Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and-active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.

Background: Neisseria gonorrhoeae infections are becoming increasingly resistant to recommended treatments. Resistance-guided therapy may mitigate the continued emergence of resistance by enabling the use of previously recommended treatments like ciprofloxacin. To describe the effectiveness of ciprofloxacin to treat "susceptible" infections, we estimated the clinical efficacy of ciprofloxacin at various minimum inhibitory concentrations (MICs) and anatomic sites. Methods:We reviewed publicly available reports using the PubMed.gov database and search terms "gonorrhea/drug therapy"[Mesh] AND "ciprofloxacin". We included clinical treatment studies in which ciprofloxacin was administered alone to treat N. gonorrhoeae, specimens were collected for N. gonorrhoeae culture from each infection, the MIC was determined for ≥90% of infective strains, and individual treatment outcomes were clearly defined. We recorded those data, ciprofloxacin dose and infection site. We calculated the frequency of treatment success and 95% confidence intervals (CIs).Results: Twenty studies from 1985 to 2020 met our inclusion criteria. Ciprofloxacin at commonly used doses eliminated 99.2% (95% CI, 98.5%-99.6%; n = 1439) of gonococcal infections with MICs <0.125 μg/mL, 76.3% (95% CI, 59.8%-88.6%; n = 38) of infections with MICs from 0.125 to 0.5 μg/mL, and 30.1% (95% CI, 20.5%-41.2%; n = 83) of infections with MICs ≥1 μg/mL across anatomic sites. Conclusions: Ciprofloxacin reliably eliminated gonococcal infectionswith MICs <0.125 μg/mL across anatomic sites. Molecular assays predicting MICs of ciprofloxacin <0.125 μg/mL of gonococcal strains can allow for reintroduction of ciprofloxacin in gonorrhea treatment. Clinicians can confidently use ciprofloxacin to treat susceptible gonococcal infections.A ntibiotic-resistant Neisseria gonorrhoeae has become a major public health problem. 1 According to the World Health Organization (WHO), more than 86.9 million people were infected with N. gonorrhoeae worldwide in 2016. 2 N. gonorrhoeae has developed resistance to nearly all classes of antibiotics including sulfonamides, penicillins, tetracyclines, macrolides, fluoroquinolones, and extended-spectrum cephalosporins. 1,3,4 Between 2009 and 2014, WHO data suggest 97% of 72 countries with gonococcal resistance surveillance programs found ciprofloxacin-resistant gonococcal isolates during at least 1 year. 4 The highest levels of ciprofloxacin-resistant N. gonorrhoeae are concentrated in eastern Asia as well as scattered regions of Europe, Africa, and South and Central America. 4 The WHO gonorrhea treatment guidelines recommend treating gonococcal infection with an intramuscular injection of ceftriaxone 250 mg (or cefixime 400 mg orally) and azithromycin 1 g as a single oral dose. 5 However, recent literature has documented strains of N. gonorrhoeae with increased minimum inhibitory concentrations (MICs) to extended-spectrum cephalosporins, including ceftriaxone and cefixime. [6][7][8][9][10][11][12] Although extensive resistance to ciprofloxacin, a fluoro...

