Regulation of adipose tissue formation by adipogenic-regulatory proteins has long been a topic of interest given the ever-increasing health concerns of obesity and type 2 diabetes in the general ...population. Differentiation of precursor cells into adipocytes involves a complex network of cofactors that facilitate the functions of transcriptional regulators from the CCATT/enhancer binding protein, and the peroxisome proliferator-activated receptor (PPAR) families. Many of these cofactors are enzymes that modulate the structure of chromatin by altering histone-DNA contacts in an ATP-dependent manner or by posttranslationally modifying the histone proteins. Here we report that inhibition of protein arginine methyltransferase 5 (Prmt5) expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes. In contrast, overexpression of Prmt5 enhanced adipogenic gene expression and differentiation. Chromatin immunoprecipitation experiments indicated that Prmt5 binds to and dimethylates histones at adipogenic promoters. Furthermore, the presence of Prmt5 promoted the binding of ATP-dependent chromatin-remodeling enzymes and was required for the binding of PPARγ2 at PPARγ2-regulated promoters. The data indicate that Prmt5 acts as a coactivator for the activation of adipogenic gene expression and promotes adipogenic differentiation.
Phagocytosis is critical to the clearance of apoptotic cells, cellular debris and deleterious metabolic products for tissue homeostasis. Phagocytosis ligands directly recognizing deleterious cargos ...are the key to defining the functional roles of phagocytes, but are traditionally identified on a case-by-case basis with technical challenges. As a result, extrinsic regulation of phagocytosis is poorly defined. Here we demonstrate that microglial phagocytosis ligands can be systematically identified by a new approach of functional screening. One of the identified ligands is reticulocalbin-1 (Rcn1), which was originally reported as a Ca2+-binding protein with a strict expression in the endoplasmic reticulum. Our results showed that Rcn1 can be secreted from healthy cells and that secreted Rcn1 selectively bound to the surface of apoptotic neurons, but not healthy neurons. Independent characterization revealed that Rcn1 stimulated microglial phagocytosis of apoptotic but not healthy neurons. Ingested apoptotic cells were targeted to phagosomes and co-localized with phagosome marker Rab7. These data suggest that Rcn1 is a genuine phagocytosis ligand. The new approach described in this study will enable systematic identification of microglial phagocytosis ligands with broad applicability to many other phagocytes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Objective To estimate the incidence of clinically detected port-site mestastases (PSM) in patients with endometrial and cervical cancer treated at two gynecologic oncology services with ...extensive experience. Methods All eligible uterine cancer patients laparoscopically staged at Centre Oscar Lambret in Lille and Institut Claudius Regaud in Toulouse, France, were reviewed. MEDLINE database was searched to identify articles on PSM after laparoscopic procedures for cervical and endometrial cancer. Results During the study period, 1216 laparoscopic procedures for uterine cancer were performed. 921 patients underwent laparoscopic staging for cervical cancer and 295 for endometrial cancer. The overall incidence of PSM in our institutions was 0.4% per procedure (5 patients), and the incidence of PSM after laparoscopy for cervical and endometrial cancer was 0.43% and 0.33%, respectively. Excluding patients with peritoneal carcinomatosis, the rate of port-site recurrence in our series lowered to 0.16%, and the rate of isolated PSM to 0%. The median time to the development of PSM was 8 months (range 6–48), the median overall survival from diagnosis for all patients was 26 months (range 7–30), and median survival from recurrence was 5 months (range 1–20). Conclusion Although PSM is recognized as a complication of laparoscopy for ovarian cancer. PSM is a rare complication of laparoscopic staging for endometrial and cervical cancer. The majority of patients with PSM presented with associated synchronous disease. The incidence of isolated PSM can be maintained virtually to 0% by an adequate operative technique. We believe that PSM in patients with uterine cancer cannot be used as an argument against laparoscopic staging in uterine cancer.
A 63-year-old woman presented with plaques covering 60 % body-surface-area and leonine facies. Blood work showed no diagnostic aberrancies. Skin biopsy contained a malignant CD4+/CD56+ mononuclear ...cell population concerning for blastic plasmacytoid dendritic cell neoplasm. A later bone marrow biopsy confirmed AML with KMT2A::MLLT10 fusion detected by next-generation sequencing (NGS). This patient's LC preceded blood and marrow based symptoms of AML. NGS of the initial skin biopsy should be considered as part of diagnostic guidelines in cases with LC in the differential as this may have led to earlier diagnosis in this case and future cases.
To reveal sleep health phenotypes in older adults and examine their associations with time to 5-year all-cause and cardiovascular mortality.
Prospective longitudinal cohorts.
The Study of ...Osteoporotic Fractures and Outcomes of Sleep Disorders in Older Men Study.
N = 1722 men and women aged ≥65 years matched 1:1 on sociodemographic and clinical measures.
Self-reported habitual sleep health characteristics (satisfaction, daytime sleepiness, timing, efficiency, and duration) measured at an initial visit and longitudinal follow-up for mortality.
