Citations

AbstractPleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome‐wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4‐rs34517439‐A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13‐1.32, P = 4.81 × 10−7). rs34517439‐A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA‐binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4‐rs34517439 as a potentially novel MM risk locus.

Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad–generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Background Obesity is increasingly common in kidney transplant candidates and may limit access to transplantation. Obesity and diabetes are associated with a high risk for post-transplant complications. The best approach to weight loss to facilitate active transplant listing is unknown, but bariatric surgery is rarely considered due to patient- and physician-related apprehension, among other factors. Methods We aimed to determine the magnitude of weight loss, listing, and transplant rates in 28 candidates with a mean BMI of 44.4±4.6 kg/m 2 and diabetes treated conservatively for 1 year post weight-loss consultations (group 1). Additionally, we evaluated 15 patients (group 2) who met the inclusion criteria but received bariatric intervention within the same time frame. All patients completed a multidisciplinary weight management consultation with at least 1 year of follow-up. Results In the conservatively managed group (group 1), the mean weight at the time of initial consultation was 126.5±18.5 kg, and the mean BMI was 44.4±4.6 kg/m 2 . At 1 year post weight-loss consultation, the mean weight decreased by 4.4±8.2 kg to 122.9±17 kg, and the mean BMI was 43±4.8 kg/m 2 , with a total mean body weight decrease of 3% ( P =0.01). Eighteen patients (64%) did not progress to become candidates for active listing/transplantation during the follow-up time of 4±2.9 years, with 15 (54%) subsequently developing renal failure/diabetes-related comorbidities prohibitive for transplantation. In contrast, mean total body weight decreased by 19% at 6 months post bariatric surgery, and the mean BMI was 34.2±4 and 32.5±3.7 kg/m 2 at 6 and 12 months, respectively. Bariatric surgery was strongly associated with subsequent kidney transplantation (HR=8.39 [95% CI 1.71 to 41.19]; P =0.009). Conclusions A conservative weight-loss approach involving multidisciplinary consultation was ineffective in most kidney transplant candidates with diabetes, suggesting that a more proactive approach is needed.

Abstract Introduction Diabetes mellitus in kidney transplant recipients is a risk factor for cardiovascular events and premature death. Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are increasingly used in nontransplant populations to improve diabetes control and cardiovascular and renal benefits. Limited literature exists regarding the safety and efficacy of these agents in renal transplant recipients. Methods We retrospectively reviewed all kidney transplant recipients within our health system who were prescribed a SGLT2i after transplantation for diabetes. The safety, tolerability, and effectiveness of SGLT2i were analyzed. Results Thirty‐nine kidney transplant recipients were initiated on SGLT2i therapy, twenty‐seven of which remained on therapy for at least 1 year. Ten (25%) patients experienced an adverse event while on a SGLT2i, with urinary tract infections (UTI) being the most common. Seventeen patients (43%) discontinued the SGLT2i at the time of chart review, most commonly due to cost and kidney function decline. The median [IQR] hemoglobin A1c (HbA1c) at SGLT2i initiation of 8.4% [7.8–9.2] decreased to 7.5% [6.8–8.0%] after 3 months and 7.5% [6.5–7.9] after 12 months. No meaningful change in kidney function or tacrolimus exposure was observed. Conclusion SGLT2i may be a safe and effective treatment for diabetes in kidney transplant recipients. Cost is a barrier to SGLT2i therapy, and UTIs were the most frequently encountered adverse events in this cohort. More studies are needed to understand the safety profile and determine the effect of SGLT2i on diabetes‐related comorbidities among kidney transplant recipients.

Background. Improving both patient and graft survival after kidney transplantation are major unmet needs. The goal of this study was to assess risk factors for specific causes of graft loss to determine to what extent patients who develop either death with a functioning graft (DWFG) or graft failure (GF) have similar baseline risk factors for graft loss. Methods. We retrospectively studied all solitary renal transplants performed between January 1, 2006, and December 31, 2018, at 3 centers and determined the specific causes of DWFG and GF. We examined outcomes in different subgroups using competing risk estimates and cause-specific Cox models. Results. Of the 5752 kidney transplants, graft loss occurred in 21.6% (1244) patients, including 12.0% (691) DWFG and 9.6% (553) GF. DWFG was most commonly due to malignancy (20.0%), infection (19.7%), cardiac disease (12.6%) with risk factors of older age and pretransplant dialysis, and diabetes as the cause of renal failure. For GF, alloimmunity (38.7%), glomerular diseases (18.6%), and tubular injury (13.9%) were the major causes. Competing risk incidence models identified diabetes and older recipients with higher rates of both DWFG and nonalloimmune GF. Conclusions. These data suggest that at baseline, 2 distinct populations can be identified who are at high risk for renal allograft loss: a younger, nondiabetic patient group who develops GF due to alloimmunity and an older, more commonly diabetic population who develops DWFG and GF due to a mixture of causes—many nonalloimmune. Individualized management is needed to improve long-term renal allograft survival in the latter group.

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA2, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA2 (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA2/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.

Abstract ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p < 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.