The role of L-type amino acid transporter 1 (Slc7a5) during in vitro myogenesis.

Satellite cells are required for muscle regeneration, remodeling, and repair through their activation, proliferation, and differentiation; however, how dietary factors regulate this process remains poorly understood. The L-type amino acid transporter 1 (LAT1) transports amino acids, such as leucine, into mature myofibers, which then stimulate protein synthesis and anabolic signaling. However, whether LAT1 is expressed on myoblasts and is involved in regulating myogenesis is unknown. The aim of this study was to characterize the expressional and functional relevance of LAT1 during different stages of myogenesis and in response to growth and atrophic conditions in vitro. We determined that LAT1 is expressed by C2C12 and human primary myoblasts, and its gene expression is lower during differentiation (P < 0.05). Pharmacological inhibition and genetic knockdown of LAT1 impaired myoblast viability, differentiation, and fusion (all P < 0.05). LAT1 protein content in C2C12 myoblasts was not significantly altered in response to different leucine concentrations in cell culture media or in two in vitro atrophy models. However, LAT1 content was decreased in myotubes under atrophic conditions in vitro (P < 0.05). These findings indicate that LAT1 is stable throughout myogenesis and in response to several in vitro conditions that induce muscle remodeling. Further, amino acid transport through LAT1 is required for normal myogenesis in vitro.

Social distancing causally impacts the spread of SARS-CoV-2: a U.S. nationwide event study.

We assess the causal impact of social distancing on the spread of SARS-CoV-2 in the U.S. using the quasi-natural experimental setting created by the spontaneous relaxation of social distancing behavior brought on by the protests that erupted across the nation following George Floyd's tragic death on May 25, 2020. Using a difference-in-difference specification and a balanced sample covering the [- 30, 30] day event window centered on the onset of protests, we document an increase of 1.34 cases per day, per 100,000 population, in the SARS-CoV-2 incidence rate in protest counties, relative to their propensity score matching non-protest counterparts. This represents a 26.8% increase in the incidence rate relative to the week preceding the protests. We find that the treatment effect only manifests itself after the onset of the protests and our placebo tests rule out the possibility that our findings are attributable to chance. Our research informs policy makers and provides insights regarding the usefulness of social distancing as an intervention to minimize the spread of SARS-CoV-2.

Trends in urodynamic testing prior to midurethral sling placement-What was the value of the VALUE trial?

BACKGROUND: Many urologists use urodynamic testing (UDS) to assist clinical decision-making. The VALUE study, a multi-institutional, randomized controlled trial published in 2012, demonstrated that UDS prior to midurethral sling placement for uncomplicated stress urinary incontinence (SUI) did not change management. We sought to determine whether use of UDS for evaluation of SUI diminished thereafter. METHODS: Records of patients who underwent isolated mid-urethral sling surgery at our tertiary-care referral center from 2008 to 2009 (pre-VALUE) and 2014 to 2016 (post-VALUE) were reviewed. Comorbidities, presenting symptoms, surgeon specialty, use of UDS, UDS results and sling type were recorded. Patients with neurologic comorbidities or prior anti-incontinence procedures were excluded. Descriptive statistics were calculated and multivariable logistic regression analyses performed. RESULTS: Three hundred and eighty-seven patients met inclusion criteria. Median age was 54 years. Patients most frequently presented with stress urinary incontinence (56% pre, 50% post), followed by stress predominant mixed urinary incontinence (40% pre, 48% post, P = 0.09). Before VALUE, UDS was performed in 70% of patients prior to primary sling; in the later cohort, this decreased to 41% (P < 0.0001). On multivariable analysis, provider specialty (P < 0.0001) and belonging to the pre-VALUE cohort (P = < 0.0001) predicted use of UDS prior to sling. CONCLUSION: It is paramount that new data be incorporated into diagnostic and treatment algorithms. We found that the rate of preoperative urodynamic testing decreased after publication of a randomized-controlled trial demonstrating that these studies did not change procedural decision-making. Future studies that identify instances of over-testing may have the ability to positively impact patient care and contain costs.

International Continence Society best practice statement for use of sacral neuromodulation.

