Small GTPases of the Rab family coordinate multiple membrane fusion and trafficking events in eukaryotes. In fungi, the Rab GTPase, Ypt7, plays a critical role in late endosomal trafficking, and is ...required for homotypic fusion events in vacuole biogenesis and inheritance. In this study, we identified a putative YPT7 homologue in Cryptococcus neoformans , a fungal pathogen causing life threatening meningoencephalitis in immunocompromised individuals. As part of an ongoing effort to understand mechanisms of iron acquisition in C. neoformans , we established a role for Ypt7 in growth on heme as the sole iron source. Deletion of YPT7 also caused abnormal vacuolar morphology, defective endocytic trafficking and autophagy, and mislocalization of Aph1, a secreted vacuolar acid phosphatase. Ypt7 localized to the vacuolar membrane and membrane contact sites between the vacuole and mitochondria (vCLAMPs), and loss of the protein impaired growth on inhibitors of the electron transport chain. Additionally, Ypt7 was required for robust growth at 39°C, a phenotype likely involving the calcineurin signaling pathway because ypt7 mutants displayed increased susceptibility to the calcineurin-specific inhibitors, FK506 and cyclosporin A; the mutants also had impaired growth in either limiting or high levels of calcium. Finally, Ypt7 was required for survival during interactions with macrophages, and ypt7 mutants were attenuated for virulence in a mouse inhalation model thus demonstrating the importance of membrane trafficking functions in cryptococcosis.
Objective
To compare the detection rates of prostate cancer between systematic biopsy and targeted biopsy using a stereotactic robot‐assisted transperineal prostate platform.
Materials and Methods
We ...identified consecutive patients with suspicious lesion(s) on multiparametric magnetic resonance imaging (mpMRI), who underwent both systematic and MRI‐transrectal ultrasonography (US) fusion targeted biopsy using our proprietary transperineal robot‐assisted prostate biopsy platform between January 2015 and January 2019 at our institution, for retrospective analysis. Comparative analysis was performed between systematic and targeted biopsy using McNemar’s test, and the cohort was further stratified by prior biopsy status and Prostate Imaging Reporting and Data System (PI‐RADS) v2.0 score. International Society of Urological Pathology (ISUP) grade group (GG) ≥2 cancers (previously known as Gleason grade ≥7) were considered to be clinically significant.
Results
A total of 500 patients were included in our final analysis, of whom 67 (13%) were patients with low‐risk cancer on active surveillance. Of the 433 patients without prior diagnosis of cancer, 288 (67%) were biopsy‐naïve. A total of 248 (57%) were diagnosed with prostate cancer, with 199 (46%) having clinically significant prostate cancer (ISUP GG ≥2). There were no statistically significant differences in the overall prostate cancer and clinically significant prostate cancer detection rate between systematic and targeted biopsy (51% vs 49% and 40% vs 38% respectively; P = 0.306 and P = 0.609). Of the 248 prostate cancers detected, 75% (187/248) were detected on both systematic and targeted biopsy, 14% (35/248) were detected on systematic biopsy alone and 11% (26/248) were detected on targeted biopsy alone. Of the 199 clinically significant cancers detected, 69% (138/199) were detected on both systematic and targeted biopsy, 17% (33/199) on systematic biopsy alone and 14% (28/199) on targeted biopsy alone. There were no statistically significant differences in the detection rate between systematic and targeted biopsy for both overall and clinically significant prostate cancer, even when the cohort was stratified by prior biopsy status and PI‐RADS score. Targeted biopsy has greater sampling efficiency compared to systematic biopsy for both overall and clinically significant prostate cancer (23.2% vs 9.8%, P < 0.001 and 14.8% vs 5.6%, P < 0.001).
Conclusions
Using our robot‐assisted transperineal prostate platform, combined MRI‐US targeted biopsy with concurrent systematic prostate systematic biopsy probably represents the optimal method for the detection of clinically significant prostate cancer.
Childhood maltreatment is relatively common and is related to a range of negative consequences, such as Posttraumatic Stress Disorder (PTSD). There are indications that various maltreatment types are ...related to PTSD severity, although not all types, such as emotional abuse, meet the PTSD Criterion-A.
