Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another

Case Study Method to Increase Preservice Teachers\u27 Experience with ELL Accommodations and Self-Efficacy

The enrollment of English language learners (ELLs) in American public schools continues to increase each year. The substantial growth in this population of learners makes it imperative for future educators to understand how to effectively support ELLs’ acquisition of academic content and English language proficiency. In past studies, preservice teachers have reported lower levels of self-efficacy when supporting these learners. This investigation examines how case study approaches can be utilized with preservice teachers to understand how they recommend strategies/accommodations for ELLs and their levels of self-efficacy in implementing these instructional approaches. Findings from this research suggest case studies are effective in increasing self-efficacy and knowledge, as preservice teachers were able to describe appropriate accommodations needed to support their future ELLs

Examination of Anger Prevalence in NCAA Division I Student-Athletes

Purpose: Anger associated with sports participation may affect inability to acutely process anger, may decrease performance and increase the likelihood of risk-taking behavior in collegiate athletes. Therefore, the purpose was to examine the prevalence of anger in collegiate student-athletes across sex, academic status, and sport type. Methods: A cross sectional study over a three-year period examined 759 NCAA Division I student-athletes at one institution (age=20±1 years; males: n=259; females: n=500) completed an optional pre-participation behavioral health screening questionnaire, personal demographic information and the Anger Index Self-Test. Results: Overall, 37.2% (n=282/759; males=127/259, 49.0%; females=155/500, 31.0%) of participants were at high-risk for anger. We identified a significant difference between the anger and sex [Χ2(2, N=759) =28.1, P≤0.01]. We also identified a significant difference between the anger and sport type [Χ2(8, N=759)=32.1, P≤0.01] with 55.2% (n=419/759) at moderate risk for anger despite sport type; with the highest percentages presenting high-risk for anger within power sports (n= 64/116, 55.2%) and ball sports (n=98/240, 40.8%). No significant differences were identified for anger risk and academic status (P=0.66). Conclusions: Female collegiate student-athletes demonstrated a higher prevalence of anger than male collegiate student-athletes, yet more males were high-risk. Most student-athletes displayed moderate-risk for anger across different sports. Anger across academic status was not significantly different implying that anger management and coping skills may need to be taught during their student-athlete tenure to mitigate the identified risk. A collegiate student-athlete’s inability to process anger may affect sports performance and have negative consequences on their personal and social life. A primary prevention mechanism exists to explore proper coping mechanisms for anger during sport before the onset of mental health conditions that could exacerbate the experience for the individual

Influence of Social Isolation During Prolonged Simulated Weightlessness by Hindlimb Unloading

The hindlimb unloading (HU) model has been used extensively to simulate the cephalad fluid shift and musculoskeletal disuse observed in spaceflight with its application expanding to study immune, cardiovascular and central nervous system responses, among others. Most HU studies are performed with singly housed animals, although social isolation also can substantially impact behavior and physiology, and therefore may confound HU experimental results. Other HU variants that allow for paired housing have been developed although no systematic assessment has been made to understand the effects of social isolation on HU outcomes. Hence, we aimed to determine the contribution of social isolation to tissue responses to HU. To accomplish this, we developed a refinement to the traditional NASA Ames single housing HU system to accommodate social housing in pairs, retaining desirable features of the original design. We conducted a 30-day HU experiment with adult, female mice that were either singly or socially housed. HU animals in both single and social housing displayed expected musculoskeletal deficits versus housing matched, normally loaded (NL) controls. However, select immune and hypothalamic-pituitary-adrenal (HPA) axis responses were differentially impacted by the HU social environment relative to matched NL controls. HU led to a reduction in % CD4+ T cells in singly housed, but not in socially housed mice. Unexpectedly, HU increased adrenal gland mass in socially housed but not singly housed mice, while social isolation increased adrenal gland mass in NL controls. HU also led to elevated plasma corticosterone levels at day 30 in both singly and socially housed mice. Thus, musculoskeletal responses to simulated weightlessness are similar regardless of social environment with a few differences in adrenal and immune responses. Our findings show that combined stressors can mask, not only exacerbate, select responses to HU. These findings further expand the utility of the HU model for studying possible combined effects of spaceflight stressors

