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Find video protocols related to scientific articles indexed in Pubmed.
Beyond controversies: sexuality education for adolescents in India.
J Family Med Prim Care
PUBLISHED: 11-07-2014
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Sexuality education for adolescents is one of the most controversial topics in the field of child health. In the past decade, policymakers in India have also struggled with the issue and there has been greater public discourse. However, policymaking and public discussions on adolescent sexuality education are frequently fueled by religious, social, and cultural values, while receiving scant scientific attention. To meet the needs of an expanding young population in India, scientific evidence for best practices must be kept at the core of policymaking in the context of sexuality education for adolescents.
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Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer.
N. Engl. J. Med.
PUBLISHED: 09-27-2014
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Background Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. Methods We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. Results The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. Conclusions In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195 .).
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Ab initio molecular dynamics simulations of water and an excess proton in water confined in carbon nanotubes.
Phys Chem Chem Phys
PUBLISHED: 07-18-2014
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Ab initio molecular dynamics simulations were performed to investigate the effects of nanoscale confinement on the structural and dynamical properties of water and slightly acidic water. Single-walled carbon nanotubes (CNTs) of two different diameters (11.0 and 13.3 Å) were used as confinement vessels, and the inner walls of the CNT were either left bare or fluorinated to explore the influence of the confined environment on the determined properties. The water molecules in the fluorinated nanotubes were found to preferentially localize near the CNT surface and exhibit highly ordered structures while those in the bare CNTs were more randomly distributed. Additionally, weak interactions that resembled hydrogen bonds between the water molecules and the fluorine atoms were observed which occurred at a greater frequency in the smaller diameter CNT indicating an influence of the confinement dimensions on these interactions. This was further pronounced when an excess proton was added where, on average, approximately half of the water molecules in the smaller tube were involved in these interactions. This also led to a structured hydrogen bond network with regular defect sites that hindered proton transfer along the channel axis. Addition of the proton in the larger fluorinated CNT, however, disrupted the structural ordering and proton transfer down the nanotube axis near the surface of the CNT wall readily occurred. Proton transfer through the channel was also observed in the smaller nonfluorinated system, however, the proton was located closer to the center of the CNT, while in the larger nonfluorinated CNT proton transfer exhibited less directional preference indicating an impact of the scale of confinement and nature of the surface on proton transfer.
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Ab initio molecular dynamics simulations of aqueous triflic acid confined in carbon nanotubes.
Phys Chem Chem Phys
PUBLISHED: 07-02-2014
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Ab initio molecular dynamics simulations were performed to investigate the effects of nanoscale confinement on the structural and dynamical properties of aqueous triflic acid (CF3SO3H). Single-walled carbon nanotubes (CNTs) with diameters ranging from ?11 to 14 Å were used as confinement vessels, and the inner surface of the CNT were either left bare or fluorinated to probe the influence of the confined environment on structural and dynamical properties of the water and triflic acidic. The systems were simulated at hydration levels of n = 1-3 H2O/CF3SO3H. Proton dissociation expectedly increased with increasing hydration. Along with the level of hydration, hydrogen bond connectivity between the triflic acid molecules, both directly and via a single water molecule, played a role on proton dissociation. Direct hydrogen bonding between the CF3SO3H molecules, most commonly found in the larger bare CNT, also promoted interactions between water molecules allowing for greater separation of the dissociated protons from the CF3SO3(-) as the hydration level was increased. However, this also resulted in a decrease in the overall proportion of dissociated protons. The confinement dimensions altered both the hydrogen bond network and the distribution of water molecules where the H2O in the fluorinated CNTs tended to form small clusters with less proton dissociation at n = 1 and 2 but the highest at n = 3. In the absence of nearby hydrogen bond accepting sites from H2O or triflic acid SO3H groups, the water molecules formed weak hydrogen bonds with the fluorine atoms. In the bare CNT systems, these involved the CF3 groups of triflic acid and were more frequently observed when direct hydrogen bonding between CF3SO3H hindered potential hydrogen bonding sites. In the fluorinated tubes, interactions with the covalently bound fluorine atoms of the CNT wall dominated which appear to stabilize the hydrogen bond network. Increasing the hydration level increased the frequency of the OH···F (CNT) hydrogen bonding which was highly pronounced in the smaller fluorinated CNT indicating an influence on the confinement dimensions on these interactions.
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Evaluation of statistical designs in phase I expansion cohorts: the Dana-Farber/Harvard Cancer Center experience.
J. Natl. Cancer Inst.
PUBLISHED: 07-01-2014
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Phase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess endpoints in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined.
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Crizotinib as salvage and maintenance with allogeneic stem cell transplantation for refractory anaplastic large cell lymphoma.
