Clear Cell Carcinomas of Müllerian origin are extremely rare within the upper urinary system. Their morphology is identical to that of the Clear Cell Carcinomas of the female genital tract. When they arise in the urinary tract, it is thought to be due to ectopic Müllerian embryogenesis. Here, we present a case of a 21-year-old woman with a Clear Cell Carcinoma, Müllerian type, arising from the renal pelvis. Histologically, it consisted of tubulopapillary architecture with associated foamy macrophages and a mucinous background. The neoplastic cells exhibited variably sized round nuclei with prominent nucleoli, eosinophilic to vacuolated cytoplasm with occasional intracytoplasmic mucin vacuoles, and a hobnail appearance. Immunohistochemical stains showed that the neoplastic cells were positive for Pax-8, p53, CK7, HMWK 903, and INI-1 and focally positive for p504s (AMACR). The neoplastic cells were negative for GATA-3, CK5/CK6, p63, CK20, and CDX-2 immunostains, ruling out urothelial or enteric phenotype. Additional immunostains performed by an outside institution showed that the neoplastic cells were positive for HNF-1β. The overall morphology and immunophenotype were consistent with Clear Cell Carcinoma of Müllerian origin arising from the renal pelvis. Follow-up revealed no metastasis or other tumor sites, supporting that this was the primary location.
https://ift.tt/2IiReb0
Σάββατο 31 Μαρτίου 2018
A Rare Case of Clear Cell Carcinoma, Müllerian Type in the Renal Pelvis of a 21-Year-Old Woman
Brief Clinical Report: Hypophosphatasia—Diagnostic Considerations and Treatment Outcomes in an Infant
Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder characterized by low serum alkaline phosphatase activity and impaired bone mineralization. Clinical manifestations and severity of symptoms vary widely in HPP, ranging from in utero death to isolated dental manifestations in adults. Treatment with enzyme replacement therapy has been reported to improve outcomes in perinatal, infantile, and childhood forms of HPP. Here, we present a case of a boy with poor linear growth, mild limb bowing, and radiographic rickets who was diagnosed with HPP before 6 months of age. Treatment with enzyme replacement therapy was initiated at 7 months of age, after which significant improvements in radiographic findings and linear growth were demonstrated. This case highlights several important challenges in the diagnosis, classification, and management of HPP.
https://ift.tt/2GDJGCD
A Rare Case of Lemierre-Like Syndrome: A Case Report and Literature Review
Lemierre's syndrome (LS) is a serious rare complication of oropharyngeal infections. It is characterized by thrombosis of internal jugular vein that rapidly progresses into sepsis and is typically caused by anaerobes. Most of the reported cases have been linked to Fusobacterium necrophorum; however, there are a handful of reported cases due to aerobes. It is primarily the disease of healthy young adults and can present in school-aged children. The early recognition and treatment of this complication results in resolution of the illness; nevertheless, there have been some concerns about chronic venous insufficiency as a long-term complication. We report a case of a 6-year-old boy, who presented with fever and headache with a history of sore throat. His blood culture was positive for group A Streptococcus (GAS) and was subsequently found to have internal jugular vein, sigmoid, and transverse sinus vein thrombosis.
https://ift.tt/2uDRGP6
Infectious Aortitis: A Life-Threatening Endovascular Complication of Nontyphoidal Salmonella Bacteremia
A 65-year-old Japanese man living in the United States presented with pyrexia and chills associated with intermittent lower abdominal and back pain for 5 days. He denied recent travel, rash, diarrhea, or rectal bleeding. Physical examination revealed spiking pyrexia, and routine laboratory tests revealed mild leukocytosis and neutrophilia. Abdominal CT with contrast showed findings highly compatible with aortitis. Comprehensive autoimmune evaluation was negative. Salmonella enterica serotype Enteritidis was isolated from blood cultures. IV antibiotics were administered, but the patient continued to experience low-grade pyrexia and mild leukocytosis, and follow-up abdominal CT showed progressive aortic inflammation. The patient therefore underwent resection of the affected aortic segment with in-situ graft replacement and lifelong suppressive antibiotics. The patient is asymptomatic with no complications at 18 weeks of follow-up. This case report illustrates that patients with infectious aortitis from nontyphoidal Salmonella may (1) present with nonspecific and nonlocalizing symptoms and signs except for sepsis; (2) have diagnostic blood cultures and abdominal CT findings; and (3) typically require aggressive, prolonged IV antibiotic therapy and surgery for potential cure of this life-threatening infection.
https://ift.tt/2J939cF
A Large Grade 5 Mobile Aortic Arch Atheromatous Plaque: Cause of Cerebrovascular Accident
Aortic atheromas (aortic atheromatous plaques) are defined by an irregular thickening of the intima ≥2 mm, and a complex plaque is defined as a protruding atheroma ≥4 mm with or without an attached mobile component. Stroke incidence is approximately 25% in patients with mobile plaques of the aortic arch and 2% in patients with quiescent nonmobile plaques. Antiplatelet agents, oral anticoagulants, and statins have been suggested in the management of atheromas. We present an 80-year-old male, with non-ST-segment elevation myocardial infarction (NSTEMI) and chronic dysarthria, found to have an acute cerebrovascular accident (CVA) secondary to embolism from a large 12 mm aortic arch plaque, treated medically with oral antiplatelet therapy, anticoagulation, and statin therapy.
https://ift.tt/2E91lNd
Uncommon Infections in Children Suggest Underlying Immunodeficiency: A Case of Infective Endocarditis in a 3-Year-Old Male
Infective endocarditis (IE) results from bacterial or fungal infection and is associated with significant morbidity and mortality. Several known risk factors exist for endocarditis, and 90% of pediatric cases have an underlying structural or congenital heart disease or prosthetic heart valve. Literature on IE in previously healthy children is relatively sparse, and the pathogenesis and underlying risk factors remain mostly unknown. Our patient was a 3-year-old male with a unique presentation of IE. His lack of structural and congenital risk factors for endocarditis prompted further workup, and labs were consistent with insufficient immunoglobulin, suggesting a primary immunodeficiency (PAD). PAD presents as heightened susceptibility to infections, commonly seen as recurrent pneumonia, meningitis, septic arthritis, and otitis media. Pediatric patients commonly have infections, yet as many as in 1 in 2000 patients have PAD. Our case emphasizes the potential need for further investigation into PAD in a young patient with no known risk factors who develops an uncommon infection such as IE.
https://ift.tt/2pVnERj
Multiple roles of lymphatic vessels in tumor progression
Qiaoli Ma | Lothar C Dieterich | Michael Detmar
https://ift.tt/2pTZNlS
Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering
May Daher | Katayoun Rezvani
https://ift.tt/2GspGzm
Synthesis and Pharmacological Valorization of Derivatives of 4-Phenyl-1,5-Benzodiazepin-2-One
The objective of our work is to make a pharmacological study of molecules derived from 4-phenyl-1,5-benzodiazepin-2-one carrying long chains so that they have a structure similar to surfactants, with the benzodiazepine as a hydrophilic head and a carbon chain as a hydrophobic tail. First, we studied the acute toxicity of the above mentioned 4-phenyl-1,5-benzodiazepin-2-one derivatives. This study was conducted according to OECD 423 guidelines in female mice and revealed that these compounds are nontoxic. We then assessed the psychotropic effects of our products on the central nervous system (CNS). The results obtained show that 4-phenyl-1,5-benzodiazepin-2-one has no sedative effect at therapeutic doses of 100 and 200 mg/kg. On the other hand, its long-chain derivatives possess them. Moreover, all these products have no cataleptic and hypnotic effects at the doses studied. But at 100 mg/kg, these compounds all have the ability to significantly prolong the hypnotic effect of thiopental sodium.