The aim of the present study was to examine the relationship between 5 types of childhood maltreatment (i.e., sexual, physical, and emotional abuse, and physical and emotional neglect) and the severity of adult PTSD and PTSD symptoms.
Adult participants (N = 147) with Childhood-related PTSD (Ch-PTSD) recruited from clinical sites completed the Childhood Trauma Questionnaire-short form (CTQ-sf) and 2 PTSD measures: The Clinician Administered PTSD Scale for DSM-5 (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5).
Childhood maltreatment predictors and 2 covariates, age and gender, were analysed in multivariate multilevel models as participants were nested within sites. A model selection procedure, in which all combinations of predictors were examined, was used to select a final set of predictors.
The results indicated that emotional abuse was the only trauma type that was significantly related to severity of PTSD and to the severity of specific PTSD symptom clusters (r between 0.130 and 0.338). The final models explained between 6.5% and 16.7% of the variance in PTSD severity.
The findings suggest that emotional abuse plays a more important role in Ch-PTSD than hitherto assumed, and that treatment should not neglect processing of childhood emotional abuse.
•Childhood maltreatment is very common and several types are related to PTSD.•Only emotional abuse appears to be robustly associated with PTSD severity.•The findings were robust across outcomes and separate PTSD symptom clusters.
A method for growing polymers directly from the surface of graphene oxide is demonstrated. The technique involves the covalent attachment of an initiator followed by the polymerization of styrene, ...methyl methacrylate, or butyl acrylate using atom transfer radical polymerization (ATRP). The resulting materials were characterized using a range of techniques and were found to significantly improve the solubility properties of graphene oxide. The surface‐grown polymers were saponified from the surface and also characterized. Based on these results, the ATRP reactions were determined to proceed in a controlled manner and were found to leave the structure of the graphene oxide largely intact.
The covalent attachment of ATRP initiators to graphene oxide followed by a surface‐initiated polymerization affords derivatives with surface‐attached polymer brushes. The product is found to have dramatically increased solubility without altering the structural properties inherent to graphene oxide.
A dibromo derivative of Dewar benzene, trans-5,6-dibromobicyclo2.2.0hex-1-ene, was polymerized using ring-opening metathesis polymerization (ROMP). The reaction proceeded in a controlled manner as ...changing the initial monomer-to-catalyst ratio afforded monodispersed polymers with tunable molecular weights and growing polymer chains were extended upon subsequent exposure to additional monomer. Treatment of the halogenated polymers with an alkyllithium reagent resulted in elimination followed by isomerization to afford trans-poly(acetylene). Based on a series of mechanistic and spectroscopic studies, the transformation was proposed to proceed through a cyclobutenyl intermediate that undergoes rearrangement. The methodology was found to be versatile as triblock copolymers containing the halogenated homopolymer were prepared and converted to their poly(acetylene)-containing derivatives. The polymers were characterized using gel permeation chromatography as well as a range of spectroscopic (NMR, FT-IR, UV–vis, and Raman) and analytical techniques.
Background:
The critical lesion size treated with bone marrow stimulation (BMS) for osteochondral lesions of the talus (OLTs) has been 150 mm2 in area or 15 mm in diameter. However, recent ...investigations have failed to detect a significant correlation between the lesion size and clinical outcomes after BMS for OLTs.
Purpose:
To systematically review clinical studies reporting both the lesion size and clinical outcomes after BMS for OLTs.
Study Design:
Systematic review.
Methods:
A systematic search of the MEDLINE and EMBASE databases was performed in March 2015 based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included studies were evaluated with regard to the level of evidence (LOE), quality of evidence (QOE), lesion size, and clinical outcomes.