AIMS: Sacral neuromodulation (SNM) is an accepted therapy for a variety of conditions. However, despite over 20 years of experience, it remains a specialized procedure with a number of subtleties. Here we present the recommendations issued from the International Continence Society (ICS) SNM Consensus Panel. METHODS: Under the auspices of the ICS, eight urologists, three colorectal surgeons and two urogynecologists, covering a wide breadth of geographic and specialty interest representation, met in January 2017 to discuss best practices for neuromodulation. Suggestions for statements were submitted in advance and specific topics were assigned to committee members, who prepared and presented supporting data to the group, at which time each topic was discussed in depth. Best practice statements were formulated based on available data. This document was then circulated to multiple external reviewers after which final edits were made and approved by the group. RESULTS: The present recommendations, based on the most relevant data available in the literature, as well as expert opinion, address a variety of specific and at times problematic issues associated with SNM. These include the use of SNM for a variety of underlying conditions, need for pre-procedural testing, use of staged versus single-stage procedures, screening for success during the trial phase, ideal anesthesia, device implantation, post-procedural management, trouble-shooting loss of device function, and future directions for research. CONCLUSIONS: These guidelines undoubtedly constitute a reference document, which will help urologists, gynecologists, and colorectal surgeons optimize their use of SNM for refractory urinary urgency and frequency, UUI, NOR, and FI.

Improving the utility of clinical phenotyping in interstitial cystitis/painful bladder syndrome: from UPOINT to INPUT.

INTRODUCTION: The phenotyping system UPOINT has proven effective in classifying patients with Urologic Pelvic Pain Syndromes in a clinically meaningful way and to guide therapy. While highly successful in men with chronic pelvic pain syndrome (CPPS), UPOINT is more limited in patients with interstitial cystitis/painful bladder syndrome (IC/PBS) since by definition all patients have the urinary and organ specific phenotype. Furthermore, AUA guidelines recommend a sequential tiered approach to therapy rather than the multimodal UPOINT scheme. We sought to modify UPOINT to be more practical and efficacious for IC/PBS. MATERIALS AND METHODS: We developed a new phenotype by removing the urinary and organ specific domains from UPOINT and adding a Hunner's ulcers (U) domain, since these patients benefit from phenotype specific therapies (fulguration, cyclosporine). This yields 'INPUT': infection, neurologic/systemic, psychosocial, ulcers and tenderness of muscles. We applied this system retrospectively to our previously validated upointmd.com IC/PBS database. Symptoms were measured by the Genitourinary Pain Index (GUPI) (valid for men and women). The database was searched for patients with complete data to assess the INPUT domains and include GUPI. Men were included if they reported pain relieved by voiding and/or presence of Hunner's ulcers. Groups were compared with ANOVA, Mann-Whitney, t test or chi squared when appropriate and correlated with Spearman r. RESULTS: There were 239 patients, 154 female (64%) with age range 18-79 (mean 41.8). Incidence of domains was infection 11%, neurologic/systemic 51%, psychosocial 81%, ulcers 18% and tenderness 85%. Mean total domains was 2.46 (range 0-5) and 65% had 2 or 3 positive domains while only 5% had none. There was a stepwise increase in GUPI score with increasing number of positive INPUT domains (ANOVA for differences between groups p < 0.0001. Correlation by Spearman r = 0.355 p < 0.0001). Presence of Hunner's ulcers increased mean symptom score (25.7 versus 29.7, p = 0.004) and indeed each of the domains significantly increased total GUPI score except for Infection. CONCLUSIONS: The INPUT phenotype in IC/PBS appears to replicate the validity and potential clinical utility of UPOINT in CPPS. Patients have a diversity of phenotypes and more positive domains correlate with more severe symptoms. Since 95% of patients have at least 1 positive domain it may benefit patients to receive multimodal therapy up front for these extra domains (eg. pelvic floor physical therapy, fulguration of ulcers) rather than relying on a sequential tiered approach.

Feasibility of same day discharge after robotic assisted pelvic floor reconstruction.

