Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.

Deconvoluting Nonlinear Catalyst-Substrate Effects in the Intramolecular Dirhodium-Catalyzed C-H Insertion of Donor/Donor Carbenes Using Data Science Tools.

Interactions between catalysts and substrates can be highly complex and dynamic, often complicating the development of models to either predict or understand such processes. A dirhodium(II)-catalyzed C-H insertion of donor/donor carbenes into 2-alkoxybenzophenone substrates to form benzodihydrofurans was selected as a model system to explore nonlinear methods to achieve a mechanistic understanding. We found that the application of traditional methods of multivariate linear regression (MLR) correlating DFT-derived descriptors of catalysts and substrates leads to poorly performing models. This inspired the introduction of nonlinear descriptor relationships into modeling by applying the sure independence screening and sparsifying operator (SISSO) algorithm. Based on SISSO-generated descriptors, a high-performing MLR model was identified that predicts external validation points well. Mechanistic interpretation was aided by the deconstruction of feature relationships using chemical space maps, decision trees, and linear descriptors. Substrates were found to have a strong dependence on steric effects for determining their innate cyclization selectivity preferences. Catalyst reactive site features can then be matched to product features to tune or override the resultant diastereoselectivity within the substrate-dictated ranges. This case study presents a method for understanding complex interactions often encountered in catalysis by using nonlinear modeling methods and linear deconvolution by pattern recognition.

Catalytic generation of ortho-quinone dimethides via donor/donor rhodium carbenes.

Substrates engineered to undergo a 1,4-C-H insertion to yield benzocyclobutenes resulted in a novel elimination reaction to yield ortho-quinone dimethide (o-QDM) intermediates that undergo Diels-Alder or hetero-Diels-Alder cycloadditions. The analogous benzylic acetals or ethers avoid the C-H insertion pathway completely and, after hydride transfer, undergo a de-aromatizing elimination reaction to o-QDM at ambient temperature. The resulting dienes undergo a variety of cycloaddition reactions with high diastereo- and regio-selectivity. This is one of the few examples of catalytic generation of o-QDM without the intermediacy of a benzocyclobutene and represents one of the mildest, ambient temperature processes to access these useful intermediates. This proposed mechanism is supported by DFT calculations. Moreover, the methodology was applied to the synthesis of (±)-isolariciresinol in 41% overall yield.

One-Pot Assembly and Synthetic Applications of Geminal Acyl/Alkoxy Tetrasubstituted Allenes.

Polysubstituted allenes are useful synthetic intermediates in many applications, offering structural complexity, modularity, and their axial chirality in further transformations. While acyl and alkoxy-substituted allenes are known, there are currently few examples of allenes containing both functionalities and no reports of geminally substituted acyl/alkoxy allenes being isolated and characterized. Herein, we report the synthesis of tetrasubstituted allenes featuring a novel geminal acyl/alkoxy substitution. These unique "push-pull" allenes are bench-stable and exhibit interesting reactivity in several applications.

1,3-Asymmetric Induction in Diastereoselective Allylations of Chiral N-Tosyl Imines.

Lewis acid mediated allylations of ß-alkoxy N-tosyl imines using allyltrimethylsilane lead to 3-alkoxy homoallylic N-tosyl amines with anti-selectivity. Two methods of Cu(OTf)2-mediated allylations are reported herein, demonstrating that diastereoselectivity can be achieved through 1,3 acyclic stereocontrol of ß-chiral aldimines. Observed selectivity trends and computational evidence suggest selectivity arises through the formation of a six-membered ring chelate. The product ratios of these allylations are dependent on conformational preferences of the chelate and steric effects in the transition-state structures.

Impact of interprofessional service-learning on the effectiveness of knowledge transfer of antimicrobial resistance to Hong Kong elders: a quasi-experiment.

