Citations

Abstract Background Cryptococcus spp is a major cause of opportunistic infections in immunocompromised patients, primarily due to Cryptococcus neoformans and Cryptococcus gattii. There are occasional reports of other Cryptococcus species causing invasive human disease. However, their epidemiology and clinical significance are not fully defined. We sought to describe cases with cultures positive for Cryptococcus species other than C neoformans and C gattii. Methods A retrospective descriptive analysis of clinical and laboratory data of patients with cultures growing Cryptococcus species other than C neoformans and C gattii from November 2011 to February 2019 was performed. Three Mayo Clinic sites in Arizona, Florida, and Minnesota were included. Results From 176 cases with a culture growing Cryptococcus spp, 54 patients (30%) had a culture for Cryptococcus other than C neoformans and C gattii in the study time frame. The most common species were Cryptococcus magnus, Cryptococcus laurentii, and Cryptococcus ater. The organisms were isolated and identified in culture of bronchoalveolar lavage (11), skin (11), urine (7), oral (4), sinus (3), intraoperative soft tissue (3), sputum (2), synovial fluid (2), cerebrospinal fluid (2), and intravenous catheter (2), among others (7). Only 8 (15%) cases were considered to be potentially pathogenic, with 1 case of invasive disease. Antifungal treatment was fluconazole, itraconazole, and griseofulvin, for a mean systemic antifungal duration of 42 days. Conclusions This large series of patients with Cryptococcus spp other than C neoformans and C gattii suggests that these species rarely cause clinically significant infection in humans. Only 1 case of invasive disease was found.

Environmental stressors, such as heat or altitude, elicit dissimilar physiological adaptations to endurance training programs. Whether these differences (i.e., increased hemoglobin mass vs plasma volume) differentially influence performance is debated. We review data in support of our novel hypothesis, which proposes altitude as the preferred environmental training stimulus for elite endurance athletes preparing to compete in temperate, sea-level climates (5°C–18°C).

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to parents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Abstract Interleukin‐6 (IL‐6) is a pleiotropic cytokine that has been shown to be produced acutely by skeletal muscle in response to exercise, yet chronically elevated with obesity and aging. The mechanisms by which IL‐6 influences skeletal muscle mitochondria acutely and chronically are unclear. To better understand the influence of extramyocellular IL‐6 on skeletal muscle mitochondrial physiology, we treated differentiated myotubes with exogenous IL‐6 to evaluate the dose‐ and duration‐dependent effects of IL‐6 on salient aspects of mitochondrial biology and the role of canonical IL‐6 signaling in muscle cells. Acute exposure of myotubes to IL‐6 increased the mitochondrial reactive oxygen species (mtROS) production and oxygen consumption rates ( J O 2 ) in a manner that was dependent on activation of the JAK/STAT pathway. Furthermore, STAT3 activation by IL‐6 was partly attenuated by MitoQ, a mitochondrial‐targeted antioxidant, suggesting that mtROS potentiates STAT3 signaling in skeletal muscle in response to IL‐6 exposure. In concert with effects on mitochondrial physiology, acute IL‐6 exposure induced several mitochondrial adaptations, consistent with the stress‐induced mitochondrial hyperfusion. Exposure of myotubes to chronically elevated IL‐6 further increased mtROS with eventual loss of respiratory capacity. These data provide new evidence supporting the interplay between cytokine signaling and mitochondrial physiology in skeletal muscle.