https://ift.tt/2GrA6mY
Soluble CD163 as a Potential Biomarker in Systemic Sclerosis
Objective. To evaluate the performance of serum and urinary sCD163 concentrations as possible biomarker in systemic sclerosis (SSc). Methods. Urine and serum samples were obtained from SSc patients and age- and sex-matched controls. Serum and urinary sCD163 concentrations were measured by commercially available ELISA kit. SSc patients were assessed following international guidelines. Cross-sectional analyses were performed. Results. Two hundred and three SSc patients were included. The control group consisted of 47 age- and sex-matched patients having noninflammatory diseases, mainly osteoporosis. Serum sCD163 levels were significantly higher in SSc patients compared with controls (mean ± SD: 529 ± 251 versus 385 ± 153 ng/mL; ). Urinary sCD163 concentrations were higher in SSc patients than controls, but this did not reach significance (236 ± 498 versus 176 ± 173 ng/mg uCr; ). The sCD163 concentrations were not associated with clinical, laboratory, and instrumental characteristics of SSc patients. Conclusion. To our knowledge, this is the first evaluation of both serum and urinary sCD163 levels in SSc. Our results show a significant difference for sera values that should be prioritized for further studies as compared to urinary measurements. Our results further support that the M2 macrophages/CD163 signaling system may play a role in the pathogenesis of SSc, although we could not identify a subset of SSc patients with higher concentrations.
https://ift.tt/2IltG5n
Non-ST Elevation Myocardial Infarction and Severe Peripheral Artery Disease in a 20-Year-Old with Perinatally Acquired Human Immunodeficiency Virus Infection
Human immunodeficiency virus (HIV) infection confers an increased risk of cardiovascular disease, including acute coronary syndrome (ACS). Patients with perinatally acquired HIV may be at increased risk due to the viral infection itself and exposure to HAART in utero or as part of treatment. A 20-year-old female with transplacentally acquired HIV infection presented with symptoms of transient aphasia, headache, palpitations, and blurry vision. She was admitted for hypertensive emergency with blood pressure 203/100 mmHg. Within a few hours, she complained of typical chest pain, and ECG showed marked ST depression. Troponin I levels escalated from 0.115 to 10.8. She underwent coronary angiogram showing 95% stenosis of the right coronary artery (RCA) and severe peripheral arterial disease including total occlusion of both common iliacs and 95% infrarenal aortic stenosis with collateral circulation. She underwent successful percutaneous intervention with a drug-eluting stent to the mid-RCA. Patients with HIV are at increased risk for cardiovascular disease. Of these, coronary artery disease is one of the most critical complications of HIV. Perinatally acquired HIV infection can be a high-risk factor for cardiovascular disease. A high degree of suspicion is warranted in such patients, especially if they are noncompliant to their ART.
https://ift.tt/2JarSNB
Myelitis due to Coccidioidomycosis in an Immunocompetent Patient
Myelitis of the spinal cord is an uncommon presentation of disseminated coccidioidomycosis. Most infected patients present subclinically, but patients, especially those who are immunocompromised, may progress to disseminated disease. We present a 50-year-old immunocompetent patient with no significant past medical history exhibiting symptoms of altered mental status, dizziness, headache, nausea, and quadriplegia. Upon investigation with lumbar puncture, cerebrospinal fluid (CSF) culture, and coccidioidal antibody studies, the patient was found to have acute coccidioidomycosis. Magnetic resonance imaging (MRI) of the brain demonstrated meningeal enhancements suggestive of meningitis, and further MRI study of the cervical spine revealed myelitis. Treatment with IV fluconazole for 2 weeks and IV voriconazole therapy over 3 weeks yielded limited improvement. The presentation of myelitis due to coccidioidomycosis infection is very rare and has infrequently reported in the literature. Awareness of this potentially fatal complication in immunocompetent patients can aid in faster recognition and treatment.
https://ift.tt/2pUBoMc
Acute Seronegative Toxoplasma gondii Hepatitis Allergic to First-Line Treatment
Toxoplasma gondii infects up to one-third of the world's population, making it the protozoan that most infects people worldwide. Among the forms of presentation of toxoplasmosis, hepatitis is probably the least frequent with only a few case reports in the world's medical literature. Despite the fact that the first diagnostic test is the serology using the ELISA technique because its sensitivity is close to 100% in our case, it was reported negative. The biopsy gave the definitive diagnosis, and we were able to start treatment immediately. Although the first line of treatment is sulfadiazine and pyrimethamine, our sulfate allergic patient received an alternative regimen of doxycycline, clindamycin, and azithromycin with a good response. This is the only case of Toxoplasma hepatitis reported in Mexico and the only one in the world with negative serology with a good response to second-line treatment.
https://ift.tt/2Jbov94
A Gigantic Anal Mass: Buschke–Löwenstein Tumor in a Patient with Controlled HIV Infection with Fatal Outcome
Buschke–Löwenstein tumor of anorectal and perianal area is a rare but highly aggressive tumor, frequently associated with human papillomavirus (HPV) types 6 and 11. It often grows over years in immunocompetent patients and can be highly destructive to local tissue. We present a case of a 61-year-old male with HIV infection who presented with worsening pain and swelling in the anorectal area for one-year duration. Exam revealed a 15 × 10 cm mass in the anorectal area with multiple sinuses and fistulas. MRI revealed extension of the mass through pelvic structures. Biopsy showed squamous epithelium with koilocytes and histochemistry positive for P16, suggestive of HPV infection. Biopsy was negative for malignant transformation. He was not a candidate for surgery or radiation due to extensive infiltration of deeper structures and multiple fistulas. He refused interferon therapy, and diverting colostomy was placed for palliation. He presented two months later with overwhelming sepsis and died despite maximal medical therapy.
https://ift.tt/2EaE9Oi
FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing
American Journal of Medical Genetics Part A, EarlyView.
https://ift.tt/2GrOOX9
Cost-Effectiveness Analysis Comparing Lumen Apposing Metal Stents with Plastic Stents in the Management of Pancreatic Walled-Off Necrosis
EUS-guided transmural drainage is effective in the management of pancreatic walled-off necrosis (WON). A lumen-apposing metal stent (LAMS) has recently been developed specifically for the drainage of pancreatic fluid collections showing promising results. However, no cost-effectiveness data have been published in comparison to endoscopic drainage with traditional plastic stents (PSs). The aim is to compare the cost-effectiveness of LAMSs to PSs in the management of WON.
https://ift.tt/2pVpgKD
Recommendations for evaluation and management of pain in patients with mucopolysaccharidosis in Latin America
The mucopolysaccharidosis (MPS) constitute a heterogeneous group of rare genetic disorders caused by enzymatic deficiencies that lead to the accumulation of glycosaminoglycans (GAGs). Several types of MPS are described, historically numbered from I to IX. Clinical observations strongly suggest the presence of chronic pain in patients with all types of MPS. There are few data in the literature on the evaluation and management of pain in these patients, a fact which can compromise the quality of life even more.
https://ift.tt/2E9Pxdw
Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer
The occurrence of upper extremity lymphedema following regional nodal irradiation (RNI) for breast cancer treatment varies significantly based on patient and treatment factors. The relationship between radiotherapy field design and lymphedema risk is not well-characterized. This study sought to correlate variations in radiotherapy field design with lymphedema outcomes.
https://ift.tt/2uAsUiG
Evaluation of XRCC-1 Gene Polymorphism as a Biomarker in Head and Neck Cancer Patients Undergoing Chemoradiotherapy
Correlation of XRCC-1 Arg194Trp polymorphismwith outcome in HNSCC patients treated with CCRTwas evaluatedin 101 patients [wild (62), polymorphic variants (39)].Polymorphic variant had higher grade > 2 mucositis (p=0.023), laryngeal toxicity (p=0.006) and dermatitis (p=0.003).2-year PFS rate for patients with polymorphic vs. wild variant was 57% vs. 42.2% (p= 0.076).Polymorphic variant HNSCC treated with CCRT have increased acute radiation morbidities and possibly better PFS.
https://ift.tt/2GIflmq
Update: Is Needle Aspiration Better Than Chest Tube Placement for the Management of Primary Spontaneous Pneumothorax?
