Increased burden of cardiovascular risk among youth suicide attempters.

BACKGROUND: Suicide and cardiovascular disease rank among the leading causes of disability and premature mortality worldwide. Young adult suicide attempters are at increased risk of mortality from cardiovascular disease even compared to those with major depressive disorder suggesting an increased burden of cardiovascular risk factors. We compared the cardiovascular risk burden between youth attempters and other high-risk individuals. METHODS: Participants were from the Collaborative Psychiatric Epidemiology Surveys (CPES), a U.S. population-based study, aged 18-30 years [suicide attempt (SA): n = 303; suicidal ideation (SI): n = 451; controls: n = 3671]; and psychiatric inpatients admitted for a SA (n = 38) or SI (n = 40) and healthy controls (n = 37) aged 15-30 years. We computed a cardiovascular risk score and high- and low-risk latent classes based on risk factors of high blood pressure, obesity, and smoking. RESULTS: Suicide attempters showed an increased cardiovascular risk score (CPES: B = 0.43, 95% confidence interval (CI) 0.31-0.54, p < 0.001; inpatient sample: B = 1.61, 95% CI 0.53-2.68, p = 0.004) compared to controls. They were also more likely to be classified in the high cardiovascular risk group (CPES: odds ratio (OR) 3.36, 95% CI 1.67-6.78, p = 0.001; inpatient sample: OR 9.89, 95% CI 1.38-85.39, p = 0.03) compared to those with SI (CPES: OR 1.15, 95% CI 0.55-2.39, p = 0.71; inpatient sample: OR 1.91, 95% CI 0.25-15.00, p = 0.53). CONCLUSIONS: Youth attempters show an increased burden for cardiovascular risk compared to other high-risk individuals in inpatient and population-based samples. Clinicians should pay particular attention to cardiovascular risk factors among suicide attempters in order to reduce their risk for cardiovascular events.

Steroidogenesis in Peripheral and Transition Zones of Human Prostate Cancer Tissue.

The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer. Androgens and their receptor are the primary driving cause of prostate cancer growth and eventually castration-resistant prostate cancer (CRPC). De novo steroidogenesis has been identified as a key mechanism that develops during CRPC. Currently, there is very limited information available on human prostate tissue steroidogenesis. The purpose of the present study was to investigate steroid metabolism in human prostate cancer tissues with comparison between PZ and TZ. Human prostate cancer tumors were procured from the patients who underwent radical prostatectomy without any neoadjuvant therapy. Human prostate homogenates were used to quantify steroid levels intrinsically present in the tissues as well as formed after incubation with 2 µg/mL of 17-hydroxypregnenolone (17-OH-pregnenolone) or progesterone. A Waters Acquity ultraperformance liquid chromatography coupled to a Quattro Premier XE tandem quadrupole mass spectrometer using a C18 column was used to measure thirteen steroids from the classical and backdoor steroidogenesis pathways. The intrinsic prostate tissue steroid levels were similar between PZ and TZ with dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone and 17-OH-pregnenolone levels higher than the other steroids measured. Interestingly, 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one, and 5-pregnan-17-ol-3,20-dione formation was significantly higher in both the zones of prostate tissues, whereas, androstenedione, testosterone, DHT, and progesterone levels were significantly lower after 60 min incubation compared to the 0 min control incubations. The incubations with progesterone had a similar outcome with 5-pregnan-3,20-dione and 5-pregnan-3-ol-20-one levels were elevated and the levels of DHT were lower in both PZ and TZ tissues. The net changes in steroid formation after the incubation were more observable with 17-OH-pregnenolone than with progesterone. In our knowledge, this is the first report of comprehensive analyses of intrinsic prostate tissue steroids and precursor-driven steroid metabolism using a sensitive liquid chromatography-mass spectrometry assay. In summary, the PZ and TZ of human prostate exhibited similar steroidogenic ability with distinction in the manner each zone utilizes the steroid precursors to divert the activity towards backdoor pathway through a complex matrix of steroidogenic mechanisms.

Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment.

Despite the substantial benefit of androgen deprivation therapy (ADT) for metastatic prostate cancer, patients often progress to castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed androgen receptor activity in tumor cells and restoration of tumor androgen levels through acquired intratumoral steroidogenesis (AIS). Although prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize testosterone (T) from an adrenal precursor, DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG. Here, we show exposure of PrSCs to a different Smoothened (Smo) agonist, Ag1.5, or to conditioned medium from sonic hedgehog overexpressing LNCaP cells induces steroidogenic enzyme expression in PrSCs and significantly increases production of T and its precursor steroids in a Smo-dependent manner from 22-OH-cholesterol substrate. Hh agonist-/ligand-treated PrSCs produced androgens at a rate similar to or greater than that of PCa cell lines. Likewise, primary bone marrow stromal cells became more steroidogenic and produced T under the influence of Smo agonist. Treatment of mice bearing LNCaP xenografts with a Smo antagonist, TAK-441, delayed the onset of CRPC after castration and substantially reduced androgen levels in residual tumors. These outcomes support the idea that stromal cells in ADT-treated primary or metastatic prostate tumors can contribute to AIS as a consequence of a paracrine Hh signaling microenvironment. As such, Smo antagonists may be useful for targeting prostate tumor stromal cell-derived AIS and delaying the onset of CRPC after ADT.

Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes.

Prostate cancer is the leading type of cancer diagnosed in men. In 2010, ~217,730 new cases of prostate cancer were reported in the United States. Prompt diagnosis of the disease can substantially improve its clinical outcome. Improving capability for early detection, as well as developing new therapeutic targets in advanced disease are research priorities that will ultimately lead to better patient survival. Eukaryotic cells secrete proteins via distinct regulated mechanisms which are either ER/Golgi dependent or microvesicle mediated. The release of microvesicles has been shown to provide a novel mechanism for intercellular communication. Exosomes are nanometer sized cup-shaped membrane vesicles which are secreted from normal and cancerous cells. They are present in various biological fluids and are rich in characteristic proteins. Exosomes may thus have potential both in facilitating early diagnosis via less invasive procedures or be candidates for novel therapeutic approaches for castration resistance prostate cancer. Because exosomes have been shown previously to have a role in cell-cell communication in the local tumor microenvironment, conferring activation of numerous survival mechanisms, we characterized constitutive lipids, cholesterol and proteins from exosomes derived from six prostate cell lines and tracked their uptake in both cancerous and benign prostate cell lines respectively. Our comprehensive proteomic and lipidomic analysis of prostate derived exosomes could provide insight for future work on both biomarker and therapeutic targets for the treatment of prostate cancer.

Complications of Infective Endocarditis: A Case Report of Intracerebral Hemorrhage Exacerbated by Enoxaparin.

Infective endocarditis (IE) can cause life-threatening intracerebral hemorrhage via the transformation of an embolic ischemic stroke. Navigating anticoagulant therapy for IE patients is challenging due to this risk. Hospitalized patients often receive anticoagulation to minimize venous thromboembolism (VTE). Those at higher VTE risk may require full anticoagulation, particularly if there is an initial suspicion of a blood clot. A timely IE diagnosis is crucial but is often delayed during inpatient stays, with the patient potentially already on anticoagulants for other conditions. Our case discusses a hemorrhagic stroke in a patient with IE while receiving therapeutic enoxaparin. Clinical signs and symptoms, echocardiographic findings, laboratory workup and microbiological data, and possibly other imaging techniques such as cerebral magnetic resonance imaging (MRI) need to be employed in a timely manner in determining endocarditis as a cause of stroke.

Elizabethkingia anophelis MSU001 Isolated from Anopheles stephensi: Molecular Characterization and Comparative Genome Analysis.

