The recent discovery of the existence of a human genitourinary microbiome has led to the investigation of its role in mediating the pathogenesis of genitourinary malignancies, including bladder, ...kidney, and prostate cancers. Furthermore, although it is largely recognized that members of the gastrointestinal microbiota are actively involved in drug metabolism, new studies demonstrate additional roles and the potential necessity of the gastrointestinal microbiota in dictating cancer treatment response.
To summarize the current evidence of a mechanistic role for the genitourinary and gastrointestinal microbiome in genitourinary cancer initiation and treatment response.
We conducted a literature search up to October 2018. Search terms included microbiome, microbiota, urinary microbiome, bladder cancer, urothelial carcinoma, renal cell carcinoma, kidney cancer, testicular cancer, and prostate cancer.
There is preliminary evidence to implicate the members of the genitourinary microbiota as causative factors or cofactors in genitourinary malignancy. Likewise, the current evidence for gastrointestinal microbes in dictating cancer treatment response is mainly correlative; however, we provide examples where therapeutic agents used for the treatment of genitourinary cancers are affected by the human-associated microbiota, or vice versa. Clinical trials, such as fecal microbiota transplant to increase the efficacy of immunotherapy, are currently underway.
The role of the microbiome in genitourinary cancer is an emerging field that merits further studies. Translating microbiome research into clinical action will require incorporation of microbiome surveillance into ongoing and future clinical trials as well as expansion of studies to include metagenomic sequencing and metabolomics.
This review covers recent evidence that microbial populations that reside in the genitourinary tract—and were previously not known to exist—may influence the development of genitourinary malignancies including bladder, kidney, and prostate cancers. Furthermore, microbial populations that exist at sites outside of the genitourinary tract, such as those that reside in our gut, may influence cancer development and/or treatment response.
There is evidence that the urinary microbiome influences the development of genitourinary malignancies, including bladder, kidney, and prostate cancers. Furthermore, the gastrointestinal microbiota may also influence genitourinary cancer development and/or treatment response via effects on drug metabolism and systemic immunity.
Metacommunity theory suggests that dispersal is a key driver of diversity and ecosystem functioning in changing environments. The capacity of dispersal to mitigate effects of environmental change ...might vary among trophic groups, potentially resulting in changes in trophic interactions and food web structure. In a mesocosm experiment, we compared the compositional response of bacteria, phyto‐ and zooplankton to a factorial manipulation of acidification and dispersal. We found that the buffering capacity of dispersal varied among trophic groups: dispersal alleviated the negative effect of acidification on phytoplankton diversity mid‐experiment, but had no effect on the diversity of zooplankton and bacteria. Likewise, trophic groups differed in whether dispersal facilitated compositional change. Dispersal accelerated changes in phytoplankton composition under acidification, possibly mediated by changes in trophic interactions, but had no effect on the composition of zooplankton and bacteria. Overall, our results suggest that the potential for spatial insurance can vary among trophic groups.
We examined whether the survival advantage of androgen-deprivation therapy with radiotherapy (ADT plus RT) relative to ADT alone for men with locally advanced prostate cancer reported in two ...randomized trials holds in real-world clinical practice and extended the evidence to patients poorly represented in the trials.
We conducted nonrandomized effectiveness studies of ADT plus RT versus ADT in three groups of patients diagnosed between 1995 and 2007 and observed through 2009 in the SEER-Medicare data set: (1) the randomized clinical trial (RCT) cohort, which included men age 65 to 75 years and was most consistent with participants in the randomized trials; (2) the elderly cohort, which included men age > 75 years with locally advanced prostate cancer; and (3) the screen-detected cohort, which included men age ≥ 65 years with screen-detected high-risk prostate cancer. We evaluated cause-specific and all-cause mortality using propensity score, instrumental variable (IV), and sensitivity analyses.
In the RCT cohort, ADT plus RT was associated with reduced cause-specific and all-cause mortality relative to ADT alone (cause-specific propensity score-adjusted hazard ratio HR, 0.43; 95% CI, 0.37 to 0.49; all-cause propensity score-adjusted HR, 0.63; 95% CI, 0.59 to 0.67). Effectiveness estimates for the RCT cohort were not significantly different from those from randomized trials (P > .1). In the elderly and screen-detected cohorts, ADT plus RT was also associated with reduced cause-specific and all-cause mortality. IV analyses produced estimates similar to those from propensity score-adjusted methods.
