Thumb carpometacarpal osteoarthritis is characterized by osteophyte growth and changes in the curvature of the articular surfaces of the trapezium and first metacarpal. The aim of this longitudinal ...study was to quantify in-vivo bone morphology changes with osteoarthritis progression.
The study analyzed an observational dataset of 86 subjects with early thumb osteoarthritis and 22 age-matched asymptomatic controls. CT scans of subjects' affected hands were acquired at enrollment (year 0), and at 1.5, 3, 4.5, and 6-year follow-up visits. Osteoarthritic subjects were classified into stable and progressive groups, as defined by osteophyte volume and the rate of osteophyte growth. Trapezium height, width, and volar facet recession, along with first metacarpal volar beak recession and recession angle, were quantified.
Mean trapezium width increased 12% over six years in the progressive osteoarthritis group. Trapezium volar recession of the progressive osteoarthritis group was significantly greater than stable at enrollment (P < 0.0001) and year 6 (P < 0.0001). The first metacarpal volar beak of the progressive osteoarthritis group recessed significantly faster than stable (P = 0.0004) and control (P = 0.0003). In year 6, volar beak surfaces in subjects with progressive osteoarthritis were flatter with reduced curvature, measuring −8.7 ± 4.0 degrees, compared to the stable osteoarthritis (P < 0.0001) and control groups (P = 0.0003), which maintained nominal curvatures, measuring 0.7 ± 2.5 and 0.2 ± 3.2 degrees, respectively.
Our results demonstrate significant recession and reduction in the angle of the first metacarpal volar beak in progressive osteoarthritis. Flattening of the first metacarpal volar beak may have important associations with carpometacarpal joint contact and loading migrations, further propagating osteophyte formation and bony remodeling. This work highlights the volar beak of the first metacarpal as a region of morphology change with disease.
•Morphological changes observed in the trapezium and first metacarpalare different in subjects with stable vs progressive osteoarthritis•The volar beak of the first metacarpal recesses rapidly in progressive thumb osteoarthritis•Flattening of the volar beak and loss of convex curvature of the first metacarpal may link instability to altered joint contact location and mechanics•Progressive changes in first metacarpal morphology are important in evaluating CMC OA disease progression and treatment
Myeloid cell leukemia 1 (Mcl‐1) is an antiapoptotic member of the Bcl‐2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. ...Mcl‐1 is amplified in many human cancers, and knockdown of Mcl‐1 using RNAi can lead to apoptosis. Thus, Mcl‐1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl‐1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl‐1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl‐1 inhibitors.
PDB ID codes
Comp. 2: 5IEZ; Comp. 5: 5IF4.
Purpose: The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer.
Results: A concentration-dependent increase in cytotoxicity ...was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining.
Methods: The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model.
Conclusions: These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.
► The effect of the antioxidant phenylaminoethyl selenide (PAESe) on doxorubicin (DOX)-mediated cardiotoxicity was determined. ► PAESe reduced evidence of DOX cardiotoxicity and weight loss in a ...prostate cancer xenograft model. ► PAESe reduced the formation of reactive oxygen species by DOX or by tert-butylhydroperoxide in human prostate cancer cells. ► PAESe did not decrease DOX antitumor activity in a prostate cancer xenograft model.
Anthracyclines are potent anticancer agents, but cardiotoxicity mediated by free radical generation limits their clinical use. This study evaluated the anticancer activity of phenyl-2-aminoethyl selenide (PAESe) and its potential to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe with DOX, and vincristine, clinically used anticancer agents, and tert-butylhydroperoxide (TBHP), a known oxidant, on the growth of human prostate carcinoma (PC-3) cells was determined. PAESe (⩽1μm) did not alter the growth of PC-3 cells, however, concomitant use of PAESe decreased the oxidative-mediated cytotoxicity of TBHP, but had limited effect on vincristine or DOX activity. Further, PAESe decreased the formation of intracellular reactive oxygen species from TBHP and DOX. The effect of PAESe on the activity of DOX was determined using a tumor (PC-3) xenograft model in mice. PAESe did not alter DOX antitumor activity and showed evidence of direct antitumor activity relative to controls. DOX treatment decreased mice body weight significantly, whereas concomitant administration of PAESe and DOX was similar to controls. Most importantly, PAESe decreased DOX-mediated infiltration of neutrophil and macrophages into the myocardium. These data suggest PAESe had in vivo antitumor activity and in combination with DOX decreased early signs of cardiotoxicity while preserving its antitumor activity.