BACKGROUND: Community perception on antimicrobials plays a role in driving the development of antimicrobial resistance (AMR). The aim of the study was to evaluate the impact of interprofessional service-learning on the effectiveness of AMR knowledge transfer in Hong Kong elders aged 65 or above and students from university and secondary schools. METHODS: A quasi-experimental pretest-posttest controlled study was carried out from July 2018 to March 2019 for elderly subjects and a pre- and post-test were conducted in students from May to August 2018. Elderly subjects were recruited from the university-based community outreach program. The community outreach team consisted of both university and secondary school students. Students were provided with training of geriatric care and AMR before they reached out to the community. The one-to-one intervention with the aid of video and verbal explanation to educate the elderly about the definition, causes, and consequences of AMR, and preventive measures against AMR was provided. Questionnaires on knowledge of antibiotics and AMR were used as tools to reflect on the effectiveness for both students and elderly subjects. The questionnaire was completed twice, before and 1 week after the intervention. Chi-square test, t tests and regression analysis were used to analyze the data. RESULTS: A total of 93 Chinese elders, 61 of them in the intervention group and 32 in the control group participated in the study. The score obtained by the intervention group increased from 40.1 to 83.3% (p < 0.001) following intervention, while that of control group increased from 33.0 to 44.0% (p < 0.001). The increase attained in the intervention group was significantly greater than that of the control group (p < 0.001). A total of 95 secondary students and 88 university students have completed the pre-post questionnaires with 42.21% and 13% increment in AMR knowledge after the training (p < 0.001). CONCLUSION: The significant change in knowledge level showed effective AMR knowledge transfer to both elders and students. The study could be used as a reference when allocating resources to implement effective interprofessional service-learning for better community health education in elderly populations. TRIAL REGISTRATION: This study was approved by the Chinese University of Hong Kong Survey and Behavioural Research Ethics Committee in December 2018 (Ref no. SBRE-18-214).

Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy.

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). NDD show great locus heterogeneity and for many of the associated genes, there is substantial phenotypic diversity, including epilepsy, intellectual disability, autism spectrum disorder, movement disorders, and combinations thereof. We report two unrelated patients, a young girl with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio-based whole-exome sequencing analysis uncovered de novo missense variants in CHRM1. Biochemical analyses of one of the NDD-associated variants proved that it caused a reduction in protein levels and impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signaling pathways. Our data strengthen the concept that brain-reduced muscarinic signaling lowers the seizure threshold and severely impairs neurodevelopment.

Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to α-Chiral N-Sulfonyl Imines.

Diastereoselective Lewis acid-mediated additions of nucleophilic alkenes to N-sulfonyl imines are reported. The canonical polar Felkin-Anh model describing additions to carbonyls does not adequately describe analogous additions to N-sulfonyl imines. Herein, we describe the development of conditions to produce both syn and anti products with high diastereoselectivity and good yields. A stereoelectronic model consistent with experimental outcomes is also proposed.

Humor therapy: relieving chronic pain and enhancing happiness for older adults.

The present study examined the effectiveness of a humor therapy program in relieving chronic pain, enhancing happiness and life satisfaction, and reducing loneliness among older persons with chronic pain. It was a quasiexperimental pretest-posttest controlled design. Older persons in a nursing home were invited to join an 8-week humor therapy program (experimental group), while those in another nursing home were treated as a control group and were not offered the program. There were 36 older people in the experimental group and 34 in the control group. Upon completion of the humor therapy program, there were significant decreases in pain and perception of loneliness, and significant increases in happiness and life satisfaction for the experimental group, but not for the control group. The use of humor therapy appears to be an effective nonpharmacological intervention. Nurses and other healthcare professionals could incorporate humor in caring for their patients.

Bolus injection of adenosine before cardioplegic induction improves postischemic global function in coronary artery bypass grafting.

