Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution.

Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression, a highly complex and dynamic process featuring changes in cancer cells and stromal cells. A comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression. To that end, we employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models. Our data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression in addition to distinct populations of macrophages with increasing inflammatory features. We also noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts may be dynamically regulated by epigenetic mechanisms. This study systematically describes the landscape of cellular heterogeneity during the progression of PDA and has the potential to act as a resource in the development of therapeutic strategies against specific cell populations of the disease.

CD123: A Novel Biomarker for Diagnosis and Treatment of Leukemia.

Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.

Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency.

Despite adequate dietary management, patients with classic galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

A brief grief over bowel relief.

Oral sodium phosphate (OSP) solution is commonly used as bowel purgative before colonoscopy. Its safety has recently been questioned with several reports of acute renal failure and chronic kidney disease following its use. All of the cases reported are following bowel preparation for colonoscopy. I present a case of acute renal failure following OSP solution given to relieve constipation. This report further highlights the dangers of OSP and the importance of caution and careful monitoring when OSP solution is used as a cathartic, or for bowel preparation before colonoscopy.

Management of acute and post-operative pain in chronic kidney disease.

Chronic kidney disease is common and patients with many co-morbid conditions frequently have to undergo surgical procedures and, therefore, require effective pain management. The pharmacokinetics of various analgesic agents are not well studied in patients with chronic kidney disease and the risk of accumulation of the main drug or their metabolites, resulting in serious adverse events, is a common scenario on medical and surgical wards. It is common for these patients to be cared for by 'non-nephrologists' who often prescribe the standard dose of the commonly used analgesics, without taking into consideration the patient's kidney function. It is important to recognize the problems and complications associated with the use of standard doses of analgesics, and highlight the importance of adjusting analgesic dosage based on kidney function to avoid complications while still providing adequate pain relief.

Emery-Dreifuss humeroperoneal muscular dystrophy: cardiac manifestations.

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder affecting skeletal and cardiac muscles and characterized by muscular atrophy, contractures, and cardiomyopathy with conduction defects. It can be X-linked or autosomal. Not all patients with EDMD develop heart involvement, but heart disease associated with EDMD can be unpredictable and may be life threatening. In rare cases heart problems may be the first symptom of EDMD. Early recognition of heart involvement is of utmost importance as placement of a pacemaker and/or defibrillator may be lifesaving.

Pretransplant serum phosphate levels and outcomes after kidney transplantation.

BACKGROUND: The relation between serum phosphate control while on dialysis and kidney transplant outcomes is uncertain. Our study assessed the effect of pretransplant serum phosphate levels (PTxP) on kidney transplant outcomes. METHODS: Hemodialysis patients included in the Dialysis Morbidity and Mortality Study of the US Renal Data System, undergoing kidney transplantation were studied (n=801). Delayed graft function (DGF) and graft failure as a function of PTxP, were assessed using multivariable logistic and Cox regression models. RESULTS: The within-quartile medians (interquartile range) of PTxP were 4.2 (3.7-4.5), 5.4 (5.1-5.7), 6.4 (6.1-6.8) and 8.5 (7.7-9.7) mg/dL. The adjusted odds ratio (OR) for DGF was significantly elevated for the fourth vs. first PTxP quartiles (OR=1.68; 95% confidence interval [95% CI], 1.05-2.71). Restricting the cohort to patients transplanted prior to the publication of the KDOQI bone metabolism and disease guidelines, PTxP measured within 1-year of transplant, or deceased donor recipients generally showed similar results. The adjusted hazard ratios for death-censored graft failure increased across PTxP quartiles (p for trend = 0.015). CONCLUSION: Higher PTxP is associated with an increased risk of adverse kidney allograft outcomes including DGF and death-censored graft failure. This suggests an important additional benefit of optimizing phosphate control in patients awaiting kidney transplantation while on dialysis.