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Abstract Lung cancers bearing oncogenic EML4-ALK fusions respond to targeted tyrosine kinase inhibitors (TKIs; e.g., alectinib), with variation in the degree of shrinkage and duration of treatment (DOT). However, factors that control this response are not well understood. While the contribution of the immune system in mediating the response to immunotherapy has been extensively investigated, less is known regarding the contribution of immunity to TKI therapeutic responses. We previously demonstrated a positive association of a TKI-induced interferon gamma (IFNγ) transcriptional response with DOT in EGFR-mutant lung cancers. Herein, we used three murine models of EML4-ALK lung cancer to test the role for host immunity in the alectinib therapeutic response. The cell lines (EA1, EA2, EA3) were propagated orthotopically in the lungs of immunocompetent and immunodeficient mice and treated with alectinib. Tumor volumes were serially measured by μCT and immune cell content was measured by flow cytometry and multispectral immunofluorescence. Transcriptional responses to alectinib were assessed by RNAseq and secreted chemokines were measured by ELISA. All cell lines were similarly sensitive to alectinib in vitro and as orthotopic tumors in immunocompetent mice, exhibited durable shrinkage. However, in immunodeficient mice, all tumor models rapidly progressed on TKI therapy. In immunocompetent mice, EA2 tumors exhibited a complete response, whereas EA1 and EA3 tumors retained residual disease that rapidly progressed upon termination of TKI treatment. Prior to treatment, EA2 tumors had greater numbers of CD8+ T cells and fewer neutrophils compared to EA1 tumors. Also, RNAseq of cancer cells recovered from untreated tumors revealed elevated levels of CXCL9 and 10 in EA2 tumors, and higher levels of CXCL1 and 2 in EA1 tumors. Analysis of pre-treatment patient biopsies from ALK+ tumors revealed an association of neutrophil content with shorter time to progression. Combined, these data support a role for adaptive immunity in durability of TKI responses and demonstrate that the immune cell composition of the tumor microenvironment is predictive of response to alectinib therapy.

We aimed to investigate prevalence and prognostic role of SOX2, PIK3CA, FGFR1 and BRF2 gene gain in patients with surgically resected non-small cell lung cancer (NSCLC).SOX2, PIK3CA, FGFR1 and BRF2 gene copy number was assessed by fluorescence in situ hybridization (FISH) in arrayed tissue cores from 447 resected NSCLCs.Increased gene copy number (FISH+) for SOX2, PIK3CA, FGFR1 and BRF2 was observed in 23.6%, 29.2%, 16.6% and 14.9% of cases, respectively. FISH+ status for each gene was significantly associated with smoking history, squamous cell carcinoma (SCC) histology, and increased copy number of the other studied genes. Multivariate analysis of overall survival indicated increased SOX2 gene copy number (P = 0.008), stage I-II (P

Background Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.Methods We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography–mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory.Results Bulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas.Conclusions Our data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.

Objective: To explore barriers and facilitators for family physicians in Saskatchewan prescribing opioid agonist therapy (OAT)., Design: Self-administered postal survey., Setting: Family medicine practices in Saskatchewan., Participants: A total of 218 Saskatchewan family physicians who were not authorized to prescribe OAT as of June 2022., Main Outcome Measures: Descriptive and inferential statistics of physicians' self-reported barriers to and facilitators of prescribing OAT for opioid use disorder (OUD)., Results: Most respondents (84.8%) had some comfort with diagnosing OUD. However, more than half (58.3%) did not feel confident or knowledgeable about prescribing OAT. Barriers to OAT prescribing included lack of time, incomplete training requirements, lack of interest, insufficient funding or support, feeling overwhelmed, and perceiving that OAT does not work and thus is not necessary. Physicians working in core neighbourhoods and those receiving fee-for-service compensation reported the least available time to prescribe OAT. Conversely, physicians working in interdisciplinary team settings had increased time for OAT prescribing compared with physicians in other settings. Having a close personal relationship with someone with OUD was correlated with increased comfort in diagnosing OUD as well as with knowledge about and confidence in prescribing OAT. Themes identified as facilitators to increasing OAT prescribing included the addition of resources and supports, increased training, more awareness about OUD and OAT, enhanced compensation, and altered prescribing regulations., Conclusion: Despite the presence of several real and perceived barriers limiting OAT prescribing by Saskatchewan family physicians, there are family physicians interested in providing this therapy. Increased clinical resources and support, including increased interdisciplinary practice, are actionable steps that should be considered by policy decision makers to address this issue. Additionally, increased OUD and OAT education, which includes the perspectives of those with lived experience of OUD, would help address physician confidence, knowledge, and awareness in this area., (Copyright © 2024 the College of Family Physicians of Canada.)