INTRODUCTION: Robotic surgical procedures have become more common in female pelvic reconstruction. Purported benefits of robotic assisted pelvic floor reconstruction (RAPFR) procedures include shorter hospital stay, faster recovery, lower blood loss, and decreased postoperative pain. Following RAPFR procedures, the current accepted practice is discharge after a one-night hospitalization. We assessed whether same day discharge (SDD) affects the short term safety of and patient satisfaction with robotic assisted pelvic floor reconstructive procedures, relative to those who remain hospitalized overnight. MATERIALS AND METHODS: We retrospectively reviewed the charts of women who underwent RAPFR procedures between October 2015 and October 2016. A same day discharge protocol for RAPFR was initiated in July 2016. To date, 10 patients have undergone SDD. These patients were compared to the consecutive patients from the prior 9 months who stayed overnight. To evaluate short term safety, we reviewed the medical record for any unscheduled Cleveland Clinic emergency department (ED) and/or office visits within 30 days of the RAPFR procedure. We then sent a mailed survey to all patients, querying their pelvic organ prolapse-related PGI-I and also offering a postoperative satisfaction questionnaire. Demographic, perioperative, postoperative data and survey results were compared using Student's t test and Fisher's exact test. RESULTS: In our series, 38 patients (95%) underwent robotic assisted sacrocolpopexy (RASC). Only 2 (5%) had a different RAPFR procedure, a robotic assisted vaginal mesh excision. Concomitant robotic assisted supracervical hysterectomy (SCH) was performed in 9 patients (30%) in the overnight group, whereas 1 of the SDD patients underwent SCH (10%). Demographics and operative characteristics did not differ between groups. Ultimately, patients in the SDD group were no more likely than the overnight group to require an unscheduled ED or office visit in the early postoperative period. With respect to satisfaction, no significant differences were observed between groups, with both groups noting substantial improvement in POP symptoms following surgery. CONCLUSIONS: In this pilot study, same day discharge after RAPFR procedures appears to be safe and feasible. RAPFR procedures were well-tolerated, with no difference in ED or non-urology office visits occurring during the early post-operative period in our series, regardless of length of stay. Patient satisfaction was equivalent between groups and universally high.

Utility Estimation for Pediatric Vesicoureteral Reflux: Methodological Considerations Using an Online Survey Platform.

PURPOSE: The advent of online task distribution has opened a new avenue for efficiently gathering community perspectives needed for utility estimation. Methodological consensus for estimating pediatric utilities is lacking, with disagreement over whom to sample, what perspective to use (patient vs parent) and whether instrument induced anchoring bias is significant. We evaluated what methodological factors potentially impact utility estimates for vesicoureteral reflux. MATERIALS AND METHODS: Cross-sectional surveys using a time trade-off instrument were conducted via the Amazon Mechanical Turk® (https://www.mturk.com) online interface. Respondents were randomized to answer questions from child, parent or dyad perspectives on the utility of a vesicoureteral reflux health state and 1 of 3 "warm-up" scenarios (paralysis, common cold, none) before a vesicoureteral reflux scenario. Utility estimates and potential predictors were fitted to a generalized linear model to determine what factors most impacted utilities. RESULTS: A total of 1,627 responses were obtained. Mean respondent age was 34.9 years. Of the respondents 48% were female, 38% were married and 44% had children. Utility values were uninfluenced by child/personal vesicoureteral reflux/urinary tract infection history, income or race. Utilities were affected by perspective and were higher in the child group (34% lower in parent vs child, p <0.001, and 13% lower in dyad vs child, p <0.001). Vesicoureteral reflux utility was not significantly affected by the presence or type of time trade-off warm-up scenario (p = 0.17). CONCLUSIONS: Time trade-off perspective affects utilities when estimated via an online interface. However, utilities are unaffected by the presence, type or absence of warm-up scenarios. These findings could have significant methodological implications for future utility elicitations regarding other pediatric conditions.

Removal of Sacral Nerve Stimulation Devices for Magnetic Resonance Imaging: What Happens Next?

INTRODUCTION: Sacral neuromodulation (SNM) devices (Medtronic, Minneapolis, MN, USA) are not approved to undergo magnetic resonance imaging (MRI) of sites other than the head. When MRIs are required, devices are often removed prior to imaging. We reviewed the prevalence of device removal for MRI at a large academic institution and the subsequent clinical course of these patients. METHODS: A retrospective review of all SNM explants from 2009-2015 was performed. Cases explanted for MRI were analyzed to collect demographics, clinical characteristics, and postremoval management. Descriptive statistics were calculated. RESULTS: Ninety patients underwent SNM device removal, with 21 (23%) occurring for MRI. At explant, 20 patients (95%) were female and median age was 66 years. Suboptimal symptom control from SNM was noted in seven (33%) of these patients preoperatively. Of those explanted, six (29%) required MRI for neurologic and 10 (48%) for orthopedic concerns. The remaining MRI indications included abdominal masses (10%), genitourinary disease (5%), surveillance for prior malignancy (5%), and cardiac disease (5%). Only 16 (76%) patients explanted ultimately underwent MRI. MRI results impacted clinical management in 9/16 (56%) of the imaged patients. Only two (10%) of explanted patients underwent device replacement. CONCLUSIONS: In patients receiving SNM therapy, device removal for MRI is most commonly due to orthopedic and neurologic pathologies. About half of the MRIs performed impacted non-GU clinical management. It is of paramount importance to confirm the necessity of MRI before removing a functional SNM device. Since SNM replacement was rare in this cohort, research is needed on the safety of various MRI types with SNM devices in vivo.

