Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution ...of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).
Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.
Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.
This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.
•The current study provides understanding of the factor structure of the EPDS, association of subscales of the EPDS, and demographic correlates of EPDS subscales.•Results suggest alternative use of ...the EPDS to track several mental health symptom categories for expectant and new mothers.•A 3-factor model (i.e. anxiety, depression, anhedonia) of the EPDS displayed the best fit to the current data.•Demographic correlates of EPDS subscales included history of depression, history of anxiety, race, and pregnancy status (i.e. first child or not).
The prevalence and negative effects of perinatal depression are well known. The Edinburgh Postnatal Depression Scale (EPDS) is a common screening tool for perinatal depression and it is recommended for use by several professional organizations. The current study tested competing EPDS factor structures and assessed EPDS change from intake to 6-week follow-up, and identified demographic correlates in an outpatient obstetric sample. Using a retrospective observational study design, medical records were coded for demographic, mental health, and EPDS patient data (n = 524). Confirmatory factor analysis, t-tests, and ANOVA were utilized. Findings included: (1) a 3-factor model (i.e. anxiety, depression, anhedonia) of the EPDS displayed the best fit to the current data; (2) small declines in all 3 subscales of the EPDS from intake to 6-week follow-up appointments and; (3) demographic correlates of EPDS subscales included history of depression, history of anxiety, race, and pregnancy status (i.e. first child or not). The 3-factor structure can be used in clinical practice to assess perinatal depression in a nuanced fashion. Given that history of depression and anxiety are risk factors for perinatal depression, a thorough assessment of these items in clinical practice is needed.
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•Novel amino sugar analogues were synthesized and purified in a one-step method.•Eighteen amino sugar analogues having either a d-GlcN, d-ManN, or d-GalN scaffold were screened ...against TcGlcK and a T. cruzi parasite infection of mammalian cells.•TcGlcK was notably inhibited by amino sugar analogues having the d-GlcN scaffold.
Eighteen amino sugar analogues were screened against Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the protozoan parasite in order to assess for viable enzyme inhibition. The analogues were divided into three amino sugar scaffolds that included d-glucosamine (d-GlcN), d-mannosamine (d-ManN), and d-galactosamine (d-GalN); moreover, all but one of these compounds were novel. TcGlcK is an important metabolic enzyme that has a role in producing G6P for glycolysis and the pentose phosphate pathway (PPP). The inhibition of these pathways via glucose kinases (i.e., glucokinase and hexokinase) appears to be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P and the formed G6P enters both pathways for catabolism. The compound screen revealed five on-target confirmed inhibitors that were all from the d-GlcN series, such as compounds 1, 2, 4, 5, and 6. Four of these compounds were strong TcGlcK inhibitors (1, 2, 4, and 6) since they were found to have micromolar inhibitory constant (Ki) values around 20 μM. Three of the on-target confirmed inhibitors (1, 5, and 6) revealed notable in vitro anti-T. cruzi activity with IC50 values being less than 50 μM. Compound 1 was benzoyl glucosamine (BENZ-GlcN), a known TcGlcK inhibitor that was the starting point for the design of the compounds in this study; in addition, TcGlcK – compound 1 inhibition properties were previously determined D’Antonio, E. L. et al. (2015) Mol. Biochem. Parasitol. 204, 64–76. As such, compounds 5 and 6 were further evaluated biochemically, where formal Ki values were determined as well as their mode of TcGlcK inhibition. The Ki values determined for compounds 5 and 6 were 107 ± 4 μM and 15.2 ± 3.3 μM, respectively, and both of these compounds exhibited the competitive inhibition mode.
Structure of the 30S ribosomal subunit Ramakrishnan, V; Wimberly, Brian T; Brodersen, Ditlev E ...
Nature (London),
09/2000, Volume:
407, Issue:
6802
Journal Article
Peer reviewed
Genetic information encoded in messenger RNA is translated into protein by the ribosome, which is a large nucleoprotein complex comprising two subunits, denoted 30S and 50S in bacteria. Here we ...report the crystal structure of the 30S subunit from Thermus thermophilus, refined to 3 A resolution. The final atomic model rationalizes over four decades of biochemical data on the ribosome, and provides a wealth of information about RNA and protein structure, protein-RNA interactions and ribosome assembly. It is also a structural basis for analysis of the functions of the 30S subunit, such as decoding, and for understanding the action of antibiotics. The structure will facilitate the interpretation in molecular terms of lower resolution structural data on several functional states of the ribosome from electron microscopy and crystallography.
Epithelial ovarian cancer Morgan, Jr, Robert J; Alvarez, Ronald D; Armstrong, Deborah K ...
Journal of the National Comprehensive Cancer Network
9, Issue:
1
Journal Article
A known virulence factor of Helicobacter pylori that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA ...exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhyd mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhyd strain showed a decreased frequency of DNA transformation, suggesting that H. pylori hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhyd strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhyd strain. By examining the hydrogenase activities from well-defined clinical H. pylori isolates, we observed that strains isolated from cancer patients (n = 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n = 6), further supporting an association between H. pylori hydrogenase activity and gastric carcinogenesis in humans.
Hydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen's (H. pylori) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H2-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H2 oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.
We have used the recently determined atomic structure of the 30S ribosomal subunit to determine the structures of its complexes with the antibiotics tetracycline, pactamycin, and hygromycin B. The ...antibiotics bind to discrete sites on the 30S subunit in a manner consistent with much but not all biochemical data. For each of these antibiotics, interactions with the 30S subunit suggest a mechanism for its effects on ribosome function.
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