Effects of a 4-Week Heart Rate Variability Biofeedback Intervention on Psychological and Performance Variables in Student-Athletes: A Pilot Study

PURPOSE: To examine the effects of a 4-week biofeedback intervention on coherence, psychological, and performance variables in collegiate student-athletes. METHODS: Thirteen student-athletes were randomly assigned to the intervention (one weekly biofeedback session for 4-weeks) or control group (no sessions). Data were collected at pre and post-intervention using weekly averaged coherence scores, psychological measures for depression, arousal, stress, resiliency, and performance outcome measures. RESULTS: A 3 (Time) x 4 (Week average) repeated measures ANOVA was independently conducted to examine differences between time and weekly coherence average for coherence scores. No significant differences were found for “at rest”, pre, or post-practice coherence scores. A 2 (treatment group) x 4 (Week) repeated measures ANOVAs were independently conducted to examine differences between treatment groups and week average for performance, resilience, and recovery. Significant differences were found for performance by time (p = .029). For the psychological variables, 2 (treatment group) X 2 (Time) repeated measures ANOVAs were independently conducted to examine differences between treatment group and time for CESD, AD-ACL, CSSS, and the ASSQ sleep score and no significant differences were found. CONCLUSIONS: Overall the biofeedback intervention did not improve coherence, psychological, or performance variables between the groups. While the biofeedback intervention did not show significant changes in this pilot study, there is potential for future research to address male participants and a change in timing during the season

Role of Mitochondrial Oxidative Stress in Spaceflight-Induced Tissue Degeneration

Microgravity and ionizing radiation in the spaceflight environment poses multiple challenges to homeostasis and may contribute to cellular stress. Effects may include increased generation of reactive oxygen species (ROS), DNA damage and repair error, cell cycle arrest, cell senescence or death. Our central hypothesis is that prolonged exposure to the spaceflight environment leads to the excess production of ROS and oxidative damage, culminating in accelerated tissue degeneration. The main goal of this project is to determine the importance of cellular redox defense for physiological adaptations and tissue degeneration in the space environment

Serum Biochemical Profile of Captive-Bred Philippine Crocodiles (Crocodylus Mindorensis Schmidt, 1935) Sub-adults

The Philippine crocodiles Crocodylus mindorensis Schmidt; 1935 are a critically endangered species that necessitate minimally invasive diagnostic tools for their physiological state and health assessment. In the current study; we determined the reference ranges for the serum biochemistry of male and female captive-bred C. mindorensis sub-adults. We collected blood samples from the post-occipital venous sinus of six male and seven female captive-bred crocodile sub-adults at the Palawan Wildlife Rescue and Conservation Center and quantified the serum biochemical values for cholesterol; triglycerides; uric acid; glucose; creatinine; aspartate aminotransferase (AST); alanine aminotransferase (ALT); albumin; total protein; and globulin. We defined reference ranges through the central 95% of the concentration values obtained. The uric acid concentrations were significantly different between male and female C. mindorensis sub-adults. Uric acid levels were higher (P = 0.035) in male sub-adults because of their higher food intake resulting from dominance and aggression during feeding times. Serum biochemical values of C. mindorensis exhibited similarities with and variations from other crocodile species. We briefly discussed the differences with other species and the influence of factors such as field and laboratory methodologies; environmental conditions; nutritional status; and size class