Comparative profiling of well-defined copper reagents and precursors for the trifluoromethylation of aryl iodides.

A number of copper reagents were compared for their effectiveness in trifluoromethylating 4-iodobiphenyl, 4-iodotoluene, and 2-iodotoluene. Yields over time were plotted in order to refine our understanding of each reagent performance, identify any bottlenecks, and provide more insight into the rates of the reactions. Interestingly, differences in reactivity were observed when a well-defined [LCuCF3] complex was employed directly or generated in situ from precursors by published reports. Relative reactivities were also found to highly dependent on the nature of the iodoarenes.

Nationwide Trends and Variations in Urological Surgical Interventions and Renal Outcome in Patients with Spina Bifida.

PURPOSE: Bladder dysfunction in patients with spina bifida can lead to significant morbidity due to renal insufficiency. Indications for surgery vary among institutions and the impact is unclear. We examined trends and variations in urological interventions and chronic renal insufficiency in patients with spina bifida. MATERIALS AND METHODS: We reviewed NIS (Nationwide Inpatient Sample) for all patients with spina bifida treated from 1998 to 2011. We used ICD-9-CM codes to identify urological surgery and chronic renal insufficiency. We calculated the Spearman correlation coefficients between rates of spina bifida related bladder surgeries and rates of chronic renal insufficiency outcomes by state. Linear regression models were fitted to investigate the associations between rates of spina bifida related surgery and chronic renal insufficiency across treatment years. RESULTS: We identified 427,616 spina bifida hospital admissions. Mean patient age was 26 years and 56% of patients were female. Of the admissions 35,249 (8%) were for chronic renal insufficiency and 11,078 (3%) were for surgery. During the study period chronic renal insufficiency rates doubled from 6% to 12% and surgery rates decreased from 2.0% to 1.8%. There was a moderately weak inverse association between surgery and chronic renal insufficiency rates with time (r = -0.3, p = 0.06) and by state (r = -0.3, p = 0.04). On multivariate analysis higher rates of surgery were associated with the state in which the patient was treated (p <0.001), and with younger age (p <0.001) and hospital teaching status (p <0.001). In contrast, chronic renal insufficiency was not associated with spina bifida related surgery (p = 0.67). CONCLUSIONS: We observed a temporal and geographic trend toward decreasing urological surgery and increasing chronic renal insufficiency rates in spina bifida and a wide variation in urological surgical rates among states. Further study is needed to determine the factors behind these trends and variations in spina bifida management.

Sialic acids in infection and their potential use in detection and protection against pathogens.

In structural terms, the sialic acids are a large family of nine carbon sugars based around an alpha-keto acid core. They are widely spread in nature, where they are often found to be involved in molecular recognition processes, including in development, immunology, health and disease. The prominence of sialic acids in infection is a result of their exposure at the non-reducing terminus of glycans in diverse glycolipids and glycoproteins. Herein, we survey representative aspects of sialic acid structure, recognition and exploitation in relation to infectious diseases, their diagnosis and prevention or treatment. Examples covered span influenza virus and Covid-19, Leishmania and Trypanosoma, algal viruses, Campylobacter, Streptococci and Helicobacter, and commensal Ruminococci.

Contemporary epidemiological trends in complex congenital genitourinary anomalies.