Objective: Indigenous suicide prevention is an important focus for national health policies. Indigenous suicide rates in formerly colonial English-speaking countries such as the United States, Australia and New Zealand are considerably higher than the general population, particularly in young males. Given the similarities in their sociocultural history, a time series analysis was conducted to assess recent sex and age trends of suicide in the Indigenous and general populations in the United States, Australia and New Zealand., Methods: Using the number of deaths by intentional self-harm and estimated resident population, suicide incidence rates were calculated for the years 2006-2019 and stratified by Indigenous status, year, time period, sex and age group (above 15 years). Incidence rates were plotted. Using the Poisson regression model, calculated suicide incidence rate ratios were used to make comparisons for sex and age., Results: Across all countries studied, Indigenous suicide rates have increased over time, with Indigenous males having higher suicide rates than Indigenous females. However, the increase in Indigenous female suicides was greater than that for Indigenous males in Australia and New Zealand. Indigenous males aged 15-44 years have the highest suicide rates across all countries., Conclusion: Indigenous suicide rates have remained consistently high in the United States, Australia and New Zealand, with Indigenous males aged 15-44 years showing the highest rate. However, suicide rates for Indigenous females in Australia and New Zealand are increasing more rapidly than males. Given this, it is critical that further research is dedicated to understanding and addressing the issues driving this problem, particularly in youth.

The increased demand for colonoscopy combined with increased incidence of colorectal cancer (CRC) among younger populations presents a need to determine FIT performance among individuals in this age group. We conducted a systematic review to assess test performance characteristics of FIT in detecting CRC and advanced neoplasia in younger age populations. A search through December 2022 identified published articles assessing the sensitivity and specificity of FIT for advanced neoplasia or CRC among populations under age 50. Following the search, 3 studies were included in the systematic review. Sensitivity to detect advanced neoplasia ranged from 0.19 to 0.36 and specificity between 0.94 and 0.97 and the overall sensitivity and specificity were 0.23 (0.17-0.30) and 0.96 (0.94-0.98), respectively. Two studies that assessed these metrics in multiple age categories found similar sensitivity and specificity across all age groups 30-49. Sensitivity and specificity to detect CRC was assessed in one study and found no significant differences by age groups. These results suggest that FIT performance may be lower for younger individuals compared to those typically screened for CRC. However, there were few studies available for analysis. Given increasing recommendations to expand screening in younger age groups, more research is needed to determine whether FIT is an adequate screening tool in this population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Background: The authors aimed to explore the treatment preferences of laypeople regarding direct-to-consumer (DTC) orthodontics and to identify whether case complexity, as perceived by laypeople, is one of the factors influencing interest in DTC orthodontics., Methods: An online cross-sectional survey was conducted. Data analysis was performed using logistic regression models., Results: A total of 1,362 surveys were completed. A significant inverse association was identified between the complexity of an orthodontic case, as measured using the American Board of Orthodontics' discrepancy index (DI) score, and the likelihood of choosing DTC treatment over an orthodontist. Participants were 3.53 times more likely to choose DTC treatment for a mild case (DI score, 0-10) compared with a complex case (DI score, > 20), although the likelihood of choosing DTC treatment for a moderate case (DI score, 11-20) was only 1.79 times higher than for a complex case., Conclusions: When laypeople were asked to consider each case as if it were their own dentition, there was a significant inverse association between the complexity of an orthodontic case, as measured using the DI score, and the likelihood of choosing DTC treatment over an orthodontist. Laypeople were seemingly more likely to choose DTC orthodontics for dentitions that did not appear crowded and were well aligned within the arches. Laypeople seemed to have an understanding that there are some limitations to DTC orthodontics., Practical Implications: Orthodontists should better understand the factors influencing consumers' decisions to select DTC orthodontics and dental organizations should focus their educational campaigns on these factors., (Copyright © 2023 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Bacteriophages, infecting bacterial hosts in every environment on our planet, are a driver of adaptive evolution in bacterial communities. At the same time, the host range of many bacteriophages-and thus one of the selective pressures acting on complex microbial systems in nature-remains poorly characterized. Here, we computationally inferred the putative host ranges of 40 cluster P mycobacteriophages, including members from 6 subclusters (P1-P6). A series of comparative genomic analyses revealed that mycobacteriophages of subcluster P1 are restricted to the Mycobacterium genus, whereas mycobacteriophages of subclusters P2-P6 are likely also able to infect other genera, several of which are commonly associated with human disease. Further genomic analysis highlighted that the majority of cluster P mycobacteriophages harbor a conserved integration-dependent immunity system, hypothesized to be the ancestral state of a genetic switch that controls the shift between lytic and lysogenic life cycles-a temperate characteristic that impedes their usage in antibacterial applications., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

