Comparison of peritoneal interposition flaps and sealants for prevention of lymphocele after robotic radical prostatectomy and pelvic lymph node dissection: a systematic review, meta-analysis, Bayesian network meta-analysis, and meta-regression.

Lymphocele is one of the most common complications after radical prostatectomy. Multiple authors have proposed the use of vessel sealants or peritoneal interposition techniques as preventive interventions. This study aimed to aggregate and analyze the available literature on different interventions which seek to prevent lymphocele through a Bayesian Network. A systematic review was performed to identify prospective studies evaluating strategies for lymphocele prevention after robot assisted laparoscopic prostatectomy + pelvic lymph node dissection. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as odds ratios (OR) with 95% credible intervals (CrI). Meta-regression was used to determine coefficient of change and adjust for pelvic lymph node dissection extent. Ten studies providing data from 2211 patients were included. 1097 patients received an intervention and 1114 patients served as controls. Interposition with fenestration had the lowest risk of developing a lymphocele (OR 0.14 [0.04, 0.50], p = 0.003). All interventions, except sealants or patches, had significant decreased odds of lymphocele rates. Meta-analysis of all the included studies showed a decreased risk of developing a lymphocele (OR 0.42 [0.33, 0.53], p < 0.00001) for the intervention group. Perivesical fixation and interposition with fenestration appear to be effective interventions for reducing the overall incidence of lymphocele.

A west African ancestry-associated SNP on 8q24 predicts a positive biopsy in African American men with suspected prostate cancer following PSA screening.

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, we determined whether this SNP can predict biopsy positivity and detection of clinically significant disease (Gleason score [GS] ≥ 7) in a cohort of AA men with suspected PCa. METHODS: SNP rs7824364 was genotyped in 199 AA men with elevated total prostate-specific antigen (PSA) (>2.5 ng/mL) or abnormal digital rectal exam (DRE) and the associations of different genotypes with biopsy positivity and clinically significant disease were analyzed. RESULTS: The variant allele carriers were significantly over-represented in the biopsy-positive group compared to the biopsy-negative group (44% vs. 25.7%, p = 0.011). In the multivariate logistic regression analyses, variant allele carriers were at a more than a twofold increased risk of a positive biopsy (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.06-4.32). Moreover, the variant allele was a predictor (OR = 2.26, 95% CI = 1.06-4.84) of a positive biopsy in the subgroup of patients with PSA < 10 ng/mL and normal DRE. The variant allele carriers were also more prevalent in cases with GS ≥ 7 compared to cases with GS < 7 and benign biopsy. CONCLUSIONS: This study demonstrated that the west African ancestry-specific SNP rs7824364 on 8q24 independently predicted a positive prostate biopsy in AA men who were candidates for prostate biopsy subsequent to PCa screening.

Oncologic Outcome of the Extent of Pelvic Lymph Node Dissection During Radical Prostatectomy: A Systematic Review, Meta-analysis, and Network Analysis.

CONTEXT: Some authors propose extended pelvic lymph node dissection (ePLND) to enhance diagnostic and therapeutic outcomes in patients with localized prostate cancer. However, recent evidence found no difference in biochemical recurrence (BCR). OBJECTIVE: To stratify and analyze available evidence on ePLND and its impact on BCR in patients with localized prostate cancer. EVIDENCE ACQUISITION: We systematically reviewed the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to identify studies up to November 2023. We identified original articles that presented statistical comparisons through Cox regressions reported as hazard ratio (HR) or survival curve data reported as Kaplan-Meier curve differences in BCR in patients undergoing radical prostatectomy and stratified by the extent of lymph node dissection for localized prostate cancer. EVIDENCE SYNTHESIS: We identified 12 studies, with two being randomized controlled trials (RCTs). The RCTs showed no benefit of ePLND with an HR of 1.03 ([0.92, 1.14], p = 0.61). A combined analysis with the ten retrospective studies revealed a notable reduction in BCR with an HR of 0.68 ([0.52, 0.88], p = 0.003). A subgroup analysis based on the extent of dissection demonstrated that studies focusing on the more conservative extended template of dissection did not show significant BCR benefit (HR 0.97 [0.72, 1.32], p = 0.86). In contrast, dissections that expanded the anatomical extent showed decreased BCR (HR 0.56 [0.41, 0.75], p < 0.0001). A Bayesian network analysis highlights significant differences in BCR reduction between different dissection approaches, indicating the potential benefits of specific dissection templates. CONCLUSIONS: Available literature on the extent of pelvic lymph node dissection needs to be improved in quality and varying definitions of the ePLND template. Dissection of the common iliac nodes may be beneficial. PATIENT SUMMARY: There is a potential benefit in removing more lymph nodes during radical prostatectomy. However, more research is needed to determine whether this strategy benefits certain patient groups.