Results:
Twenty-five studies with 1868 ankles were included; 88% were either LOE 3 or 4, and 96% did not have good QOE. The mean area was 103.8 ± 10.2 mm2 in 20 studies, and the mean diameter was 10.0 ± 3.2 mm in 5 studies. The mean American Orthopaedic Foot and Ankle Society score improved from 62.4 ± 7.9 preoperatively to 83.9 ± 9.2 at a mean 54.1-month follow-up in 14 studies reporting both preoperative and postoperative scores with a mean follow-up of more than 2 years. A significant correlation was found in 3 studies, with a mean lesion area of 107.4 ± 10.4 mm2, while none was reported in 8 studies, with a mean lesion area of 85.3 ± 9.2 mm2. The lesion diameter significantly correlated with clinical outcomes in 2 studies (mean diameter, 10.2 ± 3.2 mm), whereas none was found in 2 studies (mean diameter, 8.8 ± 0.0 mm). However, the reported lesion size measurement method and evaluation method of clinical outcomes widely varied among the studies.
Conclusion:
An assessment of the currently available data does suggest that BMS may best be reserved for OLT sizes less than 107.4 mm2 in area and/or 10.2 mm in diameter. Future development in legitimate prognostic size guidelines based on high-quality evidence that correlate with outcomes will surely provide patients with the best potential for successful long-term outcomes.
Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck ...cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In recent years, microphysiological system (MPS, also known as, organ-on-a-chip or tissue chip) platforms have emerged with great promise to improve the predictive capacity of preclinical modeling ...thereby reducing the high attrition rates when drugs move into trials. While their designs can vary quite significantly, in general MPS are bioengineered
in vitro
microenvironments that recapitulate key functional units of human organs, and that have broad applications in human physiology, pathophysiology, and clinical pharmacology. A critical next step in the evolution of MPS devices is the widespread incorporation of functional vasculature within tissues. The vasculature itself is a major organ that carries nutrients, immune cells, signaling molecules and therapeutics to all other organs. It also plays critical roles in inducing and maintaining tissue identity through expression of angiocrine factors, and in providing tissue-specific milieus (
i.e.
, the vascular niche) that can support the survival and function of stem cells. Thus, organs are patterned, maintained and supported by the vasculature, which in turn receives signals that drive tissue specific gene expression. In this review, we will discuss published vascularized MPS platforms and present considerations for next-generation devices looking to incorporate this critical constituent. Finally, we will highlight the organ-patterning processes governed by the vasculature, and how the incorporation of a vascular niche within MPS platforms will establish a unique opportunity to study stem cell development.
To successfully generate vascularized microphysiological systems, researchers must balance several engineering strategies to generate organotypic phenotypes including endothelial cell sourcing, extracellular matrix components and shear control.
Hey ho, let's GO: Graphene oxide platelets can be self‐assembled into highly ordered, mechanically flexible carbon films with tunable porous morphologies. Further nitrogen doping enhanced the ...electrical properties and supercapacitor performances of the carbon‐based assemblies, and provided chemical functionalization.
Residual renal function (RRF) confers survival in patients with ESRD but declines after initiating hemodialysis. Previous research shows that dialysate cooling reduces hemodialysis-induced ...circulatory stress and protects the brain and heart from ischemic injury. Whether hemodialysis-induced circulatory stress affects renal perfusion, and if it can be ameliorated with dialysate cooling to potentially reduce RRF loss, is unknown.
We used renal computed tomography perfusion imaging to scan 29 patients undergoing continuous dialysis under standard (36.5°C dialysate temperature) conditions; we also scanned another 15 patients under both standard and cooled (35.0°C) conditions. Imaging was performed immediately before, 3 hours into, and 15 minutes after hemodialysis sessions. We used perfusion maps to quantify renal perfusion. To provide a reference to another organ vulnerable to hemodialysis-induced ischemic injury, we also used echocardiography to assess intradialytic myocardial stunning.
During standard hemodialysis, renal perfusion decreased 18.4% (
<0.005) and correlated with myocardial injury (
=-0.33;
<0.05). During sessions with dialysis cooling, patients experienced a 10.6% decrease in perfusion (not significantly different from the decline with standard hemodialysis), and ten of the 15 patients showed improved or no effect on myocardial stunning.
This study shows an acute decrease in renal perfusion during hemodialysis, a first step toward pathophysiologic characterization of hemodialysis-mediated RRF decline. Dialysate cooling ameliorated this decline but this effect did not reach statistical significance. Further study is needed to explore the potential of dialysate cooling as a therapeutic approach to slow RRF decline.
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