Cryo-cooling is routinely performed before X-ray diffraction image collection, to reduce the damage to crystal due to ionizing radiations. It has been suggested that, while backbone structures are usually very similar between room-temperature and cryo-temperature, cryo-cooling may hamper biologically relevant dynamics. In this study, crystal of Escherichia coli dihydrofolate reductase (DHFR) is studied with replica-exchange molecular dynamics simulation and results are compared with crystal structure determined at cryo-temperature and room-temperature with time-averaged ensemble method.
https://ift.tt/2C9HLCv
Τετάρτη 12 Δεκεμβρίου 2018
Cryo-cooling effect on DHFR crystal studied by replica-exchange molecular dynamics simulations
The mechanical properties of RNA-DNA hybrid duplex stretched by magnetic-tweezers
RNA can anneal to its DNA template to generate an RNA–DNA hybrid (RDH) duplex and a displaced DNA strand, termed R-loop. RDH duplex occupies up to 5% of the mammalian genome and plays important roles in many biological processes. The functions of RDH duplex are affected by its mechanical properties including the elasticity and the conformation transitions. The mechanical properties of RDH duplex, however, are still unclear. In this work, we studied the mechanical properties of RDH duplex using magnetic-tweezers in comparisons with those of DNA and RNA duplexes with the same sequences.
https://ift.tt/2LgwVNS
Non-linear actomyosin elasticity in muscle?
Cyclic interactions between myosin II motor domains and actin filaments that are powered by turnover of ATP, underlie muscle contraction and have key roles in motility of non-muscle cells. The elastic characteristics of actin-myosin cross-bridges are central in the force-generating process and disturbances in these properties may lead to disease. Whereas the prevailing paradigm is that the cross-bridge elasticity is linear (Hookean), recent single molecule studies suggest otherwise. Despite convincing evidence for substantial non-linearity of the cross-bridge elasticity in the single molecule work, this finding has had limited influence on muscle physiology and physiology of other ordered cellular actin-myosin ensembles.
https://ift.tt/2C7Z3A2
Predicting RNA-Metal Ion Binding with Ion Dehydration Effects
Metal ions play essential roles in nucleic acids folding and stability. The interaction between metal ions and nucleic acids can be highly complicated due to the interplay between the various effects such as ion correlation, fluctuation, and dehydration. These effects may be particularly important for multivalent ions such as Mg2+ ions. Previous efforts to model ion correlation and fluctuation effects led to the development of the Monte Carlo Tightly Bound Ion (MCTBI) model. Here, by incorporating ion hydration/dehydration effects into the MCTBI model, we develop a new approach to predict ion binding.
https://ift.tt/2Lf7899
Mumps presenting with unilateral, synchronous parotid and submandibular gland swelling.
 | Related Articles |
Mumps presenting with unilateral, synchronous parotid and submandibular gland swelling.
BMJ Case Rep. 2018 Sep 04;2018:
Authors: Boyle C, Asimakopoulos P, Khatamzas E, Vernham G
Abstract
A previously healthy 22-year-old woman presented with acute, unilateral facial and neck swelling, associated with fever and malaise. She was initially treated with intravenous antibiotics; however, CT imaging showed unilateral, synchronous swelling and inflammation of the parotid and submandibular glands, and a PCR swab from the parotid duct was positive for mumps. She was fully immunised and had no contact in the preceding period with anyone diagnosed with mumps. She responded to supportive management and her symptoms resolved over the course of her admission. Unilateral, synchronous swelling and severe inflammation of both the parotid and submandibular glands in mumps is a very unusual presentation, and not one previously reported in the literature.
PMID: 30181408 [PubMed - indexed for MEDLINE]
https://ift.tt/2PxheTe
Associated anomalies in cases with anorectal anomalies
Anorectal anomalies (ARA) are common congenital anomalies. The etiology of ARA is unclear and its pathogenesis is controversial. Cases with ARA often have other non‐ARA‐associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with ARA were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population‐based registry of congenital malformations. Of the 202 cases with ARA, representing a prevalence of 5.21 per 10,000, 100 (49.5%) had associated anomalies. There were 7 (3.3%) cases with chromosomal abnormalities, and 31 (15.3%) nonchromosomal recognized dysmorphic conditions, including 17 cases with Vertebral defects, Anal atresia, Cardiac septal defects, esophageal atresia or TracheoEsophageal fistula, Renal anomalies and radial Limb defects association. Sixty two (30.7%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the urogenital, the musculoskeletal, the cardiovascular, the digestive, and the central nervous systems were the most common other anomalies in the cases with MCA. The anomalies associated with ARA could be classified into a recognizable malformation syndrome or pattern in 38 out of the 100 cases (38%) with associated anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion, the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a routine screening for other anomalies in cases with ARA.
https://ift.tt/2Uz6mYC
Useful technique for draining a large cystic tumor through the round ligament in laparoscopic left hemihepatectomy
Abstract
Introduction
Some cystic liver tumors are huge when the diagnosis is made or surgery is needed. Although reducing tumor size by preoperative aspiration or drainage of the contents of the cystic tumor is helpful for liver resection, such procedures have a risk of tumor dissemination.
Materials and Surgical Technique
After the round ligament was dissected, a 12‐Fr drainage catheter was inserted into the tumor via the round ligament under ultrasonography. At that time, close attention was paid to avoid having the catheter deviate outside the round ligament. Through the inserted catheter, fluid was drained from the cystic lesion, and the stump of the round ligament was clipped to avoid fluid leakage. The left Glissonian pedicle was then taped. Laparoscopic left hemihepatectomy was performed under a good operative field because of tumor shrinkage.
Discussion
Three cases underwent these procedures without any spillage of the contents of the cystic tumor. This method is useful for the reduction of tumor size and has a low risk of intra‐abdominal leakage of the contents, resulting in a secure and good operative field.
https://ift.tt/2BoMdMn
IL-13 Contributes to Drug Resistance of NK/T-Cell Lymphoma Cells by Regulating ABCC4
Background. Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL), represents a rare subtype of T-cell lymphomas with aggressive clinical behavior and is relatively resistant to chemotherapy. However, there is relatively poor understanding of molecular pathogenesis of multidrug resistance in ENKTL. Here, we aimed to explore the biological roles and potential mechanism of IL-13 and ABCC4 in multidrug resistance of NK/T-cell lymphoma. Methods. ELISA analysis was used to determine the level of serum IL-13 and immunohistochemical analysis was applied to detect the ABCC4 expression level in patients with human NK/T-cell lymphoma. Western blot assay was employed to measure the expression of ABCC4 in cells. Lenti-sh-ABCC4 viruses were constructed to knock down ABCC4 in YTS cells. CCK-8 assay and flow cytometric analysis were performed to detect the effects of IL-13 and ABCC4 on cell proliferation and apoptosis. CCK-8 assay was conducted to detect the effect of IL-13 and ABCC4 on cell sensitivity to adriamycin (ADM) in YTS cells. Results. Levels of serum IL-13 and ABCC4 expression were observed to be upregulated in patients with human NK/T-cell lymphoma. Moreover, ABCC4 protein expression was also increased in NK/T-cell lymphoma YTS cells compared to the normal NK cells. Interestingly, IL-13 promoted ABCC4 expression in YTS cells. IL-13 promoted proliferation and suppressed apoptosis of YTS cells and reversed the effects of ABCC4 knockdown on promotive proliferation and inhibitory apoptosis. In addition, IL-13 enhanced YTS cell chemotherapy resistance to ADM by promoting ABCC4 expression. Conclusion. Our findings concluded that IL-13 inhibited chemotherapy sensitivity of NK/T-cell lymphoma cells by regulating ABCC4, disrupting which may effectively improve the therapy protocols against resistant NK/T-cell lymphoma.
https://ift.tt/2PAdNeg
Gossypol Promotes Bone Formation in Ovariectomy-Induced Osteoporosis through Regulating Cell Apoptosis
Osteoporosis is among the most common forms of age-related diseases, especially for females, which has been a grave public health problem. Drug therapies have shown promising outcomes to promote bone formation and bone density. This study identified a novel potential drug, gossypol, for the treatment of osteoporosis. Treatments of ovariectomy-induced osteoporosis mice with gossypol significantly increased serum osteocalcin and osteoprotegerin (OPG) levels; meanwhile they decreased serum RANKL levels. Microcomputed tomography (microCT) analysis showed that treatment of gossypol improved bone density and strength and decreased bone postyield displacement for both medullar and cortical bones. In vitro experiments also showed that gossypol increased cell viability in a time- and dose-dependent manner. Furthermore, incubation of the osteoblast MC3T3-E1 cells with gossypol inhibited cell apoptosis through intrinsic apoptotic pathway as evidenced by the Annexin V/PI assay, TUNEL assay, biochemical analysis, and western blot assays. Moreover, the classical Wnt/β-catenin signaling pathway was found to be regulated by gossypol treatments. Inhibition of Wnt/β-catenin signaling reversed the prevention effects of gossypol in osteoporosis. Our findings provided novel clues for the treatment of osteoporosis in clinic.
