Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3ß2ß3 or α6/α3ß4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

D-CRSE: Diminishing chemotherapy-related side effects through patient education, a mixed-methods pilot study.

OBJECTIVES: Patient education materials regarding self-management of chemotherapy-related side effects are limited, which may result in patients using disreputable sources. We created a brochure that educates patients on common side effects, tools to address problems themselves, and guidance on when to contact their oncologist or seek emergency care. This mixed-methods study conducted at Penn State Cancer Institute evaluates the feasibility of using an educational brochure to improve patient outcomes through education. METHODS: Chemotherapy naïve patients with breast or gastrointestinal (GI) cancer were enrolled in a single-arm clinical trial from December 2021 to 2022. Participants received the educational brochure and were asked to provide their initial impressions. They completed The Emotional Thermometer Scale (ETS) and the Memorial Symptom Assessment Scale (MSAS) to measure changes in patient symptoms and mental health throughout their chemotherapy course at 0, 6, and 12-week intervals. The drop-out rate was recorded as a measure of study feasibility. RESULTS: The study participants were split between the following cancer types: 77.8% breast and 22.2% GI cancer. A significant decrease in overall mean ETS score was observed between baseline and week 6 (p = 0.001) and 12 (p = 0.0004), respectively. Moreover, the mean MSAS psychological symptoms decreased significantly at week 12 compared to baseline (p = 0.005), while no change was observed in physical symptoms (p = 0.101). Of the 40 participants who completed baseline surveys, 37 had at least one additional visit for a drop-out rate of 7.5%. CONCLUSION: This mixed-methods pilot study was successful in demonstrating the feasibility of distributing a standardized educational brochure as an intervention for chemotherapy patients. While participants' emotional scores and psychological symptoms decreased over time, physical symptoms did not, which aligns with side effect progression from cumulative chemotherapy burden.

Prospective 5-Year Analysis of the United States Radiation Oncology Job Market Using the ASTRO Career Center Website.

PURPOSE: We provide 5-year results of prospectively collected radiation oncology (RO) job opportunities and a longitudinal assessment of RO graduate numbers within the United States. METHODS AND MATERIALS: Full-time domestic RO job opportunities were collected and categorized using the American Society for Radiation Oncology (ASTRO) Career Center from July 1, 2016 to June 30, 2021. A chi-square test was used to compare regional job availability by city size and position type. The corresponding number of graduating United States (US) RO residents (2017-2021) was collected. US census and Medicare database resources were used as comparators for population and workforce estimates. Pearson's correlation coefficients were used to examine changes in data over time and a 2-tailed t test was used to assess for statistical significance. RESULTS: Over the 5-year study period, 819 unique job offers were posted, compared with 935 RO graduates (0.88 total jobs-to-graduates ratio). Most jobs were nonacademic (57.6%), located in populated areas >1 million (57.1%; median: 1.57M), with the largest proportion of jobs seen in the South region (32.4%). One-third of academic jobs were located at satellites. Regional differences were seen between academic versus nonacademic job availability (P < .01), with the highest proportion of academic jobs seen in the Northeast (60.3%) and the lowest in the Midwest (34.5%). Differences between regions were also observed for jobs in areas >1 million versus ≤1 million (P < .01), with the most jobs in areas >1 million seen in the West (64.6%) and the least in the South (51.3%). Regional job availability over time did not differ by position type (academic vs nonacademic) or population area size (P = .11 and P = .27, respectively). Annual graduate numbers increased with time (P = .02), with the highest percentage of graduates trained in the South (30.8%). Regional distribution of jobs versus graduates significantly differed (P < .01) with the lowest jobs-to-graduates ratio observed in the Northeast (0.67) and highest ratio in the West (1.07). Regional RO workforce estimates based on the 4336 radiation oncologists who were Medicare providers in 2020 were compared with total jobs and graduates by region with no difference observed between the distributions of the workforce and jobs (P = .39), but comparisons between the workforce and graduates were proportionally different (P < .01). The number of total jobs (vs graduates) per 10 million population in the Northeast, South, Midwest, and West were 30.2 (45.1), 21.0 (22.7), 30.6 (33.4), and 22.6 (21.2), respectively. CONCLUSIONS: This multiyear quantitative assessment of the RO job market and graduates identified fewer job opportunities than graduates overall in most regions, most notably in the Northeast. Regional differences were seen between available job type (academic vs nonacademic) and population size (>1 million vs ≤1 million). The findings are worrisome for trainee oversupply and geographic maldistribution. The number and distribution of RO trainees and residency programs across the US should be evaluated to minimize job market imbalance for future graduates, promote workforce stability, and continue to meet the future societal needs of patients with cancer.

