Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation

Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular genetic events driving these behaviors are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1 mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1-mutant and PBRM1-mutant tumors had different overall survival

A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice withKIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Macroplastique outcome in women with stress urinary incontinence secondary to intrinsic sphincteric deficiency

Objectives: To evaluate short-term outcomes of Macroplastique (MPQ) in women with stress urinary incontinence (SUI) using patient reported outcome and three-dimensional vaginal ultrasound (3DUS). Materials and methods: After obtaining institutional review board approval, a chart review of non-neurogenic women that received MPQ for intrinsic sphincter deficiency (ISD) was extracted from a prospective database. Patients were divided into three groups: naïve (Group I), prior incontinence surgery (Group II), and both prior incontinence surgery and bulking agent (Group III). Women with urethral hypermobility were excluded. Baseline evaluation included a history, physical examination to confirm SUI, and questionnaires [Urinary Distress Inventory-6 (UDI-6), 1 quality of life (QOL) global score based on visual analog scale], and in select patients urodynamic studies and/or standing voiding cystogram. Patient follow up included repeat questionnaires scores and 3DUS to objectively assess MPQ volume. Success was defined as sufficient improvement after one injection so that a subsequent reinjection/different SUI operation was not requested at the last follow-up visit. It was hypothesized that Group I would fare best. Results: Fifty-nine women met the inclusion criteria. Success rate was 83% for Group I, 70% for Group II, and 69% for Group III (p = 0.54) at 9 months mean follow up. Fifteen patients underwent a second 3DUS during follow up with a stable volume, compared to the first study (4.5 ± 1.5 vs. 4.4 ± 1.5, p = 0.70), which confirmed stable volumes over time. Among the failures (N = 15), nine patients proceeded with reinjection; four patients had fascial slings, and two patients had artificial sphincters. Conclusion: As confirmed by 3DUS, Macroplastique appears efficacious as a primary treatment and as a salvage treatment for SUI due to ISD in the short-term

Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014–2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells

Paternity assignment and demographic closure in the New Zealand southern right whale

The identification and characterisation of reproductively isolated subpopulations or ‘stocks’ is essential for effective conservation and management decisions. This can be difficult in vagile marine species like marine mammals. We used paternity assignment and ‘gametic recapture’ to examine the reproductive autonomy of southern right whales (Eubalaena australis) on their New Zealand (NZ) calving grounds. We derived DNA profiles for 34 mother-calf pairs from skin biopsy samples, using sex-specific markers, 13 microsatellite loci and mtDNA haplotypes. We constructed DNA profiles for 314 adult males, representing 30% of the census male abundance of the NZ stock, previously estimated from genotypic mark-recapture modelling to be 1085 (95% CL 855, 1416). Under the hypothesis of demographic closure and the assumption of equal reproductive success among males, we predict: (1) the proportion of paternities assigned will reflect the proportion of the male population sampled and (2) the gametic mark-recapture (GMR) estimate of male abundance will be equivalent to the census male estimate for the NZ stock. Consistent with these predictions, we found that the proportion of assigned paternities equalled the proportion of the census male population size sampled. Using the sample of males as the initial capture, and paternity assignment as the recapture, the GMR estimate of male abundance was 1001 (95% CL 542, 1469), similar to the male census estimate. These findings suggest that right whales returning to the NZ calving ground are reproductively autonomous on a generational timescale, as well as isolated by maternal fidelity on an evolutionary timescale, from others in the Indo-Pacific region