Background. Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandins have potent fungicidal activity against most ...Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. Methods. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. Results. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. Conclusions. Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.
Given the risk of central nervous system infection, relatively high weight‐based echinocandin dosages may be required for the successful treatment of invasive candidiasis and candidemia in young ...infants. This open‐label study assessed the safety and pharmacokinetics (PK) of micafungin in 13 young infants (>48 h and <120 days of life) with suspected candidemia or invasive candidiasis. Infants of body weight ≥1,000 and <1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4–5 days. In the 7‐mg/kg/day group, the mean baseline weight and gestational age were 2,101 g and 30 weeks, respectively; in the 10‐mg/kg/day group, they were 688 g and 25 weeks, respectively. The median pharmacokinetic values for the 7‐ and 10‐mg/kg/day groups, respectively, were as follows: area under the concentration–time curve from 0 to 24 h (AUC0–24), 258.1 and 291.2 µg·h/ml; clearance at steady state adjusted for body weight, 0.45 and 0.57 ml/min/kg; maximum plasma concentration, 23.3 and 24.9 µ g/ml; and volume of distribution at steady state adjusted for body weight, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day are well tolerated and provide exposure levels that have been shown (in animal models) to be adequate for central nervous system coverage.
Clinical Pharmacology & Therapeutics (2010) 87 1, 93–99. doi:10.1038/clpt.2009.200
Genetic hearing impairment affects approximately 1/2000 live births. Mutations in one gene, GJB2, coding for connexin 26 cause 10%-20% of all genetic sensorineural hearing loss. Mutation analysis in ...the GJB2 gene and audiology were performed on 106 families presenting with at least one child with congenital hearing loss. The families were recruited from a hospital-based multidisciplinary clinic, which functions to investigate the aetiology of sensorineural hearing loss in children and which serves an ethnically diverse population. In 74 families (80 children), the aetiology was consistent with non-syndromic recessive hearing loss. Six different connexin 26 mutations, including one novel mutation, were identified. We show that GJB2 mutations cause a range of phenotypes from mild to profound hearing impairment and that loss of hearing in the high frequency range (4000-8000 Hz) is a characteristic feature in children with molecularly diagnosed connexin 26 hearing impairment. We also demonstrate that this type of audiology and high frequency hearing loss is found in a similar-sized group of deaf children in whom a mutation could only be found in one of the connexin 26 alleles, suggesting connexin 26 involvement in the aetiology of hearing loss in these cases. In our study of the M34T mutation, only compound heterozygotes exhibited hearing loss, suggesting autosomal recessive inheritance.
In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT‐OD‐15–102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be ...factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.—Miller, L. R., Marks, C., Becker, J.B., Hurn, P.D., Chen, W.‐J., Woodruff, T., McCarthy, M.M., Sohrabji, F., Schiebinger, L., Wetherington, C.L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. FASEB J. 31, 29–34 (2017) www.fasebj.org
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but ...their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.
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•Type I interferon (IFN-I)-responsive microglia expand during developmental stress•IFN-I-responsive microglial signature is conserved in brain pathology•IFN-I-responsive microglia engulf whole neurons during cortical development•IFN-I deficiency causes excitatory/inhibitory imbalance and tactile hypersensitivity
A type-I-interferon-responsive microglial subset that engulfs neurons in the developing mouse cortex is required for normal cortical development and sensorimotor function. These data demonstrate a physiologic role for a canonical antiviral immune pathway in brain development.
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