independence. To carry on a careful characterization of the phenotypes of CaP cell lines before and after acquisition of androgen independence, we used two human CaP LNCaP sublines: LNCaP(nan), which is androgen dependent (AD), and LNCaP-HP, which is androgen independent (AI). In AD LNCaP(nan) cells, dihydrotestosterone (DHT) stimulated in an androgen receptor (AR)-dependent way a phosphorylation signaling pathway involving steroid receptor coactivator (Src)-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-1/2-ERK-1/2-cAMP-response element binding-protein (CREB). Activation of this pathway was associated with increased [(3)H]thymidine incorporation and resistance to apoptosis. Use of dominant-negative forms of MEK-1/2 and CREB demonstrated in LNCaP(nan) cells that DHT induced [(3)H]thymidiine incorporation through a thus far unidentified molecule activated downstream of MEK-1/2, and antiapoptosis through phosphorylation of the transcription factor CREB. In contrast, in AI LNCaP-HP cells, the Src-MEK-1/2-ERK-1/2-CREB pathway was constitutively active. Because it was not further stimulated by addition of DHT, no increase of [(3)H]thymidine incorporation or apoptosis resistance was demonstrated in LNCaP-HP cells. Additional experiments showed that Src and the scaffold protein MNAR coimmunoprecipitated with AR, indicating a role for Src as an apical molecule in the Src-MEK-1/2-ERK-1/2-CREB pathway. Interestingly, differences between the two cell lines were that in LNCaP-HP cells presence of an AI phenotype and lack of response to DHT were associated with constitutive activation of the protein kinase Src and interaction among Src, AR, and MNAR. In contrast, in LNCaP(nan) cells, presence of an AD phenotype and ability to respond to DHT were associated with DHT-dependent activation of Src kinase activity and interaction among Src, AR, and MNAR. Intriguingly, in LNCaP(nan) cells, we found that transcription through the prototypical CREB-responsive promoter c-fos could be induced in a DHT-dependent way, and this action was inhibited by the AR antagonist Casodex and MEK-1 inhibitor PD98059. In contrast, transcription through the PSA P/E promoter, a prototypical AR-dependent promoter directly activated by agonist, was obliterated only by Casodex. Additional experiments with genital skin fibroblasts derived from patients with a variety of AR abnormalities indicated that nongenotropic AR signaling does not depend on an intact DNA-binding domain or on the ability of AR to translocate to the nucleus. The results suggest the following: (1) Constitutive activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is associated with the AI phenotype observed in LNCaP-HP cells. (2) Activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is DHT dependent in AD LNCaP(nan) cells. (3) DHT activation of this pathway is associated with induction of [(3)H]thymidine incorporation by a molecule activated downstream of MEK-1/2 and of antiapoptosis through activation of the transcription factor CREB in AD LNCaP(nan) cells. (4) AR regulates transcription either directly upon ligand binding and nuclear translocation or indirectly through kinase pathways leading to activation of downstream transcription factors. (5) Nuclear translocation and ability of the DNA-binding domain of AR to interact with DNA are not prerequisites for nongenotropic AR activity.

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.

Clinical significance of insulin-like growth factor-binding protein-3 expression in stage I non-small cell lung cancer.

The activities of insulin-like growth factors (IGFs), including mitogenic and antiapoptotic properties, are modulated by a family of high-affinity insulin-like growth factor-binding proteins (IGFBPs), of which IGFBP-3 is the major serum carrier protein. Even though it is well known that IGFBP-3 plays an important role in cell proliferation, the expression of IGFBP-3 and its significance in primary non-small cell lung cancer (NSCLC) samples are unknown. This study explored IGFBP-3 expression in tumor samples from 74 patients with a diagnosis of pathological stage I NSCLC to determine if the expression status of IFGBP-3 influences the prognosis of patients with NSCLC. Two-sided statistical analyses were performed to correlate the clinical parameters and the prognostic effect with the IGFBP-3 expression level in this cohort. Reduced IGFBP-3 expression was found in 42 (56.8%) of 74 samples, and it was more frequent in large cell carcinoma than in squamous cell carcinoma and adenocarcinoma, although this difference was not statistically significant. This phenomenon was not associated with the other clinicopathological parameters tested, such as age, sex, histological grade, and smoking history. Significant statistical correlation between IGFBP-3 expression and disease-specific survival was noted (P = 0.019 by log-rank test). Although statistically nonsignificant, patients with decreased IGFBP-3 expression had shorter overall, disease-free, and event-free survival rates than did patients with normal IGFBP-3 expression. In a multivariate analysis using IGFBP-3 expression and other clinicopathological parameters, the level of IGFBP-3 expression remained as an independent factor for predicting a shorter disease-specific survival probability (P = 0.020). Our work demonstrates that down-regulation of IGFBP-3 is a frequent event in stage I NSCLC and correlates with the disease-specific survival probability of patients with stage I NSCLC. These results suggest that IGFBP-3 functions as a tumor suppressor and plays an important role in determining biological aggressiveness in early NSCLC.