https://ift.tt/2zWhmXr
Identifying the Growth Factors for Improving Neointestinal Regeneration in Rats through Transcriptome Analysis Using RNA-Seq Data
Using our novel surgical model of simultaneous intestinal adaptation "A" and neointestinal regeneration "N" conditions in individual rats to determine feasibility for research and clinical application, we further utilized next generation RNA sequencing (RNA-Seq) here in normal control tissue and both conditions ("A" and "N") across time to decipher transcriptome changes in neoregeneration and adaptation of intestinal tissue at weeks 1, 4, and 12. We also performed bioinformatics analyses to identify key growth factors for improving intestinal adaptation and neointestinal regeneration. Our analyses indicate several interesting phenomena. First, Gene Ontology and pathway analyses indicate that cell cycle and DNA replication processes are enhanced in week 1 "A"; however, in week 1 "N", many immune-related processes are involved. Second, we found some growth factors upregulated or downregulated especially in week 1 "N" versus "A". Third, based on each condition and time point versus normal control tissue, we found in week 1 "N" BMP2, BMP3, and NTF3 are significantly and specifically downregulated, indicating that the regenerative process may be inhibited in the absence of these growth factors. This study reveals complex growth factor regulation in small neointestinal regeneration and intestinal adaptation and provides potential applications in tissue engineering by introducing key growth factors identified here into the injury site.
https://ift.tt/2PAZSoj
High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations
Abstract
Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.10.1093/brain/awy307_video1awy307media15978667388001https://ift.tt/2RXZVwK
Diagnosis using deep-learning artificial intelligence based on the endocytoscopic observation of the esophagus
Abstract
Background and aims
The endocytoscopic system (ECS) helps in virtual realization of histology and can aid in confirming histological diagnosis in vivo. We propose replacing biopsy-based histology for esophageal squamous cell carcinoma (ESCC) by using the ECS. We applied deep-learning artificial intelligence (AI) to analyse ECS images of the esophagus to determine whether AI can support endoscopists for the replacement of biopsy-based histology.
Methods
A convolutional neural network-based AI was constructed based on GoogLeNet and trained using 4715 ECS images of the esophagus (1141 malignant and 3574 non-malignant images). To evaluate the diagnostic accuracy of the AI, an independent test set of 1520 ECS images, collected from 55 consecutive patients (27 ESCCs and 28 benign esophageal lesions) were examined.
Results
On the basis of the receiver-operating characteristic curve analysis, the areas under the curve of the total images, higher magnification pictures, and lower magnification pictures were 0.85, 0.90, and 0.72, respectively. The AI correctly diagnosed 25 of the 27 ESCC cases, with an overall sensitivity of 92.6%. Twenty-five of the 28 non-cancerous lesions were diagnosed as non-malignant, with a specificity of 89.3% and an overall accuracy of 90.9%. Two cases of malignant lesions, misdiagnosed as non-malignant by the AI, were correctly diagnosed as malignant by the endoscopist. Among the 3 cases of non-cancerous lesions diagnosed as malignant by the AI, 2 were of radiation-related esophagitis and one was of gastroesophageal reflux disease.
Conclusion
AI is expected to support endoscopists in diagnosing ESCC based on ECS images without biopsy-based histological reference.
https://ift.tt/2EuOKIT
GRIN2A-related disorders: genotype and functional consequence predict phenotype
Abstract
Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10−6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/− cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.https://ift.tt/2Qx9Wo1
Advanced glycation end products of bovine serum albumin affect the cell growth of human umbilical vein endothelial cells via modulation of MEG3/miR-93/p21 pathway
Abstract
Advanced glycation end products of BSA (AGE-BSA) contribute to the pathogenesis of diabetic vascular diseases. However, the roles and underlying mechanisms of AGE-BSA in diabetic vascular diseases remain largely unclear. Long non-coding RNAs (lncRNAs) are widely identified and known as gene regulators. However, the roles of lncRNAs in diabetic vascular disease are still vague. In this study, we sought to investigate the contributions of lncRNAs in human umbilical vein endothelial cells (HUVECs) treated with AGE-BSA. We first demonstrated that AGE-BSA reduced the cell viability and inhibited the cell proliferation of HUVECs. Then, we found that lncRNA MEG3 was up-regulated in HUVECs treated with AGE-BSA. Furthermore, inhibition of MEG3 restored the AGE-BSA–induced repression of cell viability and proliferation. In addition, our results revealed that MEG3 played its role via modulation of miR-93 expression in HUVECs treated with AGE-BSA. Furthermore, we illustrated that miR-93 played its role via regulation of p21 in HUVECs treated with AGE-BSA. Ultimately, our study displayed that AGE-BSA exerted its function via modulation of MEG3/miR-93/p21 pathway in HUVECs. Thus, for the first time, we identified the MEG3/miR-93/p21 axis in HUVECs treated with AGE-BSA, which might be a novel regulatory network in diabetic vascular cells, and possess the potential therapeutic value for diabetes mellitus.https://ift.tt/2GfniQL
Lotus seed skin proanthocyanidin extract exhibits potent antioxidant property via activation of the Nrf2–ARE pathway
Abstract
Lotus seed is well known as traditional food and medicine, but its skin is usually discarded. Recent studies have shown that lotus seed skin contains a high concentration of proanthocyanidins that have multi-functions, such as antioxidation, anti-inflammation, and anti-cancer effects. In the present study, we aimed to isolate and purify the proanthocyanidins from lotus seed skin by acetone extraction and rotary evaporation, identify their chemical structures by HPLC-MS-MS and NMR, and further investigate the antioxidant properties of the extract purified by macroporous resin (PMR) from lotus seed skin both in vitro and in vivo. The results showed that PMR mainly contained oligomeric proanthocyanidins, especially dimeric procyanidin B1 (PB1), procyanidin B2 and procyanidin B4. Although it had limited ability to directly scavenge radicals in vitro, PMR could significantly enhance the expressions of antioxidant proteins via activation of nuclear factor-E2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway in HepG2 cells. Molecular data revealed that PB1, a major component in PMR, stabilized Nrf2 by inhibiting the ubiquitination of Nrf2, which led to subsequent activation of the Nrf2–ARE pathway, including the enhancements of Nrf2 nuclear translocation, Nrf2–ARE binding and ARE transcriptional activity. Moreover, the in vivo results in high fat diet-induced mice further verified the powerful antioxidant property of PMR. These results revealed that lotus seed skin is a promising resource for functional food development.https://ift.tt/2rw0PEY
A novel detection method of Cryptosporidium parvum infection in cattle based on Cryptosporidium parvum virus 1
Abstract
Cryptosporidium parvum is an important zoonotic parasite that causes significant economic loss in the animal husbandry industry, especially the cattle industry. As there is no specific vaccine or drug against Cryptosporidium, a rapid and accurate method for the detection of C. parvum is of great significance. In this study, colloidal gold strips were developed based on Cryptosporidium parvum virus 1 (CSpV1) for the detection of C. parvum infection in cattle fecal samples. The colloidal gold solution was prepared by reducing trisodium citrate and the CSpV1 #5 monoclonal antibody was labeled with colloidal gold. A polyclonal antibody against the CSpV1 capsid protein and an anti-mouse IgG antibody were coated on the colloidal gold strips for use in the test and control lines, respectively. Our results showed that the detection sensitivity in fecal samples was up to a 1:64 dilution. There was no cross-reaction with Cryptosporidium andersoni or Giardia in the fecal samples. The different preservation conditions (room temperature, 4°C, and 37°C) and preservation time (7, 30, 60, and 90 days) were analyzed. The data showed that the strips could be preserved for 90 days at 4°C and for 60 days at room temperature or 37°C. The colloidal gold strips were used to detect the samples of 120 clinical fecal in Changchun, China. The results indicated that the rate of a positive test was 5% (6/120). This study provides a rapid and accurate method for detecting C. parvum infection in cattle and humans.https://ift.tt/2GaKlvZ
Short-term propamocarb exposure induces hepatic metabolism disorder associated with gut microbiota dysbiosis in adult male zebrafish
Abstract
Propamocarb (PM) is a pesticide that is widely used to protect cucumbers and other plants from downy mildew. Recently, some studies indicated that PM exposure had potential toxic effects in animals. In this study, adult male zebrafish were exposed to 100 and 1000 μg/l PM for 7 days to assess its effects on metabolism and the gut microbiota. We observed a significant decrease in triglyceride (TG) in the livers of zebrafish that were exposed to 1000 μg/l PM for 7 days. At the same time, some genes related to glycolysis and lipid metabolism in the livers of zebrafish, including hexokinase-1 (HK1), pyruvate kinase (PK), acyl-CoA oxidase (Aco), peroxisome proliferator activated receptor alpha (Ppar-α), apolipoprotein A-IV-like (Apo), Acetyl CoA carboxylase-1 (Acc1), diacylglycerol acyltransferase (Dgat), and fatty acid synthase (Fas), were also decreased significantly after PM exposure. Based on GC–MS metabolomics analysis, a total of 48 metabolites changed significantly in the 1000 μg/l PM treatment group in comparison with the control group. These altered metabolites were mainly associated with the glycolysis, amino acid metabolism, and lipid metabolism pathways. Interestingly, we further found that the 1000 μg/l PM treatment group also showed significant elevations in Proteobacteria, Bacteroidetes, and Firmicutes at the phylum level. Sequencing of the 16 S rRNA gene in the V3–V4 region also showed a significant change in the abundance and diversity of the gut microbiota in the 1000 μg/l PM treatment group. Our results indicated that exposure to PM for a short time could induce hepatic metabolic disorders and gut microbiota dysbiosis in adult male zebrafish.https://ift.tt/2rB4j93
Baylisascariasis: A young boy with neural larva migrans due to the emerging raccoon round worm
Abstract
A 17‐month‐old boy from Vancouver, Canada, presented with a 5‐day history of progressive somnolence, ataxia, and torticollis. Additional investigations revealed eosinophilic encephalitis with deep white matter changes on MR imaging. On day 13, serology came back positive for Baylisascaris procyonis antibodies. While prophylaxis after ingestion of soil or materials potentially contaminated with raccoon feces can prevent baylisascariasis, timely treatment can sometimes alter a disastrous outcome. Populations of infected raccoons are propagating globally, but cases of Baylisascaris neural larva migrans have so far only been reported from North America.