A total of 6 randomized controlled trials (435 patients) met inclusion criteria. Chest tube (12 to 20 French) placement had a higher immediate success rate but a longer hospital length of stay. There was no difference in 1-year success rate, hospitalization rate, or patient satisfaction. Needle aspiration had fewer adverse events. Meta-analyses were conducted only for immediate success rate and hospital length of stay (Table) because there was low or very low quality of evidence for all other outcomes.
https://ift.tt/2pSYLWc
Visualization and Quantification of Mesenchymal Cell Adipogenic Differentiation Potential with a Lineage Specific Marker
https://ift.tt/2GIU8bP
In Situ High Pressure Hydrogen Tribological Testing of Common Polymer Materials Used in the Hydrogen Delivery Infrastructure
A test methodology for quantifying tribological properties of polymers used in hydrogen infrastructure service is demonstrated and characteristic results for a common elastomer are discussed.
https://ift.tt/2J8MgP7
Nanomedicine Approaches Against Parasitic Worm Infections
Advanced Healthcare Materials, EarlyView.
https://ift.tt/2pSYofr
Optical Cross-Sectional Muscle Area Determination of Drosophila Melanogaster Adult Indirect Flight Muscles
https://ift.tt/2pVKw3V
Antenatal non-medical risk assessment and care pathways to improve pregnancy outcomes: a cluster randomised controlled trial
Abstract
Social deprivation negatively affects health outcomes but receives little attention in obstetric risk selection. We investigated whether a combination of (1) risk assessment focused on non-medical risk factors, lifestyle factors, and medical risk factors, with (2) subsequent institution of risk-specific care pathways, and (3) multidisciplinary consultation between care providers from the curative and the public health sector reduced adverse pregnancy outcomes among women in selected urban areas in the Netherlands. We conducted a cluster randomised controlled trial in 14 urban municipalities across the Netherlands. Prior to the randomisation, municipalities were ranked and paired according to their expected proportion of pregnant women at risk for adverse outcomes at birth. The primary outcome was delivery of a preterm and/or small for gestational age (SGA) baby, analysed with multilevel mixed-effects logistic regression analysis adjusting for clustering and individual baseline characteristics. A total of 33 community midwife practices and nine hospitals participated throughout the study. Data from 4302 participants was included in the Intention To Treat (ITT) analysis. The intervention had no demonstrable impact on the primary outcome: adjusted odds ratio (aOR) 1.17 (95% CI 0.84–1.63). Among the secondary outcomes, the intervention improved the detection of threatening preterm delivery and fetal growth restriction during pregnancy [aOR 1.27 (95% CI 1.01–1.61)]. Implementation of additional non-medical risk assessment and preventive strategies into general practices is feasible but did not decrease the incidence of preterm and/or SGA birth in the index pregnancy in deprived urban areas.
Trial registration Netherlands National Trial Register (NTR-3367).
https://ift.tt/2GXX4Pq
Response: Comparing the dosages of lacosamide, eslicarbazepine acetate, and controlled‐release carbamazepine in noninferiority epilepsy monotherapy trials: How much “fair” is “fair”
Epilepsia, Volume 59, Issue 4, Page 900-901, April 2018.
https://ift.tt/2Ijb7yN
Common data elements for epilepsy mobile health systems
Epilepsia, EarlyView.
https://ift.tt/2IkETmF
Comparing the dosages of lacosamide, eslicarbazepine acetate, and controlled‐release carbamazepine in noninferiority epilepsy monotherapy trials: How much “fair” is “fair”?
Epilepsia, Volume 59, Issue 4, Page 899-900, April 2018.
https://ift.tt/2pT0I5T
Issue Information–ISSN page
Epilepsia, Volume 59, Issue 4, Page i-vii, April 2018.
https://ift.tt/2pST5wk
Epilepsia – April 2018 – Announcements
Epilepsia, Volume 59, Issue 4, Page 901-904, April 2018.
https://ift.tt/2GrvEk0
International conference and workshop “Hallmarks of Epileptic Brain Activity” in Tbilisi, Georgia, October 24‐27, 2017
Epilepsia, Volume 59, Issue 4, Page 897-898, April 2018.
https://ift.tt/2pSQpyL
Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner
Abstract
Purpose
At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive.
Methods
In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC.
Results
Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment.
Conclusions
In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.
https://ift.tt/2uzYn4H
Hypothesis-free screening of large administrative databases for unsuspected drug-outcome associations
Abstract
Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995–2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug–drug sequences and all drug–disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug–drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug–disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals.
https://ift.tt/2J9CL2k
Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
https://ift.tt/2pYofmf
Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
https://ift.tt/2pYofmf
Bone inflammation and chronic recurrent multifocal osteomyelitis
Chronic recurrent multifocal osteomyelitis (CRMO) is a sporadic condition of inflammatory bone pain that occurs as recurrent flares because of osteomyelitis, which presents in the form of multiple aseptic foci. The estimated prevalence of CRMO is 1-2 per million, affecting mostly children, in the age group of 2 to 17. Main symptoms of CRMO are bone inflammation and pain, which are generally worse at night. Other symptoms seen on radiographs indicate osteolytic lesions surrounded by sclerosis, at later stages of the disease. Markers of inflammation, viz. tumor necrosis factor a and C-reactive protein are elevated in many cases. Because of similar symptoms, differential diagnosis is needed to confirm CRMO from infectious osteomyelitis, bone tumors, and other diseases. The genetic component is likely in some cases such as Majeed syndrome, deficiency of IL-1 antagonist, etc. Imaging is the essential part of diagnosing CRMO, and magnetic resonance imaging of the whole body is the most widely used and recommended method for the evaluation of multiple foci, as compared to radiography for reasons of sensitivity as well as prevention of excessive exposure of affected children to radiation. CRMO is considered an autoimmune and auto-inflammatory disorder, but its precise pathophysiology is not clear. Current treatment options are non-steroid anti-inflammatory drugs like naproxen, as the primary choice, and the bisphosphonates such as pamidronate as the second choice, to counter the symptoms and to reduce bone lesions. The surgical option is the choice for recalcitrant cases, even though recurrence may still be a problem.
L'articolo Bone inflammation and chronic recurrent multifocal osteomyelitis sembra essere il primo su European Review.
https://ift.tt/2pUuVRl
UCA1 impacts progress of rheumatoid arthritis by inducing the apoptosis of fibroblast-like synoviocyte
OBJECTIVE: Rheumatoid arthritis is a chronic autoimmune joint disease, which is characterized by the proliferation of fibroblast-like synoviocyte. Long non-coding RNA (lncRNA) has been reported to play an important role in the progression of many different diseases. The main objective of this research was to find out whether the lncRNAs influence the activity of fibroblast-like synoviocyte and the progression of this disease.