PURPOSE: Anecdotal evidence suggests that complex congenital genitourinary anomalies are occurring less frequently. However, few epidemiological studies are available to confirm or refute this suggestion. MATERIALS AND METHODS: The Kids' Inpatient Database (KID) is a national, all payer database of several million inpatient pediatric hospitalizations per year, including complicated and uncomplicated in-hospital births. We reviewed the 1997 to 2009 KID to determine the birth prevalence of spina bifida, posterior urethral valves, bladder exstrophy, epispadias, prune belly syndrome, ambiguous genitalia and imperforate anus. For posterior urethral valves and prune belly syndrome we limited our search to newborn males only. RESULTS: During the study period, there was a diagnosis of spina bifida in 3,413 neonates, bladder exstrophy in 214, epispadias in 1,127, ambiguous genitalia in 726, prune belly syndrome in 180, posterior urethral valves in 578 and imperforate anus in 4,040. We identified no significant change in the birth prevalence of spina bifida (from 33.9 new spina bifida births of 100,000 uncomplicated births to 29.0/100,000, p = 0.08), posterior urethral valves (from 10.4/100,000 to 11.0/100,000, p = 0.51), prune belly syndrome (from 4.8/100,000 to 3.3/100,000, p = 0.44) or ambiguous genitalia (from 5.82/100,000 to 5.87/100,000, p = 0.38). There was a significant decrease in the birth prevalence of bladder exstrophy (from 2.4/100,000 to 1.6/100,000 uncomplicated births, p = 0.01) and a significant increase in epispadias (from 8.0/100,000 to 11.6/100,000) and imperforate anus (from 33.6/100,000 to 35.0/100,000, each p = 0.04) during the study period. CONCLUSIONS: The birth prevalence of spina bifida, posterior urethral valves and prune belly syndrome appears to have been stable in the last 12 years. Epispadias, ambiguous genitalia and imperforate anus diagnoses in newborns became more common in the same period, while bladder exstrophy diagnoses became less common.

Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors.

BACKGROUND: Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored. METHODS: Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed. RESULTS: Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (P < 0.05) and fibro-adipogenic progenitors (FAPs) (P < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05). CONCLUSIONS: Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.

How dry is dry? A review of definitions of continence in the contemporary exstrophy/epispadias literature.

PURPOSE: Definitions of continence following surgery in children with exstrophy-epispadias complex vary widely. We assessed the most common definitions of continence and evaluated the clinical significance of usage patterns for those definitions. MATERIALS AND METHODS: We searched MEDLINE and EMBASE (2000 to 2011) for English language reports describing postoperative continence outcomes in children with exstrophy-epispadias complex. Articles were evaluated and data were abstracted by 2 reviewers. We assessed patient level factors such as age, preoperative diagnoses and use of additional therapies, as well as study level factors such as continence definition(s), country of origin and method of data collection. RESULTS: We identified 884 articles, of which 87 met inclusion criteria. In total these studies included continence outcomes data on 2,681 patients (57% male). Only 59 studies (68%) clearly defined the term "continence." The most common definition of continence was dry with voiding/catheterization every 3 hours (used in 23 studies, or 39%, defining continence). There was no association between publication date (p = 0.17), study location (p = 0.47) or study size (p = 0.81) and continence definition. There was a trend toward improved reporting of methods for continence ascertainment in more recent years (p = 0.02). Of the 2,681 children included 1,372 (51%) were dry by the definition used in their study. CONCLUSIONS: The most frequent definition of continence was "dryness with voiding or catheterization at 3-hour intervals." However, definitions were highly variable and many authors did not define continence at all. To better define outcomes, we recommend that a standardized definition of continence be established and used in future reports.

Improving Patient Experience Scores Using Simultaneous Interpretation on Family-Centered Rounds.

OBJECTIVES: Patients speaking a primary language other than English face barriers to equitable care, particularly patient-provider communications. There is no gold standard for providing inpatient medical interpretation on family-centered rounds (FCR). We aimed to implement simultaneous, in-person interpretation of FCR for Spanish-speaking families and hypothesized improved satisfaction in care. METHODS: In-person, Spanish Equipment-Assisted Simultaneous Medical Interpretation (EASMI) was implemented in March 2018 on FCR. Child Hospital Consumer Assessment of Healthcare Providers and Systems (Child HCAHPS) experience scores on communication domains were analyzed for Spanish and English-speaking families pre- (n = 118) and postimplementation (n = 552). Postimplementation, we conducted medical team surveys (n = 104) and semistructured interviews with Spanish-speaking families (n = 25) to determine satisfaction with interpretation modalities (phone, video, and EASMI). RESULTS: Spanish-speaking families exhibited statistically significant improvements in Child HCAHPS top box scores compared to English-speaking families in multiple communication and informed care-related domains. For example, "How often did your child's doctors explain things to you in a way that was easy to understand?" top box scores improved from 58% to 95% for Spanish-speaking families, compared to 85% to 83% for English speakers, with the differential effect of the intervention showing statistical significance (P = .001). Medical team surveys demonstrated high satisfaction with EASMI. Qualitative themes from interviews and open-ended survey responses emphasized multiple care benefits with EASMI, including a perceived reduction of communication errors and increased family participation. CONCLUSIONS: EASMI was associated with significant improvements in Child HCAHPS scores in communication domains and increased medical team and family members' satisfaction with interpretation. EASMI presents a novel method for equitable FCR for Spanish-speaking families.