Abstract Background: Large genome-wide association studies (GWAS) have identified hundreds of single-nucleotide polymorphisms (SNPs) associated with increased risk of prostate cancer (PRCA). The majority of these risk loci are intergenic and the underlying causal variants are presumed to confer regulatory effects on gene expression. While follow-up eQTL studies have begun to explore putative regulatory targets of PRCA risk SNPs, these have largely focused on protein-coding genes. Recent evidence demonstrates that pri-miRNA transcripts are susceptible to the same cis-acting regulatory effects as other long RNAs, and PRCA risk SNPs may confer systemic impacts on the prostate transcriptome through miRNA expression dysregulation. However, no miRNA transcriptome-wide association studies (TWAS) of PRCA risk have been conducted to date, and the role of miRNA dysregulation in PRCA risk is poorly understood. Methods: We performed a comprehensive miRNA TWAS of PRCA risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate tissue samples from Mayo Clinic along with N = 411 prostate adenocarcinoma (PRAD) tumor samples from the Cancer Genome Atlas (TCGA). Both miRNA expression datasets were uniformly processed separately using the CAP-miRSeq miRNA workflow and trimmed mean of M (TMM) normalization. Expressed mature miRNAs were identified as ≥ 5 reads in >25% of samples. PEER was used to remove known and latent factors on miRNA expression levels, and subsequent analyses were performed on residual values. Genetically regulated expression (GReX) prediction models were trained for all expressed miRNAs with evidence of cis-heritability (P<0.01) in the respective normal and tumor datasets using the FUSION TWAS software. TWAS for PRCA risk was performed with both sets of GReX models using single-SNP summary statistics from the recent PRACTICAL consortium PRCA case-control OncoArray GWAS meta-analysis. Significant TWAS associations were declared at a false discovery rate of 0.05. Results: A total of 615 and 571 distinct expressed miRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 98 (16%) normal tissue miRNAs demonstrated significant cis-heritability (median cis-h2 = 0.09, range: 0.04-0.79) for GReX model training. Similar results were obtained from TCGA tumor samples, with 63 (11%) miRNA GReX models successfully trained (median cis-h2 = 0.11, range: 0.05-0.60). Using normal tissue GReX models, we identified three significant TWAS miRNA associations with PRCA risk: over-expression of mir-941 family miRNAs (PTWAS = 3.1E-04) and reduced expression of miR-3617-5p (PTWAS = 1.7E-04) and hsa-miR-16-2-3p (PTWAS = 9.1E-04). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). All associated miRNAs have previously reported oncogenic or tumor-suppressive associations in other cancer types. Conclusions: We identified significant associations with PRCA genetic risk and miRNA expression dysregulation using tumor and normal prostate tissue data. Future work will examine downstream regulatory effects of miRNA dysregulation as well as miRNA-mediated risk mechanisms via competing endogenous RNA relationships. Citation Format: Nicholas B. Larson, Shannon K. McDonnell, Zachary Fogarty, Stephen N. Thibodeau. An miRNA transcriptome-wide association study of prostate cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 54.

4083 Background: Thymidylate synthase (TS) over-expression is associated with 5-FU resistance. Pre-clinical studies demonstrate that vorinostat down-regulates intra-tumor TS in a dose-dependent fashion and augments 5-FU antitumor activity in xenograft models. We conducted a phase I clinical trial of an intermittent schedule of QD x 3 vorinostat in combination with a fixed dose of fluorouracil (5-FU) and leucovorin (LV) in patients (pts) with refractory solid tumors. Methods: Vorinostat was escalated in a standard 3 x 3 design in combination with a fixed dose of 5-FU and LV (simplified de Gramont regimen, sFULV2). Vorinostat was given QD x 3 on an every-2-week cycle. sFULV2 started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hrs followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 over 46 hrs. Results: 24 pts were enrolled: Male/Female: 11/13; ECOG 0/1: 6/18; Age: median 60 (range 42–77) yrs. 21 pts had colorectal cancer (CRC), 1 had gastric, 1 had esophageal, and 1 had anal cancer. Vorinostat dose-levels (DL) were 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1700 mg, and 2000 mg. Dose-limiting toxicities (DLT), consisting of fatigue and hand-and-foot syndrome (H&F), were seen in 2 of 3 pts at the 2000 mg DL. None of the 6 pts at the 1700 mg DL had a DLT. Cycle 1 grade 3/4 toxicities consisted of thrombocytopenia, GI bleeding, fatigue, and H&F in 2 pts at the 2000 mg DL and a non-DLT G3 diarrhea (lasted <24 hrs) in 1 pt at the 1700 mg DL. Grade 2 nausea, fatigue, and anorexia were common; especially at DL ≥ 1700 mg. Antitumor activity was noted in pts with CRC despite prior refractoriness to 5-FU and failure to oxaliplatin, irinotecan, and cetuximab in all pts. 12/21 CRC pts had a confirmed SD (11) or PR (1). CRC pts had a median PFS of 4 months, a ≥ 6 months PFS rate of 43%, and a ≥ 8 months PFS rate of 33%. Conclusions: The maximum tolerated dose (MTD) of vorinostat in combination with sFULV2 is 1700 mg PO QD x 3 every 2 weeks. This combination is associated with considerable activity in pts with 5-FU-refractory CRC and warrants further investigation. An expanded MTD cohort is accruing to investigate 5-FU-vorinostat PK interaction and intra-tumor TS down-regulation. (This work was supported by a grant from CTEP and the ACS.) No significant financial relationships to disclose.