De novo design of potent and selective mimics of IL-2 and IL-15.

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor ßγc heterodimer (IL-2Rßγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rßγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rßγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma.

BACKGROUND: Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564). METHODS: Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability. RESULTS: Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6). CONCLUSION: In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016).

A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study.

OBJECTIVES: The objectives of this study were to assess and compare all-cause mortality rates between pioglitazone (PIO) and insulin (INS). RESEARCH DESIGN: The study population included 56,536 patients with type 2 diabetes aged ≥45 years who were first-time users of PIO or INS. Data from 1 May 2000 until 30 June 2010 from the i3 InVision Data Mart database were linked to death records of the US Social Security Administration obtained in March 2012, with approval from the Institutional Review Board and in full compliance with the Health Insurance Portability and Accountability Act of 1996. MAIN OUTCOME MEASURES: Kaplan-Meier curves were generated and hazard ratios (HRs) were estimated for the occurrence of deaths in the PIO and INS cohorts using Cox proportional hazards models adjusted with inverse probability weights derived from propensity scores. RESULTS: After adjustment for >40 covariates through inverse probability weights derived from propensity scores, the PIO group showed a significantly lower risk of all-cause mortality (HR 0.33; 95% confidence interval, 0.31, 0.36). The risk of all-cause mortality was also significantly lower in the PIO cohort than the INS cohort among subgroups based on baseline variables such as sex, age (<55 years, ≥55 years), antidiabetic medication use (sulfonylureas or metformin), lipid-altering medication use, and congestive heart failure status. The study has some limitations. Use of a claims database means a potential bias toward a younger cohort. Disease-specific mortality was not identified because of no recorded cause of death. Reliable information regarding the differences in disease deterioration rate and some clinical and lab results were not available, which limits the statistical adjustment of baseline variables. CONCLUSION: PIO was associated with a lower risk of all-cause mortality than INS.

Association between severity of depression and self-perceived cognitive difficulties among full-time employees.

OBJECTIVE: To assess the relationship between self-perceived deficits in cognition and severity of depression reported by individuals in full-time employment. METHOD: Individuals ≥ 18 years of age employed full-time with diagnosed depression excluding bipolar disorder (participants had to be told by a doctor that they had depression based on DSM-IV criteria) completed a 25-minute Web-based survey in February 2010 (study population identified by Harris Interactive, Rochester, New York). The survey used the Perceived Deficits Questionnaire (PDQ) to assess self-perceived cognitive impairment and the 9-item Patient Health Questionnaire (PHQ-9) to assess depression severity. The 20-question PDQ was used to assess self-perceived cognitive difficulties within the domains of prospective memory, retrospective memory, attention/concentration, and planning/organization (range, 0-20: higher scores indicate greater impairment). Subjects answered how often they experienced such difficulties during the previous 4 weeks (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = almost always). The scale ranges from 0-20 for each of the 4 subscales, with higher scores indicating greater cognitive impairment. The impact of depression on PDQ scores was assessed using a trend test based on an analysis of covariance controlling for potential confounders. RESULTS: Subjects (N = 1,051) (58% women) had a mean ± SD age of 47 ± 12 years; 38% held professional employment. PHQ-9 scores indicated that 423 employees (40.3%) had no depressive symptoms at the time of the survey, 319 (30.4%) had mild depression, 166 (15.8%) had moderate depression, 82 (7.8%) had moderately severe depression, and 61 (5.8%) had severe depression. Perceived cognitive functioning worsened with increasing severity of depression symptoms (P < .0001) on the basis of PDQ scores. On the basis of responses to the PDQ, in the current study, most impairment was seen in the attention/concentration and planning/organization subscales in severely depressed subjects (12.2 for both) compared with those with no depressive symptoms (4.4 and 3.5, respectively), indicating more cognitive impairment in the severely depressed subjects compared to the subjects with no depression. CONCLUSIONS: In currently employed individuals, self-perceived cognitive dysfunction worsened with increasing severity of depressive symptoms. This association was independent of antidepressant use. The greatest impairment in self-perceived cognition was observed in the planning/organization and attention/concentration subscales.

