Deep learning-enabled technologies for bioimage analysis.

Deep learning (DL) is a subfield of machine learning (ML), which has recently demonstrated its potency to significantly improve the quantification and classification workflows in biomedical and clinical applications. Among the end applications profoundly benefitting from DL, cellular morphology quantification is one of the pioneers. Here, we first briefly explain fundamental concepts in DL and then we review some of the emerging DL-enabled applications in cell morphology quantification in the fields of embryology, point-of-care ovulation testing, as a predictive tool for fetal heart pregnancy, cancer diagnostics via classification of cancer histology images, autosomal polycystic kidney disease, and chronic kidney diseases

Systems Radiology and Personalized Medicine

Medicine has evolved into a high level of specialization using the very detailed imaging of organs. This has impressively solved a multitude of acute health-related problems linked to single-organ diseases. Many diseases and pathophysiological processes, however, involve more than one organ. An organ-based approach is challenging when considering disease prevention and caring for elderly patients, or those with systemic chronic diseases or multiple co-morbidities. In addition, medical imaging provides more than a pretty picture. Much of the data are now revealed by quantitating algorithms with or without artificial intelligence. This Special Issue on “Systems Radiology and Personalized Medicine” includes reviews and original studies that show the strengths and weaknesses of structural and functional whole-body imaging for personalized medicine

Renal Disease:Senescence as a new piece of the puzzle

Senescence as a newpiece of the puzzl

Discovery of First-in-Class Small Molecule Agonists of the RXFP2 Receptor as Therapeutic Candidates for Osteoporosis

Osteoporosis is a chronic bone disease characterized by decreased bone mass and increased risk of developing fractures, predominantly observed in the elderly. The pathophysiological cause of the disease is a decrease in the activity of the bone-forming cells (osteoblasts) that alters bone remodeling in favor of bone resorption, leading to a decrease in bone mass. Recent studies identified the relaxin family peptide receptor 2 (RXFP2), the G protein-coupled receptor (GPCR) for insulin-like 3 peptide (INSL3), as an attractive target expressed in osteoblast cells to increase bone formation. The goal of this dissertation is to discover and characterize small molecule agonists of RXFP2 that are stable and can be delivered orally to promote bone growth. Several low molecular weight compounds were identified as agonists of the RXFP2 receptor using a cAMP high-throughput screen of the NCATS small molecule library. An extensive structure-activity relationship campaign resulted in highly potent and efficient full RXFP2 agonists. The selectivity and specificity of these compounds for human and mouse RXFP2 was shown in counter-screens against the related relaxin receptor RXFP1 and other GPCRs. Using a series of RXFP2/RXFP1 chimeric receptors, in silico modeling and RXFP2 point mutants, we established that the compounds are allosteric agonists of the RXFP2 receptor and identified the GPCR transmembrane domains as the specific region for compound interaction. We also showed that the candidate compounds promoted mineralization in primary human osteoblasts and had low cytotoxicity in various cell types. The compound with the highest activity in vitro was selected for pharmacokinetics profiling in mice, showing oral bioavailability and bone exposure. Moreover, an efficacy study in wild-type female mice treated orally with the lead compound showed a significant increase of the vertebral trabecular number and thickness compared to vehicle treated controls. Overall, our study has successfully identified and characterized the first-in-class small molecule series of RXFP2 agonists, which may lead to the development of a new class of orally bioavailable drugs for the treatment of diseases associated with bone loss

