The most frequent cause of isolated complex III deficits is mutations to the nuclear‐encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by ...pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease‐causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype–phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under “BCS1L Mitopathies”. Patterns in genotype–phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.
Context: Positron emission tomography imaging with 2-deoxy-2-sup.18F-fluoro- D-glucose (FDG) is used clinically for initial staging, restaging, and assessing therapy response in breast cancer. Tumor ...FDG uptake in steroid hormone receptor-positive breast cancer and physiologic FDG uptake in normal breast tissue can be affected by hormonal factors such as menstrual cycle phase, menopausal status, and hormone replacement therapy. Objective: The purpose of this study was to determine the role of the progesterone receptor (PR) in regulating glucose and FDG uptake in breast cancer cells. Methods and Results: PR-positive T47D breast cancer cells treated with PR agonists had increased FDG uptake compared with ethanol control. There was no significant change in FDG uptake in response to PR agonists in PR- negative MDA-MB-231 cells, MDA-MB-468 cells, or T47D PR knockout cells. Treatment of T47D cells with PR antagonists inhibited the effect of R5020 on FDG uptake. Using T47D cell lines that only express either the PR-A or the PR-B isoform, PR agonists increased FDG uptake in both cell types. Experiments using actinomycin D and cycloheximide demonstrated the requirement for both transcription and translation in PR regulation of FDG uptake. GLUT1 and PFKFB3 mRNA expression and the enzymatic activity of glucose-6-phosphate dehydrogenase and 6- phosphogluconate dehydrogenase were increased after progestin treatment of T47D cells. Conclusion: Thus, progesterone and progestins increase FDG uptake in T47D breast cancer cells through the classical action of PR as a ligand-activated transcription factor. Ligand-activated PR ultimately increases expression and activity of proteins involved in glucose uptake, glycolysis, and the pentose phosphate pathway. Key Words: progesterone receptor, sup.18F-fluorodeoxyglucose (FDG), glycolysis, breast cancer, progestin, pentose phosphate pathway Abbreviations: 2DG6P, 2-deoxyglucose-6-phosphate; 6PGD, 6-phosphogluconate dehydrogenase; ChIP, chromatin immunoprecipitation; CPM, counts per minute; DMEM, Dulbecco's modified Eagle's medium; ER, estrogen receptor; FDG, 2- deoxy-2-sup.18F-fluoro-D-glucose; GLUT, glucose transporter; GR, glucocorticoid receptor; LDH, lactate dehydrogenase; MA, megestrol acetate; MPA, medroxyprogesterone acetate; PBS, phosphate-buffered saline; PET, positron emission tomography; G6PD, glucose-6-phosphate dehydrogenase; MRI, magnetic resonance imaging; NADPH, nicotinamide adenine dinucleotide phosphate; PR, progesterone receptor; PRE, progesterone response element; PR KO, knockout of the PGR gene; RPMI, Roswell Park Memorial Institute; Scr, scrambled; SDS, sodium dodecyl sulfate; qPCR, quantitative real-time polymerase chain reaction; UPA, ulipristal acetate.
Efalizumab, a humanized anti-CD11a monoclonal antibody, has been shown to treat plaque psoriasis. A known association between this drug and autoimmune thrombocytopenia has already been established. ...More recently publicized, however, is efalizumab's ability to affect another cell line—that of the erythrocyte—and cause an autoimmune hemolytic anemia that typically occurs 4 to 6 months after initiating therapy. In this article, we report the case of a patient who developed autoimmune hemolytic anemia after 8 months of successful treatment with efalizumab. His delayed presentation suggests that monitoring of blood cell counts longer than 6 months may be warranted.
Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free ...survival among patients with resectable stage III or IV melanoma is unknown.
In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.
At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval CI, 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.
Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).
Human adipose stromal cells (ASCs) reside within the stromal-vascular fraction (SVF) in fat tissue, can be readily isolated, and include stem-like cells that may be useful for therapy. An important ...consideration for clinical application and functional studies of stem/progenitor cells is their capacity to maintain chromosome stability in culture. In this study, cultured ASC populations and ASC clones were evaluated at intervals for maintenance of chromosome stability. Uncultured SVF (uSVF) cells were included for comparison. G-banded chromosome analysis demonstrated that ASCs are diploid and have a normal karyotype. However since only approximately 20 cells are examined, low levels of chromosome instability would not be detected. To increase detection sensitivity, fluorescence in situ hybridization was employed, to permit chromosome enumeration in larger numbers of interphase cells. Seven cultured ASC populations, two ASC clones and four uSVF samples were examined. Chromosome X and 17 probes identified diploid, tetraploid, and aneuploid interphase cells. Both cultured ASC populations up to approximately 35 Population Doublings (PDs) and uSVF cells exhibited a similar level of diploidy (97.8% n = 6,355 and 98.83% n = 1,197, respectively) and numerical abnormalities, suggesting that cultured ASCs are genomically stable and supporting their suitability for transplantation applications. In comparison, cultured primary human chorionic villus cells exhibited marked genomic instability resulting in an 11.6% tetraploidy rate after 8-10 PD. Thus effects of culture on genomic stability may be cell type dependent and should be tested by appropriately scaled interphase fluorescence in situ hybridization analysis in any ex vivo expanded cell population destined for transplantation.