BACKGROUND: Alternative strategies to optimize preexisting cardioplegia during myocardial preservation are currently under extensive investigation. Adenosine, an endogenous purine nucleoside, has been approved for its cardioprotective potential against ischemic-reperfusion injury. Yet, little information is available with respect to the use of adenosine for cardioplegic induction in humans. The purpose of the present study was, therefore, to assess the clinical relevance of intra-aortic administration of adenosine following aortic cross-clamping with respect to the exertion of additional protection in routine coronary artery bypass surgery. METHODS: Thirty patients to receive elective coronary artery bypass grafting under cardiopulmonary bypass (CPB) were prospectively randomized into two study groups. Immediate after aortic cross-clamping and just before the application of modified St. Thomas cardioplegic (20 mL/kg), adenosine solution (250 microg/kg) was injected into the aortic root in the study group (n = 15), while the same amount of normal saline injection was administered in the control group (n = 15). Anesthesia was carried out in all patients in a similar fashion, and all the surgeries were performed by the same team. Homodynamic change, cardiac enzyme assay, and post-bypass inotropic supplementation were recorded throughout the study period to evaluate the extent of myocardial ischemic injury. RESULTS: The mean time to asystole after aortic cross-clamping was significantly shorter for the adenosine group compared with the control group (8.1 +/- 5.9 vs. 79.0 +/- 35.3 sec, respectively; P< 0.01). To compare with the baseline value, the mean cardiac index immediately post CPB and 24 hours postoperatively was increased significantly for the adenosine group (from 2.1 +/- 0.6 to 2.6 +/- 0.6 and 3.2 +/- 0.6 L/min/m2, respectively; P < 0.05), as contrasted with the control group (from 2.3 +/- 0.5 to 2.0 +/- 0.4 and 2.5 +/- 0.4 L/min/m2). Further, the requirement for inotropic support after CPB and postoperative troponin I release were significantly less in the adenosine group. There appeared no adverse effects associated with adenosine administration. CONCLUSIONS: Immediate administration of 250 microg/kg adenosine via the aortic root following aortic cross-clamping could optimize the myocardial protective effect of conventional cardioplegia, quicken cardiac standstill, and offer better postoperative myocardial performance after CPB.

Metallic stenting for treatment of central venous obstruction in hemodialysis patients.

BACKGROUND: Central venous obstruction is a serious and common complication in hemodialysis patients. The recurrence rate is high after balloon dilation, while surgical repair is hazardous in these chronically ill patients. The aim of this study was to evaluate the efficacy of primary Wallstent placement for treatment of hemodialysis-related central venous obstructions. METHODS: Eighteen hemodialysis patients with symptomatic shunt dysfunction and arm swelling due to subclavian (n = 3) or innominate (n = 15) venous obstructions were treated at Kaohsiung Veterans General Hospital with primary Wallstent placement from November 1998 to August 2001. Technical success and complications were reported. Primary and secondary patency rates of stent and hemodialysis access were calculated by survival analysis with Kaplan-Meier method. RESULTS: A total of twenty-five Wallstents were deployed for central venous stenosis (n = 18) and occlusion (n = 7) in these 18 hemodialysis patients. The initial technical success rate was 100%. Fourteen episodes of re-obstruction developed during the observation period. Of them, seven episodes occurred within the stent, four episodes outside of but abutting to the peripheral end of the stent, and another three episodes of re-obstruction were attributed to delayed shortening of the Wallstent. Six of the 14 episodes were treated percutaneously with angioplasty alone, while seven episodes necessitated additional stent placement. No stent migration or other complications were encountered. Primary patency rates of stent and hemodialysis access at 3, 6, 12 and 18 months were 100 and 89%, 73 and 68%, 49 and 42%, and 16 and 0%, respectively. Secondary patency rates of stent and hemodialysis access each were both 100% after 3 months, 93 and 100% after 6 months, 85 and 91% after 12 months and, 68 and 72% after 24 months. CONCLUSIONS: Wallstents are safe to deploy, with excellent technical success for hemodialysis-related central venous obstructions. The Wallstent provides continued use of a hemodialysis access for a substantial period. However, repeated interventions may be necessary to maintain the patency.