Patient-reported depression severity measured by the PHQ-9 and impact on work productivity: results from a survey of full-time employees in the United States.

OBJECTIVE: To examine the burden of depression on work productivity. METHODS: Full-time employees with diagnosed depression were surveyed using the Patient Health Questionnaire for depression severity, and the Health and Work Performance Questionnaire and Work Productivity and Activity Impairment (WPAI) questionnaire for absenteeism and presenteeism. RESULTS: Of the 1051 employees with depression, 40.3% had no depressive symptoms at the time of the survey, 30.4% had mild depression, 15.8% had moderate depression, 7.8% had moderately severe depression, and 5.8% had severe depression. All levels of depression were associated with decreased work productivity. Presenteeism was positively associated with severity of depression (Health and Work Performance Questionnaire, P < 0.0001; WPAI, P < 0.0001). Absenteeism was significantly positively associated with severity of depression using the WPAI. CONCLUSIONS: Decreased overall productivity was seen at all levels of depression, and as severity increased, presenteeism and absenteeism worsened.

Comparing pioglitazone to insulin with respect to cancer, cardiovascular and bone fracture endpoints, using propensity score weights.

BACKGROUND: Diabetes is an important global disease, associated with significant morbidity and an increased risk of death due to chronic end-organ complications. The thiazolidinediones, used mainly as third-line agents in type 2 diabetes mellitus (T2DM), have been associated with some safety concerns, such as an increased risk of bladder cancer, an increased risk of bone fracture and heterogeneous effects on cardiovascular events. OBJECTIVE: This study aimed to evaluate safety data on pioglitazone for several outcomes and examine them in context with each other as well as with insulin, another third-line treatment for T2DM. METHODS: This retrospective cohort study extracted data from May 1, 2000 until June 30, 2010, from the i3 InVision Data Mart™ database. To adjust for the testing of multiple hypotheses, the Holm method was applied to endpoints representing potential harm from pioglitazone treatment, separately from those representing potential benefit from pioglitazone. The study population included patients with T2DM ≥ 45 years old who were new users of either pioglitazone or insulin. Key outcomes were incident cases of a composite of myocardial infarction (MI) or stroke requiring hospitalization; bone fracture requiring hospitalization; bladder cancer; and a composite of nine other selected cancers. Kaplan-Meier curves were generated and hazard ratios (HRs) for pioglitazone versus insulin were estimated from Cox proportional hazards models adjusted with inverse probability of treatment weights derived from propensity scores. RESULTS: A total of 56,536 patients (pioglitazone group 38,588; insulin group 17,948) qualified for the study. The mean follow-up was 2.2 years for pioglitazone and 1.9 years for insulin patients. Weighted survival analysis of the composite of MI and stroke, as well as the composite of nine cancers, yielded significant differences in favour of pioglitazone. For the composite of MI and stroke, the HR for pioglitazone versus insulin was 0.44 (95 % confidence interval [CI] 0.39-0.50, p < 0.0001). Modelling of the composite of nine selected cancers produced an HR of 0.78 (95 % CI 0.71-0.85, p < 0.0001). A non-statistically significant difference in favour of pioglitazone was observed in the incidence rate of bone fracture requiring hospitalization (HR 0.86, 95 % CI 0.74-1.01, p = 0.058). For bladder cancer, the overall incidence rates were relatively low and showed no significant difference between the two groups; the HR for pioglitazone versus insulin was 0.92 (95 % CI 0.63-1.33, p = 0.64). CONCLUSION: Compared with insulin, pioglitazone was associated with a significant reduction in the risk of MI and stroke requiring hospitalization, and a significant reduction in the risk of other selected cancers. While pioglitazone treatment may be linked with a lower risk of bladder cancer and bone fracture relative to insulin, these differences were not statistically significant.