We characterized the complete genome of the cluster P mycobacteriophage Phegasus. Its 47.5-kb genome contains 81 protein-coding genes, 36 of which could be assigned a putative function. Phegasus is most closely related to two subcluster P1 bacteriophages, Mangethe and Majeke, with an average nucleotide identity of 99.63% each.

Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The recognition of novel objects is a common cognitive test for rodents, but current paradigms have limitations, such as low sensitivity, possible odor confounds and stress due to being performed outside of the homecage. We have developed a paradigm that takes place in the homecage and utilizes four stimuli per trial, to increase sensitivity. Odor confounds are eliminated because stimuli consist of inexpensive, machined wooden beads purchased in bulk, so each experimental animal has its own set of stimuli. This paradigm consists of three steps. In Step 1, the sampling phase, animals freely explore familiar objects (FO). Novel Objects (NO1 and NO2) are soiled with bedding from the homecage, to acquire odor cues identical to those of the FO. Steps 2 and 3 are test phases. Herein we report results of this paradigm from neurologically intact adult rats and mice of both sexes. Identical procedures were used for both species, except that the stimuli used for the mice were smaller. As expected in Step 2 (NO1 test phase), male and female rats and mice explored NO1 significantly more than FO. In Step 3 (NO2 test phase), rats of both sexes demonstrated a preference for NO2, while this was seen only in female mice. These results indicate robust novelty recognition during Steps 2 and 3 in rats. In mice, this was reliably seen only in Step 2, indicating that Step 3 was difficult for them under the given parameters. This paradigm provides flexibility in that length of the sampling phase, and the delay between test and sampling phases can be adjusted, to tailor task difficulty to the model being tested. In sum, this novel object recognition test is simple to perform, requires no expensive supplies or equipment, is conducted in the homecage (reducing stress), eliminates odor confounds, utilizes 4 stimuli to increase sensitivity, can be performed in both rats and mice, and is highly flexible, as sampling phase and the delay between steps can be adjusted to tailor task difficulty. Collectively, these results indicate that this paradigm can be used to quantify novel object recognition across sex and species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wooden, Spinetta, Nguyen, O’Leary and Leasure.)

