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Objective Sarcoidosis is an idiopathic inflammatory disorder that is difficult to treat. There is accumulating evidence that constitutive activation of Janus kinase–signal transducer and activator of transcription (JAK‐STAT) signaling occurs in sarcoidosis and represents a target for treatment. Here we report the efficacy of tofacitinib, a Janus kinase (JAK) inhibitor, in a single patient with multiorgan sarcoidosis. Methods A patient with long‐standing multiorgan sarcoidosis who was unresponsive to other commonly used therapies, including methotrexate, prednisone, and tumor necrosis factor α blockade, was treated with tofacitinib. Results Tofacitinib treatment resulted in clinical remission of cutaneous sarcoidosis lesions and resolution of positron emission tomography avid lesions in internal organs after 6 months. An evaluation of lesional tissue and blood before and during treatment showed resolution of granulomatous inflammation and normalization of disease biomarkers. Conclusion This case illustrates the promise of JAK inhibition as a strategy to treat recalcitrant sarcoidosis and suggests that further study of JAK inhibitors in sarcoidosis is needed.

Brain tumor initiating cells (BTICs) are self-renewing, tumorigenic cells that often reside in a necrotic and hypoxic niche in the brain. Here the authors show that BTICs can become more tumorigenic upon glucose restriction and compensate for this cellular stress by upregulating their capacity to take up glucose. Like all cancers, brain tumors require a continuous source of energy and molecular resources for new cell production. In normal brain, glucose is an essential neuronal fuel, but the blood-brain barrier limits its delivery. We now report that nutrient restriction contributes to tumor progression by enriching for brain tumor initiating cells (BTICs) owing to preferential BTIC survival and to adaptation of non-BTICs through acquisition of BTIC features. BTICs outcompete for glucose uptake by co-opting the high affinity neuronal glucose transporter, type 3 (Glut3, SLC2A3). BTICs preferentially express Glut3, and targeting Glut3 inhibits BTIC growth and tumorigenic potential. Glut3, but not Glut1, correlates with poor survival in brain tumors and other cancers; thus, tumor initiating cells may extract nutrients with high affinity. As altered metabolism represents a cancer hallmark, metabolic reprogramming may maintain the tumor hierarchy and portend poor prognosis.

Posttraumatic stress disorder (PTSD) occurs more commonly among military service members than among civilians; however, despite the availability of several evidence-based treatments, there is a need for more efficient evidence-based PTSD treatments to better address the needs of service members. Written exposure therapy is a brief PTSD intervention that consists of 5 sessions with no between-session assignments, has demonstrated efficacy, and is associated with low treatment dropout rates, but prior randomized clinical trials of this intervention have focused on civilian populations. To investigate whether the brief intervention, written exposure therapy, is noninferior in the treatment of PTSD vs the more time-intensive cognitive processing therapy among service members diagnosed with PTSD. The study used a randomized, noninferiority design with a 1:1 randomization allocation. Recruitment for the study took place from August 2016 through October 2020. Participants were active-duty military service members diagnosed with posttraumatic stress disorder. The study was conducted in an outpatient setting for service members seeking PTSD treatment at military bases in San Antonio or Killeen, Texas. Participants received either written exposure therapy, which consisted of 5 weekly sessions, or cognitive processing therapy, which consisted of 12 twice-weekly sessions. Participants were assessed at baseline and at 10, 20, and 30 weeks after the first treatment session. The primary outcome measure was PTSD symptom severity assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Noninferiority was defined as the difference between the 2 groups being less than the upper bound of the 1-sided 95% CI-specified margin of 10 points on the CAPS-5. Overall, 169 participants were included in the study. Participants were predominantly male (136 [80.5%]), serving in the Army (167 [98.8%]), with a mean (SD) age of 34 (8) years. Eighty-five participants were randomly assigned to written exposure therapy, with 65 (76.5%) completing all treatment sessions, and 84 to cognitive processing therapy, with 47 (54.8%) completing all treatment sessions. Findings indicated that written exposure therapy was noninferior to cognitive processing therapy, with the largest difference in change in outcome between the treatment conditions of 3.96 points on the outcome measure. The 1-sided 95% CI upper limit was less than 10 points across time points in both groups and ranged from 4.59 at week 30 to 6.81 at week 10. Within-condition effect sizes ranged from a Cohen d of 0.48 for the written exposure therapy group in the intention-to-treat analysis at week 10 to 0.95 for the cognitive processing therapy group in the per-protocol analysis at week 10, and between-condition effect size ranged from 0.06 in the intention-to-treat analysis at week 30 to 0.22 in the per-protocol analysis at week 10. In this randomized clinical trial, support was found for an effective and more efficient PTSD treatment approach for service members. Future research should determine who does and does not benefit from PTSD treatment to best maximize treatment outcomes. ClinicalTrials.gov Identifier: NCT03033602.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

