These results indicate that PPI therapy is associated with a significant reduction in the risk of developing dysplasia in patients with BE. However, more studies are required to confirm this finding.

We demonstrate that tuberculosis lesions in C3HeB/FeJ are hypoxic. Activities of some key tuberculosis drug regimens in development are represented differently in C3HeB/FeJ versus BALB/c mice. Because C3HeB/FeJ display key features of human tuberculosis, this strain warrants evaluation as a more pathologically relevant model for preclinical studies.

Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.Patients and Methods: The study consisted of a 3 þ 3 doseescalation stage (n ¼ 66) and a tumor-specific expansion stage (n ¼ 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day À1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.Results: Patients (n ¼ 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizu-mab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, nonsmall cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) doseescalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

BackgroundThe success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX).MethodsBALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm3. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment.ResultsHumanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor.ConclusionHu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0518-z) contains supplementary material, which is available to authorized users.

Tools for monitoring response to tuberculosis (TB) treatment are time-consuming and resource intensive. Noninvasive biomarkers have the potential to accelerate TB drug development, but to date, little progress has been made in utilizing imaging technologies. Therefore, in this study, we used noninvasive imaging to monitor response to TB treatment. BALB/c and C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered bactericidal (standard and highly active) or bacteriostatic TB drug regimens. Serial pulmonary [18 F]-2-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) was compared with standard microbiologic methods to monitor the response to treatment. [18 F]FDG-PET correctly identified the bactericidal activity of the drug regimens. Imaging required fewer animals; was available in real time, as opposed to having CFU counts 4 weeks later; and could also detect TB relapse in a time frame similar to that of the standard method. Lesion-specific [18 F]FDG-PET activity also broadly correlated with TB treatment in C3HeB/FeJ mice that develop caseating lesions. These studies demonstrate the application of noninvasive imaging to monitor TB treatment response. By reducing animal numbers, these biomarkers will allow costeffective studies of more expensive animal models of TB. Validated markers may also be useful as "point-ofcare" methods to monitor TB treatment in humans.New and shorter drug regimens for tuberculosis (TB) are needed to support global control efforts. However, tools for monitoring TB drug treatment in preclinical studies and clinical trials are time-consuming and resource intensive. For instance, typical phase 3/4 trials entail treating hundreds of patients for at least 6 months and monitoring them for at least 1 year for relapse. Phase 2 studies that monitor patients for 8 weeks for sputum culture conversion are limited because sputum bacterial burdens are not available in real time and do not always correlate closely with overall pulmonary disease. This situation is unlike clinical trials evaluating treatments against human immunodeficiency virus infection, where quantitative viral loads and CD4 counts provide well-validated biomarkers of disease burden and progression of disease, respectively. With the alarming rise of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis infections, which account for up to 20% and 2%, respectively, of the global TB disease burden (6), there is significant interest in the use of validated biomarkers to monitor TB treatment in patients. Since clinical indicators can often be misleading, these biomarkers may allow more rapid identification of patients who relapse or respond poorly to TB treatment. The TB Trials Consortium (TBTC) has expressed an urgent need for development of validated biomarkers for monitoring and detecting relapse during and after TB treatment in patients (29). Several biomarker technologies for monitoring TB treatment are under development, though none utilize imaging technologies (24). A...

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are limited therapeutic options for the prevention and treatment of SARS-CoV-2 infections. We evaluated the antiviral activity of sulforaphane (SFN), the principal biologically active phytochemical derived from glucoraphanin, the naturally occurring precursor present in high concentrations in cruciferous vegetables. SFN inhibited in vitro replication of six strains of SARS-CoV-2, including Delta and Omicron, as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN should be explored as a potential agent for the prevention or treatment of coronavirus infections.

BackgroundBacteria can be selectively imaged in experimentally-infected animals using exogenously administered 1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-[125I]-iodouracil ([125I]-FIAU), a nucleoside analog substrate for bacterial thymidine kinase (TK). Our goal was to use this reporter and develop non-invasive methods to detect and localize Mycobacterium tuberculosis.Methodology/Principal Findings We engineered a M. tuberculosis strain with chromosomally integrated bacterial TK under the control of hsp60 - a strong constitutive mycobacterial promoter. [125I]FIAU uptake, antimicrobial susceptibilities and in vivo growth characteristics were evaluated for this strain. Using single photon emission computed tomography (SPECT), M. tuberculosis Phsp60 TK strain was evaluated in experimentally-infected BALB/c and C3HeB/FeJ mice using the thigh inoculation or low-dose aerosol infection models. M. tuberculosis Phsp60 TK strain actively accumulated [125I]FIAU in vitro. Growth characteristics of the TK strain and susceptibility to common anti-tuberculous drugs were similar to the wild-type parent strain. M. tuberculosis Phsp60 TK strain was stable in vivo and SPECT imaging could detect and localize this strain in both animal models tested.ConclusionWe have developed a novel tool for non-invasive assessment of M. tuberculosis in live experimentally-infected animals. This tool will allow real-time pathogenesis studies in animal models of TB and has the potential to simplify preclinical studies and accelerate TB research.

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