The Evolving Role of Radiation Therapy in DLBCL: From Early-Stage to Refractory Disease.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Historically, radiation therapy (RT) served as the primary treatment modality for patients with localized disease. While still an option for select patients who are not candidates for systemic therapy, RT is currently used most frequently as a consolidation treatment after chemoimmunotherapy. Consolidation RT is most commonly recommended after an abbreviated course of systemic therapy in patients who have bulky disease or multiple risk factors, or in the setting of a partial response. Consolidation RT is also appropriate in some patients with advanced DLBCL, including those presenting with bulky disease (≥7.5 cm). While many patients achieve sustained remissions after first-line therapy, up to 50% of patients with DLBCL will eventually relapse. The most common salvage options include second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. RT can be used in both settings to optimize clinical outcomes. This includes consolidation RT in patients with localized presentations or bulky disease in the setting of ASCT and bridging RT in select patients undergoing CAR T-cell therapy. RT is also a valuable modality in any patient with symptomatic disease requiring palliation.

Impact of Medical Operability and Total Metastatic Ablation on Outcomes After SABR for Oligometastases.

PURPOSE: Medical operability is prognostic for survival after SABR in primary malignancies. This study investigated the prognostic significance of medical operability and total versus subtotal ablation of all oligometastatic disease sites. METHODS AND MATERIALS: Consecutive patients with 1 to 5 sites of active extracranial oligometastases had medical operability status and presence of subtotal versus total metastatic ablation recorded prospectively in an institutional database. We retrospectively compared overall survival (OS) and progression-free survival (PFS) for medically operable or inoperable patients and patients undergoing total or subtotal metastatic ablation. Secondary endpoints were patterns of failure, high-grade treatment toxic effects (Common Terminology Criteria for Adverse Events version 4.0), and freedom from systemic therapy. The threshold dose per fraction considered ablative was 8 Gy. RESULTS: A total of 401 patients with 530 treated oligometastases were included, with a median follow-up of 3 years. Three hundred and two and 99 patients had metachronous and synchronous presentations of oligometastatic disease, respectively. Common histologies included prostate (24%), lung (18%), gastrointestinal (19%), and breast (11%). More than 90% of doses delivered were Biologically Effective Dose [BED10]≥60 Gy. Cumulative incidence at 5 years of local-only failure was 6%, local and distant 2%, and distant-only 58%. The 3- and 5-year OS [95% confidence intervals {CIs}] were 68% [62-73] and 54% [47-61], and PFS was 20% [15-25] and 14% [10-20]. The 3- and 5-year freedom from systemic therapy [95% CIs] were 40% [34-46] and 31% [24-37], respectively. Seventy-six patients were inoperable and 325 were operable. Operability status was not prognostic for OS (adjusted hazard ratio [HR], 1.0; 95% CI, 0.6-1.7; P = .9) or for PFS (adjusted HR, 1.1; 95% CI, 0.8-1.6; P = .5). Total metastatic ablation was prognostic for OS (adjusted HR, 0.8; 95% CI, 0.4-0.9; P = .032) and for PFS (adjusted HR, 0.6; 95% CI, 0.4-0.8; P = .003). CONCLUSIONS: Medical operability was not prognostic in patients with oligometastatic disease treated with SABR. Total metastatic ablation was associated with superior OS and PFS compared with subtotal metastatic ablation. Our data support ablation of all sites of oligometastases wherever feasible.

Factors associated with survival in small cell lung cancer: an analysis of real-world national audit, chemotherapy and radiotherapy data.