J Natl Compr Canc Netw
PUBLISHED: 03-12-2014
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The NPM-ALK fusion protein is found in ALK(+) anaplastic large cell lymphomas harboring the t(2;5) chromosomal translocation. Patients harboring ALK translocations typically have an excellent prognosis with conventional chemotherapy and a reported 5-year survival rate of 70%. Although most patients with ALK(+) anaplastic large cell lymphoma have a good prognosis, some patients do not respond to standard therapies. In patients with refractory anaplastic large cell lymphoma who can achieve remission, allogeneic stem cell transplant is a potentially curative option. This article describes a patient with refractory ALK(+) anaplastic large cell lymphoma who experienced a complete response to the ALK inhibitor crizotinib and then underwent an allogeneic stem cell transplant followed by crizotinib maintenance therapy.
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Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma.
Clin. Cancer Res.
PUBLISHED: 01-29-2014
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Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma.
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Extended cycle combined oral contraceptives and prophylactic frovatriptan during the hormone-free interval in women with menstrual-related migraines.
J Womens Health (Larchmt)
PUBLISHED: 01-22-2014
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Migraine headaches are a significant problem for American women with many of them suffering from headaches around the time of their menstrual cycle. Women taking oral contraceptives in the standard 21/7 cycle regimen often suffer from headaches around the time of the hormone free intervals (HFIs) as well. Extended oral contraceptive regimens have been shown to decrease the frequency, but not eliminate these headaches. This study is a double-blind, randomized, placebo-controlled pilot study of participants with menstrual-related migraines (MRMs) who were initiated on extended combined oral contraceptives and given frovatriptan prophylactically during HFIs.
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Improving pre-service elementary teachers' self-reported efficacy for using the professional teacher standards in health education.
J Sch Health
PUBLISHED: 01-05-2014
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The effectiveness of health education methods courses for pre-service elementary teachers has not been assessed for improving the pre-service elementary teacher's self-efficacy for using the professional teacher standards in health education (PTSHE).
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Extent, characterization, and sources of soil lead contamination in small-urban residential neighborhoods.
J. Environ. Qual.
PUBLISHED: 11-13-2013
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We present high spatial-resolution mapping of soil lead (Pb) concentrations in a small-urban residential setting. X-ray fluorescence was used to measure soil Pb at170 properties in the City Park neighborhood of Appleton, Wisconsin. Greater than two-thirds of soil samples collected from drip lines contained more than 400 ?g g of Pb, and one third exceeded 1200 ?g g. Soils adjacent to homes built before 1960 contained significantly higher Pb levels than those near younger homes. Three front yard locations (drip line, mid-yard, and terrace) were sampled at 71 properties. A general decline in soil Pb with increasing distance from the house was observed. Detailed sampling of individual homes within a single residential block revealed Pb-contaminated soil radiating outward from homes in all directions, creating a "bulls-eye" pattern. Approximately 40% of yard space exceeded concentrations of 400 ?g g. These patterns of contamination are consistent with Pb paint as the main contributor of Pb to soil. This has important implications because spatial distribution of Pb contamination is fundamentally different if paint, rather than automobile exhaust, is the primary source. Selective sequential extraction analyses suggest that roughly half of the soil Pb resides in chemically reactive and bioavailable phases. The extent and persistence of soil Pb, the resurgence of home gardening, and the serious health consequences of Pb ingestion argue for attention to this problem, not just in dense urban centers but also in smaller urban settings across the country.
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Side chain flexibility in perfluorosulfonic acid ionomers: an ab initio study.
J Phys Chem A
PUBLISHED: 09-27-2013
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Side chain flexibility in perfluorosulfonic acid (PFSA) ionomers has been explored through ab initio electronic structure calculations. Three different PFSA side chain fragments were considered with a CF3CFCF3 backbone representation: Nafion (-OCF2CF(CF3)O(CF2)2SO3H), Aquivion or the short side chain (SSC) (-O(CF2)2SO3H), and the 3M PFSA (-O(CF2)4SO3H). Rotational potential energy surfaces for each bond along the length of the side chains were obtained using density functional theory with the B3LYP and the dispersion-corrected B97D functionals with and without the inclusion of a solvation model. Solvent effects were found to have minimal effect on bond rotations close to the tetrafluoroethylene backbone but had greater impact near the terminal sulfonic acid group. The carbon-sulfur bond was found to be the most flexible portion of the side chain in each of the fragments which was further enhanced with the inclusion of the solvent. Complete rotation about either the O-CF2 or CF-O bond in the Nafion side chain resulted in fairly high energetic barriers, but significant portions of these rotational surfaces had energetic penalties less than 1.5 kcal/mol indicating substantial conformational freedom. Fully extended and folded conformations of the Nafion side chain exhibit considerable contraction in side chain end-to-end distance and were observed to be nearly isoenergetic using B3LYP, but the folded structures with the ether oxygen atoms in gauche conformations were ~1.5 kcal/mol lower in energy using B97D. Below the second ether linkage of the Nafion side chain, the rotational potential energy profiles were identical to that determined for the SSC side chain. The 3M side chain was generally found to be the most rigid with barriers for complete rotation about the central carbon-carbon bonds of approximately 7 kcal/mol. These results indicate that minor differences in side chain length and chemistry may have a pronounced effect on the rotational potential energy surfaces, particularly those involving rotation about different carbon-carbon bonds with distinctly different character.