Older men with locally advanced or screen-detected high-risk prostate cancer who receive ADT alone risk decrements in cause-specific and overall survival.
Background
The use of biomarkers in behavioral HIV research can help to address limitations of self‐reported data. The COVID‐19 pandemic forced many researchers to transition from standard in‐person ...data collection to remote data collection. We present data on the feasibility of remote self‐collection of dried blood spots (DBS), hair, and nails for the objective assessment of alcohol use, antiretroviral therapy adherence, and stress in a sample of people with HIV (PWH) who are hazardous drinkers.
Methods
Standardized operating procedures for remote self‐collection of DBS, hair, and nails were developed for an ongoing pilot study of a transdiagnostic alcohol intervention for PWH. Prior to each study appointment, participants were mailed a kit containing materials for self‐collection, instructions, a video link demonstrating the collection process, and a prepaid envelope for returning samples.
Results
A total of 133 remote study visits were completed. For DBS and nail collection at baseline, 87.5% and 83.3% of samples, respectively, were received by the research laboratory, of which 100% of samples were processed. Although hair samples were intended to be analyzed, most of the samples (77.7%) were insufficient or the scalp end of the hair was not marked. We, therefore, decided that hair collection was not feasible in the framework of this study.
Conclusion
An increase in remote self‐collection of biospecimens may significantly advance the field of HIV‐related research, permitting the collection of specimens without resource‐intensive laboratory personnel and facilities. Further research is needed on the factors that impeded participants' ability to complete remote biospecimen collection.
We present data on the feasibility of remote self‐collection of dried blood spots (DBS), hair, and nails for the objective assessment of alcohol use, antiretroviral therapy adherence, and stress in a sample of people with HIV (PWH) who are hazardous drinkers. Our findings for the feasibility of remote biospecimen self‐collection were generally encouraging. An increase in remote self‐collection of biospecimens may significantly advance the field of HIV‐related research, permitting the collection of specimens without resource‐intensive lab personnel and facilities.
We tested within-person effects of alcohol on sexual behavior among young adults in a longitudinal burst design (N = 213, 6,487 days) using data collected from a previously published parent study. We ...differentiated effects of alcohol on likelihood of sexual activity versus use of protection against sexually transmitted diseases (STDs) or pregnancy on intercourse occasions by testing a multilevel multinomial model with 4 outcomes (no sex, oral sex without intercourse, protected intercourse, and unprotected intercourse). At the within-person level, effects of alcohol were hypothesized to be conditional upon level of intoxication (i.e., curvilinear effect). We also tested effects of four between-person moderators: gender, typical length of relationship with sexual partners, and two facets of self-control (effortful control and reactivity). Consistent with our hypothesis, low-level intoxication was associated with increased likelihood of engaging in oral sex or protected intercourse (relative to no sex) but was not related to likelihood of unprotected intercourse. The effect of intoxication on unprotected versus protected intercourse was an accelerating curve, significantly increasing likelihood of unprotected intercourse at high levels of intoxication. Between-person factors moderated associations between intoxication and sexual behavior. Effects of intoxication on both protected and unprotected intercourse were diminished for individuals with more familiar sexual partners. Effortful control exhibited a protective effect, reducing the effects of intoxication on likelihood of unprotected intercourse. Hypothesized effects of reactivity were not supported. Intoxication was a stronger predictor of oral sex and protected intercourse (but not unprotected intercourse) for women relative to men. Results highlight the inherent complexities of the alcohol-sexual behavior nexus.
Public Health Significance
Nonlinear associations between alcohol and sexual outcomes may account for discrepant findings in the literature. Effortful control acts as a buffer, reducing associations between intoxication and unprotected intercourse.
The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of ...one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4
/NFATc1
).
Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4
/NFATc1
cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models.
Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4
/NFATc1
subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index.
Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.
Alcohol use among people living with HIV (PWH) has been increasingly recognized as an important component of HIV care
.
Transdiagnostic treatments, such as Acceptance and Commitment Therapy (ACT), ...that target core processes common to multiple mental health and substance-related problems, may be ideal in HIV treatment settings where psychological and behavioral health comorbidities are high. In advance of a randomized clinical trial (RCT), the overall objective of this study was to systematically adapt an ACT-based intervention originally developed for smoking cessation, into an ACT intervention for PWH who drink at hazardous levels. Consistent with the ADAPT-ITT model, the adaptation progressed systematically in several phases, which included structured team meetings, three focus group discussions with PWH (
N
= 13), and in-depth interviews with HIV providers (
N
= 10), and development of standardized operating procedures for interventionist training, supervision, and eventual RCT implementation. The procedures described here offer a template for transparent reporting on early phase behavioral RCTs.