https://ift.tt/2C9Q29O
Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company's health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG's probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.
https://ift.tt/2Bjy56K
Obinutuzumab in Combination with Chemotherapy for the First-Line Treatment of Patients with Advanced Follicular Lymphoma
Abstract
The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended.
https://ift.tt/2UFKZVN
Comparative effectiveness of radiotherapy for early‐stage hormone receptor‐positive breast cancer in elderly women using real‐world data
Due to limited number of elderly patients' participation in randomized controlled trials, the treatment decision in elderly patients often depends on the result of RCTs on younger patients, which makes the treatment decision challenging for clinicians and patients. Thus, the result of this study may help inform clinical decision‐making.
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Background
Radiotherapy is the recommended treatment after breast‐conserving surgery (BCS) for early‐stage breast cancer (BC). However, there is no clear evidence whether radiotherapy after BCS improves the survival of elderly women diagnosed with early‐stage hormone receptor‐positive (HR+) BC. The aim of this study was to investigate the survival benefit associated with radiotherapy plus hormonal therapy vs hormonal therapy alone after BCS for early‐stage HR+ BC patients.
Methods
Using the Surveillance, Epidemiology, and End Results linked with Medicare data, we identified elderly (65 years and older) women diagnosed with early‐stage HR+ BC (2006‐2011) who received hormonal therapy with or without radiotherapy after BCS. A log‐rank test, Cox proportional hazards models, and propensity score matching were used to estimate the overall survival (OS) benefit associated with radiotherapy after BCS.
Results
Of the 5688 patients, there were 303 deaths from any cause. One hundred and eighty‐five (61%) of these deaths occurred in the hormonal therapy group, and 118 (39%) deaths occurred in the radiotherapy plus hormonal therapy group. The mean survival time in the radiotherapy plus hormonal therapy group was 5.32 ± 1.86 years compared with 4.92 ± 1.86 years in the hormonal therapy group. Based on the adjusted and propensity score matching analysis, patients in the adjuvant radiotherapy group had a lower risk of death compared with those who did not receive radiotherapy. Radiotherapy plus hormonal therapy decreased the risk of death by 32%. The effect estimates were similar in the adjusted and matched cohorts.
Conclusions
Radiotherapy plus hormonal therapy resulted in a significant improvement in the OS of elderly women diagnosed with HR+ BC.
https://ift.tt/2QrgBQm
Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice
Abstract
Cardiovascular disease, rare in premenopausal women, increases sharply at menopause and is typically accompanied by chronic inflammation. Previous work in our laboratory demonstrated that replacing senescent ovaries in post-reproductive mice with young, actively cycling ovaries restored many health benefits, including decreased cardiomyopathy and restoration of immune function. Our objective here was to determine if depletion of germ cells from young transplanted ovaries would alter the ovarian-dependent extension of life and health span. Sixty-day-old germ cell-depleted and germ cell-containing ovaries were transplanted to post-reproductive, 17-month-old mice. Mean life span for female CBA/J mice is approximately 644 days. Mice that received germ cell-containing ovaries lived 798 days (maximum = 815 days). Mice that received germ cell-depleted ovaries lived 880 days (maximum = 1046 days), 29% further past the time of surgery than mice that received germ cell-containing ovaries. The severity of inflammation was reduced in all mice that received young ovaries, whether germ cell-containing or germ cell-depleted. Aging-associated inflammatory cytokine changes were reversed in post-reproductive mice by 4 months of new-ovary exposure. In summary, germ cell depletion enhanced the longevity-extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of inflammation, but did so independent of germ cells. Based on these observations, we propose that gonadal somatic cells are programed to preserve the somatic health of the organism with the intent of facilitating future germline transmission. As reproductive potential decreases or is lost, the incentive to preserve the somatic health of the organism is lost as well.
https://ift.tt/2Bjvaei
Management of uterine sarcomas and prognostic indicators: real world data from a single-institution
Abstract
Background
Uterine sarcomas consist a heterogeneous group of mesenchymal gynecological malignancies with unclear therapeutic recommendations and unspecific but poor prognosis, since they usually metastasize and tend to recur very often, even in early stages.
Methods
We retrospectively analyzed all female patients with uterine sarcomas treated in our institution over the last 17 years. Clinico-pathological data, treatments and outcomes were recorded. Kaplan-Meier curves were plotted and time-to-event analyses were estimated using Cox regression.
Results
Data were retrieved from 61 women with a median age of 53 (range: 27–78) years, at diagnosis. Fifty-one patients were diagnosed with leiomyosarcoma (LMS), 3 with high grade endometrial stromal sarcoma (ESS), 5 with undifferentiated uterine sarcoma (UUS), 1 with Ewing sarcoma (ES) and 1 with Rhabdomyosarcoma (RS). 24 cases had stage I, 7 stage II, 14 stage III and 16 stage IV disease. Median disease-free survival (DFS) in adjuvant approach was 18.83 months, and median overall survival (OS) 31.07 months. High mitotic count (> 15 mitoses) was significantly associated with worse OS (P < 0.001) and worse DFS (P = 0.028).
Conclusions
Mitotic count appears to be independent prognostic factor while further insights are needed to improve adjuvant and palliative treatment of uterine sarcomas.
https://ift.tt/2EsfqcX
Comprehensive genotyping reveals novel CFTR variants in cystic fibrosis patients from the Russian Federation
Single nucleotide variants are represented as lines. The height of the line corresponds to the allele frequency. Gross chromosomal copy number variations are shown as arrows. Color corresponds to the mutation type. Complex alleles represented with a clip. Previously reported variants are located above the schematic gene representation. Their names are presented in Table 1 in main text. Novel variants are depicted beneath the schematic gene representation.