PATIENTS AND METHODS: qRT-PCR was used to detect the expression of UCA1 in fibroblast-like synoviocyte from normal people and rheumatoid arthritis patients. MTT assay was used to detect the viability of cells. Apoptosis was detected by Caspase-3 Colorimetric Activity Assay Kit (Millipore, Billerica, MA, USA). Western blot was used to analyze the relationship of UCA1 and apoptosis.
RESULTS: We found that the UCA1 was highly expressed in the normal fibroblast-like synoviocyte (NFLS), compared with the fibroblast-like synoviocyte of rheumatoid arthritis (RAFLS). We also found that the decrease in UCA1 expression increased the viability in NFLS and overexpressed UCA1 level in RAFLS decreased the viability. Caspase-3 was highly expressed in cells with higher viability. What's more, UCA1 could affect the viability of FLS by changing the expression of Wnt6.
CONCLUSIONS: According to the results, we found that UCA1 was closely related to rheumatoid arthritis, which could be a potential target for treating it.
L'articolo UCA1 impacts progress of rheumatoid arthritis by inducing the apoptosis of fibroblast-like synoviocyte sembra essere il primo su European Review.
https://ift.tt/2J8TsLt
Monthly News Roundup - March 2018
FDA OKs First-In-Class HIV Drug Trogarzo for Drug Resistant HIV The FDA has approved a novel HIV agent for patients who have multidrug-resistant HIV (MDR HIV-1) and have failed other therapies. Trogarzo (ibalizumab-uiyk) from TaiMed Biologics is...
https://ift.tt/2pX1Ww2
Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.
| Related Articles |
Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.
Front Immunol. 2018;9:394
Authors: Versteven M, Van den Bergh JMJ, Marcq E, Smits ELJ, Van Tendeloo VFI, Hobo W, Lion E
Abstract
Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies.
PMID: 29599770 [PubMed]
https://ift.tt/2GnBzq9
WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study.
| Related Articles |
WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study.
Anticancer Res. 2018 04;38(4):2217-2225
Authors: Yanagisawa R, Koizumi T, Koya T, Sano K, Koido S, Nagai K, Kobayashi M, Okamoto M, Sugiyama H, Shimodaira S
Abstract
BACKGROUND/AIM: Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer.
PATIENTS AND METHODS: Eight patients with resectable pancreatic cancer undergoing surgery either combined with S-1 or S-1 plus gemcitabine therapy were enrolled. Immunohistochemical analysis of WT1 was performed in 34 cases of pancreatic cancer.
RESULTS: No serious side-effects were observed, except grade I fever in five and grade I reactions at the injection site in all patients. WT1-specific cytotoxic T-lymphocytes were detected in seven patients, and WT1 and human leukocyte antigen class I antigens were positive in all 34 cases.
CONCLUSION: Our study clarified the safety and potential acquisition of immunity after vaccination targeting WT1. Further efficacy of WT1-DC vaccine to improve prognosis would be determined by a prospective clinical trial for resectable pancreatic cancer.
PMID: 29599342 [PubMed - in process]
https://ift.tt/2GqCxlE
Effect of personalised citizen assistance for social participation (APIC) on older adults health and social participation: study protocol for a pragmatic multicentre randomised controlled trial (RCT)
Introduction
The challenges of global ageing and the growing burden of chronic diseases require innovative interventions acting on health determinants like social participation. Many older adults do not have equitable opportunities to achieve full social participation, and interventions might underempower their personal and environmental resources and only reach a minority. To optimise current practices, the Accompagnement-citoyen Personnalisé d'Intégration Communautaire (APIC), an intervention demonstrated as being feasible and having positive impacts, needs further evaluation.
Methods and analysisA pragmatic multicentre, prospective, two-armed, randomised controlled trial will evaluate: (1) the short-term and long-term effects of the APIC on older adults' health, social participation, life satisfaction and healthcare services utilisation and (2) its cost-effectiveness. A total of 376 participants restricted in at least one instrumental activity of daily living and living in three large cities in the province of Quebec, Canada, will be randomly assigned to the experimental or control group using a centralised computer-generated random number sequence procedure. The experimental group will receive weekly 3-hour personalised stimulation sessions given by a trained volunteer over the first 12 months. Sessions will encourage empowerment, gradual mobilisation of personal and environmental resources and community integration. The control group will receive the publicly funded universal healthcare services available to all Quebecers. Over 2 years (baseline and 12, 18 and 24 months later), self-administered questionnaires will assess physical and mental health (primary outcome; version 2 of the 36-item Short-Form Health Survey, converted to SF-6D utility scores for quality-adjusted life years), social participation (Social Participation Scale) and life satisfaction (Life Satisfaction Index-Z). Healthcare services utilisation will be recorded and costs of each intervention calculated.
Ethics and disseminationThe Research Ethics Committee of the CIUSSS Estrie – CHUS has approved the study (MP-31-2018-2424). An informed consent form will be read and signed by all study participants. Findings will be published and presented at conferences.
Trial registration numberNCT03161860; Pre-results.
https://ift.tt/2uFo43W
Body size measures and risk of venous thromboembolism: protocol for a systematic review and meta-analysis
Introduction
Obesity is significant risk factor for venous thromboembolism (VTE); however, the related mechanisms remain unclear. Previous studies have suggested that this might be related to physical factors including anthropometric measures. We intend to conduct a systematic review and meta-analysis of prospective studies to summarise the extant literature on the associations between a set of seven measures of body size and the risk of VTE.
Methods and analysisThe current systematic review will include prospective cohort studies assessing the association between seven measures of body size (height, weight, body mass index, waist and hip circumferences, waist-to-hip ratio, waist-to-height ratio) and the risk of VTE. We will conduct comprehensive searches of MEDLINE and Excerpta Medica Database (EMBASE) for articles published from inception through 31 August 2017, without any language restriction. Two investigators will independently screen, select studies and perform data extraction and risk of bias assessment, with discrepancies resolved by a third investigator. For each body size measure, study-specific relative risks will be pooled using random effects meta-analysis models. Statistical heterogeneity will be assessed using Cochran's Q statistic, H and the I2 statistics. Sources of heterogeneity will be investigated using subgroup and meta-regression analyses as deemed appropriate. Publication bias will be assessed with funnel plots supplemented by Egger's test.
Ethics and disseminationThis systematic review will use data from published literature; therefore, ethical approval is not required. We expect our findings to supplement previous epidemiological studies by providing an updated and comprehensive synthesis of the available evidence on the association between body size measures and risk of VTE in the general population. Findings will be published in peer-reviewed journal and presented at scientific meetings.
PROSPERO registration numberhttps://ift.tt/2GHsnAj
Evolution of epilepsy prevalence and incidence in a Tanzanian area endemic for onchocerciasis and the potential impact of community-directed treatment with ivermectin: a cross-sectional study and comparison over 28 years
Introduction
Worldwide, there are an estimated 50 million people affected by epilepsy. Its aetiology is manifold, and parasitic infections play an important role, specifically onchocerciasis. In onchocerciasis endemic areas, a distinctive form of epilepsy has been described as nodding syndrome, affecting children and causing nodding seizures, mental retardation and debilitating physical development. Onchocerciasis control programmes using community-directed treatment with ivermectin (CDTI) are implemented in endemic countries. This study is designed to contribute to a better understanding of the linkage between the onset of epilepsy, onchocerciasis and CDTI. Comparing the epidemiological data on epilepsy and onchocerciasis from pre-CDTI and 20 years after its introduction will allow identifying a potential impact of ivermectin on the onset of epilepsy.