Inescapable foot shock induces a PTSD-like phenotype and negatively impacts adult murine bone.

Post-traumatic stress disorder (PTSD) is associated with osteopenia, osteoporosis and increased fracture risk in the clinical population. Yet, the development of preclinical models to study PTSD-induced bone loss remains limited. In this study, we present a previously unreported model of PTSD in adult female C57BL/6 mice, by employing inescapable foot shock and social isolation, that demonstrates high face and construct validity. A subset of mice exposed to this paradigm (i.e. PTSD mice) display long-term alterations in behavioral and inflammatory indices. Using three-dimensional morphometric calculations, cyclic reference point indentation (cRPI) testing and histological analyses, we find that PTSD mice exhibit loss of trabecular bone, altered bone material quality, and aberrant changes in bone tissue architecture and cellular activity. This adult murine model of PTSD exhibits clinically relevant changes in bone physiology and provides a valuable tool for investigating the cellular and molecular mechanisms underlying PTSD-induced bone loss.

Role of adenosine deaminase in prostate cancer progression.

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

Vascular smooth muscle cell mechanotransduction through serum and glucocorticoid inducible kinase-1 promotes interleukin-6 production and macrophage accumulation in murine hypertension.

Objective: The objective of this investigation was to demonstrate that in vivo induction of hypertension (HTN) and in vitro cyclic stretch of aortic vascular smooth muscle cells (VSMCs) can cause serum and glucocorticoid-inducible kinase (SGK-1)-dependent production of cytokines to promote macrophage accumulation that may promote vascular pathology. Methods: HTN was induced in C57Bl/6 mice with angiotensin II infusion (1.46 mg/kg/day × 21 days) with or without systemic infusion of EMD638683 (2.5 mg/kg/day × 21 days), a selective SGK-1 inhibitor. Systolic blood pressure was recorded. Abdominal aortas were harvested to quantify SGK-1 activity (pSGK-1/SGK-1) by immunoblot. Flow cytometry quantified the abundance of CD11b+/F480+ cells (macrophages). Plasma interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was assessed by enzyme-linked immunosorbent assay. Aortic VSMCs from wild-type mice were subjected to 12% biaxial cyclic stretch (Stretch) for 3 or 12 hours with or without EMD638683 (10 µM) and with or without SGK-1 small interfering RNA with subsequent quantitative polymerase chain reaction for IL-6 and MCP-1 expression. IL-6 and MCP-1 in culture media were analyzed by enzyme-linked immunosorbent assay. Aortic VSMCs from SGK-1flox+/+ mice were transfected with Cre-Adenovirus to knockdown SGK-1 (SGK-1KD VSMCs) and underwent parallel tension experimentation. Computational modeling was used to simulate VSMC signaling. Statistical analysis included analysis of variance with significance at a P value of <.05. Results: SGK-1 activity, abundance of CD11b+/F4-80+ cells, and plasma IL-6 were increased in the abdominal aorta of mice with HTN and significantly reduced by treatment with EMD638683. This outcome mirrored the increased abundance of IL-6 in media from Stretch C57Bl/6 VSMCs and attenuation of the effect with EMD638683 or SGK-1 small interfering RNA. C57Bl/6 VSMCs also responded to Stretch with increased MCP-1 expression and secretion into the culture media. Further supporting the integral role of mechanical signaling through SGK-1, target gene expression and cytokine secretion was unchanged in SGK-1KD VSMCs with Stretch, and computer modeling confirmed SGK-1 as an intersecting node of signaling owing to mechanical strain and angiotensin II. Conclusions: Mechanical activation of SGK-1 in aortic VSMCs can promote inflammatory signaling and increased macrophage abundance, therefore this kinase warrants further exploration as a pharmacotherapeutic target to abrogate hypertensive vascular pathology.

Cyanobacteria and Algal-Based Biological Life Support System (BLSS) and Planetary Surface Atmospheric Revitalizing Bioreactor Brief Concept Review.