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Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration
Rod and cone photoreceptors are specialized retinal neurons that have a fundamental role in visual perception, capturing light and transducing it into a neuronal signal. Aberrant functioning of rod and/or cone photoreceptors can ultimately lead to progressive degeneration and eventually blindness. In man, many rod and rod-cone degenerative diseases are classified as forms of retinitis pigmentosa (RP). Dogs also have a comparable disease grouping termed progressive retinal atrophy (PRA). These diseases are generally due to single gene defects and follow Mendelian inheritance. We collected 51 DNA samples from Miniature Schnauzers affected by PRA (average age of diagnosis ~3.9 ±1 years), as well as from 56 clinically normal controls of the same breed (average age ~6.6 ±2.8 years). Pedigree analysis suggested monogenic autosomal recessive inheritance of PRA. GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15. Whole genome sequencing of two affected cases, a carrier and a control identified two candidate variants within the critical interval. One was an intronic SNV in HIVEP3, and the other was a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1dci). PPT1dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. The HIVEP3 variant was found heterozygous (n=4) and homozygous wild-type (n=1) in cases either homozygous for PPT1dci or for the mapped CFA15 haplotype. We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1dci, and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1dci variant. Therefore, we propose PPT1dci as causative for a non-syndromic form of PRA (PRAPPT1) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript. To our knowledge, this is the first case of isolated retinal degeneration associated with a PPT1 variant.
https://ift.tt/2EtVEOa
A Statistical Procedure for Genome-Wide Detection of QTL Hotspots Using Public Databases with Application to Rice
Genome-wide detection of quantitative trait loci (QTL) hotspots underlying variation in many molecular and phenotypic traits has been a key step in various biological studies since the QTL hotspots are highly informative and can be linked to the genes for the quantitative traits. Several statistical methods have been proposed to detect QTL hotspots. These hotspot detection methods rely heavily on permutation tests performed on summarized QTL data or individual-level data (with genotypes and phenotypes) from the genetical genomics experiments. In this article, we propose a statistical procedure for QTL hotspot detection by using the summarized QTL (interval) data collected in public web-accessible databases. First, a simple statistical method based on the uniform distribution is derived to convert the QTL interval data into the expected QTL frequency (EQF) matrix. And then, to account for the correlation structure among traits, the QTLs for correlated traits are grouped together into the same categories to form a reduced EQF matrix. Furthermore, a permutation algorithm on the EQF elements or on the QTL intervals is developed to compute a sliding scale of EQF thresholds, ranging from strict to liberal, for assessing the significance of QTL hotspots. With grouping, much stricter thresholds can be obtained to avoid the detection of spurious hotspots. Real example analysis and simulation study are carried out to illustrate our procedure, evaluate the performances and compare with other methods. It shows that our procedure can control the genome-wide error rates at the target levels, provide appropriate thresholds for correlated data and is comparable to the methods using individual-level data in hotspot detection. Depending on the thresholds used, more than 100 hotspots are detected in GRAMENE rice database. We also perform a genome-wide comparative analysis of the detected hotspots and the known genes collected in the Rice Q-TARO database. The comparative analysis reveals that the hotspots and genes are conformable in the sense that they co-localize closely and are functionally related to relevant traits. Our statistical procedure can provide a framework for exploring the networks among QTL hotspots, genes and quantitative traits in biological studies. The R codes that produce both numerical and graphical outputs of QTL hotspot detection in the genome are available on the worldwide web https://ift.tt/2TKaS6a.
https://ift.tt/2EkdLpf
Absorbable suture. Best aesthetic outcome in cesarian scar
Abstract Purpose: To compare two suture threads, poliglecaprone 25 and nylon, used as intradermal suture for skin closure in women undergoing their first cesarean section. Methods: This is a randomized clinical trial. A total of 60 women undergoing their first cesarean section were enrolled and prospectively assessed. They were randomly allocated to group I (n=30), which received an intradermal suture with nylon 4.0 or to group II (n=30), which had an intradermal suture with poliglecaprone 25, 4.0. The main author took standardized photographs of the scar 6 months after the operation. Four independent raters, two senior obstetricians and two senior plastic surgeons (a male and a female physician from each specialty) assessed the photographs.The panelists rated the scar according to Trimbos scale, composed by the subscales hypertrophy, color and width of the scar. Results: At baseline, patients in both groups were similar regarding age and body mass index. Five patients withdraw the study, four from group and one from group II. Scars of patients from group II were significantly less hypertrophic (p=0.001), thinner (p=0.019) and had more acceptable color (p=0.019). Conclusion: The intradermal suture with poliglecaprone 25 for skin closure after cesarean incision provides better aesthetic result.
https://ift.tt/2SMF0g7
Healing effect of andiroba-based emulsion in cutaneous wound healing via modulation of inflammation and transforming growth factor beta 3
Abstract Purpose: To evaluate the effects and mechanisms of andiroba-based emulsion (ABE) topical treatment on full-thickness cutaneous wounds in rats. Methods: The wounds were harvested on days 3, 7, 15, and 20 post-surgery. Wound contraction rate, quantitative immunohistochemistry [macrophages, myofibroblasts, capillaries, collagens (col) I and III, transforming growth factor β3β (TGFβ3)], and tensile strength were assessed. Results: Treated wounds were smaller, contracted earlier and had increased angiogenesis, fewer CD68+ and M2 macrophages on days 7 and 15, but higher on day 20. Myofibroblasts appeared on days 3 to 7 in untreated wounds and on days 7 to 15 in treated wounds. TGFβ3 levels were higher in the treated wounds, less dense collagen fibers, lower col I/III ratios and a higher tensile strength. Conclusion: These results demonstrate the important anti-inflammatory role of treatment and the associated modulation of macrophages, myofibroblasts, and TGFβ3 levels. Collagen fibers in the treated wounds were more organized and less dense, similar to unwounded skin, which likely contributed to the higher tensile strength.
https://ift.tt/2SNMpfb
Hepatic retractor in an ex vivo model
Abstract Purpose: To discuss the use of models of hepatic retraction by laparoscopy, to present a new Hepatic Retractor (HR) and to evaluate its practicality, efficacy and safety in Esophageal Hiatus Exposure (EHE). Methods: Experimental cross - sectional study with a quantitative character. It was carried out in the Laboratory of Health Training of Christus University Center. The sample consisted of 12 livers of adult pigs weighing between 30 and 45 kg. A circular-shaped HR, 5 cm diameter and deformable materials was developed with a polypropylene cloth, metallic guide wire, epidural needle plastic guide and nylon string. The practicality of HR management was measured by the time required to use the instrument, efficacy by exposure to the operative field and safety by macroscopic assessment of liver damage. Results: The average time to complete the procedure was 3.24 minutes and reached less than 2 minutes after 12 repetitions. In eight experiments the maximum degree of EHE was obtained. No macroscopic lesions were observed. Conclusion: The use of HR described can broaden the operative field, without causing macroscopic liver lesions and prolonging the surgical time.
https://ift.tt/2QQUAtM
FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia
On August 3, 2017, the Food and Drug Administration (FDA) granted regular approval to Vyxeos (also known as CPX-351), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos to a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly-diagnosed t-AML or AML-MRC. Due to elemental copper concerns with the Vyxeos formulation, patients with Wilson's disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% CI: 0.52, 0.90; p=0.005) with an estimated median overall survival (OS) of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.
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Oxymatrine alleviates periodontitis in rats by inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression
Abstract Purpose: To investigate the effect of oxymatrine on periodontitis in rats and related mechanism. Methods: Ninety SD rats were divided into control, model, 10, 20 and 40 mg/kg oxymatrine and tinidazole groups. The periodontitis model was established in later 5 groups. The 10, 20 and 40 mg/kg oxymatrine groups were intragastrically administrated with 10, 20 and 40 mg/kg oxymatrine, respectively. The tinidazole group was intragastrically administrated with 100 mg/kg tinidazole. The treatment duration was 4 weeks. The tooth mobility, gingival and plaque indexes, serum inflammatory factor levels and gingival tissue matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) protein levels were detected. Results: After treatment, compared with model group, in 40 mg/kg oxymatrine group the rat general conditions were obviously improved, the tooth mobility, gingival index and plaque index were significantly decreased (P<0.05), the serum tumor necrosis factor-α, interleukin-1β and prostaglandin E2 levels were significantly decreased (P<0.05), the MMP-2 and MMP-9 protein levels were significantly decreased (P<0.05), and the TIMP-2 protein level was significantly increased (P<0.05). Conclusions: Oxymatrine can alleviate the experimental periodontitis in rats. The mechanism may be related to its inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression.
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Effects of different periods of gastric ischemia on liver as a remote organ
Abstract Purpose: To evaluate the hepatic changes associated with gastric ischemia. Methods: Thirty male rabbits were studied, distributed in 3 groups (n=10). Group 1: ligature and section of the gastric vasculature and removal of the liver after three hours; Group 2: ligature and section of the gastric vasculature and removal of the liver after 6 hours; Group 3: ligature and section of the gastric vasculature and removal of the liver after 12 hours. Blood samples were collected immediately before surgery and after the determined time of ischemia in each group to evaluate the hepatic function. After the death of the rabbits, the liver was removed for macro and microscopic study. Results: An increase in aminotransferases and bilirubin occurred in groups 2 and 3. Total protein and albumin diminished in all of the animals. All of the rabbits from groups 2 and 3 presented hepatocellular necrosis. Conclusion: The devascularization of the stomach for a period of above three hours is associated with hepatic morphological and functional disorders.
https://ift.tt/2SIV5Dy
Effectual components of Polygonum ciliinerve protects against Staphylococcus aureus infection with immunomodulatory functions in C57BL/6 mice
Abstract Purpose: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. Methods: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. Results: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. Conclusion: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.
