Phosphoinositide 3-kinase (PI3K) family members are involved in diverse cellular fates including cell growth, proliferation, and survival. While many molecular details are known about the Class I and ...III PI3Ks, less is known about the Class II PI3Ks. To explore the function of all eight PI3K isoforms in autophagy, we knock down each gene individually and measure autophagy. We find a significant decrease in autophagy following siRNA-mediated PIK3C2A (encoding the Class 2 PI3K, PI3K-C2α) knockdown. This defective autophagy is rescued by exogenous PI3K-C2α, but not kinase-dead PI3K-C2α. Using confocal microscopy, we probe for markers of endocytosis and autophagy, revealing that PI3K-C2α colocalizes with markers of endocytosis. Though endocytic uptake is intact, as demonstrated by transferrin labeling, PIK3C2A knockdown results in vesicle accumulation at the recycling endosome. We isolate distinct membrane sources and observe that PI3K-C2α interacts with markers of endocytosis and autophagy, notably ATG9. Knockdown of either PIK3C2A or ATG9A/B, but not PI3KC3, results in an accumulation of transferrin-positive clathrin coated vesicles and RAB11-positive vesicles at the recycling endosome. Taken together, these results support a role for PI3K-C2α in the proper maturation of endosomes, and suggest that PI3K-C2α may be a critical node connecting the endocytic and autophagic pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Management of External Genital Warts Karnes, Jonathan B., MD; Usatine, Richard P., MD
American family physician,
09/2014, Letnik:
90, Številka:
5
Journal Article
Recenzirano
Genital warts affect 1% of the sexually active U.S. population and are commonly seen in primary care. Human papillomavirus types 6 and 11 are responsible for most genital warts. Warts vary from ...small, flat-topped papules to large, cauliflower-like lesions on the anogenital mucosa and surrounding skin. Diagnosis is clinical, but atypical lesions should be confirmed by histology. Treatments may be applied by patients, or by a clinician in the office. Patient-applied treatments include topical imiquimod, podofilox, and sinecatechins, whereas clinician-applied treatments include podophyllin, bichloroacetic acid, and trichloroacetic acid. Surgical treatments include excision, cryotherapy, and electrosurgery. The quadrivalent human papillomavirus vaccine is active against virus subtypes that cause genital warts in men and women. Additionally, male circumcision may be effective in decreasing the transmission of human immunodeficiency virus, human papillomavirus, and herpes simplex virus.
Burns, whether caused by thermal, chemical, or electrical exposure, are common and often preventable. Burn injuries are most common in children. All patients with burns should undergo primary and ...secondary assessment, including assessment of airway, breathing, and circulation. Evaluation of the location, size, and depth of burns can help to determine the optimal setting for management. Patients with full-thickness burns, circumferential burns, or burns on the face, hands, feet, genitals, or perineum should be referred to a burn subspecialist. Minor acute pain can be managed with irrigation of the burn area with cool water, acetaminophen, or a nonsteroidal anti-inflammatory drug. Acetaminophen is the first-line treatment for pain associated with minor burns. Opioids are a mainstay of pain management for patients with severe burns. Prophylactic antibiotics are not indicated for most patients. Silver sulfadiazine is used widely as a topical therapy, and is a standard treatment for partial-thickness burns. Many other topical therapies are available but comparative data are limited. Goals of therapy are to manage pain, facilitate healing, minimize scarring, and achieve return to function.
Porphyria cutanea tarda (PCT) is characterized by a skin blistering eruption that develops in sun exposed areas of the skin. It is the most common cutaneous porphyria world-wide, and classically ...associated with hepatic injury but also estrogen use, cigarette smoking, and HIV. In any case of photodistributed persistent blistering skin condition, PCT must be high on the differential. This case of a carpenter diagnosed with PCT not only illustrates a classic case but also the opportunity to achieve significant response to therapy in a motivated patient particularly with improved access to direct-acting antivirals (DAA) for hepatitis C treatment.
Phosphoinositide 3-kinase (PI3K) family members are involved in diverse cellular fates including cell growth, proliferation, and survival. While many molecular details are known about the Class I and ...III PI3Ks, less is known about the Class II PI3Ks. To explore the function of all eight PI3K isoforms in autophagy, we knock down each gene individually and measure autophagy. We find a significant decrease in autophagy following siRNA-mediated PIK3C2A (encoding the Class 2 PI3K, PI3K-C2alpha) knockdown. This defective autophagy is rescued by exogenous PI3K-C2alpha, but not kinase-dead PI3K-C2alpha. Using confocal microscopy, we probe for markers of endocytosis and autophagy, revealing that PI3K-C2alpha colocalizes with markers of endocytosis. Though endocytic uptake is intact, as demonstrated by transferrin labeling, PIK3C2A knockdown results in vesicle accumulation at the recycling endosome. We isolate distinct membrane sources and observe that PI3K-C2alpha interacts with markers of endocytosis and autophagy, notably ATG9. Knockdown of either PIK3C2A or ATG9A/B, but not PI3KC3, results in an accumulation of transferrin-positive clathrin coated vesicles and RAB11-positive vesicles at the recycling endosome. Taken together, these results support a role for PI3K-C2alpha in the proper maturation of endosomes, and suggest that PI3K-C2alpha may be a critical node connecting the endocytic and autophagic pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate ...that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies.
•Identification of DNA-PKcs-modulated transcriptional networks and consequence•DNA-PKcs-mediated gene regulation promotes migration, invasion, and metastases•DNA-PKcs is upregulated and highly activated in aggressive human tumors•DNA-PKcs independently predicts for metastases, recurrence, and poor survival
Goodwin et al. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.
Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular ...underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.
The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical ...implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications.
Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (
= 5,239) and validation (
= 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (
= 1,170), and The Cancer Genome Atlas (
= 333).
A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly
and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis HR, 2.61; 95% confidence interval (CI), 1.22-5.60;
= 0.014. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80;
= 0.008).
Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, ...how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
PDF
