Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape due to long-term benefits in patients with advanced metastatic disease. However, robust predictive biomarkers for response are still lacking and treatment resistance is not fully understood. METHODS: We profiled approximately 800 pre-treatment and on-treatment plasma proteins from 143 ICI-treated patients with non-small cell lung cancer (NSCLC) using ELISA-based arrays. Different clinical parameters were collected from the patients including specific mutations, smoking habits, and body mass index, among others. Machine learning algorithms were used to identify a predictive signature for response. Bioinformatics tools were used for the identification of patient subtypes and analysis of differentially expressed proteins and pathways in each response group. RESULTS: We identified a predictive signature for response to treatment comprizing two proteins (CXCL8 and CXCL10) and two clinical parameters (age and sex). Bioinformatic analysis of the proteomic profiles identified three distinct patient clusters that correlated with multiple parameters such as response, sex and TNM (tumors, nodes, and metastasis) staging. Patients who did not benefit from ICI therapy exhibited significantly higher plasma levels of several proteins on-treatment, and enrichment in neutrophil-related proteins. CONCLUSIONS: Our study reveals potential biomarkers in blood plasma for predicting response to ICI therapy in patients with NSCLC and sheds light on mechanisms underlying therapy resistance.

Comprehensive healthcare resource use among newly diagnosed congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is among the most common causes of hospital admissions and readmissions in the Western world. However, the burden of ambulatory care has not been as well investigated. The objective of this study was to assess the relative burden and direct medical costs of CHF including inpatient and outpatient care. METHODS: We used longitudinal clinical data from a two-million member health organization in Israel (Maccabi Healthcare Services) to identify adults with newly diagnosed CHF between January 2006 and December 2012, either in the in- or outpatient setting. Adults without CHF were age- and sex-matched to CHF patients and healthcare utilization and all modes of healthcare costs were compared among them, excluding those in their last year of life. RESULTS: The burden posed by 6592 CHF patients was significantly (p < 0.001) larger than that of 32,960 matched controls. CHF patients had significantly higher rates of baseline comorbidity and healthcare utilization compared to non-CHF controls. This was evident in all categories of healthcare services and expenses, including in- and outpatient visits, laboratory expenses, medication costs, among younger and older, men and women. Among those who incurred any healthcare costs, younger (45-64y) and older (65 + y) subjects with CHF were observed to have about 3.25 (95% CI: 2.96-3.56) and 2.08 (95% CI: 1.99-2.17) times the healthcare costs, respectively, compared to subjects without CHF after adjusting for patient characteristics. CONCLUSION: CHF is associated with an overall two- to three-fold higher cost of healthcare services depending on patient age, accounting for over half of all healthcare costs incurred by elderly CHF patients, and more than two-thirds of all costs among younger CHF patients. Observations of the large burden posed on one of the youngest societies in the developed world are profound, implicative of great opportunities to control the costs of CHF. Further research to understand how resource use impacts health outcomes and quality of care is warranted.

Urinary albumin excretion with sitagliptin compared to sulfonylurea as add on to metformin in type 2 diabetes patients with albuminuria: A real-world evidence study.

AIM: To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy. METHOD: A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120-365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations. RESULTS: A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were -35% (IQR=-73% to 5%) and -31% (IQR=-72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99-1.47, P=0.063). CONCLUSION: Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this.

Renal impairment among postmenopausal women with osteoporosis from a large health plan in Israel.

UNLABELLED: Bisphosphonates are a first-line treatment for osteoporosis but require adequate renal function. We estimated the prevalence of renal impairment among osteoporotic women in Israeli. Approximately 2.3 % of women had renal impairment at a level that makes them inappropriate for bisphosphonate use, demonstrating the need for alternative therapies for osteoporosis treatment. PURPOSE: The purpose of this study is to estimate the prevalence of renal impairment among postmenopausal osteoporotic women within a large Israeli health plan. METHODS: This was a retrospective analysis of Maccabi electronic medical records, including Israeli women aged ≥55 with either an osteoporosis diagnosis or osteoporosis-related fracture between January 1, 2007, and December 31, 2011. The estimated glomerular filtration rate (eGFR), which was calculated from the lowest serum creatinine levels reported during the study period, was used to classify stage 1-5 renal impairment: normal ≥90, mild 60-89, moderate 30-59, severe 15-29, and failure <15 mL/min/1.73 m(2), respectively. Outcomes were distributions of renal impairment across the study population and stratified by age and osteoporosis-defining event. RESULTS: A total of 15,608 patients met all eligibility criteria. Patients with stage 1-5 renal function accounted for 25.2, 54.9, 18.5, 1.2, and 0.3 %, respectively, of all patients. Of osteoporotic patients, 2.3 % had eGFR levels (<35 mL/min/1.73 m(2)) that make them inappropriate for bisphosphonate use. This rate was 1.6 % among patients with an osteoporosis diagnosis and 3.8 % among patients with osteoporosis-related fracture. Within the group of renally impaired patients, older patients were overrepresented. Of the fracture group, patients with hip fractures had a higher prevalence of renal dysfunction (9.3 %) than those having vertebral fractures (3.2 %) or other fractures (2.0 %). CONCLUSIONS: Among postmenopausal women with osteoporosis, 2.3 % had renal impairment which makes them inappropriate for bisphosphonate use in Israel.

Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults.

BACKGROUND: Intradermal vaccine delivery has been shown to induce good immune responses with low vaccine doses. Technologies for drug-delivery which specifically target the skin may render intradermal vaccination more accessible. METHODS: We conducted a prospective, randomized trial in 180 intended-to-treat healthy adults. Study objectives were to evaluate the safety and immunogenicity of low-dose intradermal (ID) influenza vaccines delivered using a novel microneedle device (MicronJet). This device replaces a conventional needle, and is designed specifically for intradermal delivery. Subjects were randomly assigned to receive either the full-dose standard flu shot (containing 15 microg hemagglutinin per strain) delivered intramuscularly using a conventional needle (IM group), a medium dose intradermal injection (6 microg hemagglutinin per strain) delivered with the MicronJet (ID2 group), or a low-dose intradermal injection (3 microg hemagglutinin per strain) delivered with the MicronJet (ID1 group). A marketed influenza vaccine for the 2006/2007 influenza season (alpha-RIX by GSK Biologicals) was used for all injections. Adverse events were recorded over a 42-day period. Immunogenicity was evaluated by changes in hemagglutination inhibition (HAI) antibody titer, and by comparing geometric mean titers (GMTs), seroconversion, and seroprotection rates between the study groups. RESULTS: Local reactions were significantly more frequent following intradermal vaccination, but were mild and transient in nature. At 21 days after injection, GMT fold increase was 22, 18 and 22 in the ID1, ID2 and IM groups respectively for the H1N1 strain; 9, 9 and 16 for the H3N2 strain and 9, 13 and 11 for strain B. The CPMP criteria for re-licensure of seasonal influenza vaccines were met in full for all study groups. CONCLUSIONS: Low-dose influenza vaccines delivered intradermally using microneedles elicited immunogenic responses similar to those elicited by the full-dose intramuscular vaccination. The microneedle injection device used in this study was found to be effective, safe, and reliable.

A highly stereoselective synthesis of the C10-C23 fragment of (-)-dictyostatin.

A highly stereoselective synthesis of the C10-C23 fragment of (-)-dictyostatin has been achieved using a Carreira alkynylation and a Marshall-Tamaru allenylzinc addition as key steps.

A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: investigation of the unusual kinetically controlled RCM stereochemistry.

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.