Magnetized Liner Inertial Fusion (MagLIF) is a magneto-inertial fusion concept, which is presently being studied on the Z Pulsed Power Facility. The concept utilizes an axial magnetic field and laser ...heating to produce fusion-relevant conditions at stagnation despite a peak magnetically driven implosion velocity of less than 100 km/s. Initial mymargin experiments demonstrated the viability of the concept but left open questions about the amount of laser energy coupled to the fuel and the role that mix played in the stagnation conditions. In this paper, simple methodologies for estimating the laser energy coupled to the fuel and determining the stagnation pressure and mix are presented. These tools enabled comparisons across many experiments to establish performance trends, as well as allow comparisons with 2-D magnetohydrodynamics simulations. The initial experiments were affected by low laser energy coupling (0.2-0.6 kJ), which resulted in reduced neutron yields (1-<inline-formula> <tex-math notation="LaTeX">2\times 10^{12} </tex-math></inline-formula>). In addition, all early experiments utilized mid-Z (aluminum) fuel-facing components. Mixing from these components had a significant impact on stagnation and increased with laser energy. Lower neutron yields (1-<inline-formula> <tex-math notation="LaTeX">3\times 10^{11} </tex-math></inline-formula>) were measured with higher laser coupling (0.8-1.2 kJ), which significantly deviated from the predicted scaling. When all fuel-facing components were made from a low-Z material (beryllium), neutron production increased (<inline-formula> <tex-math notation="LaTeX">3.2\times 10^{12} </tex-math></inline-formula>) and scaled as expected with laser energy; experimental yields were approximately 40% of simulated yields. In addition, roughly I 4 yield scaling was observed in experiments, where the load current was varied from 16-18 MA. These results represent the first step in experimental demonstration of stagnation performance scaling with input parameters in MagLIF.
Background:
Human milk contains both arachidonic acid (ARA) and docosahexaenoic acid (DHA). Supplementation of infant formula with ARA and DHA results in fatty acid (FA) profiles, neurodevelopmental ...outcomes, and immune responses in formula-fed infants that are more like those observed in breastfed infants. Consequently, ARA and DHA have been historically added together to infant formula. This study investigated the impact of ARA or DHA supplementation alone or in combination on tissue FA incorporation, immune responses, and neurodevelopment in the young pig.
Methods:
Male pigs (
N
= 48 total) received one of four dietary treatments from postnatal day (PND) 2–30. Treatments targeted the following ARA/DHA levels (% of total FA): CON (0.00/0.00), ARA (0.80/0.00), DHA (0.00/0.80), and ARA+DHA (0.80/0.80). Plasma, red blood cells (RBC), and prefrontal cortex (PFC) were collected for FA analysis. Blood was collected for T cell immunophenotyping and to quantify a panel of immune outcomes. Myelin thickness in the corpus callosum was measured by transmission electron microscopy and pig movement was measured by actigraphy.
Results:
There were no differences in formula intake or growth between dietary groups. DHA supplementation increased brain DHA, but decreased ARA, compared with all other groups. ARA supplementation increased brain ARA compared with all other groups but did not affect brain DHA. Combined supplementation increased brain DHA levels but did not affect brain ARA levels compared with the control. Pigs fed ARA or ARA+DHA exhibited more activity than those fed CON or DHA. Diet-dependent differences in activity suggested pigs fed ARA had the lowest percent time asleep, while those fed DHA had the highest. No differences were observed for immune or myelination outcomes.
Conclusion:
Supplementation with ARA and DHA did not differentially affect immune responses, but ARA levels in RBC and PFC were reduced when DHA was provided without ARA. Supplementation of either ARA or DHA alone induced differences in time spent asleep, and ARA inclusion increased general activity. Therefore, the current data support the combined supplementation with both ARA and DHA in infant formula and raise questions regarding the safety and nutritional suitability of ARA or DHA supplementation individually.
Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency ...virus (HIV)–infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≤3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log 10 reduction between baseline and week 24. Results. The targeted pharmacokinetic parameters (AUC 0-12h and C 12h ) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related DR psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/μL (4.6%). Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. Clinical Trials Registration. NCT00485264.
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