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Development of a pre-service teachers self-efficacy instrument regarding teacher health education standards.
J Sch Health
PUBLISHED: 09-12-2013
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Whereas many education programs expect students to use national standards in various content areas, few studies have been conducted that examine pre-service teachers confidence in demonstrating their use of the professional teacher standards.
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Phase 1 study of N (1),N (11)-diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma.
Cancer Chemother. Pharmacol.
PUBLISHED: 07-19-2013
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N (1),N (11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC.
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Abundance, diversity, and distribution of mosquito vectors in selected ecological regions of Kenya: public health implications.
J. Vector Ecol.
PUBLISHED: 05-25-2013
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The diversity of mosquito arbovirus vectors was investigated to define regional risk of arbovirus transmission in Kenya. Mosquitoes were sampled between April, 2007 and December, 2010 at thirteen sites across seven administrative provinces and ecological zones. CDC light traps were used to collect mosquitoes while human-landing collection was conducted in five of the sites to target day-feeding Aedes (Stegomyia) species. Over 524,000 mosquitoes were collected and identified into 101 species, 30 of them known vectors of arboviruses endemic to Kenya. Ae. (Neomelaniconion) mcintoshi and Ae. (Aedimorphus) ochraceus were most abundant in Garissa in the arid northeastern province, and Mansonia uniformis and Mn. africana in semi-arid Baringo in the Rift Valley Province. Ae. ochraceus, Mn. africana and Mn. uniformis were also significant in Nyanza Province, while Ae. (Neomelaniconion) circumluteolus predominated in Budalangi, Western Province. Aedes (Stegomyia) aegypti was predominant in Rabai in the Coast Province but insignificant in the western and Nyanza sites. Culex pipiens was abundant in Rift Valley and Nyanza Provinces around the lake shores. This study highlights the potential for emergence and re-emergence of arboviral diseases among vulnerable populations. This calls for comprehensive mapping of vector distribution and abundance for planning focused vector control measures.
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FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience.
Oncologist
PUBLISHED: 05-08-2013
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The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.
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Histologic examination of condensing osteitis in cadaver specimens.
J Endod
PUBLISHED: 02-12-2013
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Condensing osteitis is a radiographic finding, but with no reported histologic investigations in humans. The objectives of this study were to evaluate and describe histologically condensing osteitis in human cadaver jaws. Patterns of bone formation and presence/absence and nature of inflammation were examined.
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Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer.
Pharmacol. Rev.
PUBLISHED: 01-01-2013
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The strategy for discovery and development of new cancer drugs has shifted the field from cytotoxic agents to therapies that selectively target oncogenic drivers. In the last decade, a number of targeted cancer therapies have been discovered and proven effective in a variety of hematological and solid malignancies. In this article, we review clinical pharmacokinetic characteristics of the U.S. Food and Drug Administration-approved targeted therapies and provide an overview of key clinical trials that led to approval of these drugs. The major limiting factor of targeted treatment is the development of resistance. We describe general principles of resistance and specific, clinically confirmed mechanisms of resistance to several therapies in different malignancies.
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Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab.
Oncologist
PUBLISHED: 12-30-2011
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Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.
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Ability of selected Kenyan mosquito (Diptera: Culicidae) species to transmit West Nile virus under laboratory conditions.
J. Med. Entomol.
PUBLISHED: 12-28-2011
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West Nile virus (WNV) is currently active in Kenya as evidenced by the detection of antibodies in birds bled as part of an avian influenza surveillance program in 2009. Although WNV has been isolated from several mosquito species in Kenya, no studies have ever been conducted to determine which of these species are competent vectors of this virus. Therefore, we allowed Kenyan mosquitoes to feed on 2- or 3-d-old chickens that had been infected with a Lineage one strain of WNV 24-48 h earlier. These mosquitoes were tested approximately 2 wk later to determine infection, dissemination, and transmission rates. All five species [Culex quinquefasciatus Say, Culex univittatus Theobald, Culex vansomereni Edwards, Mansonia africana (Theobald), and Mansonia uniformis (Theobald)] were susceptible to infection, but disseminated infections were detected only in the three Culex, and not the two Mansonia species. Culex mosquitoes with a disseminated infection readily transmitted virus by bite, but even when inoculated with WNV, the two Mansonia failed to transmit virus, indicating a salivary gland barrier. These studies indicate that the three Culex species may play a role in the transmission of WNV in Kenya.
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Evaluation of ULV applications against Old World sand fly (Diptera: Psychodidae) species in equatorial Kenya.
