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Objectives The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease. Methods All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR≥30 mL/min/1.73m2 were included. Moderate-to-severe TID was defined as the presence of moderate to severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate to severe TID was predictive of ESRD progression. Results Of the 131 LN patients with eGFR≥30 mL/min/1.73m2, 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR≥60 mL/min/1.73m2 and in 33% of biopsies with eGFR between 30 and 60 mL/min/1.73m2. Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI (1.4, 12.1), p=0.01 for eGFR≥30 mL/min/1.73m2; HR 6.2, 95% CI (1.7, 23.2), p=0.008 for eGFR≥60 mL/min/1.73m2. There was no association between tubulointerstitial inflammation (TII) and ESRD progression. Conclusions Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions.

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Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.

The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations.

The host immune response is characterized by a complex interplay of signal‐specific cellular transcriptional responses. The magnitude of the immune response is dependent on the strength of the external stimulus. Knowledge on leukocyte transcriptional responses altered in response to different stimulus dosages in man is lacking. Here, we sought to identify leukocyte transcriptional signatures dependent on LPS dose in humans. Healthy human volunteers were administered 1 ng/kg (n = 7), 2 ng/kg (n = 6), or 4 ng/kg (n = 7) LPS intravenously. Blood was collected before (pre‐LPS) and 4 h after LPS administration. Total RNA was analyzed by microarrays and generalized linear models. Pathway analysis was performed by using Ingenuity pathway analysis. Leukocyte transcriptomes altered per LPS dosage were predominantly shared, with 47% common signatures relative to pre‐LPS. A univariate linear model identified a set of 3736 genes that exhibited a dependency on differing LPS dosages. Neutrophil, monocyte, and lymphocyte counts explained 38.9% of the variance in the LPS dose‐dependent gene set. A multivariate linear model including leukocyte composition delineated a set of 295 genes with a dependency on LPS dose. Evaluation of the 295 gene signature in patients with sepsis due to abdominal infections showed significant correlations. Promoter regions of the LPS dose gene set were enriched for YY1, EGR1, ELK1, GABPA, KLF4, and REL transcription factor binding sites. Intravenous injection of 1, 2, or 4 ng/kg LPS was accompanied by both shared and distinct leukocyte transcriptional alterations. These data may assist in assessing the severity of the insult in patients with abdominal sepsis.