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Adipose tissue derived mesenchymal stem cell transplantation in the treatment of ischemia/reperfusion induced acute kidney injury in rats. Application route and therapeutic window
Abstract Purpose: To evaluate renal repair in rats who had renal infarction induced by the obstruction of blood flow in the renal artery and were treated with transplantation of adipose tissue derived mesenchymal stem cell Methods: 16-week-old Wistar rats (n=72) were used, submitted to celiotomy and had of the renal artery and vein clipped for 24 hours. The animals were randomly assigned to 10 experimental homogeneous groups, corresponding to the treatments with phosphate-buffered saline (PBS) or adipose tissue derived mesenchymal stem cell (ADSC), duration of application (24 or 48 hours), and site of transplantation (lateral vein of the tail or intrarenal). After the treatments were performed, at 8 and 31 days, four animals in each group were subjected to left nephrectomy for histological studies. Results: Histologically, a higher amount of cell debris and tubules devoid of the epithelium and a higher degree of necrosis were observed in the groups treated with PBS, as opposed to a low degree of necrosis and higher tubular vascularization in the groups treated with ADSC, particularly in the group treated with intrarenal ADSC 48 hours after injury. Conclusion: The transplantation of ADSC positively contributed to the replacement of necrotic tissue by renal tubular cells, vascularization of the renal parenchyma, and restoration of the organ function.
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The cardiopulmonary bypass and cancer dissemination puzzle
Abstract Early cancer diagnosis, new therapies that increased survival of patients, besides the increasingly elderly population are some factors would be associated with possible cancer dissemination in patients under cardiopulmonary bypass (CPB) cardiac surgery. Also, the benefits, and risks, regarding long-term survival, have not yet been established. Therefore, cardiac surgery morbimortality may be superior in patients with cancer disease. Also, immunologic and inflammatory changes secondary to CPB can also increase tumor recurrence. After a brief introduction and CPB immunologic the two main topic subjects included: 1) Combined heart surgery and lung resection and; 2) Possible influence of neoplasia type. After observing the relative literature scarcity, we keep the opinion that "CPB has a modest association with cancer progression" and that "CPB and cancer dissemination should be a logical but unlikely association."
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Enrollment Under the Affordable Care Act Down From Last Year
WEDNESDAY, Dec. 12, 2018 -- Enrollment for health insurance under the Affordable Care Act is down with just days left to sign up, according to the U.S. Centers for Medicare & Medicaid Services. The agency said nearly 20 percent fewer new people...
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Sleep Length, Quality Linked to Risk for Falls, Fractures
WEDNESDAY, Dec. 12, 2018 -- Both short and long sleep duration and poor sleep quality are associated with increased odds of recurrent falls in women, according to a study published online Nov. 21 in the Journal of Bone and Mineral Research. Jane A....
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Recalled Kotex Tampons Can Unravel Inside Body
WEDNESDAY, Dec. 12, 2018 -- Certain Kotex tampons are being recalled by Kimberly-Clark because they can unravel and leave pieces inside women's bodies. There have been "a small number of reports of infections, vaginal irritation, localized vaginal...
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Antipsychotics Up Risk for Unexpected Death in Youths
WEDNESDAY, Dec. 12, 2018 -- Antipsychotic use is associated with an increased risk for unexpected death among children and youths, according to a study published online Dec. 12 in JAMA Psychiatry. Wayne A. Ray, Ph.D., from the Vanderbilt University...
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FDA: Some E-Cigarette Liquids Contain Erectile Dysfunction Meds
WEDNESDAY, Dec. 12, 2018 -- Consumers should not use two electronic cigarette liquids that contain erectile dysfunction drugs because they may pose health risks, according to the U.S. Food and Drug Administration. Lab tests revealed both sildenafil...
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Identification of Gardnerella vaginalis and Atopobium vaginae in Women With Bacterial Vaginosis in Northern Iran
Background Bacterial vaginosis is the most common lower genital tract infection among women of reproductive age. Its causative agent is often the bacterium Gardnerella vaginalis, which exists in synergism with other mostly anaerobic bacteria such as Atopobium vaginae, Mobiluncus curtisii, and Megasphaera type I. Methods A total of 211 women, who referred to obstetrics and gynecology clinics in Rasht City for suspected vaginal infections, were tested for possible bacterial vaginosis. The presence of G. vaginalis and A. vaginae was verified by 5 different laboratory methods based on the Amsel criteria. These methods included determination of pH, whiff test, and observation of clue cells in a direct smear. Polymerase chain reaction using specific primers was performed on the extracted DNA from the vaginal specimens. Results Sixty cases of bacterial vaginosis, of the 211 women tested for suspected vaginal infections, were confirmed using Amsel criteria. In 44% (29/66) and 29% (19/66) of these bacterial vaginosis cases, the presence of G. vaginalis and A. vaginae was confirmed by polymerase chain reaction, respectively. Conclusions Gardnerella vaginalis had a very high prevalence in the 18- to 35-year-old women suffering from bacterial vaginosis in this region of Iran. Presumably, these cases were recommended for appropriate treatment, but the wider issue is about prevention in this age group and appropriate public health messages to raise awareness. Correspondence to: Nour Amirmozafari, PhD, Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran, 1449614535, Iran. E-mail: amirmozafari@yahoo.com. This work was supported by Islamic Azad University, Tehran; and Department of Microbiology, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. The authors have no conflicts of interest to disclose. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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https://ift.tt/2BfhPE0
Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N=24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy whereas, non-responders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared to molecular responders (5.2 vs 14.5 and 8.4 vs 18.7 months, HR=5.36, 95% CI: 1.57-18.35, p=0.007 and HR=6.91, 95% CI: 1.37-34.97, p=0.02 respectively), which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T cell receptor (TCR) productive frequencies mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of early stage NSCLC patients (N=14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
https://ift.tt/2RW5UlE
Natural Killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms.
In neuroblastoma, the interplay between immune cells of the tumor microenvironment and cancer cells contributes to immune escape mechanisms and drug resistance. In this study, we show that NK cell-derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines. The cytotoxic potential of these exosomes was partly dependent upon expression of miR-186. MiR-186 was downregulated in high-risk neuroblastoma patients, and its low expression represented a poor prognostic factor that directly correlated with NK activation markers (i.e. NKG2D and DNAM-1). Expression of MYCN, AURKA, TGFΒR1 and TGFΒR2 was directly inhibited by miR-186. Targeted delivery of miR-186 to MYCN-amplified neuroblastoma or NK cells resulted in inhibition of neuroblastoma tumorigenic potential and prevented the TGFb1-dependent inhibition of NK cells. Altogether, these data support the investigation of a miR-186-containing nanoparticle formulation to prevent tumor growth and TGFb1-dependent immune escape in high-risk neuroblastoma patients as well as the inclusion of ex vivo derived NK exosomes as a potential therapeutic option alongside NK cell-based immunotherapy.
https://ift.tt/2Qq6jjz
Mutation Clearance after Transplantation for Myelodysplastic Syndrome
New England Journal of Medicine, Volume 379, Issue 24, Page 2379-2380, December 2018.
https://ift.tt/2Pzx7bV
Radical Prostatectomy or Watchful Waiting in Prostate Cancer — 29-Year Follow-up
New England Journal of Medicine, Volume 379, Issue 24, Page 2319-2329, December 2018.
https://ift.tt/2PC9Pls
Case 28-2018: A Man with Epistaxis, Pain and Erythema of the Forearm, and Pancytopenia
New England Journal of Medicine, Volume 379, Issue 24, Page 2381-2382, December 2018.
https://ift.tt/2PCygiZ
Remembering William
New England Journal of Medicine, Volume 379, Issue 24, Page 2293-2295, December 2018.
https://ift.tt/2zUxE2W
MACRA’s Patient Relationship Codes — Measuring Accountability for Costs
New England Journal of Medicine, Volume 379, Issue 24, Page 2288-2290, December 2018.
https://ift.tt/2zV3ooN
Neurodevelopment in Infants Exposed to Zika Virus In Utero
New England Journal of Medicine, Volume 379, Issue 24, Page 2377-2379, December 2018.
https://ift.tt/2zSXfJt
Influenza Cataclysm, 1918
New England Journal of Medicine, Volume 379, Issue 24, Page 2285-2287, December 2018.
https://ift.tt/2zVRriB
Erythroderma and a Pulmonary Nodule
New England Journal of Medicine, Volume 379, Issue 24, December 2018.
https://ift.tt/2A5pXav
Heat-Stable Carbetocin to Prevent Postpartum Hemorrhage
New England Journal of Medicine, Volume 379, Issue 24, Page 2380-2381, December 2018.
https://ift.tt/2PAki0L
Case 38-2018: A 54-Year-Old Man with New Heart Failure
New England Journal of Medicine, Volume 379, Issue 24, Page 2362-2372, December 2018.
