Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9.

NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-γ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3(+) population of low-dose IL-12/IL-18-activated primary NK cells significantly increased IFN-γ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-γ production, and Tim-3 cross-linking induced ERK activation and degradation of IκBα. Exposure to Gal-9-expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-γ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-γ production, which has important implications for control of infectious disease and cancer.

Postoperative Complications of Appendectomy in Gynecologic Laparoscopic Surgery for Benign Indications.

OBJECTIVE: To assess whether concomitant appendectomy in patients who undergo laparoscopic surgery for benign gynecologic indications is associated with increased rates of complications in the 30-day postoperative period. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify patients who underwent laparoscopic surgery by a gynecologist. Patients were excluded if they underwent open abdominal surgeries, bowel resections, urogynecologic surgeries, or if diagnoses of cancer or appendicitis were present. There were 246,987 patients included in the population cohort from 2010 to 2020. Demographic information and postoperative outcomes of patients who underwent concomitant appendectomy were compared with patients who did not undergo appendectomy. A matched cohort was created by computing propensity scores, and outcomes were again compared between groups. All patients undergoing appendectomy were 1:1 matched to a unique patient who did not undergo appendectomy using a greedy matching based on the propensity score calculated from demographic and surgical characteristics. RESULTS: A total of 1,760 patients (0.7%) underwent concomitant appendectomy. There was an 8.0% complication rate in the appendectomy group, compared with 5.5% in the group of those without appendectomy ( P <.001), and this was similar to the results in the propensity-matched sample. Patients who underwent appendectomy had significantly higher rates of readmission (4.3% vs 2.3%), which remained significant in the propensity-matched sample. There were no differences in the rates of postoperative thromboembolic events, blood transfusion, or reoperation. CONCLUSION: Patients who are undergoing concomitant appendectomy have an increased risk of any complication and hospital readmission. Additional studies may be conducted to identify patients with optimal risk benefit profiles when considering performing concomitant appendectomy at time of gynecologic surgery.

In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus.

Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient. We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that administration of a viral DNA polymerase inhibitor, MBV, and/or a viral terminase inhibitor in combination has the potential to address the resistance/cross-resistance problems associated with currently available therapeutics.