Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.

Despite their importance, natural killer (NK) cell responses are frequently dysfunctional during human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, even irrespective of antiretroviral therapies, with poorly understood underlying mechanisms. NK cell surface receptor modulation in lentivirus infection has been extensively studied, but a deeper interrogation of complex cell signaling is mostly absent, largely due to the absence of any comprehensive NK cell signaling assay. To fill this knowledge gap, we developed a novel multiplex signaling analysis to broadly assess NK cell signaling. Using this assay, we elucidated that NK cells exhibit global signaling reduction from CD16 both in people living with HIV-1 (PLWH) and SIV-infected rhesus macaques. Intriguingly, antiretroviral treatment did not fully restore diminished CD16 signaling in NK cells from PLWH. As a putative mechanism, we demonstrated that NK cells increased surface ADAM17 expression via elevated plasma IL-18 levels during HIV-1 infection, which in turn reduced surface CD16 downregulation. We also illustrated that CD16 expression and signaling can be restored by ADAM17 perturbation. In summary, our multiplex NK cell signaling analysis delineated unique NK cell signaling perturbations specific to lentiviral infections, resulting in their dysfunction. Our analysis also provides mechanisms that will inform the restoration of dysregulated NK cell functions, offering potential insights for the development of new NK cell-based immunotherapeutics for HIV-1 disease.

POSTOPERATIVE INSULIN REQUIREMENTS IN BARIATRIC SURGERY.

OBJECTIVE: Though insulin dose reduction months after surgery is a well-studied outcome, there are limited data on immediate postoperative changes. The goals of the present study were to ( 1) To determine peri-operative glycemic control in patients with type 2 diabetes mellitus (DM) on insulin who have undergone Roux-en-Y gastric bypass (RYGB) and ( 2) to compare pre- and postoperative insulin regimens and dosages in these patients. METHODS: A retrospective chart review was conducted on patients with type 2 DM on insulin who underwent RYGB surgery. Blood glucose (BG) levels and insulin doses were compared prior to surgery, on the day of surgery (DOS), and postoperative days (POD) 1 and 2. Subgroup analysis was performed to see if insulin dose was related to glucose control. RESULTS: There were 114 subjects with a mean (SD) age of 52.8 ± 9.8 years, body mass index (BMI) 46.2 ± 8.0 kg/m2, glycated hemoglobin A1c (HbA1c) 8.3% (67 mmol/mol) ± 1.7%, and 66% on insulin plus noninsulin medications and 34% on insulin only. Mean blood glucose (BG) significantly decreased from the DOS (185 ± 43 mg/dL) through POD2 (160 ± 36, P<.0001). The median daily insulin dose significantly decreased from before surgery on usual diet (75 units [36, 116 interquartile range (IQR)]) through POD2 (6 [2, 15 IQR]), P<.0001). The median insulin dose per body weight decreased significantly from before surgery on usual diet (0.58 units/kg [0.35, 0.84 IQR]) through POD2 (0.04 [0.02, 0.11 IQR]), P<.0001). The subgroup with relatively good control experienced a larger percentage reduction in insulin requirements versus subjects with poor control. CONCLUSION: An 87.5% reduction in total daily insulin dose was seen by POD2. This will assist in developing algorithms for insulin titration postbariatric surgery. ABBREVIATIONS: BG = blood glucose DM = diabetes mellitus DOS = day of surgery HbA1c = glycated hemoglobin IQR = interquartile range IV = intravenous NPH = neutral protamine Hagedorn POD = postoperative day RYGB = Roux-en-Y gastric bypass SSRI = sliding scale regular insulin.

Promoter Hypermethylation and Decreased Expression of Syncytin-1 in Pancreatic Adenocarcinomas.

Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1). Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s) in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.

Expression and diagnostic value of HE4 in pancreatic adenocarcinoma.

Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 mRNA level in tumor adjacent tissues and pancreatic adenocarcinoma tissues were tested by real time-PCR. Tissue microarray containing normal, adenocarcinoma, and adjacent pancreatic tissue was tested by immunohistochemistry (IHC). Serum level of HE4, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) were detected by ELISA assay in control and tumor patients. Further we compared the sensitivity and specificity of determining HE4, CA19-9, CA15-3, and CA125 for diagnosis of pancreatic adenocarcinoma and assessed the complementary diagnostic value of HE4, CA19-9, CA15-3 and CA125. Real time PCR showed significantly increased HE4 mRNA level in pancreatic adenocarcinoma compared with control. Result of IHC showed that HE4 significantly higher expressed in the human pancreatic carcinoma tissues than in both normal and adjacent non-tumorous pancreatic tissues, and the staining intensity is inversely correlated with the clinical stage. HE4 was highly expressed in early stage of pancreatic adenocarcinoma. Serum HE4 level is higher in cases with pancreatic adenocarcinoma than in the controls. Serum HE4 levels could research to a sensitivity of 45.83% and specificity of 93.75% when the Cutoff was set at 4.59 ng/mL. The Combined HE4 and CA19-9 increased the sensitivity to 83.33%; and interestingly, the combination of HE4 with CA15-3 led to the most powerful sensitivity of 87.5%. Combined with CA19-9 and CA15-3, HE4 could be a potential biomarker to improve the diagnostic power for pancreatic adenocarcinoma.

Development, implementation, and evaluation of a comprehensive fall risk program.

PURPOSE: The purpose was to develop and implement I'M SAFE, a comprehensive patient fall-risk assessment tool linked to a tiered-intervention falls prevention program. DESIGN AND METHOD: A fall-risk evaluation tool was incorporated into electronic nurse documentation along with risk-specific nursing interventions. RESULTS: Intrinsic fall rates declined significantly (preimplementation: .67 falls/1,000 patient days; postimplementation: .51 falls/1,000 patient days, p = .015) and has been sustained 2 years following implementation. PRACTICE IMPLICATIONS: The I'M SAFE tool identifies patients at increased risk for falls. When linked to a multidisciplinary fall prevention program, the incidence of preventable falls can be reduced. The program's impact has persisted across two facilities.