Methods and analysisThe study will be conducted in the Mahenge highlands in Tanzania. Study site selection is based on an in-depth study on epilepsy in that area dating from 1989. CDTI was introduced in 1997. By a door-to-door approach, the population will be screened for epilepsy using a validated questionnaire. Suspected cases will be invited for a neurological examination for case verification. Onchocerciasis prevalence will be assessed by a rapid epidemiological assessment. As an indicator for ongoing transmission, children younger than 10 years of age will be tested for Ov16 antibodies. Ivermectin use will be assessed at household level. Epilepsy data will be analysed in comparison with the 1989 data to reveal pre-CDTI and post-CDTI prevalence and incidence.
Ethics and disseminationThe protocol has received ethical approval from the ethics committees of the University of Antwerp, Belgium, and of the National Institut of Medical Research, Dar es Salaam, Tanzania. The findings will be published in peer-reviewed journals, and presented to the health authorities in Tanzania, at national, regional and village level.
https://ift.tt/2uEYHiO
Παρασκευή 30 Μαρτίου 2018
Missing Data in Trauma Registries: A Systematic Review
Publication date: Available online 30 March 2018
Source:Injury
Author(s): Gowri Shivasabesan, Biswadev Mitra, Gerard M. O'Reilly
BackgroundTrauma registries play an integral role in trauma systems but their valid use hinges on data quality. The aim of this study was to determine, among contemporary publications using trauma registry data, the level of reporting of data completeness and the methods used to deal with missing data.MethodsA systematic review was conducted of all trauma registry-based manuscripts published from 01 January 2015 to current date (17 March 2017). Studies were identified by searching MEDLINE, EMBASE, and CINAHL using relevant subject headings and keywords. Included manuscripts were evaluated based on previously published recommendations regarding the reporting and discussion of missing data. Manuscripts were graded on their degree of characterization of such observations. In addition, the methods used to manage missing data were examined.ResultsThere were 539 manuscripts that met inclusion criteria. Among these, 208 (38.6%) manuscripts did not mention data completeness and 88 (16.3%) mentioned missing data but did not quantify the extent. Only a handful (n = 26; 4.8%) quantified the 'missingness' of all variables. Most articles (n = 477; 88.5%) contained no details such as a comparison between patient characteristics in cohorts with and without missing data. Of the 331 articles which made at least some mention of data completeness, the method of managing missing data was unknown in 34 (10.3%). When method(s) to handle missing data were identified, 234 (78.8%) manuscripts used complete case analysis only, 18 (6.1%) used multiple imputation only and 34 (11.4%) used a combination of these.ConclusionMost manuscripts using trauma registry data did not quantify the extent of missing data for any variables and contained minimal discussion regarding missingness. Out of the studies which identified a method of managing missing data, most used complete case analysis, a method that may bias results. The lack of standardization in the reporting and management of missing data questions the validity of conclusions from research based on trauma registry data.
https://ift.tt/2GEFulR
Performance of the modified TRISS for evaluating trauma care in subpopulations: a cohort study
Publication date: Available online 30 March 2018
Source:Injury
Author(s): Leonie de Munter, Suzanne Polinder, Daan Nieboer, Koen W.W. Lansink, Ewout W. Steyerberg, Mariska A.C. de Jongh
IntroductionPrevious research showed that there is no agreement on a practically applicable model to use in the evaluation of trauma care. A modification of the Trauma and Injury Severity Score (modified TRISS) is used to evaluate trauma care in the Netherlands. The aim of this study was to evaluate the prognostic ability of the modified TRISS and to determine where this model needs improvement for better survival predictions.MethodsPatients were included if they were registered in the Brabant Trauma Registry from 2010 through 2015. Missing values were imputed according to multiple imputation. Subsets were created based on age, length of stay, type of injury and injury severity. Probability of survival was calculated with the modified TRISS. Discrimination was assessed with the Area Under the Receiver Operating Curve (AUROC). Calibration was studied graphically.ResultsThe AUROC was 0.84 (95% CI: 0.83, 0.85) for the total cohort (N = 69,747) but only 0.53 (95% CI: 0.51, 0.56) for elderly patients with hip fracture. Overall, calibration of the modified TRISS was adequate for the total cohort, with an overestimation for elderly patients and an underestimation for patients without brain injury.ConclusionsOutcome comparison conducted with TRISS-based predictions should be interpreted with care. If possible, future research should develop a simple prediction model that has accurate survival prediction in the aging overall trauma population (preferable with patients with hip fracture), with readily available predictors.
https://ift.tt/2IinNWC
Clinician tasking in ambulance control improves the identification of major trauma patients and pre-hospital critical care team tasking
Publication date: Available online 30 March 2018
Source:Injury
Author(s): Neil Sinclair, Paul A. Swinton, Michael Donald, Lisa Curatolo, Peter Lindle, Steph Jones, Alasdair R. Corfield
IntroductionTrauma remains the fourth leading cause of death in western countries and is the leading cause of death in the first four decades of life. NICE guidance in 2016 advocated the attendance of pre-hospital critical care trauma team (PHCCT) in the pre-hospital stage of the care of patients with major trauma. Previous publications support dispatch by clinicians who are also actively involved in the delivery of the PHCCT service; however there is a lack of objective outcome measures across the current reviewed evidence base. In this study, we aimed to assess the accuracy of PHCCT clinician led dispatch, when measured by Injury Severity Score (ISS).MethodsA retrospective cohort study over a 2 year period pre and post implementation of a PHCCT clinician led dispatch of PHCCT for potential major trauma patients, using national ambulance data combined with national trauma registry data.ResultsA total of 99,702 trauma related calls were made to SAS including 495 major trauma patients with an ISS >15, and a total of 454 dispatches of a PHCCT. Following the introduction of a PHCCT clinician staffed trauma desk, the sensitivity for major trauma was increased from 11.3% to 25.9%. The difference in sensitivity between the pre and post trauma desk group was significant at 14.6% (95% CI 7.4%–21.4%, p < 0.001).DiscussionThe results from the study support the results from other studies recommending that a PHCCT clinician should be located in ambulance control to identify major trauma patients as early as possible and co-ordinate the response.
https://ift.tt/2GHBH7m
Impact of timing on soft tissue augmentation during implant treatment: A systematic review and meta‐analysis
Clinical Oral Implants Research, EarlyView.
https://ift.tt/2pTS5Ya
Anti‐thymocyte globulin improves survival free from relapse and graft‐versus‐host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia‐negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT
Cancer, EarlyView.
https://ift.tt/2IkuIyz
HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children
Cancer, EarlyView.
https://ift.tt/2GlSgq1
A Translational Model of Incomplete Catch‐Up Growth: Early‐Life Hypoxia and the Effect of Physical Activity
Clinical and Translational Science, EarlyView.
https://ift.tt/2Ih2JQe
Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation
British Journal of Surgery, EarlyView.
https://ift.tt/2GZuoWj
Pain management for patients with cancer
CA: A Cancer Journal for Clinicians, EarlyView.
https://ift.tt/2GF6eTo
Optimal pain management for patients with cancer in the modern era
CA: A Cancer Journal for Clinicians, EarlyView.