Exercise Improves Cancer-free Survival and Health Span in a Model of Radiation-induced Cancer.

INTRODUCTION: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. METHODS: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d·wk-1; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. RESULTS: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = -1) relative to CTRL/SED. CONCLUSION: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.

Weight loss with exercise improves muscle architecture and progenitor cell populations compared with weight loss alone in mice with preneoplastic colorectal lesions.

Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofiber characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofiber cross-sectional area was not different between groups. There were more smaller-sized fibres in HFD-EX (p < 0.05 vs. CON), and more fibrosis in HFD-SED (p < 0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p = 0.059) and more fibro-adipogenic progenitors in HFD-EX (p < 0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB was markedly reduced in the interstitium of HFD-EX (p < 0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty: Exercise improves muscle architecture in mice with preneoplastic colorectal lesion Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions.

Effect of isocaloric low fat diet on prostate cancer xenograft progression in a hormone deprivation model.

PURPOSE: Previous mouse studies suggesting that low fat diets slow prostate cancer growth often used corn oil (omega-6), which enhances prostate cancer growth, as the primary fat. Using a saturated fat based diet we previously found no significant difference in tumor growth between low and high fat fed SCID mice (Taconic Farms, Hudson, New York) xenografted with LAPC-4 cells. Whether similar results would hold in a castration model is unclear. MATERIALS AND METHODS: A total of 80 male SCID mice were fed a Western diet (40% fat and 44% carbohydrate) and injected with LAPC-4 human prostate cancer cells. When tumors were 200 mm(3), the mice were castrated and randomized to an isocaloric Western or a low fat diet (12% fat and 72% carbohydrate). Animals were sacrificed when tumors were 1,000 mm(3). Serum was collected and assayed for prostate specific antigen, insulin, insulin-like growth factor 1 and insulin-like growth factor binding protein 3. Tumors were assayed for total and phosphorylated Akt. RESULTS: Mouse weight was equivalent in the 2 groups. Overall dietary group was not significantly associated with survival (log rank p = 0.32). There were no statistically significant differences in prostate specific antigen (p = 0.53), insulin-like growth factor axis parameters (each p >0.05) or p-Akt-to-t-Akt ratios (p = 0.22) between the groups at sacrifice. CONCLUSIONS: In this xenograft model we found no difference in tumor growth or survival between low fat vs Western fed mice when the fat source was saturated fat. These results conflict with those of other studies in which corn oil was used to show that low fat diets delay prostate cancer growth, suggesting that fat type may be as important as fat amount in the prostate cancer setting.

Estimated blood loss as a predictor of PSA recurrence after radical prostatectomy: results from the SEARCH database.

STUDY TYPE: Diagnosis (exploratory cohort). LEVEL OF EVIDENCE: 2b. OBJECTIVE: To clarify the relationship between estimated blood loss (EBL) and biochemical recurrence, assessed by prostate-specific antigen (PSA) level, as blood loss is a long-standing concern associated with radical prostatectomy (RP), and no studies to date have examined the association between blood loss and cancer control. PATIENTS AND METHODS: In all, 1077 patients were identified in the Shared Equal-Access Regional Cancer Hospital database who underwent retropubic RP (between 1998 and 2008) and had EBL and follow-up data available. We examined the relationship between EBL and recurrence using multivariate Cox regression analyses. RESULTS: Increased EBL was correlated with PSA recurrence in a multivariate-adjusted model (P = 0.01). When analysed by 500-mL EBL categories, those with an EBL of <1500 mL had a similar risk of recurrence. However, the risk of PSA recurrence tended to increase for an EBL of 1500-3499 mL, before decreasing again for patients with an EBL of > or =3500 mL. Men with an EBL of 2500-3499 mL had more than twice the risk of recurrence than men with an EBL of <1500 mL (P = 0.02). EBL was not associated with adverse tumour stage, grade or margin status. CONCLUSIONS: There was a significant correlation between EBL at the time of RP and biochemical recurrence. We hypothesized that this association might be due to transfusion-related immunosuppression, excessive blood obscuring the operative field, EBL being a marker of aggressive disease, or EBL being a marker of poor surgical technique. However, our data did not completely fit any one of these hypotheses, and thus the ultimate cause for the increased risk of recurrence remains unclear and requires further study.