Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer.

BACKGROUND: The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production. METHODS: Co-culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class, IDO1/TDO2 dual inhibitor AT-0174 at 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated. RESULTS: CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8+ T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8+ T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved immunity in CR tumors which in turn extended overall survival in mice. CONCLUSION: Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.

Clients' Perspectives on Patient-Centeredness: a Qualitative Study with Low-Income Minority Women Receiving HIV Care in South Florida.

Low-income, minority women living with HIV often experience multiple barriers in care that contribute to suboptimal care outcomes. Medical case managers (MCM) and medical providers are key players involved in care coordination and aid women along the HIV care continuum. The objective of this study was to identify current and potential patient-centered practices that facilitate adherence to medication and retention in care, from the perspective of racially and ethnically diverse women living with HIV. We implemented a qualitative study using semi-structured interviews with 75 African American, Hispanic/Latina, and Haitian women who were enrolled in the Ryan White HIV/AIDS Program in South Florida in 2019. We organized domains of exploration using a patient-centered care framework to identify practices in which providers acknowledged, respected, and responded to clients' preferences, needs, and values. Interviews were analyzed using consensual thematic analysis approach. Findings reflect women valued MCMs who were proactive and directive in care, provided motivation, and aided with navigation of shame, fear, and stigma. Women valued medical providers who upheld simple educational communication. Moreover, women reported that providers who reviewed medical results with clients, incorporated questions about families, and inquired about multiple physical and clinical needs beyond HIV created opportunities for women to feel respected, valued, and in turn, enhanced their involvement in their care. Findings identify specific interpersonal practices that can enhance the ability to better meet the needs of diverse groups of women, specifically those from racial/ethnic minority groups who face multiple sociocultural barriers while in care.

Assessment of BRAF V600E (VE1) immunochemistry for the detection of BRAF V600E mutation in non-small cell lung carcinoma cytology specimens.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) patients with BRAF V600E-mutated tumors respond to targeted therapy. Testing for BRAF V600E is commonly performed with molecular methods; however, a mutation-specific VE1 antibody clone can provide an alternative testing option using immunohistochemistry (IHC) for practices using single-gene testing and in situations when the specimen is inadequate for molecular testing. This study evaluates the usefulness of VE1 IHC in screening for BRAF V600E mutations in NSCLC cytology specimens. METHODS: The authors retrospectively identified cytology cases with a diagnosis of NSCLC that had BRAF V600E IHC performed on cell block sections with the monoclonal VE1 antibody clone. The BRAF V600E IHC results were compared with those of molecular testing performed with an amplicon-based next-generation sequencing assay. RESULTS: There were 201 NSCLC cases evaluated. The VE1 IHC was positive in seven of seven BRAF V600E-mutated tumors (100%) and was negative in 158 of 158 nonmutated BRAF V600E tumors (100%). Thirty cases did not undergo molecular testing, primarily because of insufficient tissue or because molecular testing was performed on an alternative specimen. Six cases showed equivocal weak/focal staining: Two cases demonstrated BRAF V600E mutations, and four cases were negative by molecular testing. CONCLUSIONS: This study suggests that BRAF V600E IHC can be used reliably to screen NSCLC cytology specimens, and negative results strongly indicate the absence of a BRAF V600E mutation. Having a low threshold for equivocal staining is recommended with molecular confirmation of BRAF V600E for any cases demonstrating weak and/or focal cytoplasmic staining.

Draft Genome Sequence of Paenibacillus sp. Strain OT2-17, a Triclosan-Degrading Rhizobacterium.

We report the draft genome sequence of a strain (OT2-17) of Paenibacillus isolated from the rhizosphere of onions irrigated with triclosan. Strain OT2-17 demonstrated the use of triclosan as the sole carbon source. A genome assembly of approximately 5.8 Mb was generated with a calculated G+C content of 45.5%.

Fatal Intracranial Hemorrhage in a Young Pregnant Patient with Acute Promyelocytic Leukemia.

Acute promyelocytic leukemia during pregnancy is associated with a high risk of fetal and obstetrical complications. Although the prognosis of acute promyelocytic leukemia is favorable due to disease-specific drugs, such as all-trans retinoic acid, early death due to fatal intracranial hemorrhage has been observed in some cases. In this study, we present a case of catastrophic intracranial hemorrhage in a young pregnant patient with the finding of leukemic involvement of the placenta. To our knowledge, this is the first confirmed case of acute promyelocytic leukemia involving the placenta. The clinical history, pertinent histological findings, and clinical outcomes will be discussed.

Wound botulism caused by Clostridium subterminale after a heroin injection.

Botulism is caused by toxin production from many species of Clostridium, most commonly Clostridium botulinum as well as C. baratii and C. butyricum. Development of wound botulism is associated with injection drug users but has also been described in traumatic injuries with exposure to soil. A patient presented to the emergency department with a complaint of descending, progressive weakness. He recently reported skin popping with heroin injections. Heptavalent botulinum antitoxin was obtained from the [Center for Disease Control and Prevention (CDC)]. On hospital day seven, the anaerobic wound cultures resulted with growth of Clostridium subterminale.

miR-132 couples the circadian clock to daily rhythms of neuronal plasticity and cognition.