Exploring austere environments required a reimagining of resource acquisition and utilization. Cyanobacterial in situ resources utilization (ISRU) and biological life support system (BLSS) bioreactors have been proposed to allow crewed space missions to extend beyond the temporal boundaries that current vehicle mass capacities allow. Many cyanobacteria and other microscopic organisms evolved during a period of Earth's history that was marked by very harsh conditions, requiring robust biochemical systems to ensure survival. Some species work wonderfully in a bioweathering capacity (siderophilic), and others are widely used for their nutritional power (non-siderophilic). Playing to each of their strengths and having them grow and feed off of each other is the basis for the proposed idea for a series of three bioreactors, starting from regolith processing and proceeding to nutritional products, gaseous liberation, and biofuel production. In this paper, we discuss what that three reactor system will look like, with the main emphasis on the nutritional stage.

Optimizing human performance in extreme environments through precision medicine: From spaceflight to high-performance operations on Earth.

Humans operating in extreme environments often conduct their operations at the edges of the limits of human performance. Sometimes, they are required to push these limits to previously unattained levels. As a result, their margins for error in execution are much smaller than that found in the general public. These same small margins for error that impact execution may also impact risk, safety, health, and even survival. Thus, humans operating in extreme environments have a need for greater refinement in their preparation, training, fitness, and medical care. Precision medicine (PM) is uniquely suited to address the needs of those engaged in these extreme operations because of its depth of molecular analysis, derived precision countermeasures, and ability to match each individual (and his or her specific molecular phenotype) with any given operating context (environment). Herein, we present an overview of a systems approach to PM in extreme environments, which affords clinicians one method to contextualize the inputs, processes, and outputs that can form the basis of a formal practice. For the sake of brevity, this overview is focused on molecular dynamics, while providing only a brief introduction to the also important physiologic and behavioral phenotypes in PM. Moreover, rather than a full review, it highlights important concepts, while using only selected citations to illustrate those concepts. It further explores, by demonstration, the basic principles of using functionally characterized molecular networks to guide the practical application of PM in extreme environments. At its core, PM in extreme environments is about attention to incremental gains and losses in molecular network efficiency that can scale to produce notable changes in health and performance. The aim of this overview is to provide a conceptual overview of one approach to PM in extreme environments, coupled with a selected suite of practical considerations for molecular profiling and countermeasures.

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than EA PCa. Increased uracil and pyrimidine lesions occurred in AA tumors, while EA tumors had more oxidative lesions. AA PCa have higher levels of UMP and folate cycle metabolites than their EA counterparts. AA PCa showed higher levels of UNG, the uracil-specific glycosylase, than EA, despite uracil lesions being retained within the genome. AA patients also had lower levels of the base excision repair protein XRCC1. These results indicate dysfunction in the base excision repair pathway in AA tumors. Further, these findings reveal how metabolic rewiring in AA PCa drives biological disparities and identifies a targetable axis for cancer therapeutics.

Illness representations and psychological outcomes in chronic lymphocytic leukaemia.

OBJECTIVES: Chronic lymphocytic leukaemia (CLL) is a lifelong cancer with subtle symptoms. Treatment is not curative and often involves repeated relapses and retreatments. Illness perceptions - cognitive and emotional representations of illness stimuli - were studied in CLL patients to: 1) identify illness perception 'profiles' prior to treatment; and 2) test whether profile membership predicts psychological responses 12 months later as treatment continued. DESIGN: CLL patients (N = 259), randomized to one of four cancer treatment trials testing targeted therapy, were assessed before starting treatment and at 12 months. METHODS: The Brief Illness Perception Questionnaire (BIPQ) assessed perceived consequences, timeline, personal/treatment control, identity, comprehension, concern, and emotions toward CLL. Psychological outcomes were depressive symptoms (PHQ-9/BDI-II), negative mood (POMS), and cancer stress (IES-R). Latent profile analysis (LPA) determined number of profiles and differential BIPQ items for each profile. Multilevel models tested profiles as predictors of 12-month psychological outcomes. RESULTS: LPA selected the three-profile model, with profiles revealing Low (n = 150; 57.9%), Moderate (n = 21; 8.1%), and High-impact (n = 88; 34.0%) illness representations. Profiles were defined by differences in consequences, identity, concern, and emotions. Profile membership predicted all psychological outcomes (ps<.038). Low-impact profile patients endorsed minimal psychological symptoms; High-impact profile patients reported substantial symptoms. CONCLUSIONS: Results of the first CLL illness representation study provide directions for future clinical efforts. By identifying differences among patients' perceptions of CLL consequences, symptom burden, concerns, and emotional responses, an at-risk patient group might receive tailored psychological treatment. Treatments may address negative perceptions, to reduce psychological risk associated with chronic cancer.

