Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: a general property and evidence of a tissue type-independent effect

Hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (HS-NSAIDs) are an emerging novel class of compounds with significant anti-inflammatory properties. They consist of a traditional NSAID to which an H(2)S-releasing moiety is covalently attached. We examined the effects of four different HS-NSAIDs on the growth properties of eleven different human cancer cell lines of six different tissue origins. Human colon, breast, pancreatic, prostate, lung, and leukemia cancer cell lines were treated with HS-aspirin, -sulindac, -iburofen, -naproxen, and their traditional counterparts. HS-NSAIDs inhibited the growth of all cancer cell lines studied, with potencies of 28- to >3000-fold greater than that of their traditional counterparts. HS-aspirin (HS-ASA) was consistently the most potent. HS-NSAIDs inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Metabolism of HS-ASA by colon cells showed that the acetyl group of ASA was hydrolyzed rapidly, followed by hydrolysis of the ester bond linking the salicylate anion to the H(2)S releasing moiety, producing salicylic acid and ADT-OH from which H(2)S is released. In reconstitution studies, ASA and ADT-OH were individually less active than the intact HS-ASA towards cell growth inhibition. Additionally, the combination of these two components representing a fairly close approximation to the intact HS-ASA, was 95-fold less active than the intact HS-ASA for growth inhibition. Taken together, these results demonstrate that HS-NSAIDs have potential anti-growth activity against a wide variety of human cancer cells.     

Treatment of coronary artery perforations complicating percutaneous coronary intervention with a polytetrafluoroethylene-covered stent graft

Coronary artery perforation is a rare, but dreaded, complication of percutaneous coronary intervention. Conventional treatment, including reversal of anticoagulation and prolonged balloon inflation, is associated with a high incidence of death, Q-wave myocardial infarction, and emergency coronary bypass surgery. Although a number of case reports have demonstrated the feasibility of sealing coronary perforations with synthetic material-covered stent grafts, the efficacy of this treatment has not been reported in a large, multicenter series. We used a retrospective international registry to examine the outcomes of the polytetrafluoroethylene-coated JOSTENT coronary stent graft (CSG) in 41 cases of coronary perforations. Perforations were relatively severe: 16.7% Ellis grade 1, 54.2% grade 2, and 29.1% grade 3. Of the 41 patients, > 1/3 (n = 14) experienced life-threatening complications before stent graft implantation, including pericardial tamponade (12.2%), cardiogenic shock (9.8%), and cardiac arrest (2.4%). A total of 52 CSGs were used to treat the 41 perforations (mean 1.3 per lesion). All CSGs were placed successfully, with 92.9% of the perforations sealed completely and 7.1% partially. One patient developed abrupt vessel closure after CSG deployment, resulting in an overall procedure success rate of 96.4%. No in-hospital Q-wave myocardial infarctions, emergency coronary bypass surgeries, or deaths resulted. The CSG may be a reliable and highly effective treatment option for sealing coronary perforations complicating percutaneous coronary interventions.     

Evaluation of four proposed bleeding criteria for the onset of late menopausal transition

CONTEXT: The current criterion for onset of late menopausal transition is amenorrhea of 90 d or more. The Stages of Reproductive Aging Workshop proposed alternative criteria based on a shorter period of amenorrhea. Empirical data comparing proposed criteria are not available. OBJECTIVE: This paper evaluates the several bleeding criteria that served as the basis of these recommendations. The goal was to provide empirically based guidance regarding which bleeding criterion may be optimal for widespread application in clinical and research settings. DESIGN/SETTING: The study used prospective menstrual calendar data from four community and population-based cohort studies: TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation. PARTICIPANTS: The study included 735 TREMIN, 279 Seattle Midlife Women's Health Study, 216 Melbourne Women's Midlife Health Project, and 2270 Study of Women's Health Across the Nation women aged 35-57 yr at baseline who contributed 10 menstrual cycles or more. MAIN OUTCOME MEASURE(S): The main measures were the frequency of and median age at occurrence and time from occurrence to final menstrual period (FMP) for four criteria: skipped segment, 10-segment running range, 60- and 90-d amenorrhea. RESULTS: A skipped segment, 10-segment running range greater than 42 d and 60-d amenorrhea identify a similar time in women's reproductive lives. The latter two identify the exact same date in two thirds of women. All three criteria occur in a greater proportion of women than the 90-d criterion and are equally predictive of the FMP, although they occur 1-2 yr earlier. CONCLUSIONS: These findings support the recommendation of the Stages of Reproductive Aging Workshop that 60 d of amenorrhea be used to define onset of the late menopausal transition.     

Time-lapse electrical recordings of single neurons from the mouse neocortex

The ability of the brain to adapt to environmental demands implies that neurons can change throughout life. The extent to which single neurons actually change remains largely unstudied, however. To evaluate how functional properties of single neurons change over time, we devised a way to perform in vivo time-lapse electrophysiological recordings from the exact same neuron. We monitored the contralateral and ipsilateral sensory-evoked spiking activity of individual L2/3 neurons from the somatosensory cortex of mice. At the end of the first recording session, we electroporated the neuron with a DNA plasmid to drive GFP expression. Then, 2 wk later, we visually guided a recording electrode in vivo to the GFP-expressing neuron for the second time. We found that contralateral and ipsilateral evoked responses (i.e., probability to respond, latency, and preference), and spontaneous activity of individual L2/3 pyramidal neurons are stable under control conditions, but that this stability could be rapidly disrupted. Contralateral whisker deprivation induced robust changes in sensory-evoked response profiles of single neurons. Our experiments provide a framework for studying the stability and plasticity of single neurons over long time scales using electrophysiology.     

Synthesis,Structural Elucidation,and In Vitro Antitumor Activities of Some Pyrazolopyrimidines and Schiff Bases Derived from 5-Amino-3-(arylamino)-1H-pyrazole-4-carboxamides

The reaction of 5-amino-3-(arylamino)-1H-pyrazole-4-carboxamides 1a,b with acetylacetone 2 and arylidenemalononitriles 5a–c yielded the pyrazolo[1,5-a]-pyrimidine derivatives 4a,b and 7a–f respectively. On the other hand, Schiff bases 9a,b and 12a–j were obtained upon treatment of carboxamides 1a,b with isatin 8 and some selected aldehydes 11a–e. The newly synthesized compounds were characterized by analytical and spectroscopic data. Representative examples of the synthesized products 4a,b, 7e, 7f, 9b, 12b–f, 12h, and 12j were screened for their in vitro antitumor activities against different human cancer cell lines and the structure-activity relationship (SAR) was discussed.     

Meta‐analysis of massively parallel reporter assays enables prediction of regulatory function across cell types

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data‐driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta‐analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell‐type‐specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation “Regulation Saturation” Challenge for predicting effects of single‐nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest.     

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia

Ataxia-telangiectasia (AT) is an autosomal recessive multisystent disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3–77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or α-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT. Received: 29 October 1998 Received in revised form: 5 February 1999 Accepted: 7 February 1999