Background: Evidence suggests the renin-angiotensin system (RAS) plays key immunomodulatory roles. In particular, angiotensin-converting enzyme (ACE) has been shown to play a role in antimicrobial host defense. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are some of the most commonly prescribed medications, especially in patients undergoing invasive surgery. Thus, the current study assessed the immunomodulatory effect of RAS-modulation in a preclinical model of implant infection. Methods: In vitro antimicrobial effects of ACEi and ARBs were first assessed. C57BL/6J mice subsequently received either an ACEi (lisinopril; 16 mg/kg/day), an ARB (losartan; 30 mg/kg/day), or no treatment. Conditioned mice blood was then utilized to quantify respiratory burst function as well as Staphylococcus aureus Xen36 burden ex vivo in each treatment group. S. aureus infectious burden for each treatment group was then assessed in vivo using a validated mouse model of implant infection. Real-time quantitation of infectious burden via bioluminescent imaging over the course of 28 days post-procedure was assessed. Host response via monocyte and neutrophil infiltration within paraspinal and spleen tissue was quantified by immunohistochemistry for F4/80 and myeloperoxidase, respectively. Results: Blood from mice treated with an ACEi demonstrated a decreased ability to eradicate bacteria when mixed with Xen36 as significantly higher levels of colony forming units (CFU) and biofilm formation was appreciated ex vivo (p < 0.05). Mice treated with an ACEi showed a higher infection burden in vivo at all times (p < 0.05) and significantly higher CFUs of bacteria on both implant and paraspinal tissue at the time of sacrifice (p < 0.05 for each comparison). There was also significantly decreased infiltration and respiratory burst function of immune effector cells in the ACEi group (p < 0.05). Conclusion: ACEi, but not ARB, treatment resulted in increased S. aureus burden and impaired immune response in a preclinical model of implant infection. These results Trikha et al. ACE Inhibition Increases Staphylococcal Burden suggest that perioperative ACEi use may represent a previously unappreciated risk factor for surgical site infection. Given the relative interchangeability of ACEi and ARB from a cardiovascular standpoint, this risk factor may be modifiable.

Objectives: To understand the acceptability and feasibility of sexually transmitted infection (STI) testing during antenatal care, along with the prevalence of STIs, in Rawalpindi, Pakistan. Methods: We enrolled pregnant women seeking antenatal care and performed STI testing using Cepheid GeneXpert® CT/NG and TV kits and Alere Determine™ HIV and syphilis tests. We used interviewer-administered surveys to collect medical, social, and sexual histories. Participants testing positive for STIs and their partners were treated. Results: We enrolled 1001 women from September to December 2019. Nearly all women offered to participate in this study enrolled. Most women understood the effects an STI can have on their pregnancy (99.6%) and valued STI screening during pregnancy (98.1%). 11 women tested positive for any STI: ( Chlamydia trachomatis = 4, Neisseria gonorrhoeae = 1, and Trichomonas vaginalis = 6). Of those, six presented for a test-of-cure, and two were positive for Trichomonas vaginalis. None tested positive for HIV infection or syphilis ( n = 503). Conclusions: STI testing during antenatal care in Rawalpindi was acceptable, valued, understood, and feasible. The prevalence of STIs in pregnant women was low. Continued prevalence monitoring is warranted.

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Pre-clinical syngeneic mouse models are at the forefront of testing and understanding emerging novel immune based therapies prior to their translation in patients. We generated distinct imageable syngeneic GBM-tumor models and assessed tumor infiltrating immune cells from end-stage tumors by utilizing RNA sequencing, CyTOF (mass Cytometry by Time of Flight) and correlative immunohistochemistry. CyTOF facilitates multiparametric analysis of up to 40 different markers which is useful especially in the case of GBM where number of TILs is limiting. We identified immunologically-inert and active syngeneic tumor types and show that inert tumors have an immune-suppressive phenotype with numerous MDSCs (Ly6C+ CD11b+), exhausted CD8 T cells and fewer eosinophils. To mimic the clinical settings of first line of GBM treatment, we performed tumor resection in an immunologically inert tumor model. We show that tumor-resection invigorates an anti-tumor response via significant increase in CD8+ T cells, monocyte/macrophages and decrease in Ly6G+ myeloid cells. A comparative CyTOF analysis of resected-tumor samples from GBM patients and mouse GBM tumors showed stark similarities in one of the mouse GBM tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients. Citation Format: Jasneet K. Khalsa, Joshua W. Keegan, Nina Cheng, Joseph Driver, Ameen Chaudry, Wenya Linda Bi, James A. Lederer, Khalid Shah. Immune phenotyping of diverse syngeneic brain tumors identifies critical tumor micro-environmental differences [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-354.