Abstract
Context
Positron emission tomography imaging with 2-deoxy-2-18F-fluoro-D-glucose (FDG) is used clinically for initial staging, restaging, and assessing therapy response in breast cancer. ...Tumor FDG uptake in steroid hormone receptor–positive breast cancer and physiologic FDG uptake in normal breast tissue can be affected by hormonal factors such as menstrual cycle phase, menopausal status, and hormone replacement therapy.
Objective
The purpose of this study was to determine the role of the progesterone receptor (PR) in regulating glucose and FDG uptake in breast cancer cells.
Methods and Results
PR-positive T47D breast cancer cells treated with PR agonists had increased FDG uptake compared with ethanol control. There was no significant change in FDG uptake in response to PR agonists in PR-negative MDA-MB-231 cells, MDA-MB-468 cells, or T47D PR knockout cells. Treatment of T47D cells with PR antagonists inhibited the effect of R5020 on FDG uptake. Using T47D cell lines that only express either the PR-A or the PR-B isoform, PR agonists increased FDG uptake in both cell types. Experiments using actinomycin D and cycloheximide demonstrated the requirement for both transcription and translation in PR regulation of FDG uptake. GLUT1 and PFKFB3 mRNA expression and the enzymatic activity of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were increased after progestin treatment of T47D cells.
Conclusion
Thus, progesterone and progestins increase FDG uptake in T47D breast cancer cells through the classical action of PR as a ligand-activated transcription factor. Ligand-activated PR ultimately increases expression and activity of proteins involved in glucose uptake, glycolysis, and the pentose phosphate pathway.
Positron emission tomography imaging with 2-deoxy-2-
F-fluoro-D-glucose (FDG) is used clinically for initial staging, restaging, and assessing therapy response in breast cancer. Tumor FDG uptake in ...steroid hormone receptor-positive breast cancer and physiologic FDG uptake in normal breast tissue can be affected by hormonal factors such as menstrual cycle phase, menopausal status, and hormone replacement therapy.
The purpose of this study was to determine the role of the progesterone receptor (PR) in regulating glucose and FDG uptake in breast cancer cells.
PR-positive T47D breast cancer cells treated with PR agonists had increased FDG uptake compared with ethanol control. There was no significant change in FDG uptake in response to PR agonists in PR-negative MDA-MB-231 cells, MDA-MB-468 cells, or T47D PR knockout cells. Treatment of T47D cells with PR antagonists inhibited the effect of R5020 on FDG uptake. Using T47D cell lines that only express either the PR-A or the PR-B isoform, PR agonists increased FDG uptake in both cell types. Experiments using actinomycin D and cycloheximide demonstrated the requirement for both transcription and translation in PR regulation of FDG uptake.
and
mRNA expression and the enzymatic activity of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were increased after progestin treatment of T47D cells.
Thus, progesterone and progestins increase FDG uptake in T47D breast cancer cells through the classical action of PR as a ligand-activated transcription factor. Ligand-activated PR ultimately increases expression and activity of proteins involved in glucose uptake, glycolysis, and the pentose phosphate pathway.
Background A subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum. ...Objective This National Institute of Allergy and Infectious Diseases–funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH+ and ADEH− subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals. Methods We analyzed the data from 901 subjects (ADEH+ subjects, n = 134; ADEH− subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers. Results ADEH+ subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell–attracting chemokine) than ADEH− subjects ( P < .001). ADEH+ subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens ( P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH+ subjects (78% and 8%, respectively) than in ADEH− subjects (29% and 2%, respectively; P < .001). Conclusion Subjects with AD in whom eczema herpeticum develops have more severe TH 2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S aureus or molluscum contagiosum.
Objective To compare maternal and neonatal outcomes between planned cesarean delivery and induction of labor in women with class III obesity (body mass index ≥40 kg/m2 ). Study Design In this ...retrospective cohort study, we identified all women with a body mass index ≥40 kg/m2 who delivered a singleton at our institution from January 2007 to February 2013 via planned cesarean or induction of labor (regardless of eventual delivery route) at 37-41 weeks. Patients in spontaneous labor were excluded. The primary outcome was a composite of maternal morbidity including death as well as operative, infection, and thromboembolic complications. The secondary outcome was a neonatal morbidity composite. Additional outcomes included individual components of the composites. Student t , χ2 , and Fisher exact tests were used for statistical analysis. To calculate adjusted odds ratios, covariates were analyzed via multivariable logistic regression. Results There are 661 mother-infant pairs that met enrollment criteria—399 inductions and 262 cesareans. Groups were similar in terms of prepregnancy weight, pregnancy weight gain, and delivery body mass index. Of the 399 inductions, 258 had cervical ripening (64.7%) and 163 (40.9%) had a cesarean delivery. After multivariable adjustments, there was no significant difference in the maternal morbidity composite (adjusted odds ratio, 0.98; 95% confidence interval, 0.55–1.77) or in the neonatal morbidity composite (adjusted odds ratio, 0.81; 95% confidence interval, 0.37–1.77) between the induction and cesarean groups. Conclusion In term pregnant women with class III obesity, planned cesarean does not appear to reduce maternal and neonatal morbidity compared with induction of labor.
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