Mechanical activation of the angiotensin II type 1 receptor contributes to abdominal aortic aneurysm formation.

OBJECTIVE: The angiotensin II type 1 receptor (AT1R) can be activated under conditions of mechanical stretch in some cellular systems. Whether this activity influences signaling within the abdominal aorta to promote to abdominal aortic aneurysm (AAA) development remains unknown. We evaluated the hypothesis that mechanical AT1R activation can occur under conditions of hypertension (HTN) and contribute to AAA formation. METHODS: BPH/2 mice, which demonstrate spontaneous neurogenic, low-renin HTN, and normotensive BPN/3 mice underwent AAA induction via the calcium chloride model, with or without an osmotic minipump delivering 30 mg/kg/d of the AT1R blocker Losartan. Systolic blood pressure (SBP) was measured at baseline and weekly via a tail cuff. The aortic diameter (AoD) was measured at baseline and terminal surgery at 21 days by digital microscopy. Aortic tissue was harvested for immunoblotting (phosphorylated extracellular signal-regulated kinase-1 and -2 [pERK1/2] to ERK1/2 ratio) and expressed as the fold-change from the BPN/3 control mice. Aortic vascular smooth muscle cells (VSMCs) underwent stretch with or without Losartan (1 µM) treatment to assess the mechanical stimulation of ERK1/2 activity. Statistical analysis of the blood pressure, AoD, and VSMC ERK1/2 activity was performed using analysis of variance. However, the data distribution was determined to be log-normal (Shapiro-Wilk test) for ERK1/2 activity. Therefore, it was logarithmically transformed before analysis of variance. RESULTS: At baseline, the SBP was elevated in the BPH/2 mice relative to the BPN/3 mice (P < .05). Losartan treatment significantly reduced the SBP in both mouse strains (P < .05). AAA induction did not affect the SBP. At 21 days after induction, the percentage of increase in the AoD from baseline was significantly greater in the BPH/2 mice than in the BPN/3 mice (101.28% ± 4.19% vs 75.59% ± 1.67% above baseline; P < .05). Losartan treatment significantly attenuated AAA growth in both BPH/2 and BPN/3 mice (33.88% ± 2.97% and 43.96% ± 3.05% above baseline, respectively; P < .05). ERK1/2 activity was increased approximately fivefold in the BPH/2 control mice relative to the BPN/3 control mice (P < .05). In the BPH/2 and BPN/3 mice with AAA, ERK1/2 activity was significantly increased relative to the respective baseline control (P < .05) and effectively reduced by concomitant Losartan therapy (P < .05). Biaxial stretch of the VSMCs in the absence of angiotensin II demonstrated increased ERK1/2 activation (P < .05 vs static control), which was significantly inhibited by Losartan. CONCLUSIONS: In BPH/2 mice with spontaneous neurogenic, low-renin HTN, AAA growth was amplified compared with the normotensive control and was effectively attenuated using Losartan. ERK1/2 activity was significantly elevated in the BPH/2 mice and after AAA induction in the normotensive and hypertensive mice but was attenuated by Losartan treatment. These data suggest that AT1R activation contributes to AAA development. Therefore, further investigation into this signaling pathway could establish targets for pharmacotherapeutic engineering to slow AAA growth. (JVS-Vascular Science 2021;2:194-206.). CLINICAL RELEVANCE: Hypertension (HTN) and abdominal aortic aneurysm (AAA) have been epidemiologically linked for decades; however, a biomechanical link has not yet been identified. Using a murine model of spontaneous neurogenic HTN experimentally demonstrated to have low circulating renin, mechanical activation of the angiotensin II type 1 receptor (AT1R) was identified with elevated blood pressure and AAA induction. HTN amplified AAA growth. However, more importantly, blocking the activation of AT1R with the angiotensin receptor blocker Losartan effectively abrogated AAA development. Although inhibiting the production of angiotensin II has previously been unsuccessful in altering AAA growth, the results from the present study suggest that blocking the activation of AT1R through direct ligand binding or mechanical stimulation might alter aortic wall signaling and warrants further investigation.

Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-ß Signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-ß signaling, and will discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

Pathophysiology and Pathogenesis of Marfan Syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease manifests in many different ways, the most life-threatening manifestations are related to cardiovascular complications including mitral valve prolapse, aortic insufficiency, dilatation of the aortic root, and aortic dissection. In the past 30 years, research efforts have not only identified the genetic locus responsible but have begun to elucidate the molecular pathogenesis underlying this disorder, allowing for the development of seemingly rational therapeutic strategies for treating affected individuals. In spite of these advancements, the cardiovascular complications still remain as the most life-threatening clinical manifestations. The present chapter will focus on the pathophysiology and clinical treatment of Marfan syndrome, providing an updated overview of the recent advancements in molecular genetics research and clinical trials, with an emphasis on how this information can focus future efforts toward finding betters ways to detect, diagnose, and treat this devastating condition.

Increased Intraocular Pressure in Glaucomatous, Ocular Hypertensive, and Normotensive Space Shuttle Crew.

BACKGROUND: Glaucoma and ocular hypertension (OHT) are prevalent diseases with baseline intraocular pressure (IOP) elevations that future astronauts and spaceflight participants may suffer from. Preflight, in-flight, and postflight IOP measurements were collected aboard two U.S. Space Shuttle Program missions in normotensive control, OHT, and glaucomatous crewmembers. METHODS: Five subjects (three controls, one glaucomatous, one OHT) were studied aboard 2-wk Space Shuttle missions. Baseline IOP (triplicate; handheld tonometry) was recorded during training 12 mo preflight, in flight (114 d), and postflight (329 d). Subjective symptoms were recorded via questionnaires. Data were analyzed using a spreadsheet with two-sample t-tests. P-value < 0.05 determined significance. RESULTS: IOP increased for all in-flight vs. preflight measurements for controls (N 3, 48.9, 16.9, 5.85), OHT (N 1, 20.3), and glaucomatous (N 1, 32.2) groups. IOP eventually returned to baseline postflight [Return (R)35 d], except for the astronaut with OHT (R917). Subjective symptoms, likely multifactorial, included blurredvision, decreased visual acuity, and headaches. DISCUSSION: IOP increased during spaceflight and normalized upon return. Astronauts and commercial spaceflight participants may need screening for elevated IOP to potentially prevent sequelae related to glaucoma and OHT, the former which requires treatment in flight and the latter which may need prophylaxis. Previous studies have shown elevated IOP upon entry into microgravity with various normalization timeframes in flight and postflight. It is unclear how increased IOP relates to spaceflight-associated neuro-ocular syndrome (SANS); however, several hypotheses exist. Treatment strategies should be available for acute and chronic ocular pathology during spaceflight despite the unique challenges of eye-drop application in microgravity. Dalal SR, Ramachandran V, Khalid R, Manuel FK, Knowles JR, Jones JA. Increased intraocular pressure in glaucomatous, ocular hypertensive, and normotensive space shuttle crew. Aerosp Med Hum Perform. 2021; 92(9):728733.

miR-133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice.

Background Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR-133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study tested the hypothesis that miR-133a modulates aortic fibroblast phenotype, and overexpression by lentivirus attenuates the development of TAA in a murine model. Methods and Results TAA was induced in mice. Copy number of miR-133a was reduced in TAA tissue and linear regression analysis confirmed an inverse correlation between aortic diameter and miR-133a. Analyses of phenotypic markers revealed an mRNA expression profile consistent with myofibroblasts in TAA tissue. Fibroblasts were isolated from the thoracic aortae of mice with/without TAA. When compared with controls, miR-133a was reduced, migration was increased, adhesion was reduced, and the ability to contract a collagen disk was increased. Overexpression/knockdown of miR-133a controlled these phenotypes. After TAA induction in mice, a single tail-vein injection of either miR-133a overexpression or scrambled sequence (control) lentivirus was performed. Overexpression of miR-133a attenuated TAA development. The pro-protein convertase furin was confirmed to be a target of miR-133a by luciferase reporter assay. Furin was elevated in this murine model of TAA and repressed by miR-133a replacement in vivo resulting in reduced proteolytic activation. Conclusions miR-133a regulates aortic fibroblast phenotype and over-expression prevented the development of TAA in a murine model. These findings suggest that stable alterations in aortic fibroblasts are associated with development of TAA and regulation by miR-133a may lead to a novel therapeutic strategy.

