Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer.

Pancreatic ductal adenocarcinomas (PDAs) are notoriously aggressive and resistant to treatment. They distinguish themselves further by their robust fibroinflammatory, or desmoplastic, stromal reaction and degree of hypovascularity. Recent findings have revealed multiple mechanisms of stromal complicity in disease pathogenesis and resistance. In this review, we focus on altered physicomechanics as one mechanism of what we term as 'stromal resistance' in PDA. Extremely high interstitial fluid pressures and a dense extracellular matrix combine to limit the delivery and distribution of therapeutic agents. We discuss the genesis and consequences of altered fluid dynamics in PDA and strategies to restore them.

The relationship of donor source and age on short- and long-term allograft survival in pediatric renal transplantation.

Limited pediatric data on allograft survival from advanced aged kidney donors exist. To determine the influence of donor source and age on allograft survival in pediatric renal transplant recipients, we analyzed the OPTN database. Allograft survival for 7291 pediatric renal transplants was evaluated. Up to five yr post-transplantation, graft survival was higher for LD vs. DD recipients. At seven yr, allograft survival was 71% in 18-54 yr-old LD recipients, 59.1% in >or=55 yr-old LD, and 45.1% in >or=50 yr-old DD recipients. An approximate 35% improvement in allograft survival in 18-54 yr-old LD recipients was observed. Multivariate results showed that recipients of LD 35-49 (aRR 0.66, 95% CI 0.55-0.80) and LD 50-54 (aRR 0.65, 95% CI 0.45-0.94) have a graft survival advantage over the ideal DD. In LD >or=55 yr, no improvement in graft survival was observed when compared with the 18-34 yr-old DD. In summary, we observed in a pediatric population, <55 yr-old LD kidneys afford improved long-term allograft survival when compared with DD kidney recipients. Increasing awareness of the long-term graft survival advantage for children receiving an LD kidney, even from older donors, should be a priority.

Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation.

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.

Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation.

Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients >2 years old undergoing their first HCT at Fred Hutchinson Cancer Research Center participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal-Wallis test was used to determine the associations between day 100 urinary albumin to creatinine ratios and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with the development of AKI. D-dimer was associated with a slightly increased risk of AKI (relative risk=1.76; P-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant.

Twin fetuses with abnormalities that overlap with three midline malformation complexes.

Twin fetuses aborted at an estimated gestational age of 145 days were concordant for oral, facial, skeletal, and central nervous system malformations. The twins were discordant for other anomalies including cardiac defects, polydactyly, and malrotated short bowel. The combination of malformations observed overlaps with that of the oral-facial-digital syndrome, hydrolethalus syndrome, and Pallister-Hall syndrome. The problem of phenotypic overlap between these syndromes is discussed.

Ductal pancreatic cancer in humans and mice.

Pancreatic ductal adenocarcinoma (PDA) eludes early detection and resists current therapies, earning its distinction as the most lethal malignancy by organ site in the western world. This dire reality prompted extensive yet generally disappointing efforts to generate transgenic mouse models of this malignancy. Recently, mutant mice that develop pancreatic intraepithelial neoplasms (PanIN), the presumed preinvasive stage of PDA, were produced by conditionally expressing an endogenous oncogenic Kras allele in the developing murine pancreas. Mice with PanIN demonstrated promise in the pursuit of biomarkers of early pancreatic cancer, and, importantly, such mice eventually developed and succumbed to PDA after a long latency, establishing PanINs as true precursors to the invasive disease. Furthermore, the incorporation of conditional mutations in tumor suppressor alleles known to be altered in human PDA synergized with oncogenic Kras to produce advanced PDA with a short latency, recapitulating central pathophysiological events in human PDA. These models facilitate a variety of biological and clinical investigations such as explorations of the cellular origins of PDA and the development of treatment strategies for advanced PanIN and PDA. In addition, lessons from modeling PDA may be applicable to other tumor types and illuminate general principles of carcinogenesis.

A rapid ion-exchange assay for detergent-solubilized inositol 1,4,5-trisphosphate receptors.

We describe a rapid ion-exchange syringe assay for [3H]inositol 1,4,5-trisphosphate binding to detergent-solubilized receptors. In extracts of rat cerebellar membranes, the assay resolves rapidly dissociating ligand complexes, detecting two to three times higher receptor abundance than conventional gel filtration spun column assays, and provides evidence for two classes of IP3-binding sites, representing 0.5-1.0% of total cerebellar membrane protein. Receptors purified from bovine and rat cerebellum exhibit a single class of high-affinity sites, with equilibrium dissociation constants (Kd = 4-8 nM) reflecting 20 to 25-fold higher affinity than reported in studies with spun-column methods.

Isthmico-cervical ectopic pregnancy following caesarean section.

A 30 year old woman (gravida 4, para 2) presented with 2 1/2 mth amenorrhoea and vaginal spotting. On bimanual pelvic examination, an old tear was felt on posterior cervical lip with enlarged cervix and normal sized uterus. Ultrasonography revealed ectopic pregnancy with placenta implanted on isthmus and upper cervix. Dilatation and curettage was done with cervical packing.