Objective: Sex steroid hormones are thought to contribute to the growth, differentiation, and progression of prostate cancer.
We investigated plasma levels of sex steroid hormones and length of the ...androgen receptor gene CAG repeat in relation to incident
prostate cancer diagnosed in the prostate-specific antigen (PSA) era.
Methods: Using a nested case-control design, we included 460 prostate cancer cases diagnosed after providing a blood specimen
in 1993 but before February 1998 among men in the Health Professionals Follow-up Study. Controls were 460 age-matched men
without prostate cancer who had a screening PSA test after the date of providing a blood specimen. We measured plasma concentrations
of total testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, estradiol, and sex hormone binding
globulin (SHBG) and determined the length of the androgen receptor gene CAG repeat. Conditional logistic regression was used
to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer.
Results: Mean concentrations of the sex steroids adjusted for SHBG, and mean CAG repeat length did not differ significantly
between the prostate cancer cases and controls. No significant associations with total prostate cancer were detected for plasma
total testosterone concentration (comparing highest versus lowest quartiles: OR, 0.78; 95% CI, 0.48-1.28; P trend = 0.73) or the other sex hormones after adjusting for SHBG. However, plasma total testosterone concentration was positively
associated with low-grade disease (Gleason sum < 7: OR, 1.91; 95% CI, 0.89-4.07; P trend = 0.02) and inversely associated with high-grade disease (Gleason sum ≥ 7: OR, 0.26; 95% CI, 0.10-0.66; P trend = 0.01). Similar patterns for grade were observed for free testosterone. Short CAG repeat length was not associated with
total prostate cancer (≤ 19 versus ≥ 24: OR, 0.84; 95% CI, 0.57-1.23; P trend = 0.22) or grade of disease. No clear associations with regionally invasive or metastatic (≥ T3b, N1, or M1) were found for
any of the hormones or the CAG repeat, although the number of these cases was small.
Conclusions: The overall lack of association of prostate cancer diagnosed in the PSA era with sex steroid hormones and the
androgen receptor gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute
to the development of early prostate cancer in the PSA era. The influence of plasma total and free testosterone concentrations
on prostate cancer grade merits further evaluation.
The trace amines (TAs), tryptamine, tyramine, and β-phenylethylamine, are synthesized from precursor amino acids via aromatic-L-amino acid decarboxylase (AADC). We explored their role in the ...neuromodulation of neonatal rat spinal cord motor circuits. We first showed that the spinal cord contains the substrates for TA biosynthesis (AADC) and for receptor-mediated actions via trace amine-associated receptors (TAARs) 1 and 4. We next examined the actions of the TAs on motor activity using the in vitro isolated neonatal rat spinal cord. Tyramine and tryptamine most consistently increased motor activity with prominent direct actions on motoneurons. In the presence of N-methyl-D-aspartate, all applied TAs supported expression of a locomotor-like activity (LLA) that was indistinguishable from that ordinarily observed with serotonin, suggesting that the TAs act on common central pattern generating neurons. The TAs also generated distinctive complex rhythms characterized by episodic bouts of LLA. TA actions on locomotor circuits did not require interaction with descending monoaminergic projections since evoked LLA was maintained following block of all Na(+)-dependent monoamine transporters or the vesicular monoamine transporter. Instead, TA (tryptamine and tyramine) actions depended on intracellular uptake via pentamidine-sensitive Na(+)-independent membrane transporters. Requirement for intracellular transport is consistent with the TAs having much slower LLA onset than serotonin and for activation of intracellular TAARs. To test for endogenous actions following biosynthesis, we increased intracellular amino acid levels with cycloheximide. LLA emerged and included distinctive TA-like episodic bouts. In summary, we provided anatomical and functional evidence of the TAs as an intrinsic spinal monoaminergic modulatory system capable of promoting recruitment of locomotor circuits independent of the descending monoamines. These actions support their known sympathomimetic function.
The purpose of this study was to evaluate the ability of two concurrent randomized controlled interventions based on social cognitive theory to increase walking. A second purpose was to compare the ...efficacy of the intervention between two distinct groups: dog owners and non-dog owners. Adult dog owners (n = 40) and non-dog owners (n = 65) were randomized into control or intervention groups. Intervention groups received bi-weekly emails for first 4 weeks and then weekly email for the next 8 weeks targeting self-efficacy, social support, goal setting, and benefits/barriers to walking. Dog owner messages focused on dog walking while non-dog owners received general walking messages. Control groups received a 1-time email reviewing current physical activity guidelines. At 6 months, both intervention groups reported greater increases in walking and maintained these increases at 12 months. The greatest increases were seen in the dog owner intervention group. In conclusion, dog owners accumulated more walking, which may be attributed to the dog–owner relationship.
Display omitted
Effective communication is essential in mental healthcare, where language often represents the primary means of treatment. In intercultural counseling sessions, communicating with ...Limited English Proficient (LEP) clients calls for skillful collaboration with language interpreters. However, best practices in medical interpretation may not be equally effective in mental health settings. This study examined the factors promoting and hindering successful communication during interpreter-mediated counseling sessions with LEP Bhutanese and Iraqi refugee men. Researchers observed eight substance use counseling sessions in real-time to make note of communication patterns and key communication breakdowns. Then, researchers conducted video-elicitation interviews with the client, clinician and interpreter immediately after each session to dissect communication events from each party’s perspective. Session videos and interview transcripts underwent qualitative analysis to identify factors that predict or prevent communication breakdowns. Findings indicate important differences between mental health interpretation and interpretation in other healthcare settings. Common practices such as simultaneous interpreting and first person interpreting were found to function differently in a mental health setting. Some therapeutic maneuvers, such as irreverence and humor, were difficult to employ cross-culturally. The adaptation and negotiation of interpersonal relationships between clinician, client and interpreter were central to the success of communication. Trust and flexibility were key to the functioning of the triadic relationship. Clinicians, clients and interpreters were found to adopt different roles and responsibilities throughout the session in an ongoing manner. Implications for the training of interpreters and clinicians are discussed.