BACKGROUND: The mainstay of treatment for small cell lung cancer (SCLC) involves platinum doublet chemotherapy but the optimal duration, 4 vs. 6 cycles, is not known. Concurrent thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is recommended for fit individuals with limited stage. However, outside of clinical trials, the efficacy of sequential thoracic radiotherapy and PCI for extensive stage is uncertain. METHODS: This retrospective, observational, cohort study used English national lung cancer data to determine the factors associated with survival for all people diagnosed with SCLC. More precisely, for individuals who received chemotherapy, we examined survival by the chemotherapy duration, thoracic radiotherapy dose and the use of PCI. RESULTS: In total 6,438 people were diagnosed with SCLC. We identified that male sex (OR 0.7; 95% CI: 0.62-0.80), increasing age (P=0.01) greater comorbidity (P≤0.01), extensive stage (OR 0.21; 95% CI: 0.19-0.25) and worse performance status (PS2 vs. PS0 adjusted OR 0.38 95% CI: 0.31-0.48) were associated with reduced 1-year survival. Receipt of chemotherapy augmented survival. We analysed data for 1,761 people who had received chemotherapy. Thoracic radiotherapy (≥30 Gy for extensive stage and ≥40 Gy for limited stage) and PCI were independently associated with better survival (P≤0.01 for each), but 6 cycles of chemotherapy instead of 4 was not (limited stage adjusted OR 0.97; 95% CI: 0.48-1.97) extensive stage adjusted OR 1.34; 95% CI: 0.81-2.21). CONCLUSIONS: Extending chemotherapy beyond 4 cycles to 6 does not augment survival. Appropriately prescribed thoracic radiotherapy and PCI can prolong survival in both limited and extensive stage SCLC.

Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.

BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.

A systematic review of survival following anti-cancer treatment for small cell lung cancer.

OBJECTIVES: We conducted a systematic review and meta-analysis of survival following treatment recommended by the European Society of Medical Oncology for SCLC in order to determine a benchmark for novel therapies to be compared with. MATERIALS AND METHODS: Randomized controlled trials and observational studies reporting overall survival following chemotherapy for SCLC were included. We calculated survival at 30 and 90-days along with 1-year, 2-year and median. RESULTS: We identified 160 for inclusion. There were minimal 30-day deaths. Survival was 99 % (95 %CI 98.0-99.0 %, I233.9 %, n = 77) and 90 % (95 %CI 89.0-92.0 %, I279.5 %, n = 73) at 90 days for limited (LD-SCLC) and extensive stage (ED-SCLC) respectively. The median survival for LD-SCLC was 18.1 months (95 %CI 17.0-19.1 %, I277.3 %, n = 110) and early thoracic radiotherapy (thoracic radiotherapy 18.4 months (95 %CI 17.3-19.5, I278.4 %, n = 100)) vs no radiotherapy 11.7 months (95 %CI 9.1-14.3, n = 10), prophylactic cranial irradiation (PCI 19.7 months vs No PCI 13.0 months (95 %CI 18.5-21.0, I275.7 %, n = 78 and 95 %CI 10.5-16.6, I281.1 %, n = 15 respectively)) and better performance status (PS0-1 22.5 months vs PS0-4 15.3 months (95 %CI 18.7-26.1, I272.4 %, n = 11 and 95 %CI 11.5-19.1 I277.9 %, n = 13)) augmented this. For ED-SCLC the median survival was 9.6 months (95 %CI 8.9-10.3 %, I295.2 %, n = 103) and this improved when irinotecan + cisplatin was used, however studies that used this combination were mostly conducted in Asian populations where survival was better. Survival was not improved with the addition of thoracic radiotherapy or PCI. Survival for both stages of cancer was better in modern studies and Asian cohorts. It was poorer for studies administering carboplatin + etoposide but this regimen was used in studies that had fewer patient selection criteria. CONCLUSION: Early thoracic radiotherapy and PCI should be offered to people with LD-SCLC in accordance with guideline recommendations. The benefit of the aforementioned therapies to treat ED-SCLC and the use of chemotherapy in people with poor PS is less clear.

Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy.

With immunotherapy innovations for cancer treatment, in particular chimeric antigen receptor (CAR) T cells, becoming more successful and prevalent, strategies to mitigate and manage their toxicities are required. Anti-CD19 CAR T-cell therapy has revolutionized the treatment of relapsed/refractory pediatric and adult acute lymphoblastic leukemia and refractory adult non-Hodgkin lymphoma, resulting in the expanded use of CAR T cells in multicenter trials and as US FDA-approved products. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity, which can occur independently or concurrently with CRS, are two potentially life-threatening toxicities of CAR T-cell therapy. In this review, we will focus on describing the pathophysiology behind CRS, the proposed definitions of and grading systems for CRS, and innovative options for treating this potentially lethal systemic inflammatory condition.