Rare Kidney Diseases

Rare kidney diseases comprise a large group of different life-threatening or chronically debilitating disorders that affect very small numbers of people (<1 in 2000 individuals in Europe and <200,000 in USA) with local or systemic manifestations. For several years, the research and development of treatments in this field have been neglected in favor of more common diseases. The main reasons for the lack of interest in rare kidney diseases seem to be the small numbers of patients and limited epidemiological data on the natural history of many of these diseases. Rare diseases can affect people differently. Even patients with the same condition can exhibit very different signs and symptoms, or there may be many subtypes of the same condition. This diversity constitutes a significant challenge to healthcare practitioners and scientists alike, in terms of being able to acquire sufficient experience for the most appropriate and timely definition, diagnosis, and management. Fortunately, in the last ten years, concerted efforts have led to a marked improvement in the understanding of these disorders. In particular, an important step forward has been taken with the employment of innovative technologies (including next-generation sequencing), in order to replace obsolete phenotypic classifications and to discover new useful diagnostic biomarkers. These new tools are, in fact, becoming part of routine clinical practice, increasing diagnostic accuracy and facilitating genetic counseling. Moreover, biomedical research, providing insights into the pathologies of these rare diseases and elucidating their underlying mechanisms, is revealing new therapeutic avenues and driving the industry to develop safer and more effective orphan drugs. Finally, in this field, it is desirable that, in the future, the crosstalk between basic scientists and clinicians could achieve a great clinical benefit by improving the quality of life of these patients as well. This Special Issue welcomes scientific contributions and critical reviews describing new pathogenetic insights, reporting novel and specific disease biomarkers, and underlying new pharmacological targets or therapies for rare diseases of the kidney and urinary tract

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes

Diet and lifestyle interventions to improve co-morbid conditions of chronic kidney disease

Chronic kidney disease is a progressive inflammatory disorder affecting approximately 15% of US adults, and the prevalence is increasing rapidly. Advanced chronic kidney disease requiring hemodialysis is associated with multiple co-morbid conditions that greatly reduce physical function and quality of life, including muscle wasting, bone disorders, and cardiovascular disease. Protein-energy malnutrition is especially common for reasons including poor nutrient intake, amino acid losses during dialysis, and elevated intradialytic catabolism; these factors promote loss of lean mass and declines in physical function. Low physical function and adverse changes in body composition accelerate development of other co-morbid conditions, highlighting the cycle of disease and disability characteristic of this population. Numerous pharmacological therapies are commonly used in an effort to reduce the incidence or severity of chronic kidney disease co-morbidities, but these treatments are associated with high costs and significant side effects. Furthermore, the complexity of chronic kidney disease suggests multiple therapeutic approaches may be beneficial in this population. Intradialytic protein supplementation and exercise training during dialysis are two lifestyle interventions that have been suggested as potential methods to mitigate the cycle of disease and disability. Studies have shown that both parenteral and oral intradialytic supplementation improve protein homeostasis, increase serum albumin and prealbumin levels, and have anabolic effects on skeletal muscle. However, the effect of intradialytic protein on functional disease outcomes in this population is not known. Similarly, numerous studies have demonstrated that intradialytic exercise training has beneficial effects on physical function and quality of life, but surprisingly few studies have examined its effect on other clinical outcomes, particularly cardiovascular disease. The goal of this research was to examine the relationships between the comorbid conditions associated with advanced chronic kidney disease, and determine the efficacy of intradialytic protein supplementation and exercise training as therapeutic approaches. This goal was accomplished through a series of studies both in animal models and also in clinical populations. In a mouse model of renal insufficiency, a combination of soy protein and exercising improved bone microarchitecture and a main effect of soy protein consumption was observed for improvements plasma urea as an indicator of renal function; results from this study an others prompted consideration of these effects in a clinical population. In a cross-sectional analysis of sixty hemodialysis patients, we found multiple aspects of chronic kidney disease to be interrelated, supporting the idea of the cycle of disease and disability characteristic of these patients. This study was notable for its comprehensive inclusion of functional outcome variables associated with hemodialysis treatment in an effort to characterize relationships among these factors, and possibly provide information on how best to intervene to improve health outcomes in this extremely sick population. For the first clinical intervention study, seventeen hemodialysis patients completed a four month intradialytic cycling program; exercising during dialysis improved physical functioning and improved cardiovascular disease risk as measured by serum alkaline phosphatase and epicardial fat thickness. Protein intake during dialysis, either soy or whey protein, attenuated inflammation associated with a single dialysis session and reduced the acute phase protein response after a six month supplementation program. Long-term protein intake also improved physical functioning and reduced circulating alkaline phosphatase levels, similar to the findings after four months of intradialytic cycling. Taken together, these data suggest modest benefits of intradialytic exercise and protein supplementation on functional outcomes in this critically ill population. Future directions include investigating the combined effects of intradialytic protein and exercise in maintenance dialysis patients, as the complexity of the disease suggests multiple therapeutic strategies may be necessary to improve health outcomes and quality of life for this population