https://ift.tt/2Gr36ax
Identification of Proteins Required for Precise Positioning of Apc2 in Dendrites
In Drosophila neurons, uniform minus-end-out polarity in dendrites is maintained in part by kinesin-2-mediated steering of growing microtubules at branch points. Apc links the kinesin motor to growing microtubule plus ends and Apc2 recruits Apc to branch points where it functions. Because Apc2 acts to concentrate other steering proteins to branch points, we wished to understand how Apc2 is targeted. From an initial broad candidate RNAi screen, we found Miro (a mitochondrial transport protein), Ank2, Axin, spastin and Rac1 were required to position Apc2-GFP at dendrite branch points. YFP-Ank2-L8, Axin-GFP and mitochondria also localized to branch points suggesting the screen identified relevant proteins. By performing secondary screens, we found that energy production by mitochondria was key for Apc2-GFP positioning and spastin acted upstream of mitochondria. Ank2 seems to act independently from other players, except its membrane partner, Neuroglian (Nrg). Rac1 likely acts through Arp2/3 to generate branched actin to help recruit Apc2-GFP. Axin can function in a variety of wnt signaling pathways, one of which includes heterotrimeric G proteins and Frizzleds. Knockdown of Gas, Gao, Fz and Fz2, reduced targeting of Apc2 and Axin to branch points. Overall our data suggest that mitochondrial energy production, Nrg/Ank2, branched actin generated by Arp2/3 and Fz/G proteins/Axin function as four modules that control localization of the microtubule regulator Apc2 to its site of action in dendrite branch points.
https://ift.tt/2J5UaJ8
Genome-Wide Analysis of Mycoplasma bovirhinis GS01 Reveals Potential Virulence Factors and Phylogenetic Relationships
Mycoplasma bovirhinis is a significant etiology in bovine pneumonia and mastitis, but our knowledge about the genetic and pathogenic mechanisms of M. bovirhinis is very limited. In this study, we sequenced the complete genome of M. bovirhinis strain GS01 isolated from the nasal swab of pneumonic calves in Gansu, China, and we found that its genome forms a 847,985 bp single circular chromosome with a GC content of 27.57% and with 707 protein-coding genes. The putative virulence determinants of M. bovirhinis were then analyzed. Results showed that three genomic islands and 16 putative virulence genes, including one adhesion gene enolase, seven surface lipoproteins, proteins involved in glycerol metabolism, and cation transporters, might be potential virulence factors. Glycerol and pyruvate metabolic pathways were defective. Comparative analysis revealed remarkable genome variations between GS01 and a recently reported HAZ141_2 strain, and extremely low homology with others mycoplasma species. Phylogenetic analysis demonstrated that M. bovirhinis was most genetically close to M. canis, distant from other bovine Mycoplasma species. Genomic dissection may provide useful information on the pathogenic mechanisms and genetics of M. bovirhinis.
https://ift.tt/2pTMIrK
Genome-Wide Association Mapping Uncovers Fw1, a Dominant Gene Conferring Resistance to Fusarium Wilt in Strawberry
Fusarium wilt, a soil-borne disease caused by the fungal pathogen Fusarium oxysporum f. sp. fragariae, threatens strawberry (Fragaria x ananassa) production worldwide. The spread of the pathogen, coupled with disruptive changes in soil fumigation practices, have greatly increased disease pressure and the importance of developing resistant cultivars. While resistant and susceptible cultivars have been reported, a limited number of germplasm accessions have been analyzed, and contradictory conclusions have been reached in earlier studies to elucidate the underlying genetic basis of resistance. Here, we report the discovery of Fw1, a dominant gene conferring resistance to Fusarium wilt in strawberry. The Fw1 locus was uncovered in a genome-wide association study of 565 historically and commercially important strawberry accessions genotyped with 14,408 SNP markers. Fourteen SNPs in linkage disequilibrium with Fw1 physically mapped to a 2.3 Mb segment on chromosome 2 in a diploid F. vesca reference genome. Fw1 and 11 tightly linked GWAS-significant SNPs mapped to linkage group 2C in octoploid segregating populations. The most significant SNP explained 85% of the phenotypic variability and predicted resistance in 97% of the accessions tested-broad-sense heritability was 0.96. Several disease resistance and defense-related gene homologs, including a small cluster of genes encoding nucleotide-binding leucine-rich-repeat proteins, were identified in the 0.7 Mb genomic segment predicted to harbor Fw1. DNA variants and candidate genes identified in the present study should facilitate the development of high-throughput genotyping assays for accurately predicting Fusarium wilt phenotypes and applying marker-assisted selection.
https://ift.tt/2J6cwtG
A Whole Genome Assembly of the Horn Fly, Haematobia irritans, and Prediction of Genes with Roles in Metabolism and Sex Determination
Haematobia irritans, commonly known as the horn fly, is a globally distributed blood-feeding pest of cattle that is responsible for significant economic losses to cattle producers. Chemical insecticides are the primary means for controlling this pest but problems with insecticide resistance have become common in the horn fly. To provide a foundation for identification of genomic loci for insecticide resistance and for discovery of new control technology, we report the sequencing, assembly, and annotation of the horn fly genome. The assembled genome is 1.14 Gb, comprising 76,616 scaffolds with N50 scaffold length of 23 Kb. Using RNA-Seq data, we have predicted 34,413 gene models of which 19,185 have been assigned functional annotations. Comparative genomics analysis with the Dipteran flies Musca domestica L., Drosophila melanogaster, and Lucilia cuprina, show that the horn fly is most closely related to M. domestica, sharing 8,748 orthologous clusters followed by D. melanogaster and L. cuprina, sharing 7,582 and 7,490 orthologous clusters respectively. We also identified a gene locus for the sodium channel protein in which mutations have been previously reported that confers target site resistance to the most common class of pesticides used in fly control. Additionally, we identified 276 genomic loci encoding members of metabolic enzyme gene families such as cytochrome P450s, esterases and glutathione S-transferases, and several genes orthologous to sex determination pathway genes in other Dipteran species.
https://ift.tt/2pTMDUY
Loss of NF-{kappa}B1 Promotes Inflammation and Immune Checkpoint Regulators [Research Watch]
Polymorphisms that reduce NF-B1 in epithelial and hematopoietic cells promote gastric cancer.
https://ift.tt/2pU7Rms
Increasing Fc{gamma}R Binding Activity May Enhance Anti-CTLA4 Efficacy [Research Watch]
Anti-CTLA4 antibodies induce an FcR-dependent depletion of Tregs to promote tumor rejection.
https://ift.tt/2IelQub
Inhibiting PTPN12-Regulated RTKs May Be Therapeutic in TNBC [Research Watch]
PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC.
https://ift.tt/2pRKzgX
LHPP Is a Histidine Phosphatase and a Tumor Suppressor [Research Watch]
Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC).
https://ift.tt/2uzyZvR
Machine Learning Improves Diagnosis of CNS Cancers [News in Brief]
Algorithm spots patterns in genome-wide methylation profiles to help classify brain and spinal cord tumors.
https://ift.tt/2pSpzH8
Retraction: ‘Sunlight exposure is important for preventing hip fractures in patients with Alzheimer's disease, Parkinson's disease, or stroke’ by J. Iwamoto, T. Takeda and H. Matsumoto
Acta Neurologica Scandinavica, EarlyView.
https://ift.tt/2GlD501
SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy
Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by Flow Cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-L-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions:Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy.
https://ift.tt/2E6Py1V
Novel Metabolites Provide Insight to Health Benefits of Coffee
FRIDAY, March 30, 2018 -- Metabolomic profiling highlights potential mechanisms to explain coffee's health effects, according to a study published online March 15 in the Journal of Internal Medicine. Marilyn C. Cornelis, Ph.D., from Northwestern...
https://ift.tt/2GrZ0yz
Bariatric Surgery Lessens Knee OA Pain More in Certain Patients
FRIDAY, March 30, 2018 -- Laparoscopic gastric band (LAGB) surgery is associated with more improvement in knee osteoarthritis (OA) in younger patients and those without prior knee injury, according to a study published recently in Seminars in...
https://ift.tt/2GGMkrg
Receptivity to Tobacco Ads Linked to Progression to Use
FRIDAY, March 30, 2018 -- For adolescents, receptivity to tobacco advertising is associated with progression toward use, according to a study published online March 26 in JAMA Pediatrics. John P. Pierce, Ph.D., from the University of California, San...