https://ift.tt/2zSXd4j
Substance-Use Disorders in Later Life
New England Journal of Medicine, Volume 379, Issue 24, Page 2351-2360, December 2018.
https://ift.tt/2PAkcGr
Development of a modified score system as prediction model for successful vaginal birth after cesarean delivery
Abstract
This study was designed to establish a modified prediction score system to improve the safety and success rate of vaginal birth after cesarean delivery (VBAC). We recruited 406 patients (between January 2012 and December 2016) and generated a modified score system in predicting the success rate of VBAC. All patients were required to sign informed consent forms. 87.2% of patients had successful VBAC and 12.8% patients had repeated cesarean section. We conducted multivariable logistic regression, and found seven variables that were associated with VBAC success, including previous primary indication of cesarean delivery [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.4–3.0], previous vaginal birth history (OR 2.5, 95% CI 1.8–3.8), less than 40 years of age (OR 2.1, 95% CI 1.2–3.3), less than 20 kg weight gain (OR 1.5, 95% CI 1.2–2.3), no labor induction (OR 1.9, 95% CI 1.5–2.9), high score of pelvic/birth weight (OR 1.4, 95% CI 1.1–2.1) and Bishop score (OR 1.3, 95% CI 1.2–1.4). After adjustment for optimism, the area under the receiver operating characteristic curve was 0.849 (95% CI 0.78–0.89), and the modified VBAC score was positively correlated with the success rate of TOLAC (trial of labor after cesarean delivery). A valid and useful score system was established to predict VBAC success rate.
This article is protected by copyright. All rights reserved.
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Tranilast treatment attenuates cerebral ischemia‐reperfusion injury in rats through the inhibition of inflammatory responses mediated by NF‐ κB and PPARs
Abstract
Ischemia‐reperfusion injury (IRI) occurs when blood supply returns to tissue after interruption, which is associated with life‐threatening inflammatory response. Tranilast is a widely used anti‐allergic agent in the treatment against bronchial asthma and keloid. To study the function of tranilast, we used IRI rat model. The brain tissues of IRI rats with or without tranilast treatment were collected. Neuronal apoptosis in the brain was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and pro‐inflammatory cytokine levels were measured by qRT‐PCR and enzyme‐linked immunosorbent assay. The expression levels of nuclear factor‐κB (NF‐κB), inhibitor of κB (IκB) and peroxisome proliferator‐activated receptors (PPARs) were detected by Western blot. The results showed that tranilast treatment reduced neuronal apoptosis in the brain of IRI rats. Tranilast enhanced the short term and long term memory to novel object recognition paradigm. Tranilast treatment decreased the mRNA and protein levels of multiple pro‐inflammatory cytokines, and affected NF‐κB and IκB protein expressions. Tranilast promoted the expressions of PPAR‐α and PPAR‐γ. Our findings demonstrate that tranilast treatment could attenuate cerebral IRI by regulating the inflammatory cytokine production and PPAR expression. Tranilast is a potential drug for IRI treatment in clinic.
This article is protected by copyright. All rights reserved.
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Heat-Stable Carbetocin to Prevent Postpartum Hemorrhage
New England Journal of Medicine, Volume 379, Issue 24, Page 2380-2381, December 2018.
https://ift.tt/2PAki0L
MACRA’s Patient Relationship Codes — Measuring Accountability for Costs
New England Journal of Medicine, Volume 379, Issue 24, Page 2288-2290, December 2018.
https://ift.tt/2zV3ooN
Case 28-2018: A Man with Epistaxis, Pain and Erythema of the Forearm, and Pancytopenia
New England Journal of Medicine, Volume 379, Issue 24, Page 2381-2382, December 2018.
https://ift.tt/2PCygiZ
Percutaneous Repair of Secondary Mitral Regurgitation — A Tale of Two Trials
New England Journal of Medicine, Volume 379, Issue 24, Page 2374-2376, December 2018.
https://ift.tt/2PA0VVQ
Substance-Use Disorders in Later Life
New England Journal of Medicine, Volume 379, Issue 24, Page 2351-2360, December 2018.
https://ift.tt/2PAkcGr
Parvovirus B19 Infection
https://ift.tt/2PyRqWU
Remembering William
New England Journal of Medicine, Volume 379, Issue 24, Page 2293-2295, December 2018.
https://ift.tt/2zUxE2W
Influenza Cataclysm, 1918
https://ift.tt/2zVRriB
Radical Prostatectomy or Watchful Waiting in Prostate Cancer — 29-Year Follow-up
New England Journal of Medicine, Volume 379, Issue 24, Page 2319-2329, December 2018.
https://ift.tt/2PC9Pls
Mutation Clearance after Transplantation for Myelodysplastic Syndrome
New England Journal of Medicine, Volume 379, Issue 24, Page 2379-2380, December 2018.
https://ift.tt/2Pzx7bV
Neurodevelopment in Infants Exposed to Zika Virus In Utero
https://ift.tt/2zSXfJt
Case 38-2018: A 54-Year-Old Man with New Heart Failure
New England Journal of Medicine, Volume 379, Issue 24, Page 2362-2372, December 2018.
https://ift.tt/2zSXd4j
A Meta-Analysis of Efficacy and Safety of Infliximab for Prevention of Postoperative Recurrence in Patients with Crohn’s Disease
Objective. We sought to investigate the efficacy and safety of Infliximab for prevention of postoperative recurrence in patients with Crohn's disease (CD), in a meta-analysis of clinical trial results. Methods. The Medline, Embase, PubMed, and Web of Science databases were systematically searched for suitable studies. A meta-analysis of enrolled studies was performed to analyze the efficacy of Infliximab on outcomes regarding the prevention of postoperative recurrence of CD. A Galbraith radial plot was used to quantify the heterogeneity. Funnel plot and Egger test were performed to describe the bias of publication. A Forest plot was prepared to indicate the efficacy outcomes. Results. A total of 7 prospective trials were included in our meta-analysis (N=455). The Funnel plot and Egger test showed there was no significant bias in the included publications. The Cochrane collaboration tool indicated that all 7 prospective trials were of high quality. The results of Galbraith radial plot showed that no study was the source of heterogeneity. Compared with the placebo group, Infliximab decreased the rates of endoscopic recurrence (RR =0.421; 95% CI 0.328 to 0.539; p
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The abilities of three Nickel‐Titanium mechanized systems to negotiate and shape MB2 canals in extracted maxillary first molars. A Micro‐Computed Tomographic study
Abstract
Aim
To evaluate the influence of three engine‐driven NiTi file systems manufactured with different NiTi alloys for the preparation of second mesiobuccal (MB2) canals in extracted maxillary first molars using a micro‐computed tomography scanner (Micro‐CT).
Methodology
Thirty maxillary molars with two canals in the mesiobuccal root were selected and randomly divided into 3 groups (n=10): Reciproc [REC; size 25, .08 taper; VDW, Munich, Germany], Prodesign R [PDR; size 25, .06 taper; Easy, Belo Horizonte, Brazil] and Mtwo [MO; size25, .06 taper; VDW, Munich, Germany]. Before and after root canal preparation of the MB2 canal, the teeth were scanned using a Micro‐CT to evaluate canal transportation, centering ability, dentine thickness and volume change. The working time to achieve working length was also evaluated. All parameters were compared statistically using the Kruskal‐Wallis and Dunn test for multiple comparisons, with a significance level of 5%.
Results
There was no significant difference among the groups regarding canal transportation and centering ability (P>0.05). However, the PDR size 25, .06 taper group had significantly lower canal volume and volume of dentine removal compared with a MO size 25, .06 taper and REC size 25, .06 taper (P<0.05). A root perforation was detected in MO size 25, .06 taper and REC size 25, .06 taper groups, respectively. Regarding the working time, the PDR size 25, .06 taper required a significantly longer time to achieve working length than MO size 25, .06 taper and REC size 25, .08 taper (P<0.05).
Conclusions
All NiTi systems had similar canal transportation, centering ability and increase of apical volume after preparation of MB2 canals. However, the PDR size 25, .06 taper had less volume of dentine removal, absence of root canal perforation and required a longer time to accomplish the root canal preparation.
This article is protected by copyright. All rights reserved.
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Photodynamic therapy in endodontics
Abstract
Photodynamic therapy (PDT) is a treatment modality that was initiated in 1900; however, it was not until the last decade that PDT regained attention again for its several favourable features during the treatment of microbial infections in Endodontics. Recently, several papers advocated its use for root canal treatment. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components and consequently produce cell inactivation and death.
Recently, PDT was suggested as a promising effective adjunct to standard antimicrobial intracanal cleaning and shaping for clinical treatment of periapical lesions. Current publications tested PDT in terms of bacterial load reduction in vivo, in vitro and ex vivo, showing promising results.
