Citations

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show that ZIP10 homologs transport Zn2+, as well as ZIP10, kidney localization across species. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human, and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule, but also in the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10.

e21681 Background: Maintaining quality of life with minimal symptoms is an important goal of cancer treatment. We surveyed patients undergoing cancer treatment about their preferences for information about the long-term symptom burden associated with their current treatment. Methods: Patients undergoing active cancer treatment were enrolled at two large cancer centers from 1/2014 to 7/2015. At the time of enrollment patients reported their household income, employment, performance status and their agreement with the statement, “It would be useful to know the percentage of patients having persistent symptoms more than a year after getting the same treatment I am getting.” Treatment intention (curative vs. palliative) was reported by the treating oncologist. Results: 196 patients completed the survey. The mean age was 55.7 (range 20-80); 54% were female, 69% were white, and 60% were receiving palliative treatment. The majority (83%) of patients either strongly agreed or somewhat agreed that it would be helpful to have information about future symptoms. In univariable analyses, this preference did not significantly differ based on patient-reported performance status, sex, age, treatment intent, race, or household income. Using a more stringent criterion to dichotomize the outcome, 59% of participants strongly agreed that it would be helpful to have information about future symptoms. Patients undergoing treatment with curative intent were significantly more likely to strongly agree (72% vs. 51%, p = 0.0035). In a multivariable analysis adjusting for age, sex, income level, employment status, and patient-reported performance status, participants undergoing curative versus palliative treatment had 3.1 times the odds (95% CI 1.47-6.65) of strongly agreeing. Conclusions: The majority of patients undergoing cancer treatment wanted to know what symptoms to expect in the future, and this was independent of patient demographics. Patients undergoing treatment with curative intent are significantly more likely to want this information than patients undergoing palliative treatment. Symptom data collected through research studies and registries should be summarized by treatment and other key predictors and made available to patients.

6523 Background: Treatment for most types of cancer results in work disruptions. The aim of this study is to identify risk factors for not working during cancer therapy using a patient-reported outcome tool. Methods: Patients of all cancer types, who were undergoing treatment with curative or palliative intent, were enrolled in a survey-based study at Memorial Sloan Kettering Cancer Center and the North Carolina Cancer Hospital from 1/2014 to 7/2015. All patients working full- or part- time at the time of cancer diagnosis were included in this analysis. Patient reported outcomes were collected using a survey tool at any time during active cancer treatment. The primary outcome of this analysis was self-reported work status at the time of survey completion. Results: Of 119 patients who were working before their cancer diagnosis, 68% were working at the time of survey completion. The mean age was 52.9 (range 20-80). Younger age was associated with working: 82% of patients age < 40 were working during treatment vs. 31% of patients age > 65 (p=0.01). The number of days patients reported being completely unable to work in the past month was significantly associated with work status; only 26% of patients who missed > 10 days continued to work compared to 69% who missed ≤ 10 days (p<0.01). Patients who report having a flexible work schedule were 23% more likely to continue to work during treatment (69% vs. 46%, p=0.01). In a multivariable model controlling for having an employer contingent health plan, and household income > 200% of the federal poverty level (fpl), only age, having a flexible work schedule, and inability to work > 10 days were independently associated with work status during treatment (Table). Conclusions: Having a flexible work schedule allowed for more work interruptions without job loss. Patients who are likely to miss more than 10 days of work and who have inflexible work schedules are at high risk of unemployment and should be targeted for employment retention initiatives. [Table: see text]

Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities. Methods We studied kidney biopsy specimens from living kidney donors ( n =2453) and patients who underwent radical nephrectomy for a renal tumor ( n =780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel–Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen. Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli ( P <0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume. Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity.