The microRNA miR-132 serves as a key regulator of a wide range of plasticity-associated processes in the central nervous system. Interestingly, miR-132 expression has also been shown to be under the control of the circadian timing system. This finding, coupled with work showing that miR-132 is expressed in the hippocampus, where it influences neuronal morphology and memory, led us to test the idea that daily rhythms in miR-132 within the forebrain modulate cognition as a function of circadian time. Here, we show that hippocampal miR-132 expression is gated by the time-of-day, with peak levels occurring during the circadian night. Further, in miR-132 knockout mice and in transgenic mice, where miR-132 is constitutively expressed under the control of the tetracycline regulator system, we found that time-of-day dependent memory recall (as assessed via novel object location and contextual fear conditioning paradigms) was suppressed. Given that miRNAs exert their functional effects via the suppression of target gene expression, we examined the effects that transgenic miR-132 manipulations have on MeCP2 and Sirt1-two miR-132 targets that are associated with neuronal plasticity and cognition. In mice where miR-132 was either knocked out, or transgenically expressed, rhythmic expression of MeCP2 and Sirt1 was suppressed. Taken together, these results raise the prospect that miR-132 serves as a key route through which the circadian timing system imparts a daily rhythm on cognitive capacity.

Evaluating the impact of prescription drug monitoring program implementation: a scoping review.

BACKGROUND: Prescription drug monitoring programs (PDMPs) have been implemented in 49 out of 50 states in an effort to reduce opioid-related misuse, abuse, and mortality, yet the literature evaluating the impact of PDMP implementation remains limited. We conducted a scoping review to: (1) describe available evidence regarding impact of PDMPs in the U.S.; and (2) propose a conceptual model to inform future PDMP implementation and evaluation efforts. METHODS: Scoping systematic review following Arksey and O'Malley's (2005) methodology. We identified 11 relevant studies based on inclusion criteria using a PubMed database search of English-language studies published 1/1/2000-5/31/16. Data were extracted and thematic analysis conducted to synthesize results. RESULTS: Extant evidence for the impact of PDMPs as an opioid risk mitigation tool remains mixed. Thematic analysis revealed four domains of opioid-related outcomes frequently examined in original studies evaluating PDMP implementation: (1) opioid prescribing; (2) opioid diversion and supply; (3) opioid misuse; and (4) opioid-related morbidity and mortality. An evaluation framework incorporating these domains is presented that highlights significant gaps in empirical research across each of these domains. CONCLUSIONS: Evidence for the impact of state-level PDMPs remains mixed. We propose a conceptual model for evaluating PDMP implementation toward the goals of clarifying PDMP mechanisms of impact, identifying characteristics of PDMPs associated with best outcomes, and maximizing the utility of PDMP policy and implementation to reduce opioid-related public health burden.

A reevaluation of the specimens of Mesocoelium (Trematoda: Mesocoeliidae) in the Colección Nacional de Helmintos, Mexico.

Species of Mesocoelium Odhner, 1901 (Digenea) are generally similar and are often difficult to distinguish. Currently there are 42 specimens of this genus held in the Colección Nacional de Helmintos (CNHE) of the Instituto de Biología, Universidad Nacional Autónoma de Mexico, which previously have been assigned to three species: M. monas Rudolphi, 1819, M. travassosi Pereira & Cuocolo, 1940 and M. leiperi Bhalerao, 1936. Upon reevaluation of these specimens it was determined that 27, could not be assigned to species level and 15 could only be assigned to body type (carli and leiperi) because of the poor conditions of preservation of the material. The remaining 15 specimens were of sufficient quality to be identified to species and were found to represent M. americanum Harwood, 1932, M. danforthi Hoffman, 1935, M. meggitti Bhalerao, 1927, M. cf. americanum Harwood, 1932, and M. cf. danforthi Hoffman, 1935. Neither M. monas nor M. travassosi could be confirmed among these specimens; however, Mesocoelium meggitti (syn. M. travassosi) was confirmed. Mesocoelium danforthi is recorded for the first time in the Mexican collection. The presence of M. cf. gonocephali Singh, 1967 and M. cf. microon Nicoll, 1914 also among the 15 specimens of sufficient quality to be identified to species, needs to be confirmed through collects of new material. Finally, in future studies, we propose to improve the quality of specimens by fixing them considering the modifications to this process proposed herein, and compliment these morphological studies with molecular studies.

Differential diagnosis of deep gluteal pain in a female runner with pelvic involvement: a case report.

BACKGROUND: Gluteal injuries, proximal hamstring injuries, and pelvic floor disorders have been reported in the literature among runners. Some suggest that hip, pelvis, and/or groin injuries occur in 3.3% to 11.5% of long distance runners. The purpose of this case report is to describe the differential diagnosis and treatment approach for a patient presenting with combined hip and pelvic pain. CASE DESCRIPTION: A 45-year-old female distance runner was referred to physical therapy for proximal hamstring pain that had been present for several months. This pain limited her ability to tolerate sitting and caused her to cease running. Examination of the patient's lumbar spine, pelvis, and lower extremity led to the initial differential diagnosis of hamstring syndrome and ischiogluteal bursitis. The patient's primary symptoms improved during the initial four visits, which focused on education, pain management, trunk stabilization and gluteus maximus strengthening, however pelvic pain persisted. Further examination led to a secondary diagnosis of pelvic floor hypertonic disorder. Interventions to address the pelvic floor led to resolution of symptoms and return to running. OUTCOMES: Pain level on the Visual Analog Scale decreased from 7/10 to 1/10 over the course of treatment. The patient was able to return to full sport activity and improved sitting tolerance to greater then two hours without significant discomfort. DISCUSSION: This case suggests the interdependence of lumbopelvic and lower extremity kinematics in complaints of hamstring, posterior thigh and pelvic floor disorders. This case highlights the importance of a thorough examination as well as the need to consider a regional interdependence of the pelvic floor and lower quarter when treating individuals with proximal hamstring pain. LEVEL OF EVIDENCE: Level 4.