Elizabethkingia anophelis MSU001, isolated from Anopheles stephensi in the laboratory, was characterized by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-ToF/MS), biochemical testing, and genome sequencing. Average nucleotide identity analysis revealed 99% identity with the type species E. anophelis R26. Phylogenetic placement showed that it formed a clade with other mosquito-associated strains and departed from a clade of clinical isolates. Comparative genome analyses further showed that it shared at least 98.6% of genes with mosquito-associated isolates (except E. anophelis As1), while it shared at most 88.8% of common genes with clinical isolates. Metabolites from MSU001 significantly inhibited growth of E. coli but not the mosquito gut symbionts Serratia marcescens and Asaia sp. W12. Insect-associated E. anophelis carried unique glycoside hydrolase (GH) and auxiliary activities (AAs) encoding genes distinct from those of clinical isolates, indicating their potential role in reshaping chitin structure and other components involved in larval development or formation of the peritrophic matrix. Like other Elizabethkingia, MSU001 also carried abundant genes encoding two-component system proteins (51), transcription factor proteins (188), and DNA-binding proteins (13). E. anophelis MSU001 contains a repertoire of antibiotic resistance genes and several virulence factors. Its potential for opportunistic infections in humans should be further evaluated prior to implementation as a paratransgenesis agent (by transgenesis of a symbiont of the vector).

An Uncommon Encounter of Roseomonas gilardii Bacteremia: A Case Report.

Roseomonas genus was initially described in 1993 as a "pink coccoid." It is a non-fermentative, aerobic, and gram-negative bacteria. This genus has been uncovered in diverse environmental niches, ranging from water and soil to air and plants. Despite its prevalence in the natural world, human infections stemming from Roseomonas species remain a rare occurrence. This organism is also known to be resistant to standard antibiotics. We present a case of an 85-year-old woman with Roseomonas gilardii (RG) bacteremia who is a resident at an assisted living facility. Healthcare providers should consider this bacterium in slow-developing gram-negative infections, potentially opting for broad-spectrum antibiotics as an initial treatment.

Type B Lactic Acidosis Secondary to Metastatic Liver Cancer in the Setting of Normal Renal Function: A Case Report and Literature Review.

Lactic acidosis occurs from an overproduction of lactate or decreased metabolism. It is common in critically ill patients, especially those with hematological conditions such as multiple myeloma, leukemia, and lymphoma. There are two types of lactic acidosis, Type A and Type B, with Type B presenting more commonly in hematological conditions that require prompt diagnosis and treatment of the underlying condition. We present a case of a 43-year-old male with Type B lactic acidosis secondary to stage IV colon cancer with metastasis to the liver. Initial laboratory work was significant for lactic acid of 16.52 mmol/L. Arterial blood gas (ABG) showed pH 7.26, pCO2 21 mmHg, pO2 111 mmHg, and HCO3 9 mEq/L, revealing an anion gap and metabolic acidosis with compensatory respiratory alkalosis. Initially, the patient was treated with aggressive fluid management, IV antibiotics, and sodium bicarbonate; however, his lactic acid continued to rise. The recommendation was made for urgent dialysis. Despite treatments, the prognosis is poor.

Cannabis use prevalence among Baby Boomers before and after implementation of recreational retail sales in California.

BACKGROUND: As of 2021, 21 US states and territories allowed recreational cannabis use. Although previous research has identified an overall increase in prevalence of cannabis use after legalization, it has been less clear how this change will affect different parts of the population, including older adults, and specifically Baby Boomers, born 1946-1964, given their historically higher rates of use and a higher prevalence of comorbid conditions that could be either exacerbated or addressed by cannabis use. In this study we assessed whether implementation of recreational retail sales in California was associated with increased prevalence of cannabis use among Baby Boomers. METHODS: We conducted a retrospective study of cannabis use prevalence one year before and after the implementation of recreational retail sales in California using the California Health Interview Survey (CHIS), a statewide public health surveillance dataset. RESULTS: We found that cannabis use prevalence did not change among Baby Boomers but increased among non-Baby Boomers. Most of the factors found to be predictive of cannabis use in past research did not predict cannabis use among Baby Boomers. CONCLUSIONS: Baby Boomers did not change their consumption of cannabis in the first year after opening the retail market, despite previous research suggesting that cannabis consumption increases with access, and most previously identified predictors of use did not identify people who use cannabis in this generation. Further research is needed to determine whether these effects persist over time.