Latent class analysis revealed 3 sleep health phenotypes: (1) heightened sleep propensity (HSP; medium to long duration, high sleepiness, high efficiency/satisfaction; n = 322), (2) average sleep (AS; medium duration, average efficiency, high satisfaction, low sleepiness; n = 1,109), and (3) insomnia with short sleep (ISS; short to medium duration, low efficiency/satisfaction, moderate sleepiness; n = 291). Phenotype predicted time to all-cause mortality (χ2 = 9.4, P = .01), with HSP conferring greater risk than AS (hazard ratio 95% confidence interval = 1.48 1.15-1.92) or ISS (1.52 1.07-2.17), despite ISS reporting the poorest mental and physical health. Although sex did not formally moderate the relationship between phenotype and mortality, subgroup analyses indicated that these findings were driven primarily by women. Phenotype did not predict cardiovascular mortality.
These analyses support the utility of examining multidimensional sleep health profiles by suggesting that the combination of long sleep, high efficiency/satisfaction, and daytime sleepiness—previously identified as independent risk factors—may be components of a single high-risk sleep phenotype, HSP. Further investigation of sex differences and the mechanisms underlying mortality risk associated with HSP is warranted.
Abstract The bone morphogenetic proteins (BMPs) are cytokines of the transforming growth factor beta family. Some BMPs such as BMP-2 and BMP-7 play a major role in the development of the skeleton and ...the maintenance of homeostasis during bone remodelling. To date, only BMP-2 and BMP-7 have been approved by the Food and Drug Administration for specific orthopaedic applications. However, due to BMP cost, peptides derived from their knuckle epitope with osteogenic properties have been developed. BMPs are involved in many other biological events, including embryogenesis, angiogenesis and cancer. BMPs therefore have great biomedical potential as osteogenic factors and as anti-cancer agents. This review focuses on the use of BMPs and their derived peptides in biomedical delivery systems and gene therapy.
Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, ...histological subtypes, stage) induces multiple and complex therapeutic strategies.
Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website,www.ovaire-rare.org.
Over a 5-year activity, 4612 patients have been included. Patients’ inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients’ files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5–9% every year. The rate of patients’ files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards.
Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research.
Purpose
Patients with locally advanced cervical cancer (LACC) are usually treated with concurrent chemoradiotherapy. Extended-field chemoradiotherapy is indicated in case of para-aortic node ...involvement at initial assessment. 18-Fluoro-2-deoxy-
d
-glucose positron emission tomography/computed tomography (18-FDG PET/CT) is currently considered to be the most accurate method of detection of node or distant metastases. The goal of this study was to evaluate the accuracy of PET at detecting para-aortic lymph node metastases in LACC patients with a negative morphological imaging.
Methods
Patients from five French institutions with LACC and both negative morphologic (magnetic resonance imaging, CT scan) and functional (PET or PET/CT) findings at the para-aortic level and distantly were submitted to a systematic infrarenal para-aortic node dissection either by laparoscopy or laparotomy. On the basis of pathological results, sensitivity, specificity, and positive and negative predictive values of PET/CT were assessed for para-aortic lymph node involvement.
Results
A total of 125 LACC patients (stage IB2–IVA disease with two local recurrences) fulfilled the inclusion criteria. All had an ilio-infrarenal para-aortic lymphadenectomy, either by laparoscopy (
n
= 117) or laparotomy (
n
= 8). Twenty-one patients (16.8%) had pathologically proven para-aortic metastases. Among them, 14 (66.7%) had negative PET/CT. Overall morbidity of surgery was 7.2%. All but one of the complications were mild and did not delay chemoradiotherapy. Sensitivity, specificity, and positive and negative predictive value of the PET/CT were 33.3, 94.2, 53.8, and 87.5%, respectively, for the detection of microscopic lymph node metastases.
Conclusions
Laparoscopic staging surgery seems warranted in LACC patients with negative PET scan who are candidates for definitive concurrent chemoradiotherapy or exenteration.
Objective: To investigate the relationship between self-reported osteoarthritis (OA) and reproductive factors in the Women's Health Initiative (WHI).
Method: We used multivariable logistic regression ...to study the association of self-reported OA and reproductive factors in the WHI Observational Study and Clinical Trial cohorts of 145 965 postmenopausal women, in a retrospective cross-sectional format.
Results: In our cohort, we observed no clinically significant associations between reproductive factors and OA given small effect sizes. The following factors were associated with statistically significant increased likelihood of developing OA: younger age at menarche (p < 0.001), history of hysterectomy adjusted odds ratio (aOR) 1.013, 95% confidence interval (CI) 1.004-1.022, p = 0.04 vs no hysterectomy, history of unilateral oophorectomy (aOR 1.015, 95% CI 1.004-1.026, p < 0.01 vs no oophorectomy), parity (aOR 1.017, 95% CI 1.009-1.026, p < 0.001), ever use of oral contraceptives (aOR 1.008, 95% CI 1.001-1.016, p < 0.01 vs never use), and current use of hormonal therapy (reference current users, aOR 0.951, 95% CI 0.943-0.959 for never users; aOR 0.981, 95% CI 0.972-0.989 for past users; global p < 0.001). Age at menopause, first birth, and pregnancy were not associated with OA. Among parous women, no clear pattern was observed with number of pregnancies, births, or duration of breastfeeding in relation to OA.
Conclusion: Our study showed that reproductive factors did not have significant clinical associations with OA after controlling for confounders. This may be due to complex hormonal effects. Additional investigation is warranted in prospective cohort studies.
The Women's Health Initiative is registered under ClinicalTrials.gov. Trial registration ID: NCT00000611.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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