https://ift.tt/2Gq8bzI
Simple Lung Function Tests in Primary Care Help ID Early COPD
FRIDAY, March 30, 2018 A peak flow meter or microspirometer can be used routinely in primary care among patients with suspected chronic obstructive pulmonary disease (COPD) for early case identification, according to a study published online March...
https://ift.tt/2GHFtgV
After Hockey Win, Fans' Heart Attack Risk Rises
FRIDAY, March 30, 2018 -- Following a professional hockey game victory, there is an increase in heart attack-related hospital admissions among male fans, according to a study published online March 29 in the Canadian Journal of Cardiology. Caroline...
https://ift.tt/2Gnor4q
Nanomedicine Approaches Against Parasitic Worm Infections
Advanced Healthcare Materials, EarlyView.
https://ift.tt/2pSYofr
Shelf‐life enhancement of whole rainbow trout (Oncorhynchus mykiss) treated with Reshgak ice coverage
Food Science &Nutrition, EarlyView.
https://ift.tt/2pXfCaK
Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
Journal Name: Biological Chemistry
Issue: Ahead of print
https://ift.tt/2uyv6r8
Functional characterization of the mouse Serpina1 paralog DOM-7
Journal Name: Biological Chemistry
Issue: Ahead of print
https://ift.tt/2GmROb9
O-1-35. The verification for stimulation characteristics of Cortical Stimulator
Bipolar stimulation (BS) used in intraoperative mapping is said to have less influence of leakage current. Its characteristics were actually verified while comparing with monopolar stimulation (MS).
https://ift.tt/2H0FA5i
S15-3. Why is theta burst stimulation effective?
As the first patterned protocol of repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation (TBS) gives bursts containing 3 pulses at 50 Hz at 5 Hz in either an uninterrupted continuous train (continuous TBS, cTBS) or short trains with pauses in between (intermittent TBS, iTBS). TBS induces a cortical modulation effect outlasting the stimulation for up to an hour after 20–192 s of stimulation. Since TBS is usually given at a low intensity for a short period of time, coil overheat is rarely seen before the end of stimulation.
https://ift.tt/2E7OgDQ
O-1-25. Task-dependent modulation of cerebellar brain inhibition during motor imagery
The aim of study was to investigate cerebellar brain inhibition (CBI) is affected by imaginary muscle contraction (Contract-I) and relaxation (Relax-I) using paired pulse paradigm with transcranial magnetic stimulation (TMS) in healthy human. Participants performed tonic actual contraction and relaxation of right first dorsal interosseous (FDI) muscle with visual feedback using electromyography. The motor evoked potential (MEP) in right FDI induced by TMS over the left primary motor cortex with or without conditioning TMS over the right cerebellum was measured during no-imagery (No-I), Contract-I (1st experiment, n = 9) and Relax-I (2nd experiment, n = 20).
https://ift.tt/2GYWAsB
O-2-17. Influence of different types of orthoses on muscle synergy control during gait in stroke patients with hemiparesis
The purpose of this study was to verify the influence of lower limb orthoses on muscle synergy control during gait in stroke patients with hemiparesis. In four subjects with acute stroke, surface EMG signals from eight muscles of the paretic lower limb were measured during gait in two conditions (ankle foot orthosis; AFO or knee ankle foot orthosis; KAFO). The number of modules, muscle weightings and activation timing profile of each module were analyzed using non-negative matrix factorization. In two subjects (Fugl Meyer Assessment; FMA > 20) who walked with mild assistance, three modules were identified during gait with KAFO, whereas two modules were identified with AFO.
https://ift.tt/2GZMyay
O-2-24. Multimodal evoked potential study following posterior quadrantectomy in children with intractable epilepsy
To identify surgical effects on brainstem and cortical function objectively, we compared auditory brainstem response (ABR), somatosensory evoked potential (SEP) and flash visual evoked potential (fVEP) before and after posterior quadrantectomy (PQ) in 11 young children with intractable epilepsy associated with posterior quadrant cortical dysplasia. Mean age of seizure onset and the surgery was 1.4 months and 7.7 months old, respectively. Seven patients showed spasm and 2 had tonic seizures preoperatively.
https://ift.tt/2pVoZr9
O-1-24. Cortical silent period during force control task
We investigated whether transcranial magnetic stimulation (TMS)-induced cortical silent period (cSP), which reflects activation of the GABAergic inhibitory neural circuit in the primary motor cortex (M1), was modulated with dependency on actual output force and corticospinal excitability. Eleven healthy participants were asked to control the force of abduction of the right index finger to 10–100% of the maximum voluntary contraction. TMS was delivered to the left M1 during the task. The results showed that actual output force level, background electromyography activity (bEMG) and area of motor evoked potential (aMEP) in the right first dorsal interosseous muscle gradually increased with increasing target force level while cSP gradually decreased with increasing target force level.
https://ift.tt/2E7NZki
S19-4. Establishment of evidence-based physical therapy
Motor imagery and imitation have been widely used by physical therapist as part of rehabilitation program. However, there have been few evidences for the effect of these approaches on the physical therapy in terms of the neuroscience. Understanding of their neural mechanisms leads to establishment of evidence-based physical therapy (EBPT). Recently, we demonstrated some of the neural mechanism of motor imagery and imitation using MEG.
https://ift.tt/2H3mgEx
Transition Points for the Routine Integration of Palliative Care in Patients with Advanced Cancer
Increasing emphases are being placed upon early integration of palliative care for patients with advanced cancers, yet barriers to implementation in clinical practice remain. Criteria to standardise referral have been endorsed, but their application are yet to be tested at the population level.
https://ift.tt/2J7j9f3
Treatment of Anal Cancer Pain – A Case Report
Treatment of pain related to anal cancer remains challenging. A literature review shows very little data on how best to treat such pain. Opioids are frequently used to manage localized pain associated with anal cancer, but the efficacy of such treatment remains largely unknown. In addition, many expensive opioids and procedures tried in other studies and countries are lacking in less developed countries such as ours. We present that case of a young man diagnosed with stage III anal cancer and extreme sharp pain treated with suppositories containing a steroid and anesthetic resulting in significant improvement in his pain.
https://ift.tt/2E6RRlx
Cost-Effectiveness of Early Insertion of Transjugular Intrahepatic Portosystemic Shunts for Recurrent Ascites
Treatment options for recurrent ascites resulting from decompensated cirrhosis include serial large volume paracentesis and albumin infusion (LVP+A) or insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Insertion of TIPSs with covered stents during early stages of ascites (early TIPS, defined as 2 LVPs within the past 3 weeks and less than 6 LVPs in the prior 3 months) significantly improves chances of survival and reduces complications of cirrhosis compared to LVP+A. However, it is not clear if TIPS insertion is cost-effective in these patients.
https://ift.tt/2GGo4Fz
Equivalent Efficacies of Reverse Hybrid and Bismuth Quadruple Therapies in Eradication of Helicobacter pylori Infection in a Randomized Controlled Trial
Bismuth quadruple therapy is recommended as a first-line treatment for Helicobacter pylori infection in the United States but hybrid therapy is an alternative option. Reverse hybrid therapy (proton pump inhibitor plus amoxicillin for 14 days, and clarithromycin plus metronidazole for the initial 7 days) is a simplified hybrid treatment. We aimed to assess the efficacies of reverse hybrid therapy vs bismuth quadruple therapy as first-line treatments for patients with H pylori infection in a randomized trial.