The purpose of this article is to review the existing literature on PDT in the endodontic field regarding its mechanism of action, photosensitizers and light sources, limitations and clinical procedures. Although positive results have been demonstrated in vitro, there are considerably fewer in vivo investigations. In conclusion, more in vivo studies are needed on the use of antimicrobial PDT in root canal treatment.
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Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis
Abstract
Aim
To assess the connection between mitophagy and hypoxia‐induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of mitophagy‐related apoptosis.
Methodology
Hypoxia‐induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated respectively by MitoSOX and JC‐1 fluorescence dye signaling. Accumulation of mitophagy markers PTEN‐induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved‐poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. ANOVA, Fisher's and Student's t test were used to for data analysis.
Results
Hypoxia induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia‐augmented apoptotic activity. Simvastatin alleviated hypoxia‐induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its anti‐mitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts.
Conclusions
The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.
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Digital pathology is a practical alternative to on‐site intra‐operative frozen section diagnosis in thoracic surgery
Abstract
Introduction
Telepathology uses digitised image transfer to allow off‐site reporting of histopathology slides. This technology could facilitate the centralisation of pathology services, which may improve their quality and cost‐effectiveness. The benefits may be most apparent in frozen section reporting, where turnaround times are vital. We moved from onsite to offsite telepathology reporting of thoracic surgery frozen section specimens in 2016. This study compares turnaround times (TAT) before and after this service change.
Method
All thoracic frozen section specimens analysed 4 months prior and 4 months following the service change were included. Demographics, operation, sample type, time taken from theatre, time received by lab, time reported by lab, TAT, frozen section diagnosis, final histopathological diagnosis, and final TNM staging were recorded. Results were analysed using SPSS statistical software version 24.
Results
In total there were 65 samples from 59 patients; 34 before, and 31 after the change. Specimens included 51 lung, 6 lymph node, 3 bronchial, 3 chest wall, and 2 pleural biopsies.
Before the change, the median TAT was 25 (IQR 20‐33) minutes. No diagnoses were deferred. No diagnoses were changed on subsequent paraffin analysis.
After the change, using digital pathology, the median TAT was 27.5 (IQR 21.75‐38.5) minutes. This difference was not significant (p=0.581). Diagnosis was deferred in one case (3.23%). There was one (3.23%) mid‐case technical failure where the sample had to be transported by courier, resulting in a TAT of 106 mins. No diagnoses were changed on subsequent paraffin analysis.
Conclusion
There was no significant difference in reporting times using digital technology compared with an on‐site service, although one sample was affected by a technical failure requiring physical transportation of the specimen for analysis. Our study was underpowered to detect differences in accuracy.
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The Australian Trauma Registry
Introduction
Injuries are a major cause of disability and lost productivity. The case for a national trauma registry has been recognized by the Australian Commission on Safety and Quality in Health Care and at a policy level.
Background
The need was flagged in 1993 by the Royal Australasian College of Surgeons and the Australasian Trauma Society. In 2003, the Centre of National Research and Disability funded the Australian and New Zealand National Trauma Registry Consortium, which produced three consecutive annual reports. The bi‐national trauma minimum dataset was also developed during this time. Operations were suspended thereafter.
Method
In response to sustained lobbying the Australian Trauma Quality Improvement Program including the Australian Trauma Registry (ATR) commenced in 2012, with data collection from 26 major trauma centres. An inaugural report was released in late 2014.
Result
The Federal Government provided funding in December 2016 enabling the work of the ATR to continue. Data are currently being collected for cases that meet inclusion criteria with dates of injury in the 2017–2018 financial year. Since implementation, the number of submitted records has been increased from fewer than 7000 per year to over 8000 as completeness has improved. Four reports have been released and are available to stakeholders.
Conclusion
The commitment shown by the College, other organizations and individuals to the vision of a national trauma registry has been consistent since 1993. The ATR is now well placed to improve the care of injured people.
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Buccal bone thickness at dental implants in the maxillary anterior region with large bony defects at time of immediate implant placement: A 1‐year cohort study
Abstract
Background
There is lack of studies regarding preservation and possible changes in BBT at dental implants.
Purpose
To assess, on cone beam computer tomograms, the presence of bone at the time of tooth extraction in the maxillary esthetic region and the mean buccal bone thickness 1 month and 1 year after final restoration placement in patients with large bony defects.
Material and Methods
In a cohort study, patients were selected presenting a failing tooth with a large bony defect (test group [n = 20]: large bony defect, immediate placed implant and delayed provisionalization). Results were compared with a group in which patients presented a failing tooth without or with a small bony defect: (control group [n = 20]: without or small bony defect, immediate placed implant and delayed provisionalization). Cone beam computer tomograms were made preoperatively, and 1 month and 1 year after placement of the restoration, and buccal bone thickness was analyzed.
Results
In both groups approximately 1 mm of buccal bone thickness was present after 1 month and 1 year, without a significant difference between the groups.
Conclusion
In patients with large bony defects at a failing tooth it was possible to create a bone layer buccally of the implant and this bone layer remained stable during a 1‐year follow‐up; there were no significant differences between thickness of buccal bone at 1 month and 1 year in patients with large buccal bony defects and patients without or with small bony defects.
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Cyclosporine levels > 195 μg/L on day 10 post-transplant was associated with significantly reduced acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation
Abstract
Acute graft-versus-host disease (aGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prophylaxis with cyclosporine A (CsA) is the backbone of GvHD prevention. In a retrospective analysis of patients treated with allo-HSCT, we correlated CsA levels on the day of transplantation (day 0) and on day + 10 with the incidence of acute and chronic GvHD. We assessed 660 patients with either AML n = 248, lymphoma/myeloma n = 127, MDS/MPN n = 124, ALL n = 79, CLL n = 36, CML n = 23, or bone marrow failure n = 22. In patients with clinically relevant aGvHD grade ≥ 2, mean CsA levels was lower on day 0 and day + 10 (142 ± 88 μg/L and 183 ± 64 μg/L, respectively) compared to patients without aGvHD (156 ± 81 μg/L and 207 ± 67 μg/L, respectively; day 0: p = 0.003; day + 10: p = 7.57 × 10−9). In patients with CsA level < 200 μg/L, the incidence of aGvHD was significantly more frequent compared to patients with CsA levels > 200 μg/L [(234/356 (66%) versus 91/248 (37%); p = 1.34 × 10−12]. In patients with cGvHD, there was no significant difference between CsA levels < 200 μg/L (128/330) compared to CsA levels > 200 μg/L (96/233; p = 0.312). The optimal CsA cutoff level for the prevention (i.e., roughly 50% incidence reduction) of aGvHD was > 201 μg/L at day 0 and > 195 μg/L at day + 10. In a competing risk analysis, time to aGvHD grade ≥ 2 (using death of other causes as competing risk) was associated with CsA levels > 200 μg/L on day 0 and on day 10, unrelated donors, myeloablative conditioning (MAC), and for the diagnosis lymphoma/myeloma. Our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels above 195 μg/L in the first 10 days of allo-HCST to reduce aGvHD.
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Influence of the storage conditions (frozen vs dried) in health‐related lipid indexes and antioxidants of bee pollen
Abstract
Following harvest, bee pollen must be submitted to processing in order to maintain properties for consumers' health insurance. In this study it were evaluated the changes on the lipid profile, contents of vitamin C, β‐carotene and lycopene of bee pollen samples submitted to two conservation methods (freezing and drying).
It were quantified 11 fatty acids, eight saturated, one monounsaturated and two polyunsaturated. The PUFA/SFA ratio ranged from 1.18 to 3.95 g 100−1g−1 and was significantly higher in the frozen extracts. On the other hand, the ratio n6:n3 (ranging between 0.36 and 0.86 g 100−1g−1) did not differ among processing methodologies, for most of the cases.
The atherogenicity (AI) and thrombogenecity (TI) indexes were similar among preservation processes and coherent with the found on other health‐promoting foods. The contents of vitamin C, β‐carotene and lycopene were, for all samples, significantly superior in the frozen bee pollen.
Practical applications: In the recent years the interest in natural products has mushroomed. Indeed, in addition to the good nutritional composition bee pollen possesses important bioactive compounds and promising health promoting activities that remain unstudied. In this study it was evaluated the influence of the geographical origin and two storage methods (drying and freezing) in the fatty‐acid profile, lycopene, vitamin C and β‐carotene contents and on two lipid indexes of bee pollen. Results suggested that bee pollen may act as a complement for the prevention of atherosclerosis and thrombogenesis. Regarding storage it was inferred that freezing allows preserving the bioactive compounds in a greater extent and, therefore, must be the preferred method. Further studies may be performed in order to take advantage of this natural products' potential.