Background and objective. Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under-studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. Methods. This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (ρ) >0.3 or <−0.3 (more and less correlated, respectively) were considered potentially clinically significant. Results. Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (ρ = 0.46), physical (ρ = 0.61), role (ρ = 0.48), and emotional functioning (ρ = 0.40) scores as well as lower depression (ρ = −0.40), dyspnea (ρ = −0.54), and pain (ρ = −0.37) scores. Conclusion. Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study.

In this randomized trial involving patients with Clostridium difficile infection, treatment with monoclonal antibodies against C. difficile toxins A and B, in addition to metronidazole or vancomycin, reduced the rate of recurrence of infection, as compared with placebo (7% vs. 25%). In patients with C. difficile infection, treatment with monoclonal antibodies against C. difficile toxins A and B, in addition to metronidazole or vancomycin, reduced the rate of recurrence of infection, as compared with placebo (7% vs. 25%). During the past decade, there has been a striking increase in the prevalence of Clostridium difficile infection and in associated mortality in the United States, Canada, and Europe. 1 – 5 The widespread use of broad-spectrum antibiotics places patients at risk for C. difficile diarrhea or colitis and has changed the epidemiology of C. difficile infection. This has been characterized by the emergence of a hypervirulent strain of C. difficile (BI/NAP1/027) and an increasing risk of treatment failure and recurrent infection. 1 , 6 – 14 We developed one fully human monoclonal antibody targeted against C. difficile toxin A (CDA1) and a second against toxin . . .

Introduction: People experiencing unsheltered homelessness (PEUH) have higher disease burden yet limited access to healthcare. COVID-19 introduced even greater risk for PEUH aged 65+ years with an underlying chronic health condition and were temporarily housed in hotels/motels for Project RoomKey (PRK). This study aimed to characterize a PRK cohort who received primary care from a street medicine program. Methods: This observational case series study included a sample of 35 PRK participants receiving primary care from a street medicine team at a single site from July to September 2020. We used the HOUSED BEDS assessment tool for taking history on PEUH. Results: Participants were 63% male, 40% Hispanic/Latino/a, 40% white, 94% English-speaking, and 73% had chronic health conditions. Assessment revealed: average Homelessness (H) of 4 years; 76% had no prior social service Outreach (O); average Utilization (U) was 4 emergency department visits in prior 6-months; 68% received Salary (S) from government income; Food access or Eat (E) was commonly purchased (29%) or donated (26%); clean water to Drink (D) for 59% of participants; 86% had access to a Bathroom (B); Encampment (E) was varied and 38% reported safety concerns; Daily routine (D) showed 76% could access a telephone, 32% received social support from family; 79% reported past or current Substance use (S). No participants contracted COVID-19 during study period. Conclusions: This study describes health and demographic characteristics of PRK participants in Southern California. Findings inform policies to continue PRK that includes onsite healthcare such as via street medicine.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.