J. Med. Entomol.
PUBLISHED: 12-28-2011
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Reducing populations of phlebotomine sand flies in areas prevalent for human leishmaniases is of ongoing importance to United States military operations and civilian populations in endemic regions. However, not enough is known regarding the efficacy of Department of Defense-approved pesticides and equipment against sand flies; specifically, the potential for ultra-low volume (ULV) pesticide applications to control Old World sand fly vectors. In this study we examine two sprayers, the Terminator ULV and the Grizzly ULV, with UV-labeled Duet and Fyfanon in four combinations against caged Phlebotomus duboscqi (Neveu-Lemaire) and wild sand fly populations in a natural environment in western Kenya. All equipment and Fyfanon have United States military National Stock Numbers and both pesticides are registered with the United States Environmental Protection Agency. Caged sand flies were reared from local P. duboscqi and the area has long been studied because of high incidences of human cutaneous and visceral Leishmania. Patterns of mortality across grids of caged sand flies showed greater efficacy from the Grizzly ULV regardless of chemical. The Terminator ULV performed well with Duet but with a less uniform and overall lower rate of mortality across the spray grid. Sampling of wild populations before and after treatments suggested local population suppression from ULV treatments, as well as a possible repellent effect in nearby untreated areas. Surprisingly, ULV active ingredient deposition inferred from patterns of UV-labeled droplets captured on cotton ribbons adjacent to sand fly cages in spray plots did not match patterns of mortality. We discuss the implications of this study, the first of its kind, for future military preventive medicine activities, including relative performance costs and benefits of larger or smaller sprayers, and the relative stability of ULV-induced mortality patterns in varied or sub-optimal conditions.
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Field evaluation of a wicking assay for the rapid detection of Rift Valley fever viral antigens in mosquitoes.
J. Am. Mosq. Control Assoc.
PUBLISHED: 12-18-2011
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Rift Valley fever virus (RVFV) causes outbreaks of severe disease in domestic ungulates as well as humans in Africa. There is a concern that outbreaks of Rift Valley fever may continue and that this virus may spread into regions where it had not previously been detected. Surveillance and rapid detection are critical to the initiation of an effective disease control program. Here we report on the field evaluation in Kenya of the VectorTest RVFV antigen assay, modeled on the VecTest assay for West Nile virus. The dipsticks provided results in <20 min, were easy to use, and did not require a laboratory with containment facilities. Although none of the field-collected mosquitoes were infected with RVFV, the dipstick provided a clear positive result with pools of field-collected mosquitoes spiked with a single positive, irradiated (to inactivate any infectious virus) mosquito. Similarly, the dipstick was able to detect virus from pools of mosquitoes captured during the RVFV outbreak in 2007. The RVFV dipstick assay was highly specific with only a single weak false positive out of 266 pools tested (specificity > 99.6%). The RVFV assay can provide a rapid, safe, easy-to-use preliminary test to alert public health personnel to the presence of RVFV in mosquitoes in a given area. Results from this assay will allow for more rapid medical threat assessments and the focusing of vector control measures on high-risk areas.
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Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.
Oncologist
PUBLISHED: 12-16-2011
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Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
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A qualitative analysis of success stories from Michiana Coordinated School Health Leadership institute participants.
J Sch Health
PUBLISHED: 11-11-2011
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The purpose of this study was to detect and document common themes among success stories, along with challenges, as related by participants in the Michiana Coordinated School Health Leadership Institute. Four-member teams from 18 Michigan and Indiana school districts participated in semiannual Institute workshops over a 3-year period and were tasked with implementing Coordinated School Health Programs (CSHPs).
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MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.
J. Clin. Oncol.
PUBLISHED: 10-31-2011
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Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study.
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Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
Lancet Oncol.
PUBLISHED: 09-18-2011
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ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.
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Minimally Invasive versus Open Cervical Foraminotomy: A Systematic Review.
Global Spine J
PUBLISHED: 09-05-2011
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Posterior cervical laminoforaminotomy is an effective treatment for cervical radiculopathy due to disc herniations or spondylosis. Over the last decade, minimally invasive (i.e., percutaneous) procedures have become increasingly popular due to a smaller incision size and presumed benefits in postoperative outcomes. We performed a systematic review of the literature and identified studies of open or percutaneous laminoforaminotomy that reported one or more perioperative outcomes. Of 162 publications found by our initial screening, 19 were included in the final analysis. Summative results indicate that patients undergoing percutaneous cervical laminoforaminotomy have lower blood loss by 120.7 mL (open: 173.5 mL, percutaneous: 52.8 mL, n?=?670), a shorter surgical time by 50.0 minutes (open: 108.3 minutes, percutaneous: 58.3 minutes, n?=?882), less inpatient analgesic use by 25.1 Eq (open: 27.6 Eq, percutaneous: 2.5 Eq, n?=?356), and a shorter hospital stay by 2.2 days (open: 3.2 days, percutaneous: 1.0 days, n?=?1472), compared with patients undergoing open procedures. However, the heterogeneous nature of published data calls into question the reliability of these summative results. Further structured trials should be conducted to better characterize the risks and benefits of percutaneous laminoforaminotomy.