Objective: To characterize agreement in the ascertainment of surgical site infections (SSIs) between the National Surgical Quality Improvement Program (NSQIP), National Healthcare Safety Network (NHSN), and administrative data. Background: The NSQIP, NHSN, and administrative data are the primary systems used to monitor and report SSIs for the purpose of quality control and benchmarking of hospitals and surgeons. These systems have different methods for identifying SSIs. Methods: We queried the NHSN, NSQIP, and administrative data systems for patients who had an operation at 1 of 4 hospitals within a single health system between January 2013 and September 2015. The detection of an SSI during a postoperative hospitalization was the outcome of analysis. Any SSI detected by one (or more) of these systems was analyzed by 2 reviewers to determine the presence of discrete elements of documentation constituting evidence of SSI. Concordance between the 3 systems (NHSN, NSQIP, and administrative data) was analyzed using Cohen's kappa. Results: After application of appropriate exclusion criteria, a cohort of 9447 inpatient operations was analyzed. In total, 130 SSIs were detected by 1 or more of the 3 systems, with reported SSI rates of 0.5% (NHSN), 0.7% (administrative data), and 1.0% (NSQIP). Of these 130 SSIs, only 17 SSIs were reported by all 3 systems. The concordance between these 3 systems was moderate (kappa values NSQIP-NHSN = 0.50 [0.40–0.60], administrative-NHSN = 0.36 [0.24–0.47], and administrative-NSQIP = 0.47 [0.38–0.57]). Chart review found that reasons for discordance were related to issues of different criteria as well as inaccuracies. Conclusion: There is significant discordance in the determination of SSIs reported by the NHSN, NSQIP, and administrative data. The differences and limitations of each of these systems have to be recognized, especially when using these data for quality reports and pay for performance.

Fibrillary GN (FGN) is a rare primary glomerular disease. Histologic and histochemical features of FGN overlap with those of other glomerular diseases, and no unique histologic biomarkers for diagnosing FGN have been identified. We analyzed the proteomic content of glomeruli in patient biopsy specimens and detected DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) as the fourth most abundant protein in FGN glomeruli. Compared with amyloidosis glomeruli, FGN glomeruli exhibited a >6-fold overexpression of DNAJB9 protein. Sanger sequencing and protein sequence coverage maps showed that the DNAJB9 protein deposited in FGN glomeruli did not have any major sequence or structural alterations. Notably, we detected DNAJB9 in all patients with FGN but not in healthy glomeruli or in 19 types of non-FGN glomerular diseases. We also observed the codeposition of DNAJB9 and Ig- γ . Overall, these findings indicate that DNAJB9 is an FGN marker with 100% sensitivity and 100% specificity. The magnitude and specificity of DNAJB9 overabundance in FGN also suggests that this protein has a role in FGN pathogenesis. With this evidence, we propose that DNAJB9 is a strong biomarker for rapid diagnosis of FGN in renal biopsy specimens.

Abstract Mature peripheral double negative T (DNT) cells expressing αβ TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ αβ TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ αβ TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

AbstractToxic shock syndrome toxin‐1 (TSST‐1) is a potent superantigen produced by Staphylococcus aureus. In addition to menstrual and nonmenstrual toxic shock syndromes, TSST‐1 is also implicated in the immunopathogenesis of pneumonia, infective endocarditis, neonatal exanthematous disease, and atopic dermatitis among others. Superantigens first bind to major histocompatibility complex (MHC) class II molecules and then activate a large proportion of T cells by cross‐linking their T cell receptor. As binding to MHC class II molecules is a critical step in the robust activation of the immune system by TSST‐1 and other superantigens, polymorphic variations between different HLA‐DR alleles could potentially influence the magnitude of immune activation and immunopathology caused by TSST‐1. As TSST‐1 is highly toxic to humans and given that multiple variations of alleles of HLA‐DR and HLA‐DQ are expressed in each individual, it is difficult to determine how HLA‐DR polymorphisms quantitatively and qualitatively impact immune activation caused by TSST‐1 in humans. However, such investigations can be conducted on transgenic mice lacking all endogenous MHC class II molecules and expressing specific HLA class II alleles. Therefore, transgenic mice expressing different HLA‐DRB1 alleles (HLA‐DRB1*15:01, HLA‐DRB1*15:02, HLA‐DRB1*03:01, HLA‐DRB1*04:01), and sharing HLA‐A1*01:01 chain, were systemically challenged with purified TSST‐1 and multiple immune parameters were assessed. Among the HLA‐DR alleles, mice expressing HLA‐DRB1*15:01 allele elicited a significantly higher serum cytokine/chemokine response; greater splenic T cell expansion and most severe organ pathology. Our study highlights the potential utility of human leukocyte antigen (HLA) transgenic mice in understanding the impact of HLA polymorphisms on the outcomes of diseases caused by TSST‐1 and other superantigens.