Abstract: We assess the utility of a Centers for Disease Control and Prevention (CDC) guidelines-based coronavirus disease 2019 (COVID-19) screening checklist for postmortem severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surveillance, detailing the relationship between the histologic findings at autopsy and attribution of death to COVID-19.SARS-CoV-2 nasopharyngeal swabs were collected at the time of autopsy in all "checklist-positive" decedents. Additional "checklist-negative" decedents were randomly tested daily. Lung slides were blindly reviewed by 3 pathologists, assessing for the presence of diffuse alveolar damage (DAD) and other findings. Sixteen decedents had positive postmortem SARS-CoV-2 nasopharyngeal swabs and underwent complete autopsies. Seven decedents had positive screening checklists. Of these, 4 had DAD and 1 had COVID-19-associated thromboembolic disease. Of the 9 decedents with negative screening checklists, 2 had DAD, but only 1 was attributed to COVID-19; the other was likely drug related. Acute bronchopneumonia was the second most common finding, and aspiration was the likely etiology in cases without concomitant DAD. COVID-19-related DAD was identified more commonly in decedents who screened positive by CDC checklist, but false-negatives did occur. Medical examiner offices should maintain a low threshold for random testing of decedents even when COVID-19 is not suspected., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Given the challenges in implementing widespread testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is increasing interest in alternative surveillance strategies., Methods: We tested nasopharyngeal swabs from 1094 decedents in the Wayne County Medical Examiner's Office for SARS-CoV-2. All decedents were assessed using a coronavirus disease 2019 (COVID-19) checklist, and decedents flagged using the checklist (298) were preferentially tested. A random sample of decedents not flagged using the checklist were also tested (796). We statistically analyzed the characteristics of decedents (age, sex, race, and manner of death), differentiating between those flagged using the checklist and not and between those SARS-CoV-2-positive and not., Results: A larger percentage of decedents overall were male (70% vs 48%) and black (55% vs 36%) compared with the catchment population. Seven-day average percent positivity among flagged decedents closely matched the trajectory of percent positivity in the catchment population, particularly during the peak of the outbreak (March and April 2020). After a lull in May to mid-June, new positive tests in late June coincided with increased case detection in the catchment. We found large racial disparities in test results; SARS-CoV-2-positive decedents were substantially more likely to be black than SARS-CoV-2-negative decedents (82% vs 51%). SARS-CoV-2-positive decedents were also more likely to be older and to have died of natural causes, including of COVID-19 disease., Conclusions: Disease surveillance through medical examiners and coroners could supplement other forms of surveillance and serve as a possible early outbreak warning sign., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Specific fat distributions are risk factors for complex diseases, including coronary heart disease and obstructive sleep apnea. To demonstrate the utility of high-diversity mouse models for elucidating genetic associations, we describe the phenotyping and heritability of fat distributions within the five classical inbred and three wild-derived founder mouse strains of the Collaborative Cross and Diversity Outbred mice. Measurements of subcutaneous and internal fat volumes in the abdomen, thorax and neck, and fat volumes in the tongue and pericardium were obtained using magnetic resonance imaging in male mice from the A/J (n = 12), C57BL/6J (n = 17), 129S1/SvlmJ (n = 12), NOD/LtJ (n = 14), NZO/HILtJ (n = 12), CAST/EiJ (n = 14), PWK/PhJ (n = 12), and WSB/EiJ (n = 15) strains. Phenotypes were compared across strains using analysis of variance and heritability estimated as the proportion of phenotypic variability attributable to strain. Heritability ranged from 44 to 91% across traits, including >70% heritability of tongue fat. A majority of heritability estimates remained significant controlling for body weight, suggesting genetic influences independent of general obesity. Principal components analysis supports genetic influences on overall obesity and specific to increased pericardial and intra-neck fat. Thus, among the founder strains of the Collaborative Cross and Diversity Outbred mice, we observed significant heritability of subcutaneous and internal fat volumes in the neck, thorax and abdomen, pericardial fat volume and tongue fat volume, consistent with genetic architecture playing an important role in explaining trait variability. Findings pave the way for studies utilizing high-diversity mouse models to identify genes affecting fat distributions and, in turn, influencing risk for associated complex disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Cancer virotherapy is a paradigm-shifting treatment modality based on virus-mediated oncolysis and subsequent antitumor immune responses. Clinical trials of currently available virotherapies showed that robust antitumor immunity characterizes the remarkable and long-term responses observed in a subset of patients. These data suggest that future therapies should incorporate strategies to maximize the immunotherapeutic potential of oncolytic viruses. In this review, we highlight the recent evidence that the antiviral immunity of the patients may limit the immunotherapeutic potential of oncolytic viruses and summarize the most relevant approaches to strategically redirect the immune response away from the viruses and toward tumors to heighten the clinical impact of viro-immunotherapy platforms., Competing Interests: Competing interests: FL, JF and CG-M are reporting ownership interest (including patents). CG-M and JF are consultants and shareholders of DNATrix., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Undiagnosed significant hydrocephalus is an uncommon finding at forensic autopsy as many cases present in life with complex neurological symptoms. We present a case of a 46-year-old man with no neurological deficits or history of head trauma that was incidentally found to have a massive hydrocephalus at autopsy. This was found to be associated with an unruptured arteriovenous malformation completely confined to the choroid plexus as well as complete agenesis of the corpus callosum. The arteriovenous malformation was found to form a calcified obstruction at the foramen of Monro analogous to a mass lesion, such as a colloid cyst of the third ventricle. The association of this malformation and agenesis of the corpus callosum has never been described. Histologic examination of the brain confirmed significant loss of white matter tracts and thinning of the cortical ribbon due to pressure atrophy of the ependymal lining without significant gliosis, cortical dysplasia, or evidence of other developmental malformations. Autopsy is a vital tool in the evaluation of such rare cases, enhances epidemiologic data, and increases the understanding of these pathophysiological associations.