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Clinical presentation and manual therapy for lower quadrant musculoskeletal conditions.
J Man Manip Ther
PUBLISHED: 07-26-2011
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Chronic lower quadrant injuries constitute a significant percentage of the musculoskeletal cases seen by clinicians. While impairments may vary, pain is often the factor that compels the patient to seek medical attention. Traumatic injury from sport is one cause of progressive chronic joint pain, particularly in the lower quarter. Recent studies have demonstrated the presence of peripheral and central sensitization mechanisms in different lower quadrant pain syndromes, such as lumbar spine related leg pain, osteoarthritis of the knee, and following acute injuries such as lateral ankle sprain and anterior cruciate ligament rupture. Proper management of lower quarter conditions should include assessment of balance and gait as increasing pain and chronicity may lead to altered gait patterns and falls. In addition, quantitative sensory testing may provide insight into pain mechanisms which affect management and prognosis of musculoskeletal conditions. Studies have demonstrated analgesic effects and modulation of spinal excitability with use of manual therapy techniques, with clinical outcomes of improved gait and functional ability. This paper will discuss the evidence which supports the use of manual therapy for lower quarter musculoskeletal dysfunction.
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Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer.
Cancer
PUBLISHED: 07-21-2011
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Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow-up.
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Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification.
J Thorac Oncol
PUBLISHED: 05-31-2011
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Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.
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Promoting mental health and preventing substance abuse and violence in elementary students: a randomized control study of the Michigan Model for Health.
J Sch Health
PUBLISHED: 05-20-2011
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In elementary grades, comprehensive health education curricula mostly have demonstrated effectiveness in addressing singular health issues. The Michigan Model for Health (MMH) was implemented and evaluated to determine its impact on multiple health issues, including social and emotional skills, prosocial behavior, and drug use and aggression.
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Intraductal papillary mucinous adenocarcinoma of the pancreas: clinical outcomes, prognostic factors, and the role of adjuvant therapy.
Gastrointest Cancer Res
PUBLISHED: 05-17-2011
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Pancreatic ductal adenocarcinoma (PDAC) arising in intraductal papillary mucinous neoplasms (IPMN) may represent a different biologic entity than classic PDAC, and there is little evidence to inform adjuvant treatment decisions. The purpose of this study was to identify prognostic factors for PDAC arising in IPMN and determine the benefit of postoperative adjuvant therapy.
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A phase 2 study of oral MKC-1, an inhibitor of importin-?, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer.
Invest New Drugs
PUBLISHED: 05-13-2011
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MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-? family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer.
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Structure of filamin A immunoglobulin-like repeat 10 from Homo sapiens.
Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun.
PUBLISHED: 04-29-2011
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Filamin A (FlnA) plays a critical role in cytoskeletal organization, cell motility and cellular signaling. FlnA utilizes different binding sites on a series of 24 immunoglobulin-like domains (Ig repeats) to interact with diverse cytosolic proteins and with cytoplasmic portions of membrane proteins. Mutations in a specific domain, Ig10 (FlnA-Ig10), are correlated with two severe forms of the otopalatodigital syndrome spectrum disorders Melnick-Needles syndrome and frontometaphyseal dysplasia. The crystal structure of FlnA-Ig10 determined at 2.44?Å resolution provides insight into the perturbations caused by these mutations.
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Risk of oral clefts in twins.
Epidemiology
PUBLISHED: 03-23-2011
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Small studies have indicated that twinning increases the risk of oral cleft.
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The AFHSC-Division of GEIS Operations Predictive Surveillance Program: a multidisciplinary approach for the early detection and response to disease outbreaks.
BMC Public Health
PUBLISHED: 03-04-2011
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The Armed Forces Health Surveillance Center, Division of Global Emerging Infections Surveillance and Response System Operations (AFHSC-GEIS) initiated a coordinated, multidisciplinary program to link data sets and information derived from eco-climatic remote sensing activities, ecologic niche modeling, arthropod vector, animal disease-host/reservoir, and human disease surveillance for febrile illnesses, into a predictive surveillance program that generates advisories and alerts on emerging infectious disease outbreaks. The programs ultimate goal is pro-active public health practice through pre-event preparedness, prevention and control, and response decision-making and prioritization. This multidisciplinary program is rooted in over 10 years experience in predictive surveillance for Rift Valley fever outbreaks in Eastern Africa. The AFHSC-GEIS Rift Valley fever project is based on the identification and use of disease-emergence critical detection points as reliable signals for increased outbreak risk. The AFHSC-GEIS predictive surveillance program has formalized the Rift Valley fever project into a structured template for extending predictive surveillance capability to other Department of Defense (DoD)-priority vector- and water-borne, and zoonotic diseases and geographic areas. These include leishmaniasis, malaria, and Crimea-Congo and other viral hemorrhagic fevers in Central Asia and Africa, dengue fever in Asia and the Americas, Japanese encephalitis (JE) and chikungunya fever in Asia, and rickettsial and other tick-borne infections in the U.S., Africa and Asia.