Space Radiation Protection Countermeasures in Microgravity and Planetary Exploration.

BACKGROUND: Space radiation is one of the principal environmental factors limiting the human tolerance for space travel, and therefore a primary risk in need of mitigation strategies to enable crewed exploration of the solar system. METHODS: We summarize the current state of knowledge regarding potential means to reduce the biological effects of space radiation. New countermeasure strategies for exploration-class missions are proposed, based on recent advances in nutrition, pharmacologic, and immune science. RESULTS: Radiation protection can be categorized into (1) exposure-limiting: shielding and mission duration; (2) countermeasures: radioprotectors, radiomodulators, radiomitigators, and immune-modulation, and; (3) treatment and supportive care for the effects of radiation. Vehicle and mission design can augment the overall exposure. Testing in terrestrial laboratories and earth-based exposure facilities, as well as on the International Space Station (ISS), has demonstrated that dietary and pharmacologic countermeasures can be safe and effective. Immune system modulators are less robustly tested but show promise. Therapies for radiation prodromal syndrome may include pharmacologic agents; and autologous marrow for acute radiation syndrome (ARS). CONCLUSIONS: Current radiation protection technology is not yet optimized, but nevertheless offers substantial protection to crews based on Lunar or Mars design reference missions. With additional research and human testing, the space radiation risk can be further mitigated to allow for long-duration exploration of the solar system.

Biologically-Based and Physiochemical Life Support and In Situ Resource Utilization for Exploration of the Solar System-Reviewing the Current State and Defining Future Development Needs.

The future of long-duration spaceflight missions will place our vehicles and crew outside of the comfort of low-Earth orbit. Luxuries of quick resupply and frequent crew changes will not be available. Future missions will have to be adapted to low resource environments and be suited to use resources at their destinations to complete the latter parts of the mission. This includes the production of food, oxygen, and return fuel for human flight. In this chapter, we performed a review of the current literature, and offer a vision for the implementation of cyanobacteria-based bio-regenerative life support systems and in situ resource utilization during long duration expeditions, using the Moon and Mars for examples. Much work has been done to understand the nutritional benefits of cyanobacteria and their ability to survive in extreme environments like what is expected on other celestial objects. Fuel production is still in its infancy, but cyanobacterial production of methane is a promising front. In this chapter, we put forth a vision of a three-stage reactor system for regolith processing, nutritional and atmospheric production, and biofuel production as well as diving into what that system will look like during flight and a discussion on containment considerations.

Oncogene targeted therapy for metastatic primary scrotal melanoma.

Primary scrotal melanoma represents the rarest genitourinary malignancy. We describe the 25th reported case. The 79-year-old patient presented with a rapidly enlarging right cutaneous scrotal mass which after local excision demonstrated pT4b nodular malignant melanoma (BRAF V600E mutation positive). The patient underwent wide local excision of his hemiscrotum and inguinal lymph node dissection demonstrating nodes positive for melanoma (pN2b). Postoperatively, the patient developed a left sided malignant pleural effusion (M1b). Per American Joint Commission Cancer staging, BRAF mutant targeted therapy (dabrafenib) was initiated. This case documents the first instance in which metastatic scrotal melanoma will be treated with oncogene targeted therapy.

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Lipid Alterations in African American Men with Prostate Cancer.

African-American (AA) men are more than twice as likely to die of prostate cancer (PCa) than European American (EA) men. Previous in silico analysis revealed enrichment of altered lipid metabolic pathways in pan-cancer AA tumors. Here, we performed global unbiased lipidomics profiling on 48 matched localized PCa and benign adjacent tissues (30 AA, 24 ancestry-verified, and 18 EA, 8 ancestry verified) and quantified 429 lipids belonging to 14 lipid classes. Significant alterations in long chain polyunsaturated lipids were observed between PCa and benign adjacent tissues, low and high Gleason tumors, as well as associated with early biochemical recurrence, both in the entire cohort, and within AA patients. Alterations in cholesteryl esters, and phosphatidyl inositol classes of lipids delineated AA and EA PCa, while the levels of lipids belonging to triglycerides, phosphatidyl glycerol, phosphatidyl choline, phosphatidic acid, and cholesteryl esters distinguished AA and EA PCa patients with biochemical recurrence. These first-in-field results implicate lipid alterations as biological factors for prostate cancer disparities.