Factors influencing treatment selection and 30-day mortality after chemotherapy for people with small-cell lung cancer: An analysis of national audit data.

BACKGROUND: Thirty-day mortality after treatment for lung cancer is a measure of unsuccessful outcome and where treatment should have been avoided. Guidelines recommend offering chemotherapy to individuals with small-cell lung cancer (SCLC) who have poorer performance status (PS) because of its high initial response rate. However, this comes with an increased risk of toxicity and early death. We quantified real-world 30-day mortality in SCLC after chemotherapy, established the factors associated with this and compared these with the factors that influence receipt of chemotherapy. METHODS: We used linked national English data sets to define the factors associated with both receiving chemotherapy and 30-day mortality after chemotherapy. RESULTS: We identified 3715 people diagnosed with SCLC, of which 2235 (60.2%) received chemotherapy. There were 174 (7.8%) deaths within 30 days of chemotherapy. The adjusted odds of receiving chemotherapy decreased with older age, worsening PS and increasing comorbidities. Thirty-day mortality was independently associated with poor PS [PS 2 vs PS 0, adjusted odds ratio (OR) 3.75, 95% confidence interval (CI) 1.71-8.25] and stage (extensive vs limited adjusted OR 1.68, 95% CI 1.03-2.74) but in contrast was not associated with increasing age. Both chemotherapy administration and 30-day mortality varied by hospital network. CONCLUSIONS: To reduce variation in chemotherapy administration, predictors of 30-day mortality could be used as an adjunct to improve suboptimal patient selection. We have quantified 30-day mortality risk by the two independently associated factors, PS and stage, so that patients and clinicians can make better informed decisions about the potential risk of early death after chemotherapy.

Recent advances in the management of lung cancer.

Historically, the prognosis for individuals diagnosed with lung cancer has been bleak. However, the past 10 years have seen important advances in treatment and diagnosis which have translated into the first improvements seen in lung cancer survival. This review highlights the major advances in treatments with curative intent, systemic targeted therapies, palliative care and early diagnosis in lung cancer. We discuss the pivotal research that underpins these new technologies/strategies and their current position in clinical practice.

Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth.

UNLABELLED: Aberrant WNT signaling is associated with the formation and growth of numerous human cancer types. The low-density lipoprotein receptor-related protein 6 (LRP6) is the least redundant component of the WNT receptor complex with two independent WNT ligand-binding sites. Using domain antibody (dAb) technology, a bispecific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of WNT and R-spondin (RSPO) ligands in vitro GSK3178022 was also efficacious in reducing WNT target gene expression in vivo, in both cancer cell line and patient-derived xenograft models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal cancer. IMPLICATIONS: This article demonstrates the inhibition of a key oncogenic receptor, intractable to mAb inhibition due to multiple independent ligand interaction sites, using an innovative dAb approach. Mol Cancer Res; 14(9); 859-68. ©2016 AACR.

Computational and experimental investigations of one-step conversion of poly(carbonate)s into value-added poly(aryl ether sulfone)s.

It is estimated that ∼2.7 million tons poly(carbonate)s (PCs) are produced annually worldwide. In 2008, retailers pulled products from store shelves after reports of bisphenol A (BPA) leaching from baby bottles, reusable drink bottles, and other retail products. Since PCs are not typically recycled, a need for the repurposing of the PC waste has arisen. We report the one-step synthesis of poly(aryl ether sulfone)s (PSUs) from the depolymerization of PCs and in situ polycondensation with bis(aryl fluorides) in the presence of carbonate salts. PSUs are high-performance engineering thermoplastics that are commonly used for reverse osmosis and water purification membranes, medical equipment, as well as high temperature applications. PSUs generated through this cascade approach were isolated in high purity and yield with the expected thermal properties and represent a procedure for direct conversion of one class of polymer to another in a single step. Computational investigations performed with density functional theory predict that the carbonate salt plays two important catalytic roles in this reaction: it decomposes the PCs by nucleophilic attack, and in the subsequent polyether formation process, it promotes the reaction of phenolate dimers formed in situ with the aryl fluorides present. We envision repurposing poly(BPA carbonate) for the production of value-added polymers.

Novel Interaction Mechanism of a Domain Antibody-based Inhibitor of Human Vascular Endothelial Growth Factor with Greater Potency than Ranibizumab and Bevacizumab and Improved Capacity over Aflibercept.