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Tolerability of combined modality therapy for rectal cancer in elderly patients aged 75 years and older.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 03-04-2011
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To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older.
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A multicenter retrospective study on clinical characteristics, treatment patterns, and outcome in elderly patients with hepatocellular carcinoma.
Oncologist
PUBLISHED: 02-24-2011
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There is a paucity of information on the clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients. We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients.
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Potential drug development candidates for human soil-transmitted helminthiases.
PLoS Negl Trop Dis
PUBLISHED: 02-19-2011
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Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.
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Phase 1/2 study of everolimus in advanced hepatocellular carcinoma.
Cancer
PUBLISHED: 02-15-2011
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The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single-arm, phase 1/2 study of everolimus in patients with advanced HCC.
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Native and recombinant Slc26a3 (downregulated in adenoma, Dra) do not exhibit properties of 2Cl-/1HCO3- exchange.
Am. J. Physiol., Cell Physiol.
PUBLISHED: 11-10-2010
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The recent proposal that Dra/Slc26a3 mediates electrogenic 2Cl(-)/1HCO(3)(-) exchange suggests a required revision of classical concepts of electroneutral Cl(-) transport across epithelia such as the intestine. We investigated 1) the effect of endogenous Dra Cl(-)/HCO(3)(-) activity on apical membrane potential (V(a)) of the cecal surface epithelium using wild-type (WT) and knockout (KO) mice; and 2) the electrical properties of Cl(-)/(OH(-))HCO(3)(-) exchange by mouse and human orthologs of Dra expressed in Xenopus oocytes. Ex vivo (36)Cl(-) fluxes and microfluorometry revealed that cecal Cl(-)/HCO(3)(-) exchange was abolished in the Dra KO without concordant changes in short-circuit current. In microelectrode studies, baseline V(a) of Dra KO surface epithelium was slightly hyperpolarized relative to WT but depolarized to the same extent as WT during luminal Cl(-) substitution. Subsequent studies indicated that Cl(-)-dependent V(a) depolarization requires the anion channel Cftr. Oocyte studies demonstrated that Dra-mediated exchange of intracellular Cl(-) for extracellular HCO(3)(-) is accompanied by slow hyperpolarization and a modest outward current, but that the steady-state current-voltage relationship is unaffected by Cl(-) removal or pharmacological blockade. Further, Dra-dependent (36)Cl(-) efflux was voltage-insensitive in oocytes coexpressing the cation channels ENaC or ROMK. We conclude that 1) endogenous Dra and recombinant human/mouse Dra orthologs do not exhibit electrogenic 2Cl(-)/1HCO(3)(-) exchange; and 2) acute induction of Dra Cl(-)/HCO(3)(-) exchange is associated with secondary membrane potential changes representing homeostatic responses. Thus, participation of Dra in coupled NaCl absorption and in uncoupled HCO(3)(-) secretion remains compatible with electroneutrality of these processes, and with the utility of electroneutral transport models for predicting epithelial responses in health and disease.
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Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor.
N. Engl. J. Med.
PUBLISHED: 10-29-2010
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Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
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Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
N. Engl. J. Med.
PUBLISHED: 10-29-2010
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Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
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Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value.
Clin. Cancer Res.
PUBLISHED: 09-15-2010
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Sunitinib--a multitargeted tyrosine kinase inhibitor--can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study.
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Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery.
Anesthesiology
PUBLISHED: 08-10-2010
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Ketamine is an N-methyl-d-aspartate receptor antagonist that has been shown to be useful in the reduction of acute postoperative pain and analgesic consumption in a variety of surgical interventions with variable routes of administration. Little is known regarding its efficacy in opiate-dependent patients with a history of chronic pain. We hypothesized that ketamine would reduce postoperative opiate consumption in this patient population.
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A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer.
Oncologist
PUBLISHED: 07-28-2010
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Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy.
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Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.
Oncologist
PUBLISHED: 05-18-2010
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We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.
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Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine.
EMBO Mol Med
PUBLISHED: 05-01-2010
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Targeted cancer therapy requires the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. We sought to develop a high-throughput genotyping platform that would allow prospective patient selection to the best available therapies, and that could readily and inexpensively be adopted by most clinical laboratories. We developed a highly sensitive multiplexed clinical assay that performs very well with nucleic acid derived from formalin fixation and paraffin embedding (FFPE) tissue, and tests for 120 previously described mutations in 13 cancer genes. Genetic profiling of 250 primary tumours was consistent with the documented oncogene mutational spectrum and identified rare events in some cancer types. The assay is currently being used for clinical testing of tumour samples and contributing to cancer patient management. This work therefore establishes a platform for real-time targeted genotyping that can be widely adopted. We expect that efforts like this one will play an increasingly important role in cancer management.
