Synthesis and Structure-Activity Relationships of Vasicine Analogues as Bronchodilatory Agents

The series of vasicine (1) analogues, an alkaloid from Adhatoda vasica Nees., were synthesized with changes in A, B or C rings. Compounds 13-19 were evaluated for in vitro bronchodilatory activity using isolated guinea pig tracheal chain. Compounds 3-8 were also synthesized in good yields using microwave-mediated synthesis under solvent free conditions. Compounds 5 and 8 with seven-member C ring were more active than etofylline and caused 100% relaxation of both the histamine and acetycholine pre-contracted guinea pig tracheal chain. The structure-activity relationship studies showed that the quinazoline and oxo functionalities were essential for activity. The compounds without C ring and instead having aliphatic and phenyl substitutions in B ring showed relaxation against histamine pre-contracted tracheal chain only, 2-methyl substituted analogues, 12 and 13, being most active with 100% relaxation effect.     

Is there a definition of remission in late-life depression that predicts later relapse?

Remission of depressive symptoms is the goal of all antidepressant therapy. Rating scales define remission in clinical trials, but it is unclear how well these definitions predict risk of later relapse. We measured the sensitivity and specificity of a range of Montgomery-Asberg Depression Rating Scale (MADRS) cutoff scores at 3- and 6-months, wherein scores above a given cutoff would predict relapse over an 18-month period. We examined 153 elderly depressed subjects exhibiting a MADRS < or = 15 after 3 or 6 months of antidepressant therapy. Subjects who subsequently exhibited a MADRS > 15 during the 18-month study period were defined as relapsed. Receiver operating characteristic (ROC) curves were developed and area under the curve (AUC) values calculated for the sensitivity and specificity of 3- and 6-month MADRS scores to predict future relapse. The 3-month ROC had an AUC value of 0.63; the 6-month ROC had an AUC value of 0.66. There was no MADRS cutoff found that could predict likelihood of relapse with good sensitivity and specificity. A post hoc analysis where relapse rate was adjusted by controlling for medical comorbidity, disability, and social support showed no change in the ROCs or AUC values. The higher the MADRS score at 3 and 6 months, the greater the likelihood of relapse. With no clean MADRS cutoff score, the goal of antidepressant therapy should be the lowest possible degree of depressive symptomatology to minimize risk of later relapse. Definitions of remission that are better associated with longer-term outcomes are needed.     

Perioperative interstitial irradiation in the conservative management of early breast cancer

Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.     

HLA‐A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein–Barr virus type 1 (EBV‐1) infection. We carried out a genome‐wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA‐A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10^?9). HLA‐A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p_{HLA‐A‐aa‐site‐99} = 3.79 × 10^?8, p_rs1136697 = 3.79 × 10^?8) and T‐cell receptor binding site (p_{HLA‐A‐aa‐site‐145} = 1.41 × 10^?4, p_rs1059520 = 1.41 × 10^?4) of the HLA‐A. We also detected strong association signals in the 5′‐UTR region with predicted active promoter states (p_rs41545520 = 7.91 × 10^?8). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520‐G correlated with reduced HLA‐A expression. Multivariate logistic regression diminished the effects of HLA‐A amino acid variants and SNPs, indicating a correlation with the effects of HLA‐A*11:01, and to a lesser extent HLA‐A*02:07. We report the strong genetic influence of HLA‐A on NPC susceptibility in the Malaysian Chinese.     

Recent advances and clinical pharmacology aspects of Chimeric Antigen Receptor (CAR) T‐cellular therapy development

Advances in immuno‐oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno‐therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non‐solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno‐therapies, especially CAR‐T cells. Here, we summarize the current knowledge of TCR and CAR‐T cell immunotherapy with particular focus on the structure of CAR‐T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR‐T cell therapies are described.     

Current status of DNA vaccines in veterinary medicine

DNA vaccination entails administration of the DNA itself encoding antigen to direct synthesis of the antigen directly in the target organism. The target organism's immune system recognizes the antigen, and generates humoral (antibody)- and/or cell-mediated immune response. DNA vaccines afford numerous advantages over conventional vaccines, including ease of production, stability and transport. They overcome the need to cultivate dangerous infectious agents, and provide a possibility to vaccinate against multiple pathogens in a single shot. DNA vaccination is beginning to be explored for many pathogens of veterinary interest. The status of DNA vaccines in poultry, livestock and companion animals is reviewed here. While examples of DNA vaccines being tested in the veterinary field are not numerous, the early studies highlight the potential DNA vaccinology offers in veterinary medicine.     

Effect of one-rescuer compression/ventilation ratios on cardiopulmonary resuscitation in infant, pediatric, and adult manikins.

OBJECTIVE: Optimal chest compression to ventilation ratio (C:V) for one-rescuer cardiopulmonary resuscitation (CPR) is not known, with current American Heart Association recommendations 3:1 for newborns, 5:1 for children, and 15:2 for adults. C:V ratios influence effectiveness of CPR, but memorizing different ratios is educationally cumbersome. We hypothesized that a 10:2 ratio might provide adequate universal application for all age arrest victims. DESIGN: Clinical study. SETTING: Tertiary care children's hospital. SUBJECTS: Thirty-five health care providers. INTERVENTIONS: Thirty-five health care providers performed 5-min epochs of one-rescuer CPR at C:V ratios of 3:1, 5:1, 10:2, and 15:2 in random order on infant, pediatric, and adult manikins. Compressions were paced at 100/min by metronome. The number of effective compressions and ventilations delivered per minute was recorded by a trained basic life support instructor. Subjective assessments of fatigue (self-report) and exertion (change in rescuer pulse rate compared with baseline) were assessed. Analysis was by repeated measures analysis of variance and paired Student's t-test. MEASUREMENTS AND MAIN RESULTS: Effective infant compressions per minute did not differ by C:V ratio, but ventilations per minute were greater at 3:1 vs. 5:1, 10:2, and 15:2 (p < .05). Effective pediatric compressions per minute were less at 3:1 vs. 5:1, 10:2, and 15:2 (p < .05) and not different between 5:1, 10:2, and 15:2 ratios. Effective pediatric ventilations per minute were greater at 3:1 than all other ratios and both 5:1 and 10:2 were >15:2 (p < .05). Effective adult compressions per minute were progressively greater with 3:1 vs. 5:1 vs. 10:2 vs. 15:2 (p < .05). Self-efficacy was assessed, and rescuers always subjectively rated 10:2 and 15:2 ratios as easier than 5:1 or 3:1 ratios for all manikins. Rescuer pulse change (exertion) was greater after pediatric and adult vs. infant CPR (p < .05), with no significant difference by C:V ratio. CONCLUSIONS: C:V ratio and manikin size have a significant influence on the number of effective compressions and ventilations delivered during ideal, metronome-paced, one-rescuer CPR. Low ratios of 3:1, 5:1, and 10:2 favor ventilation, and high ratios of 15:2 favor compression, especially in adult manikins. Rescuers subjectively preferred C:V ratios of 10:2 and 15:2 over 3:1 or 5:1. Infant CPR caused less exertion and subjective fatigue than pediatric or adult CPR technique, without significant difference by C:V ratio. We speculate that a universal 10:2 C:V ratio for one-rescuer layperson CPR is physiologically reasonable but warrants further study with particular attention to educational value and technique retention.