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Background There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. Methods We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. Results There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1–8.4). Conclusions This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

BACKGROUNDMore than half of adults in the United States do not attain the minimum recommended level of physical activity to achieve health benefits. The optimal design of financial incentives to promote physical activity is unknown.OBJECTIVETo compare the effectiveness of individual versus team-based financial incentives to increase physical activity.DESIGNRandomized, controlled trial comparing three interventions to control.PARTICIPANTSThree hundred and four adult employees from an organization in Philadelphia formed 76 four-member teams.INTERVENTIONSAll participants received daily feedback on performance towards achieving a daily 7000 step goal during the intervention (weeks 1– 13) and follow-up (weeks 14– 26) periods. The control arm received no other intervention. In the three financial incentive arms, drawings were held in which one team was selected as the winner every other day during the 13-week intervention. A participant on a winning team was eligible as follows: $50 if he or she met the goal (individual incentive), $50 only if all four team members met the goal (team incentive), or $20 if he or she met the goal individually and $10 more for each of three teammates that also met the goal (combined incentive).MAIN MEASURESMean proportion of participant-days achieving the 7000 step goal during the intervention.KEY RESULTSCompared to the control group during the intervention period, the mean proportion achieving the 7000 step goal was significantly greater for the combined incentive (0.35 vs. 0.18, difference: 0.17, 95 % confidence interval [CI]: 0.07–0.28, p <0.001) but not for the individual incentive (0.25 vs 0.18, difference: 0.08, 95 % CI: -0.02–0.18, p = 0.13) or the team incentive (0.17 vs 0.18, difference: -0.003, 95 % CI: -0.11–0.10, p = 0.96). The combined incentive arm participants also achieved the goal at significantly greater rates than the team incentive (0.35 vs. 0.17, difference: 0.18, 95 % CI: 0.08–0.28, p < 0.001), but not the individual incentive (0.35 vs. 0.25, difference: 0.10, 95 % CI: -0.001–0.19, p = 0.05). Only the combined incentive had greater mean daily steps than control (difference: 1446, 95 % CI: 448–2444, p ≤ 0.005). There were no significant differences between arms during the follow-up period (weeks 14– 26).CONCLUSIONSFinancial incentives rewarded for a combination of individual and team performance were most effective for increasing physical activity.Trial RegistrationClinicaltrials.gov identifier: NCT02001194.

It is well established that Toll-like receptors (TLRs) play a critical role in the generation of innate immune responses and thereby also play an important, indirect role in the initiation of subsequent adaptive T cell responses. However, T cells also express certain TLRs, and we have focused on the physiological importance of direct TLR signaling in T cells. TLRs can function as co-stimulatory receptors that complement TCR-induced signals to enhance effector T cell proliferation, survival and cytokine production. We also found that TLR signaling pathways in T cells are required for the effective clonal expansion of antigen-specific T cells during infection in vivo. Thus, the importance of TLRs in T cell-mediated immunity reflects both T cell-extrinsic and T cell-intrinsic components, which warrants a reconsideration of the dogma that restricts germ-line encoded pattern recognition to cells of the innate immune system.

Systemic lupus erythematosus (SLE) impacts multiple organ systems, although the causes of many individual SLE pathologies are poorly understood. This study was designed to elucidate organ-specific inflammation by identifying proteins that correlate with SLE organ involvement and to evaluate established biomarkers of disease activity across a diverse patient cohort. Plasma proteins and autoantibodies were measured across seven SLE manifestations. Comparative analyses between pathologies and correlation with the SLE Disease Activity Index (SLEDAI) were used to identify proteins associated with organ-specific and composite disease activity. Established biomarkers of composite disease activity, SLE-associated antibodies, type I interferon (IFN), and complement C3, correlated with composite SLEDAI, but did not significantly associate with many individual SLE pathologies. Two clusters of proteins were associated with renal disease in lupus nephritis samples. One cluster included markers of infiltrating leukocytes and the second cluster included markers of tissue remodelling. In patients with discoid lupus, a distinct signature consisting of elevated immunoglobulin A autoantibodies and interleukin-23 was observed. Our findings indicate that proteins from blood samples can be used to identify protein signatures that are distinct from established SLE biomarkers and SLEDAI and could be used to conveniently monitor multiple inflammatory pathways present in different organ systems.

Background Detailed epidemiologic descriptions of large populations of advanced stage ovarian cancer patients have been lacking to date. This study aimed to describe the patient characteristics, treatment patterns, survival, and incidence rates of health outcomes of interest (HOI) in a large cohort of advanced stage ovarian cancer patients in the United States (US). Methods This cohort study identified incident advanced stage (III/IV) ovarian cancer patients in the US diagnosed from 2010 to 2018 in the HealthCore Integrated Research Database (HIRD) using a validated predictive model algorithm. Descriptive characteristics were presented overall and by treatment line. The incidence rates and 95% confidence intervals for pre-specified HOIs were evaluated after advanced stage diagnosis. Overall survival, time to treatment discontinuation or death (TTD), and time to next treatment or death (TTNT) were defined using treatment information in claims and linkage with the National Death Index. Results We identified 12,659 patients with incident advanced stage ovarian cancer during the study period. Most patients undergoing treatment received platinum agents (75%) and/or taxanes (70%). The most common HOIs (> 24 per 100 person-years) included abdominal pain, nausea and vomiting, anemia, and serious infections. The median overall survival from diagnosis was 4.5 years, while approximately half of the treated cohort had a first-line time to treatment discontinuation or death (TTD) within the first 4 months, and a time to next treatment or death (TTNT) from first to second-line of about 6 months. Conclusions This study describes commercially insured US patients with advanced stage ovarian cancer from 2010 to 2018, and observed diverse treatment patterns, incidence of numerous HOIs, and limited survival in this population.