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Patient-reported acute gastrointestinal symptoms during concurrent chemoradiation treatment for rectal cancer.
Cancer
PUBLISHED: 02-19-2010
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Although it is known that standard 5-fluorouracil-based chemoradiation therapy for rectal cancer causes significant acute gastrointestinal (GI) toxicity, research on patient-reported outcomes (PROs) is limited. The authors undertook the current study to assess the feasibility of incorporating PRO measurement into routine clinical practice and to describe the trajectory of symptom development during treatment.
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Phase II study of pemetrexed in patients with advanced neuroendocrine tumors.
Cancer Chemother. Pharmacol.
PUBLISHED: 01-09-2010
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In some reports, 5-fluorouracil has been associated with modest activity in patients with neuroendocrine tumors. Pemetrexed is a multitargeted antifolate with activity in tumor types not significantly responsive to other antifolates. We evaluated the efficacy of pemetrexed in a phase II study of patients with advanced neuroendocrine tumors.
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Operational vector-borne disease surveillance and control: closing the capabilities gap through research at overseas military laboratories.
US Army Med Dep J
PUBLISHED: 12-04-2009
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Malaria, dengue fever, chikungunya virus, leishmaniasis, and a myriad of other vector-borne diseases pose significant threats to the warfighter and to the overall combat effectiveness of units. Military preventive medicine (PM) assets must accurately evaluate the vector-borne disease threat and then implement and/or advise the commander on countermeasures to reduce a particular threat. The success of these measures is contingent upon the biology of the disease vector and on the tools or methods used to conduct vector/pathogen surveillance and vector control. There is a significant gap between the tools available and those required for operational PM assets to provide real-time, effective surveillance and control. A network of US Army and US Navy overseas laboratories is focused on closing the current capabilities gap. Their mission is to develop and field test tools and methods to enhance the combatant commanders ability to identify and mitigate the threat posed by these vector-borne diseases.
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Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.
Lancet Oncol.
PUBLISHED: 11-20-2009
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Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome.
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Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer.
Cancer Res.
PUBLISHED: 10-13-2009
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Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.
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Treatment of chorea associated with Huntingtons disease: focus on tetrabenazine.
Consult Pharm
PUBLISHED: 08-20-2009
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Review Huntingtons disease (HD) and the role of tetrabenazine (TBZ) in treating chorea associated with this disease. Discuss the pharmacology, side-effect profile, drug interactions, precautions, and contraindications of TBZ.
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gammaH2AX: A potential DNA damage response biomarker for assessing toxicological risk of tobacco products.
Mutat. Res.
PUBLISHED: 06-01-2009
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Differentiation among American cigarettes relies primarily on the use of proprietary tobacco blends, menthol, tobacco substitutes, paper porosity, paper additives, and filter ventilation. These characteristics substantially alter per cigarette yields of tar and nicotine in standardized protocols promulgated by government agencies. However, due to compensatory alterations in smoking behavior to sustain a preferred nicotine dose (e.g., by increasing puff frequency, inhaling more deeply, smoking more cigarettes per day, or blocking filter ventilation holes), smokers actually inhale similar amounts of tar and nicotine regardless of any cigarette variable, supporting epidemiological evidence that all brands have comparable disease risk. Consequently, it would be advantageous to develop assays that realistically compare cigarette smoke (CS)-induced genotoxicity regardless of differences in cigarette construction or smoking behavior. One significant indicator of potentially carcinogenic DNA damage is double strand breaks (DSBs), which can be monitored by measuring Ser 139 phosphorylation on histone H2AX. Previously we showed that phosphorylation of H2AX (defined as gammaH2AX) in exposed lung cells is proportional to CS dose. Thus, we proposed that gammaH2AX may be a viable biomarker for evaluating genotoxic risk of cigarettes in relation to actual nicotine/tar delivery. Here we tested this hypothesis by measuring gammaH2AX levels in A549 human lung cells exposed to CS from a range of commercial cigarettes using various smoking regimens. Results show that gammaH2AX induction, a critical event of the mammalian DNA damage response, provides an assessment of CS-induced DNA damage independent of smoking topography or cigarette type. We conclude that gammaH2AX induction shows promise as a genotoxic bioassay offering specific advantages over the traditional assays for the evaluation of conventional and nonconventional tobacco products.
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The effect of abdominal binders on postoperative pulmonary function.