Progressive heart failure leading to transplantation or death is common in pediatric dilated cardiomyopathy (DCM), and treatment options are limited. Select children with DCM have improved after ...cardiac resynchronization therapy (CRT), but predicting response is challenging. Nonetheless, considering the frequency of death or transplantation in this population, identifying any candidate would be valuable. Classic-pattern dyssynchrony (CPD) identifies mechanical dyssynchrony patterns consistent with underlying electrical activation delays and strongly predicts CRT response in adult DCM but has not been evaluated in pediatric DCM. The aim of this study was to test the hypothesis that CPD is present in a subgroup of patients with pediatric DCM and is associated with activation delays.
Fifty-nine subjects with pediatric DCM (left ventricular end-diastolic diameter Z score > 2 and left ventricular ejection fraction < 40%) who underwent echocardiography with a functional protocol with apical images optimized for two-dimensional speckle-tracking strain analysis (EchoPAC) were retrospectively analyzed for CPD. Electrocardiograms were evaluated for activation delays (prolonged QRS duration and strict criteria for left bundle branch block LBBB). Forty control subjects with no cardiac disease and good imaging widows were also analyzed.
The mean age was 5.4 years (range, 1 day to 20 years); idiopathic DCM was most common (57%). Severe cardiomyopathy was present in 75% (end-diastolic diameter Z score > 4.6 and left ventricular ejection fraction < 32%). CPD was identified in seven subjects (12%), and prolonged QRS durations were present in 13 (22%), but only two subjects met strict criteria for LBBB. Six of seven subjects in the CPD group had prolonged QRS durations, and two of seven had LBBB. No control subjects had CPD. The CPD analysis was highly feasible and reproducible.
In this severely affected cohort, the small CPD subgroup is potentially important because their progressive disease may respond to CRT. CPD is associated with activation delays, although not necessarily strict LBBB. This has important potential implications for prospective evaluation of CRT in this disease.
Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we ...performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM).
Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided.
Strong signals were detected for CDKN2A (Pmin = 6.16 × 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 × 10-6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75 × 10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37 × 10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels.
The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.
Abstract Background Quantifying the risk of advanced proximal colorectal neoplasia might allow tailoring of colorectal cancer screening, with colonoscopy for those at high risk and less invasive ...screening for very low-risk persons. Methods We analyzed findings from 10,124 consecutive adults aged ≥ 50 years who underwent screening colonoscopy to the cecum. We quantified the risk of advanced neoplasia (tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or adenocarcinoma) both proximally (cecum to splenic flexure) and distally (descending colon to anus). The prevalence of advanced proximal neoplasia was quantified by age, gender, and distal findings. Results The mean (standard deviation) age was 57.5 (6.0) years; 44% were women; 7835 (77%) had no neoplasia, and 1856 (18%) had 1 or more nonadvanced adenomas. Overall, 433 subjects (4.3%) had advanced neoplasia (267 distally, 196 proximally, 30 both), 33 (0.33%) of which were adenocarcinoma (18 distal, 15 proximal). The risk of advanced proximal neoplasia increased with age decade (1.13%, 2.00%, and 5.26%, respectively; P = .001) and was higher in men (relative risk RR, 1.91; confidence interval CI, 1.32-2.77). In women aged less than 70 years, the risk was 1.1% overall (vs 2.2% in men; RR, 1.98; CI, 1.42-2.76) and 0.86% in those with no distal neoplasia (vs 1.54% in men; RR, 1.81; CI, 1.20-2.74). Conclusions Risk of advanced proximal neoplasia is a function of age and gender. Women aged less than 60 to 70 years have a very low risk, particularly those with no distal adenoma. Sigmoidoscopy with or without occult blood testing may be sufficient and even preferable for screening these subgroups.
The
proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the
20S proteasome (
20S) β5 active site and ...that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of
compared with a human cell line and exhibit high potency against field isolates of
and
They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against
infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to
20S than to human constitutive 20S (
20Sc). Comparison of the cryo-electron microscopy (EM) structures of
20S and
20Sc in complex with MPI-5 and
20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in
, underpinning the design of potent and selective antimalarial proteasome inhibitors.
Background/Objectives
Anthracyclines are used in induction therapy of pediatric acute lymphoblastic leukemia (ALL) and are known to generate oxidative stress; whether this translates into enhanced ...antileukemic activity or hemolytic effects in patients with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is unknown.
Design/Methods
Among 726 pediatric patients with newly diagnosed ALL treated at St. Jude Children's Research Hospital, 22 had deficient G6PD activity. We compared the prevalence of positive minimal residual disease (MRD) ≥1% at Day 15/Day 19 of induction or ≥0.01% at Day 42/Day 46 (end of induction) and the number of red blood cell (RBC) transfusions after daunorubicin in induction between patients with or without G6PD deficiency, adjusting for ALL risk group, treatment protocol, age, and gender.
Results
There was no difference in Day 15/19 (P = 1) or end of induction MRD (P = 0.76) nor in the number of RBC transfusions (P = 0.73); the lack of association with MRD was confirmed in a dataset of 1192 newly diagnosed male patients enrolled in a Children's Oncology Group trial (P = 0.78).
Conclusion
We found no evidence that G6PD deficiency affects daunorubicin activity during induction treatment for ALL.
PDF