Aims: Diffuse alveolar damage (DAD) is a ubiquitous finding in inpatient coronavirus disease 2019 (COVID-19)-related deaths, but recent reports have also described additional atypical findings, including vascular changes. An aim of this study was to assess lung autopsy findings in COVID-19 inpatients, and in untreated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive individuals who died in the community, in order to understand the relative impact of medical intervention on lung histology. Additionally, we aimed to investigate whether COVID-19 represents a unique histological variant of DAD by comparing the pathological findings with those of uninfected control patients., Methods and Results: Lung sections from autopsy cases were reviewed by three pulmonary pathologists, including two who were blinded to patient cohort. The cohorts included four COVID-19 inpatients, four cases with postmortem SARS-CoV-2 diagnoses who died in the community, and eight SARS-CoV-2-negative control cases. DAD was present in all but one SARS-CoV-2-positive patient, who was asymptomatic and died in the community. Although SARS-CoV-2-positive patients were noted to have more focal perivascular inflammation/endothelialitis than control patients, there were no significant differences in the presence of hyaline membranes, fibrin thrombi, airspace organisation, and 'acute fibrinous and organising pneumonia'-like intra-alveolar fibrin deposition between the cohorts. Fibrinoid vessel wall necrosis, haemorrhage and capillaritis were not features of COVID-19-related DAD., Conclusions: DAD is the primary histological manifestation of severe lung disease in COVID-19 patients who die both in hospital and in the community, suggesting no contribution of hyperoxaemic mechanical ventilation to the histological changes. There are no distinctive morphological features with which to confidently differentiate COVID-19-related DAD from DAD due to other causes., (© 2020 John Wiley & Sons Ltd.)

Background: The objective of this study is to characterize changes in hemodynamics, pain, and anxiety during office-based endoscopic sinus procedures performed under local anesthesia., Methods: We conducted a prospective study of adults undergoing in-office endoscopic sinus procedures under local anesthesia. Patients with American Society of Anesthesiologists (ASA) Physical Status Classification System class 1 or 2 were included. Anesthesia was administered by topical 4% lidocaine/oxymetazoline and submucosal injection of 1% lidocaine/1:200,000 epinephrine. Vital signs and pain were measured at baseline, postinjection, and 5-minute intervals throughout the procedure. Anxiety levels were scored using the State-Trait Anxiety Inventory (STAI). Univariate and multivariate regression analyses were performed to identify factors significantly associated with changes in each hemodynamic metric., Results: Twenty-five patients were studied. This cohort was 52% male, mean age of 57.8 ± 14.4 years, and Charlson Comorbidity Index (CCI) median of 2. Mean procedure duration was 25.0 ± 10.3 minutes. Mean maximal increase in systolic blood pressure (SBP) was 24.6 ± 17.8 mmHg from baseline. Mean maximal heart rate increase was 22.8 ± 10.8 beats per minute (bpm) from baseline. In multivariate regression analysis, when accounting for patient age, cardiac comorbidity, CCI, and ASA, older age was significantly associated with an increase of >20 mmHg in SBP (p = 0.043). Mean pain score during procedures was 1.5 ± 1.3 with a mean maximum of 4.0 ± 2.6. STAI anxiety scores did not change significantly from preprocedure to postprocedure (32.8 ± 11.6 to 31.0 ± 12.6, p = 0.46). No medical complications occurred., Conclusion: Although patients appear to tolerate office procedures well, providers should recognize the potential for significant fluctuations in blood pressure during the procedure, especially in older patients., (© 2019 ARS-AAOA, LLC.)