Am Surg
PUBLISHED: 03-14-2009
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Abdominal binders are ordered by some surgeons postoperatively for patient comfort and to prevent wound complications. There has been some question as to the compressive effect that an abdominal binder has on pulmonary function. We prospectively randomized 54 patients undergoing a midline laparotomy incision to two groups: a "binder" group and a "no binder" group. Preoperative pulmonary function tests (vital capacity and incentive spirometry) were measured. Postoperatively, pulmonary function tests, pulse oximetry, oxygen requirement, pulmonary and wound complications, pain control, time to ambulation, and hospital length of stay were examined. Vital capacity as a per cent of preoperative values on postoperative Day 1 for the binder and nonbinder groups were 64.7 and 54.6 per cent, respectively, but this was not statistically significant. Average level of pain using the visual analog pain scale on postoperative Days 1 through 3 in the binder versus nonbinder groups was 4 versus 8, 3 vs 6, and 3 versus 7, respectively. Time to ambulation was 18.6 hours in the binder group and 16.7 hours in the nonbinder group. Hospital length of stay in the binder and nonbinder groups was 3.9 days and 3.7 days, respectively. We conclude that abdominal binders in our patients with midline abdominal incisions had no significant effect on postoperative pulmonary function, but seemed to help with pain control.
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Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer.
J. Clin. Oncol.
PUBLISHED: 01-17-2009
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The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.
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Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.
PLoS ONE
PUBLISHED: 01-12-2009
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Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads).
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Long term survivors with metastatic pancreatic adenocarcinoma treated with gemcitabine: a retrospective analysis.
J Hematol Oncol
PUBLISHED: 01-05-2009
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Metastatic pancreatic adenocarcinoma has a short median overall survival (OS) of 5-6 months. However, a subgroup of patients survives more than 1 year. We analyzed the survival outcomes of this subgroup and evaluated clinical and pathological factors that might affect survival durations.
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Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors.
Clin. Cancer Res.
PUBLISHED: 01-02-2009
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A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks.
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O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors.
Clin. Cancer Res.
PUBLISHED: 01-02-2009
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Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O(6)-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens.
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The effect of hydrogen bond reorganization and equivalent weight on proton transfer in 3M perfluorosulfonic acid ionomers.
Phys Chem Chem Phys
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We present an investigation into the energetics associated with proton transfer in ionomeric fragments of the 3M™ perfluorosulfonic acid (PFSA) membrane at different equivalent weights (EW). Electronic structure calculations were performed on two fragments each with two pendant side chains separated along a poly(tetrafluoroethylene) (PTFE) backbone with chemical formula CF(3)CF(-O(CF(2))(4)SO(3)H)(CF(2))(n)CF(-O(CF(2))(4)SO(3)H)CF(3), where n = 5 or 7, corresponding to membrane equivalent weights of 590 and 690 g mol(-1). Potential energy surface (PES) scans were performed for the transfer of a proton in various hydrogen bonds between water molecules, sulfonic acid groups, and charged species. The scans involved incrementally increasing an O-H bond length in steps of 0.02 Å with geometry optimizations performed at each step at the B3LYP/6-31G** level over all other degrees of freedom. The nature of the hydrogen bond network and the degree of dissociation were found to be critical factors in determining the resulting energetic barrier for proton transfer. The smaller fragment was found to more readily reorient to compensate for the transfer of charge resulting in a lower energetic barrier to proton transfer through stabilization of the new hydrogen bonds. However, when each ionomer had the same degree of dissociation, reprotonation of the sulfonate groups was the most energetically unfavorable in EW 590 when no structural reorganization was observed to occur due to its greater propensity to exist in a dissociated state.
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Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
Lancet Oncol.
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ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.
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Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors.
J. Clin. Oncol.
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Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs.
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Analysis of MLL2 gene in the first Brazilian family with Kabuki syndrome.
Am. J. Med. Genet. A
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Most patients with Kabuki syndrome (KS) are the only person in their family with the condition. However, familial cases of KS have been described showing evidence that this syndrome can be inherited as a dominant trait with variable expressivity. We report on two related individuals with facial findings characteristic of KS. The proposita had arched eyebrows, long and upward slanting palpebral fissures, cleft lip and palate, retromicrognathia, brachydactyly of hands and feet, stubby fingers, nail hypoplasia, and prominent finger pads. Her mother had eyebrows with dispersed lateral half, long and upward slanting palpebral fissures, retrognathia, abnormal and posteriorly rotated ears, prominent finger pads, brachydactyly of feet, learning difficulties, and psychomotor development delay. DNA sequencing revealed a novel missense mutation in the MLL2 gene in both the proposita and her mother. The mutation (p.R5432Q) was found in the exon 51, within the SET domain of the gene, which confers methyltransferase activity on the protein. Therefore, the epigenetic and transcriptional regulatory properties of this protein may be altered and this suggests that the mutation is the cause of phenotype observed in both the patient and her mother. The clinical signs and the molecular evidence in this family further support the notion that KS is an autosomal dominant condition with variable expressivity. To our knowledge this is the first report of a Brazilian family with recurrence of this syndrome.
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Drug interactions: the importance of looking inside cancer cells.
Cancer Discov
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nab-Paclitaxel increased intratumoral gemcitabine levels by reactive oxygen species-mediated degradation of cytidine deaminase, the rate-limiting enzyme in gemcitabine inactivation. This not only has implications for how this drug combination mediates anticancer effects but also demonstrates the importance of evaluating mechanisms of drug activity within malignant cells.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.