Evaluation of Mass Spectrometric Methods for Screening Polycyclic Aromatic Hydrocarbons in the Particulate Phase of Wildfire/Biomass Smoke.

Polycyclic aromatic hydrocarbons (PAHs) are a class of compounds containing multiple aromatic rings formed during incomplete combustion. Since many of them are known mutagens and carcinogens, PAHs found in the particulate matter (PM) from the wildfire smoke may pose significant health risks to the wildland firefighters. It is pivotal to determine the levels of PAHs in the PM to evaluate the health effects of their inhalation exposure. However, the determination of PAHs using the conventional chromatographic approaches is often time-consuming and laborious. Herein, we describe a novel method for screening nonpolar and polar PAHs in the PM of smoke by direct analysis in real-time mass spectrometry (DART-MS). PM2.5 and PM10 samples were collected on the quartz filters with a sampling system consisting of a cascade impactor with a portable sampling pump. Various indoor and outdoor experiments from biomass burns were conducted to evaluate the PM sampling systems. PAHs were analyzed by DART-MS and gas chromatography-mass spectrometry (GC-MS) methods. The PM samples were collected in California during the wildfire season of fall 2020, and significant levels of multiple nonpolar PAHs and polar PAHs were detected. Overall, the DART-MS method has shown promising ability for high-throughput screening of PAHs in the PM of smoke. Further studies are currently under way to apply this method to study the particulate phase PAH exposures of wildland firefighters during their firefighting activities.

Rosa damascena decreased mortality in adult Drosophila.

The effects of a rose-flower extract, Rosa damascena, on the mortality rate of Drosophila melanogaster was evaluated in this study. R. damascena is a potent antioxidant that has many therapeutic uses in addition to its perfuming effects. Supplementing Drosophila with this rose extract resulted in a statistically significant decrease in mortality rate in male and female flies. Moreover, the observed anti-aging effects were not associated with common confounds of anti-aging properties, such as a decrease in fecundity or metabolic rate.

Blood pressure recovery to social stress in parentally bereaved and non-bereaved youths.

OBJECTIVE: To examine differences in blood pressure response and recovery in a sample of bereaved and non-bereaved youths during an acute stress task conducted 5 years after time of parental death. METHODS: One-hundred and ninety-two (n = 192) bereaved and non-bereaved offspring (ages 11-29) participated in an adaptation of the Trier Social Stress Task (TSST) 5-years after the time of parental death. Blood pressure measurements were collected before, during, and after the laboratory stress protocol. Mixed models for repeated measures were used to analyze the effects of bereavement status and course of psychiatric disorder in the 5-year period after parental death in both offspring and caregivers on blood pressure response; linear regression was used to examine these associations with blood pressure recovery. RESULTS: Although there were no differences across groups in diastolic (DBP) or systolic blood pressure (SBP) response to stress, bereaved offspring demonstrated less SBP recovery to the TSST as compared to non-bereaved offspring. A significant interaction between bereavement status and race, and a marginally significant interaction between bereavement status and sex indicated poor SBP recovery for parentally bereaved racial/ethnic minority offspring as compared to parentally bereaved Caucasian offspring, and for parentally bereaved males compared to parentally bereaved females. CONCLUSIONS: Parentally bereaved youths demonstrate blood pressure response to social stress tasks similar to that of non-bereaved youths, but parentally bereaved ethnic/racial minority youths and parentally bereaved males evidence a less complete recovery from the effects of stress. The health consequences of poor blood pressure recovery in bereaved youths are discussed.