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Phenoxy‐alkyl maleates as phase‐selective organogelators for gelation of edible oils
Abstract
Phase selective gelation may solve environmental problems such as water pollution and fire accidents during oil storage, a major problem for aquatic bodies. The objective of this work was to synthesize a series of phenoxy‐alkyl maleates (n‐PAM) oleogelators with homologous alkyl chain lengths for efficient phase selective gelation. The n‐PAM molecules have been found to form oleogel in various edible oils among which sunflower oil shows best gelation. The gelation behavior increases with increase in alkyl chain length of the n‐PAM gelators as observed from their low minimum gelation concentration (MGC) values. Oleogels thermal stability was examine through tube inversion method and differential scanning calorimetry (DSC). The rheological studies suggest that the oleogel of sunflower oil is mechanically stable and show typical viscoelastic properties. The field emission scanning electron microscopy (FE‐SEM) study of the gels showed sheet‐like morphology. Furthermore, the n‐PAM gelators exhibited quick phase selective gelation of edible oils at low MGC. Both the edible oil and gelator were quantitatively regained from recovered oleogel by employing the vacuum distillation. We believe that these n‐PAMs could aid in reducing the environmental impacts of oil spills.
Practical Applications: The phenoxy‐alkyl maleates gelators present in the MS show gelation ability in various edible oils at low minimum gelation concentration. These molecules also form efficient phase selective gelation with edible oils. Both oil and gelator can be recovered through vacuum distillation and gelator can be reused multiple times. Thus, all these advantages strongly point out their bright future in particular in edible oil spill recovery, could aid in reducing the environmental impacts from oil spills.
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T‐705‐modified ssRNA in complex with Lassa Virus Nucleoprotein exhibits nucleotide splaying and increased water influx into the RNA‐binding pocket
‐705‐modified ssRNA is associated with out‐of‐plane spaying of the modified bases within the RNA resulting in loss of base‐stacking interaction
T‐705‐modified ssRNA bound to Lassa virus nucleoprotein ssRNA binding pocket promotes the influx of water into the ssRNA binding pocket with resultant loss of electrostatic potentials of the amino acids lining the pocket
T‐705‐modified ssRNA bound to Lassa virus nucleoprotein ssRNA binding pocket alters essential dynamics of the protein
Abstract
Lassa virus infection is clinically characterized by multi‐organ failure in humans. Without an FDA‐approved vaccine, ribavirin is the frontline drug for treatment but with attendant toxicities. 6‐fluoro‐3‐hydroxy‐2‐pyrazinecarboxamide (T‐705) is an emerging alternative drug with proven anti‐Lassa virus activity in experimental model. One of the mechanisms of action is its incorporation into nascent single strand RNA (ssRNA) which forms complex with Lassa nucleoprotein (LASV‐NP). Here, using Molecular Dynamics simulation, the structural and electrostatics changes associated with LASV‐NP‐ ssRNA complex has been studied when none, one or four of its bases has been substituted with T‐705. The results demonstrated that glycosidic torsion angle χ (O4′‐C1′‐N1‐C2) rotated from high‐anti‐ (‐110° and ‐60°) to the syn‐ conformation (+30) in with increased T‐705 substitution. Similarly, increased T‐705 substitution resulted in increased splaying (55°‐70°), loss of ssRNA‐LASV‐NP H‐bond interaction, increased water influx into the ssRNA binding pocket and decreased electrostatic potentials of ssRNA pocket. Furthermore, strong positively correlated motion observed between α6 residues (aa: 128–145) and its contact ssRNA bases (5‐7) is weakened in apo biosystem and transitioned into anti‐correlated motions in ssRNA‐bound LASV‐NP biosystem. Finally, LASV genome may become more accessible to cellular ribonuclease access with T‐705 incorporation due to loss of NP interaction.
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Clinical significance of the mutational landscape and fragmentation of circulating‐tumor DNA in renal cell carcinoma
Summary
Reliable biomarkers for renal cell carcinoma (RCC) have yet to be found. Circulating‐tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. This study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed as clear cell RCC were enrolled. Targeted sequencing was performed using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. The association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n=6) and VHL (n=5), and median mutant allele frequency of ctDNA was 10%. We designed specific droplet digital PCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P=0.033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P<0.001, P=0.011). In conclusion, our study demonstrates the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.
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Programmed death ligand‐1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder
Tumoral and stromal PD‐L1 expression was associated with poorer OS and RFS in UCB. High stromal CD8+ TIL density had an unappreciated poor prognosis and was associated with high PD‐L1 expression, indicating an adaptive immune resistance mechanism.
Drugs blocking programmed death ligand‐1 (PD‐L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD‐L1 with tumor‐infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD‐L1 expression and stromal CD8+ TIL, Th1 orientation T cell (T‐bet+) and PD‐1+ TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD‐L1 expression in tumor cells and 55% in tumor‐infiltrating immune cells. CD8+ TIL, T‐bet+ TIL and PD‐1+ TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD‐L1+ tumor cells and PD‐L1+ immune cells were positively associated with aggressive clinical features (all P < .05). Both PD‐L1+ tumor cells and PD‐L1+ immune cells were associated with poorer recurrence‐free and overall survival (all P < .05). Multivariate analysis showed that PD‐L1+ immune cells were an independent prognostic factor for overall (P = .001) and recurrence‐free survival (P = .024). Notably, high stromal CD8+ TIL and PD‐1+ TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8+ TIL density has strong positive association with PD‐L1+ immune cells and PD‐1+ TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune‐checkpoint inhibitors may be effective for resectable patients with UCB.
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B7‐H5/CD28H is a co‐stimulatory pathway and correlates with improved prognosis in pancreatic ductal adenocarcinoma
Abstract
B7‐H5 and its cognate receptor CD28H, are T lymphocyte second signaling transduction molecules. Here we aim to explore the function of this pathway in pancreatic cancer in vitro and in vivo, and evaluated the clinical significance in 136 patients with pancreatic ductal adenocarcinoma enrolled from January 2012 to February 2017 in our hospital. Surgical tumor specimens were collected for immunohistochemical staining to evaluate B7‐H5 expression. Patients' baseline characteristics including gender, age, tumor size, tumor location, tumor grading, clinical TNM staging, tumor infiltrating lymphocytes, CA19‐9 and chemotherapy treatment, along with the subsequent follow‐up data, were documented and analyzed. When co‐cultured with T cells, pancreatic cancer PC cells with high B7‐H5 expression induced a more potent immune reaction indicated by elevated cytokine release and increased proliferation of T lymphocytes compared with cells exhibiting low B7‐H5 expression. Xenograft pancreatic tumors derived from high B7‐H5 expression PC cells exhibited attenuated growth compared to tumors from low B7‐H5 expression cells after transfusion with T lymphocytes in immune‐deficient mice. Of the 136 PDAC tumor tissues, 93 (68.38%) were strong and 43 (31.62%) were weak B7‐H5 expression. Patients with strong B7‐H5 expression had significantly longer overall survival than those of weak expression (median: 16.5 vs 11.5 months, P=0.017). TNM staging, tumor location and subsequent chemotherapy were also prognostic factors in these patients. Collectively, B7‐H5/CD28H is a co‐stimulatory signal pathway, and expression of B7‐H5 is associated with improved disease prognosis in patients with pancreatic cancer.
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Histopathological analysis of papillary thyroid carcinoma detected during ultrasound screening examinations in Fukushima
Abstract
Thyroid ultrasound screening of young residents in Fukushima prefecture of Japan demonstrated high detection rate of papillary thyroid carcinoma (PTC). Detailed morphological analysis of these tumors was not presented to date. This study sets out to evaluate changes in histopathological and invasive characteristics of Fukushima PTC with time after the nuclear accident of March 2011 in all available cases and in different age subgroups. Histological specimens of 115 PTCs from patients aged ≤ 18 years at the time of Fukushima Dai‐ichi Nuclear Power Plant accident operated at Fukushima Medical University during 2012‐2016 were reviewed. Patients were divided into those treated during the first 4 years after the accident (n=78, shorter‐onset) or later (n=37, longer‐onset). The whole group and three age subgroups: children (aged < 15 years), adolescents (aged from 15 to < 19 years), and young adults (aged from 19 years) at surgery were analyzed. No statistically significant time‐related changes in tumor structure and invasiveness were found in the whole group or in age‐matched subgroups. Statistically significant age‐related downtrend was observed for intrathyroid spread in the whole group of patients. The absence of temporal changes in tumor morphological characteristics and tumor invasiveness strongly suggests common etiology of the shorter‐ and longer‐onset Fukushima PTCs, which are unlikely related to the effect of exposure to very low doses of radiation.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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