Background: Viroimmunotherapy is evolving as a strong alternative for the standard treatment of malignant gliomas. Promising results from a recent clinical trial testing the anticancer effect of Delta-24-RGD in patients with glioblastoma suggested the induction of antitumoral immunity after viral administration. To further enhance the anti-glioma immune effect, we have armed Delta-24-RGD with the costimulatory ligand GITRL (Delta-24-GREAT [Glucocorticoid Receptor Enhanced Activity of T cells])., Methods: We tested the infectivity and replication of Delta-24-GREAT, and the expression of ectopic GITRL in human and murine glioma cell lines. In vivo experiments involved the intracranial implantation of glioma cells into an immunocompetent model to study the anticancer effect, and rechallenging experiments to study long-term protection. Phenotypic and functional characterization of lymphocyte populations were performed by FACS and ELISA for Th1 cytokines expression, respectively., Results: Our results showed that Delta-24-GREAT infects and induces the expression of GITRL. Delta-24-GREAT prolonged the survival of glioma-bearing immunocompetent mice and resulted in both anti-viral and anti-glioma immune responses, including increased frequency of central memory CD8 + T cells. Rechallenging the surviving mice with a second implantation of glioma cells did not lead to tumor growth; however, the surviving mice developed lethal tumors when B16/F10 melanoma cells were implanted intracranially, strongly indicating that the immune response was specific for glioma antigens., Conclusions: GITRL-armed Delta-24-RGD treatment results in an antigen-restricted antitumor memory, an enhanced anti-glioma effect, and the generation of central immune memory. Our results strongly indicate that this strategy represents a vertical advance in virotherapy designed to treat patients with malignant brain tumors., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Na v 1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Na v 1.7. Compound 24 showed a robust PK/PD response in a Na v 1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.

With the progress of immunotherapy in cancer, oncolytic viruses (OVs) have attracted more and more attention during the past decade. Due to their cancer-selective and immunogenic properties, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. The main challenge in OV approaches is how to redirect the host immunity from anti-virus to anti-tumor and optimize the clinical outcome of cancer patients. Here, we summarize the conceptual updates on oncolytic virotherapy and immunotherapy in cancer, and the development of strategies to enhance the virus-mediated anti-tumor immune response, including: (1) arm OVs with cytokines to modulate innate and adaptive immunity; (2) combining OVs with immune checkpoint inhibitors to release T cell inhibition; (3) combining OVs with immune co-stimulators to enhance T cell activation. Future studies need to be enforced on developing strategies to augment the systemic effect on metastasized tumors.

Background and Purpose: Previous research at colleges and schools of pharmacy showed that simulation learning is an effective method to teach pharmacy students about the issues patients face when prescribed complicated medication regimens. The purpose of this analysis was to compare reported medication adherence rates, perceived barriers, and methods used to increase adherence between undergraduate students and pharmacy students based on a medication-taking simulation course activity., Educational Activity and Setting: In spring semesters 2014 and 2015, students in both a pharmacy course and an undergraduate seminar course participated in a short simulation involving a complicated medication regimen. Within one week of participating in the simulation activity, the students answered survey questions about the assignment through an online course sharing platform., Findings: Almost all students enrolled in the courses (237/246 pharmacy students and 34/36 undergraduate students) completed the assignment (> 96% response rate). A large percentage of each group reported some non-adherence; 95% (225/237) of first-year pharmacy students and 82% (28/34) of undergraduate students. The top two barriers reported were 1) simply forgetting and 2) difficulty following the food- and/or alcohol-related restrictions associated with some of the simulated medications. The top two methods used to increase adherence were phone/electronic reminders and paper/spreadsheet reminders., Discussion: A limitation to this study was the small sample size of undergraduate students. Even though the response rate was over 96%, the course was a small seminar-type course. Although it might be expected that pharmacy students would be more adherent since they may have had experience with non-adherence issues while working in a pharmacy, opposite results were found. Since the students were relatively young, most had not personally dealt with a complicated medication regimen., Summary: Pharmacy students reported lower adherence to a complicated medication regimen than undergraduate students. The most common reasons for non-adherence and most common methods used to increase adherence were similar between the two cohorts. The use of electronic reminders was common for both groups of students, and should be included in discussions about methods to improve adherence rates., (Published by Elsevier Inc.)

Competing Interests: Conflicts of interests:The authors declare no conflict of interest.

Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi-dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O₂ consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)