The Burden of Bereavement: Early-Onset Depression and Impairment in Youths Bereaved by Sudden Parental Death in a 7-Year Prospective Study.

OBJECTIVE: The authors sought to determine the long-term impact of sudden parental death on youths and pathways between youth bereavement and impairment. METHODS: Youths (N=216) who lost a parent to suicide, accident, or sudden natural death and nonbereaved youths (N=172) were followed periodically for up to 7 years. The incidence and prevalence of disorder and of functional impairment, as well as pathways to impairment, were assessed using Cox and mixed-effects logistic regression and structural equation modeling. RESULTS: Prior to parental death, bereaved youths had higher rates of psychiatric disorder, parental psychiatric disorder, and maltreatment. Even after adjustment for predeath risk factors, bereavement was associated with an increased incidence of depression, posttraumatic stress disorder, and functional impairment. The peak incidence of depression was in the first 2 years postbereavement, with incident depression occurring mainly in those who lost a parent at age 12 or younger. Youths bereaved by all three causes of death showed higher rates of impairment at all time points. Structural equation modeling found that bereavement had a direct effect on impairment and was also linked to impairment via its effects on early and later depression and through negative life events. Child psychiatric disorder prior to parental loss also contributed to functional impairment. CONCLUSIONS: Parental death increased the incidence of depression in offspring early in the course of bereavement. Early identification and treatment of depression in bereaved youths and augmentation of family resilience may protect against later sequelae of functional impairment.

Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models.

Castration-resistant prostate tumors acquire the independent capacity to generate androgens by upregulating steroidogenic enzymes or using steroid precursors produced by the adrenal glands for continued growth and sustainability. The formation of steroids was measured by liquid chromatography-mass spectrometry in LNCaP and 22Rv1 prostate cancer cells, and in human prostate tissues, following incubation with steroid precursors (22-OH-cholesterol, pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone). Pregnenolone, progesterone, 17-OH-pregnenolone, and 17-OH-progesterone increased C21 steroid (5-pregnan-3,20-dione, 5-pregnan-3,17-diol-20-one, 5-pregnan-3-ol-20-one) formation in the backdoor pathway, and demonstrated a trend of stimulating dihydroepiandrosterone or its precursors in the backdoor pathway in LNCaP and 22Rv1 cells. The precursors differentially affected steroidogenic enzyme messenger RNA (mRNA) expressions in the cell lines. The steroidogenesis following incubation of human prostate tissue with 17-OH-pregnenolone and progesterone produced trends similar to those observed in cell lines. Interestingly, the formation of C21 steroids from classical pathway was not stimulated but backdoor pathway steroids (e.g., 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one) were elevated following incubations with prostate tissues. Overall, C21 steroids were predominantly formed in the classical as well as backdoor pathways, and steroid precursors induced a diversion of steroidogenesis to the backdoor pathway in both cell lines and human prostate tissue, and influenced adaptive steroidogenesis to form C21 steroids.

Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population.

We assessed the association of metformin use with survival in colorectal cancer in a population consists mostly of African-American and Afro-Caribbean patients. We identified 585 colorectal cancer patients, 167 (28.6%) and 418 (71.5%) were as diabetic (DM) and nondiabetic, respectively. The diagnosis of diabetes did not impact cancer survival or extent of disease. Overall, DMs with metformin use (D+M+) have better overall survival than both DMs without metformin use (D+M∼) and nondiabetics (D∼M∼), with a mean survival of 109.9 months compared with 95.7 and 106.1 months, respectively (log-rank p < 0.05). The use of metformin shows significant reduction of risk of mortality compared with nonusers (hazard ratio: 0.34; 95% CI: 0.15-0.81; p = 0.01). Use of insulin and status of diabetes did not have a significant impact on overall cancer survival.

Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.

VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism.

Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro.

Castration resistant prostate cancer (CRPC) is often lethal and inevitably develops after androgen ablation therapy. However, in the majority of cases it remains androgen dependent. CRPC tumors have the ability to synthesize their own androgens from cholesterol by engaging in de novo steroidogenesis. We investigated the potential of 22RV1 prostate cancer cells to convert the supplemented steroid precursors within this pathway under the effects of current clinical steroidogenesis inhibitors such as abiraterone and dutasteride, either alone or in combination. Under steroid starved conditions, enzymes responsible for de novo steroidogenesis were upregulated. Testosterone and dihydrotestosterone (DHT) were formed by using both dehydroepiandrosterone (DHEA) and progesterone as substrates. Formation of testosterone and DHT was higher following incubation with DHEA compared to progesterone. Progesterone decreased the mRNA expression of enzymes responsible for steroidogenesis. Abiraterone treatment decreased testosterone production but increased several precursor steroids in both classical and backdoor pathways in the presence of progesterone. In contrast, the DHT levels were elevated following treatment with abiraterone when progesterone was absent. Dutasteride decreased the formation of testosterone, DHT and precursor steroids in the backdoor pathway but increased steroid precursors in the classical steroidogenesis pathway. The combination of abiraterone and dutasteride decreased testosterone and DHT in the presence of progesterone but increased DHT in the absence of progesterone. Abiraterone inhibited androgen receptor (AR) activation but not to the same extent as MDV3100. However, abiraterone and dutasteride treatment, either alone or in combination, were more effective in decreasing prostate specific antigen secretion into the media than MDV3100. Thus, while interventions with these drugs alone or in combination fail to completely inhibit steroidogenesis in the 22RV1 cells, the combined inhibition of androgen production and blockade of AR can exceed the effect of MDV3100. Further characterization of bypass mechanisms that may develop as a response to these inhibitors is necessary to achieve optimal suppression of testosterone and DHT synthesis as a part of therapeutic regimens for the treatment of CRPC.

Pomegranate extracts impact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo.

Castration-resistant prostate cancer (CRPC) remains largely dependent on androgen receptor (AR). Residual tissue androgens are consistently detected within CRPC tumors and play a critical role in facilitating AR-mediated signaling pathways which lead to disease progression. Testosterone and dihydrotestosterone (DHT) are the major androgens detected in tumors. They are produced through three biosynthesis pathways: Δ(4), Δ(5), and backdoor pathways. Both androgens bind to and stimulate AR activation. The current study investigates the effects of pomegranate extracts (POM) and their ability to inhibit androgen biosynthesis using PCa cell lines (22RV1 and LNCaP) in vitro as well as the PTEN knockout mouse model representing prostate cancer. Steroids were extracted using ethyl acetate or solid phase extraction, and then analyzed by UPLC/MS/MS. The results showed that POM (0-12µg/mL) reduced the production of testosterone, DHT, DHEA, androstenedione, androsterone, and pregnenolone in both cell lines. In addition our in vivo data supports this observation with a reduction in serum steroids determined after 20 weeks of POM treatment (0.17 g/L in drinking water). In accordance with these results, Western blotting of cell lysates and tPSA analysis determined that PSA was significantly decreased by the treatment of POM. Interestingly, AKR1C3 and AR levels were shown to be increased in both cell lines, perhaps as a negative feedback effect in response to steroid inhibition. Overall, these results provide mechanistic evidence to support the rationale for recent clinical reports describing efficacy of POM in CRPC patients.

Nonautonomous regulation of neuronal migration by insulin signaling, DAF-16/FOXO, and PAK-1.

Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration; conversely, when signaling is enhanced, DAF-16 is inactivated, and migration is inhibited. We show that DAF-16 acts nonautonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of insulin/IGF-1-DAF-16 signaling in the nonautonomous control of HSN migration. Because a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are most likely conserved from C. elegans to higher organisms.