A potent VEGF inhibitor with novel antibody architecture and antigen binding mode has been developed. The molecule, hereafter referred to as VEGF dual dAb (domain antibody), was evaluated in vitro for binding to VEGF and for potency in VEGF-driven models and compared with other anti-VEGF biologics that have been used in ocular anti-angiogenic therapeutic regimes. VEGF dual dAb is more potent than bevacizumab and ranibizumab for VEGF binding, inhibition of VEGF receptor binding assays (RBAs), and VEGF-driven in vitro models of angiogenesis and displays comparable inhibition to aflibercept (Eylea). VEGF dual dAb is dimeric, and each monomer contains two distinct anti-VEGF domain antibodies attached via linkers to a human IgG1 Fc domain. Mechanistically, the enhanced in vitro potency of VEGF dual dAb, in comparison to other anti-VEGF biologics, can be explained by increased binding stoichiometry. A consistent model of the target engagement has been built based on the x-ray complexes of each of the two isolated domain antibodies with the VEGF antigen.

Computational and experimental studies on the mechanism of formation of poly(hexahydrotriazine)s and poly(hemiaminal)s from the reactions of amines with formaldehyde.

Combined experimental and computational studies have been performed on the mechanism of formation of poly(hexahydrotriazine) and hemiaminal dynamic covalent network (PHT and HDCN) thermosetting polymers from the reactions of diamines with formaldehyde (Science 2014, 344, 732-735). Results suggest that these polymers are formed by a mechanism involving the water promoted stepwise addition of amines with formaldehyde in preference to dimerization or cyclotrimerization of imine intermediates or self-catalysis by the amine reagents. The predicted mechanism also explains experimentally observed electronic effects for hexahydrotriazine formation.

Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.

Computational investigations on base-catalyzed diaryl ether formation.

We report investigations with the dispersion-corrected B3LYP density functional method on mechanisms and energetics for reactions of group I metal phenoxides with halobenzenes as models for polyether formation. Calculated barriers for ether formation from para-substituted fluorobenzenes are well correlated with the electron-donating or -withdrawing properties of the substituent at the para position. These trends have also been explained with the distortion/interaction energy theory model which show that the major component of the activation energy is the energy required to distort the arylfluoride reactant into the geometry that it adopts at the transition state. Resonance-stabilized aryl anion intermediates (Meisenheimer complexes) are predicted to be energetically disfavored in reactions involving fluorobenzenes with a single electron-withdrawing group at the para position of the arene, but are formed when the fluorobenzenes are very electron-deficient, or when chelating substituents at the ortho position of the aryl ring are capable of binding with the metal cation, or both. Our results suggest that the presence of the metal cation does not increase the rate of reaction, but plays an important role in these reactions by binding the fluoride or nitrite leaving group and facilitating displacement. We have found that the barrier to reaction decreases as the size of the metal cation increases among a series of group I metal phenoxides due to the fact that the phenoxide becomes less distorted in the transition state as the size of the metal increases.

Mechanisms of organocatalytic amidation and trans-esterification of aromatic esters as a model for the depolymerization of poly(ethylene) terephthalate.

We describe investigations with B3LYP density functional theory to probe mechanisms for the organocatalyzed depolymerization of poly(ethylene) terephthalate (PET) into ester and amide products. These investigations utilize model systems involving the trans-esterification and amidation of methylbenzoate (MB) with ethylene glycol (EG), ethylenediamine (EDA), and ethanolamine (EA) organocatalyzed by 1,5,7-triazabicyclododecene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Mechanisms for reactions in which TBD acts as the lone catalyst have been compared with pathways in which TBD and DBU catalyze these processes with an additional molecule of the amine or alcohol acting as a cocatalyst. Calculations suggest that the combination of an organocatalyst with a molecule of an alcohol or amine cocatalyst is slightly more activating than a lone catalyst. Our results predict that nucleophilic attack is the rate-determining step in reactions involving EDA and EG and that TBD is a better catalyst than DBU in the amidation of MB with EDA; in addition, both organocatalysts activate alcohols more than amines during nucleophilic attack. Amidation and trans-esterification possess similar barriers for reactions involving EA; but the amide, which is the thermodynamic product, is preferentially formed instead of the ester.