Several new supramolecular s-tetrazines have been prepared and studied. Their electrochemical and spectroscopic properties have been investigated, especially in the presence of quenchers. Fluorescence quenching has been shown to occur as expected through a charge transfer mechanism and the cyclophane structure has been shown to lead to an acceleration of the quenching process.Scheme 1 Formula of the s-tetrazines.

Background/Objectives Off-label use of antipsychotics is common in the hospital, most often for delirium management. Antipsychotics have been associated with aspiration pneumonia in community and nursing home settings. However, the association in hospitalized patients is unexplored. We aimed to investigate the association between antipsychotic exposure and aspiration pneumonia during hospitalization. Design Retrospective cohort study Setting Large academic medical center Participants All adult hospitalizations between 1/2007 and 7/2013. We excluded outside hospital transfers, those with a hospitalization < 48 hours, and psychiatric patients. Measurements Antipsychotic use defined as any pharmacy charge for an antipsychotic medication. Aspiration pneumonia defined by a discharge diagnosis code for aspiration pneumonia not present on admission, and validated by chart review. A generalized estimating equation was used to control for 43 potential confounders. Results Our cohort included 146,552 hospitalizations (median age = 56 years; 39% male). Antipsychotics were used in 10,377 (7.1%) hospitalizations (80% atypical, 35% typical, 15% both). Aspiration pneumonia occurred in 557 (0.4%) hospitalizations. The incidence of aspiration pneumonia was 0.3% in unexposed and 1.2% in those with antipsychotic exposure (OR 3.9, 95% confidence interval [CI] 3.2 to 4.8). After adjustment, antipsychotic exposure was significantly associated with aspiration pneumonia (adjusted OR [aOR] 1.5, 95% CI 1.2 to 1.9). Similar results were demonstrated in a propensity-matched analysis and in an analysis restricted to those with delirium or dementia. The magnitude of the association was similar for typical (aOR 1.4, 95% CI 0.94 to 2.2) and atypical antipsychotics (aOR 1.5, 95% CI 1.1 to 2.0). Conclusion Antipsychotics were associated with increased odds of aspiration pneumonia after extensive adjustment for patient characteristics. This risk should be considered when prescribing antipsychotics in the hospital.

Darinaparsin is a novel organic arsenic compound that is being developed to improve the efficacy and therapeutic index of arsenic as an antineoplastic agent. It has activity in preclinical models of hematological malignancies and we set out to test it in patients with refractory lymphoma. In this multicenter, Phase II trial, patients with relapsed or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) were treated with darinaparsin 300 mg/m 2 intravenously daily for five consecutive days every 28 days, for up to six cycles. The primary endpoint was the overall response rate. Twenty-nine heavily pretreated patients with lymphoma (22 with NHL and 7 with HL) were enrolled. There was one complete response (CR), one unconfirmed CR (CRu), three partial responses (PRs), and four with stable disease (SD), with an overall response rate of 17% (95% confidence interval (CI) 6-36%). Among the seven patients with peripheral T-cell lymphoma (PTCL), there was one CR, one CRu, and two with prolonged SD. The most common toxicities were fatigue, nausea, diarrhea, and anemia. Darinaparsin was safe and showed preliminary activity in this heavily pretreated population of relapsed/refractory lymphoma patients. Encouraging responses were seen in PTCL and further study in this subtype is planned. An estimated 74,030 people in the United States are diagnosed with HL or NHL every year with a global disease burden of approximately 350,000 new cases per year [1,2]. Major advances have been made over the last few decades in the treatment of these disorders in the form of combination chemotherapy, monoclonal antibody therapy, and stem cell transplantation [3-5], resulting in cure for a substantial proportion of cases. However, there remains a subgroup of patients who do not respond to standard therapy or relapse after an initial response. PTCL accounts for 7-10% of NHL cases and is a particularly unfavorable subtype [6]. Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the usual treatment approach for PTCL, but outcomes are generally poor even with more intensive regimens [7]. Darinaparsin (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine; S-dimethylarsino-glutathione, ZIO-101, Zinapar TM) is a novel organic arsenic molecule consisting of dimethylated arsenic conjugated to glutathione [8]. Darinaparsin achieves higher intracellular levels compared to inorganic arsenic trioxide (ATO), and has activity in vitro against leukemia, myeloma, lymphoma, and various solid tumor cell lines [9,10]. Darinaparsin's multifaceted mechanisms of action include disruption of mitochondrial functions, increase in reactive oxygen species (ROS), and effects on signal transduction. Darinaparsin induces cell cycle arrest and apoptosis and has potent anti-angiogenic activity [11]. Unlike ATO, darinaparsin lacks affinity for the ABCC1 efflux proteins and is cytotoxic to certain ATO-resistant cell lines [12]. While other arsenicals have been used clinically, particularly for the treatment of acute promye...

Immune checkpoint inhibitors (ICI) are designed to activate exhausted tumor-reactive T cells thereby leading to tumor regression. Durvalumab, an ICI that binds to the programmed death ligand-1 (PD-L1) molecule, is approved as a consolidation therapy for treatment of patients with stage III, unresectable, non-small cell lung cancer (NSCLC). Immunophenotypic analysis of circulating immune cells revealed increases in circulating proliferating CD4 + and CD8 + T cells earlier after durvalumab treatment. To examine durvalumab’s mechanism of action and identify potential predictive biomarkers, we assessed the circulating T cells phenotypes and TCR genes of 71 NSCLC patients receiving durvalumab enrolled in a Phase I trial (NCT01693562, September 14, 2012). Next-generation sequencing of TCR repertoire was performed on these NSCLC patients’ peripheral blood samples at baseline and day 15. Though patients’ TCR repertoire diversity showed mixed responses to the treatment, patients exhibiting increased diversity on day 15 attained significantly longer overall survival (OS) (median OS was not reached vs 17.2 months for those with decreased diversity, p = 0.015). We applied network analysis to assess convergent T cell clonotypes indicative of an antigen-driven immune response. Patients with larger TCR clusters had improved OS (median OS was not reached vs 13.1 months for patients with smaller TCR clusters, p = 0.013). Early TCR repertoire diversification after durvalumab therapy for NSCLC may be predictive of increased survival and provides a mechanistic basis for durvalumab pharmacodynamic activity.