Resistance to Toxoplasma gondii depends on dendritic cells to recognize this pathogen and secrete IL-12, in turn promoting IFN-γ production from responding T cells. The adaptor protein, myeloid differentiation primary-response gene 88 (MyD88), is important for most Toll-like receptor (TLR) signaling, as well as IL-1R/IL-18R signals. There is considerable evidence that MyD88 is required for the innate sensing of T. gondii and IL-12 responses. Although Myd88⁻/⁻ mice challenged with T. gondii have defective IL-12 and Th1 effector responses and succumb to disease, administration of IL-12 to Myd88⁻/⁻ mice partially restores the Th1 response and yet fails to prolong survival. This finding suggested that MyD88 may mediate signals within T cells important for resistance to this pathogen. To evaluate the role of MyD88 in T cells under noncompetitive conditions, bone marrow chimeras were generated, in which the T cells lacked MyD88, but MyD88-dependent innate immune responses were intact. Upon challenge with T. gondii, these chimeric mice were more susceptible to disease, developing severe toxoplasmic encephalitis and succumbing within 30 days. Splenocytes and brain mononuclear cells isolated from infected chimeric mice produced less IFN-γ when cultured with a T. gondii-derived antigen. The increase in susceptibility observed was independent of signals via the IL-1R and IL-18R, suggesting a role for TLRs in MyD88-mediated T cell responses to T. gondii. These observations show that, in addition to a role for MyD88 in innate responses, T cell expression of MyD88 is necessary for prolonged resistance to a pathogen.

The induction and maintenance of immune tolerance to transplanted tissues constitute an active process involving multiple mechanisms that work cooperatively to prevent graft rejection. These mechanisms are similar to inherent tolerance toward self antigens and have a requirement for active immunoregulation, largely T cell mediated, that promotes specific unresponsiveness to donor alloantigens. This review outlines our current understanding of the Treg subsets that contribute to allotolerance and the mechanisms by which these cells exert their effects as well as their potential for therapy.

One of the greatest barriers against harnessing the potential of CD4+ CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4+ T cells inhibits IL-2-dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the \"anergic\" response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.

BackgroundCeralasertib is a specific ATR inhibitor (ATRi) that hinders the DNA damage response in tumor cells, making them more susceptible to death in situations of high replication stress. Ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. The mechanism of this effect remained unclear.MethodsIn this study, we employed different mouse tumor models treated with ceralasertib to investigate the effect of the ATRi on tumor microenvironment.ResultsAntitumor effect of ceralasertib was dependent on the presence of CD8 cells, since in vivo depletion of CD8 cells abrogated therapeutic effect of the ATRi. Analysis of the gene expression profile using RNAseq demonstrated significant up-regulation of type I interferon (IFNI) pathway in tumors of mice treated with ceralasertib. Neutralizing anti IFNI receptor (IFNAR1) antibody abrogated antitumor effect of ceralasertib. Antitumor effect of ceralasertib in combination with anti-PD-L1 was eliminated in mice reconstituted with bone marrow from IFNAR1-KO mice. Reconstitution with bone marrow from mice with constitutively active IFNAR1 markedly enhanced antitumor effect of ceralasertib. Treatment of tumor-bearing mice with ceralasertib caused accumulation of DCs with activated phenotype (up-regulation of CD40, CD86, MHC class II). DCs isolated from tumor of ceralasertib-treated mice demonstrated an enhanced ability to stimulate T cells in a mixed lymphocyte reaction assay. Notably, this effect was reversed when DCs were isolated from IFNAR1 KO mice. Moreover, in vitro-generated DCs treated with ceralasertib exhibited activation similar to that induced by lipopolysaccharide (LPS), but this effect was not observed in DCs generated from IFNAR1 KO mice. Treatment with ceralasertib led to the depletion in tumor of M-MDSC and TAMs, but not PMN-MDSC. However, PMN-MDSCs suppressive activity was abrogated after the treatment. This was associated with increased IFNI signature observed in tumor PMN-MDSC. Treatment with ceralasertib enhanced tumor antigen-specific response of T cells.ConclusionsOur findings demonstrate IFNI mediated modulation of TME by ceralasertib resulting in enhanced antitumor activity of T cells and potentiated effect of PD-L1 antibody.

Coronary artery disease is the single leading cause of death in the United States, and medications can significantly reduce the rate of repeat cardiovascular events and treatment procedures. Adherence to these medications, however, is very low. HeartStrong is a national randomized trial offering 3 innovations. First, the intervention is built on concepts from behavioral economics that we expect to enhance its effectiveness. Second, the implementation of the trial takes advantage of new technology, including wireless pill bottles and remote feedback, to substantially automate procedures. Third, the trial's design includes an enhancement of the standard randomized clinical trial that allows rapid-cycle innovation and ongoing program enhancement. Using a system involving direct data feeds from 6 insurance partners followed by mail, telephone, and email contact, we enrolled 1,509 patients discharged from the hospital with acute myocardial infarction in a 2:1 ratio of intervention:usual care. The intervention period lasts 1 year; the primary outcome is time to first fatal or nonfatal acute vascular event or revascularization, including acute myocardial infarction, unstable angina, stroke, acute coronary syndrome admission, or death. Our randomized controlled trial of the HeartStrong program will provide an evaluation of a state-of-the-art behavioral economic intervention with a number of important pragmatic features. These include a tailored intervention responding to patient activity, streamlining of consent and implementation processes using new technologies, outcomes centrally important to patients, and the ability to implement rapid-cycle innovation.