Potential Dietary Countermeasure Against Spaceflight-Induced Bone Loss

As humans venture further into space and beyond low Earth orbit, space radiation is one of the main challenges for astronauts' health. Radiation-induced bone loss is a potential health problem for long duration habitation in space. We showed that a dietary countermeasure prevents bone loss in mice exposed to total body irradiation (TBI). We used a range of ionizing radiation, gamma (137Cs), proton (1H), iron (56Fe), and a combination of sequential proton and iron beam (1H/56Fe/1H) to evaluate skeletal responses. These TBI cover a range of linear energy transfer (LET), from low-LET such as proton, to high-LET such as 56Fe (HZE: high Z- high energy) at doses between 1-2 Gy. The countermeasure diet, composed of 25% Dried Plum (DP) was effective at preventing radiation-induced cancellous bone loss in appendicular bone (tibia). Furthermore, exposing mice to HZE radiation, such as 56Fe (1Gy), impaired ex vivo growth of marrow-derived, bone-forming osteoblasts, which led to reduced mineralization capacity (-77%). In contrast, mice fed the DP diet did not display these deficits, showing the diet's capacity to protect marrow-derived osteoprogenitors. Dietary DP prevented the increase of bone resorbing osteoclast cells, inflammation and oxidative stress, while protecting the osteoprogenitors and mesenchymal stem cells, which few drugs against osteoporosis may achieve. Spaceflight is a combination of multiple factors including microgravity, in addition to space radiation. Therefore, we conducted additional studies to determine if the DP diet could prevent simulated spaceflight (simulated microgravity and radiation combined) bone loss. Mice were exposed to gamma (TBI, 137Cs, 2 Gy), simulated microgravity (using the hindlimb unloading system, HU) or TBI+HU. While we observed bone loss in mice fed the control diet (CD) due to both treatments (TBI=14%, HU=20%), and a worse effect with combined treatments (TBI+HU=25%), mice fed the DP diet did not sustain significant bone loss relative to untreated controls. The DP diet prevented microarchitectural decrements in both appendicular bone (tibia) and axial bone (vertebrae). In addition, the DP diet mitigated HU-induced deficits in osteoblastogenesis. Interestingly, lower doses of DP diet (5%, 10%) did not appear to prevent cancellous bone loss, which shows the importance of identifying the active component(s) of DP. Finally, we have preliminary data showing the potential of DP to prevent radiation-induced damage at a systematic level.. In summary, this novel dietary countermeasure is a promising candidate nutritional countermeasure for spaceflight-induced bone loss and tissue damage

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy

Molecular radiotherapy using 177Lu-DOTATATE is a most effective treatment for somatostatin receptor-expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor-positive tumor xenografts were treated with 17

Examining provider perceptions and practices for comprehensive geriatric assessment among cancer survivors: a qualitative study with an implementation science focus

Introduction: Cancer rates increase with age, and older cancer survivors have unique medical care needs, making assessment of health status and identification of appropriate supportive resources key to delivery of optimal cancer care. Comprehensive geriatric assessments (CGAs) help determine an older person’s functional capabilities as cancer care providers plan treatment and follow-up care. Despite its proven utility, research on implementation of CGA is lacking.Methods: Guided by a qualitative description approach and through interviews with primary care providers and oncologists, our goal was to better understand barriers and facilitators of CGA use and identify training and support needs for implementation. Participants were identified through Cancer Prevention and Control Research Network partner listservs and a national cancer and aging organization. Potential interviewees, contacted via email, were provided with a description of the study purpose. Eight semi-structured interviews were conducted via Zoom, recorded, and transcribed verbatim by a professional transcription service. The interview guide explored providers’ knowledge and use of CGAs. For codebook development, three representative transcripts were independently reviewed and coded by four team members. The interpretive process involved reflecting, transcribing, coding, and searching for and identifying themes.Results: Providers shared that, while it would be ideal to administer CGAs with all new patients, they were not always able to do this. Instead, they used brief screening tools or portions of CGAs, or both. There was variability in how CGA domains were assessed; however, all considered CGAs useful and they communicated with patients about their benefits. Identified facilitators of implementation included having clinic champions, an interdisciplinary care team to assist with implementation and referrals for intervention, and institutional resources and buy-in. Barriers noted included limited staff capacity and competing demands on time, provider inexperience, and misaligned institutional priorities.Discussion: Findings can guide solutions for improving the broader and more systematic use of CGAs in the care of older cancer patients. Uptake of processes like CGA to better identify those at risk of poor outcomes and intervening early to modify treatments are critical to maximize the health of the growing population of older cancer survivors living through and beyond their disease