https://ift.tt/2Gq6pyH
Expression of C19MC miRNAs in HCC associates with stem-cell features and the cancer-testis genes signature
Intratumor heterogeneity of hepatocellular carcinoma (HCC) and, among HCC cell subsets, the cancer stem cell population (hCSC), is responsible for therapeutic resistance and disease relapse.
https://ift.tt/2pRrMli
Diagnostic Ability of Blue Laser Imaging Combined with Magnifying Endoscopy for Early Esophageal Cancer
Blue laser imaging (BLI) is a new image-enhanced endoscopy technique that utilizes a laser light source developed for narrow-band light observation.
https://ift.tt/2GWOZKQ
Cost-Effectiveness Analysis of Routine Magnetic Resonance Imaging in the Follow-Up of Patients with Nasopharyngeal Carcinoma after Intensity-Modulated Radiotherapy
To estimate the clinical benefit and cost-effectiveness of routine head and neck magnetic resonance imaging (MRI) in the follow-up of patients with nasopharyngeal carcinoma (NPC) after definitive intensity-modulated radiotherapy (IMRT).
https://ift.tt/2GlrQot
Partial Laryngeal IMRT for T2N0 Glottic Cancer: Impact of Image Guidance and Radiotherapy Intensification
This single institution study shows a high local control for partial laryngeal IMRT in T2 glottic cancer over a transition from IGRT matching surrogate from initial bone to laryngeal soft tissue, and further enhancement without increasing late toxicity when biological effective dose (α/β=10 Gy) was increased from 66.7 to 72 Gy using 2.0 Gy/fraction instead of 2.4 Gy/fraction. The results underline the importance of appropriate IGRT strategies and radiotherapy intensification using partial laryngeal IMRT.
https://ift.tt/2IednqX
Daily Image-Guidance with Cone Beam Computed Tomography May Reduce Radiation Pneumonitis in Unresectable Non-Small Cell Lung Cancer
We found a decreased rate of Grade ≥ 2 radiation pneumonitis among inoperable non-small cell lung cancer patients receiving daily image-guided radiation therapy (IGRT) with cone-beam computed tomography (CBCT) after an initial 4-dimensional computed tomography simulation compared to daily IGRT with 2-dimensional orthogonal kilovoltage imaging. Future studies should consider the ability of CBCT to improve tumor localization and potentially reduce subacute pulmonary toxicity.
https://ift.tt/2Ijw1hb
Emerging MR Imaging Technologies for Radiation Therapy Planning and Response Assessment
Functional and molecular MRI techniques are capable of measuring biologic properties of tumor tissue. Knowledge of these biologic properties may improve radiation treatment by more accurately identifying tumor volumes, characterizing radioresistant subvolumes of tumor before radiation therapy (RT) and identifying recurrent disease following RT. Intravoxel incoherent motion (IVIM) MRI, blood oxygenation level dependent (BOLD) MRI, tissue oxygenation level dependent (TOLD) MRI, hyperpolarized 13C MRI, and chemical exchange saturation transfer (CEST) MRI are relatively new MRI techniques that have shown promise for contributing to RT planning and response assessment.
https://ift.tt/2GkyRpD
Mentorship experiences of early career academic radiation oncologists in North America
Given concerns about gender equity and career outcomes of academic radiation oncologists, we sought to gather evidence regarding mentorship experiences. We surveyed early career academic radiation oncologists within five years of board certification, using a pre-tested questionnaire. Our results suggest a need for increased facilitation of mentorship of all junior faculty through deliberate, structured programs, and further study is required to elucidate the mechanism driving gender imbalance in laboratory and translational research participation.
https://ift.tt/2GlgPDv
Study on the relationship between changes of immune cells and TNF-α in peripheral blood of patients with multidrug-resistant and extensively drug-resistant tuberculosis
OBJECTIVE: To investigate the relationship between changes in CD4- and CD8-positive immune cells and TNF-α in the peripheral blood of patients affected by multidrug-resistant and extensively drug-resistant tuberculosis.
PATIENTS AND METHODS: 179 patients suffering from tuberculosis treated in the Chest Hospital of Hebei from April 2010 to December 2015 were selected for the study. There were 47 cases affected by drug-resistant tuberculosis and 132 cases affected by non-drug-resistant tuberculosis. The control group included 183 healthy subjects examined during the same period. ELISA was used to compare and analyze serum levels of TNF-α, CD4- and CD8-positive cell levels, and CD4/CD8 ratio in the two groups.
RESULTS: CD4- and CD8-positive cell count, CD4/CD8 ratio, and serum TNF-a were significantly higher in patients with drug-resistant tuberculosis compared with healthy controls and the non-drug-resistant tuberculosis patients (p < 0.05). There was a positive correlation between TNF-α level and CD4/CD8 ratio (r=0.892, p < 0.05). Before treatment, the differences in the levels of TNF-a in the different groups of drug-resistant patients were insignificant (p >0.05). After treatment, the levels of TNF-a in the different groups of drug-resistant patients were decreased, except for patients with extensively drug-resistant tuberculosis, whose levels were significantly decreased compared with before treatment (t = 0.648, p>0.05). The differences in the levels of TNF-α in the other groups of patients before and after treatment were statistically significant (t = 8.497, 6.258, 5.346, p < 0.05, fully sensitive tuberculosis single drug-resistant tuberculosis, multidrug-resistant tuberculosis, respectively).
CONCLUSIONS: The level of TNF-α plays a critical role in the evaluation of the severity of patients with drug-resistant tuberculosis and it has a clinical value.
L'articolo Study on the relationship between changes of immune cells and TNF-α in peripheral blood of patients with multidrug-resistant and extensively drug-resistant tuberculosis sembra essere il primo su European Review.
https://ift.tt/2GZB9aH
Fibrosis‐4 index predicts cirrhosis risk and liver‐related mortality in 2075 patients with chronic HBV infection
Alimentary Pharmacology &Therapeutics, EarlyView.
https://ift.tt/2GGoJXI
Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti‐β7 integrin therapy for inflammatory bowel disease
Alimentary Pharmacology &Therapeutics, EarlyView.
https://ift.tt/2GrRfso
Neuron-Macrophage Co-cultures to Activate Macrophages Secreting Molecular Factors with Neurite Outgrowth Activity
The current protocol presents experimental procedures to stimulate cultured macrophages to be endowed with capacity to release molecular factors that promote neurite outgrowth. Treatment of cAMP to the neuron-macrophage co-cultures induces the macrophages to produce conditioned medium that possesses strong neurite outgrowth activity.
https://ift.tt/2uApfS4
Survival benefit of lymph node dissection in surgery for colon cancer in elderly patients: A multicenter propensity score‐matched study in Japan
Asian Journal of Endoscopic Surgery, EarlyView.
https://ift.tt/2Iji2aT
Study of candidate gene cHRNA4 for familial epilepsy syndrome
OBJECTIVE: To screen a three-generation familial partial epilepsy with variable foci (FPEVF) family with epilepsy to identify the cHRNA4 gene (a candidate gene).
PATIENTS AND METHODS: A total of 18 members of the three-generation FPEVF family with partial epilepsy were selected, and 18 blood samples were collected for investigation. Among them, five members were affected by epilepsy, and another 13 members were not affected. A pedigree chart was mapped to comprehensively analyze the clinical characteristics of each member, including ictal semiology, electroencephalogram (EEG), past medical history, MRI features, neuropsychological MMSE (mini-mental state examination) scores, etc. PCR and Sanger sequencing method were used to screen the mutant gene cHRNA4.
RESULTS: cHRNA4 genes of all affected members were positively mutated, and that of the unaffected members were negative. The positive mutation was base A instead of base G.
CONCLUSIONS: cHRNA4 is the causative gene of FPEVF, and genes of the affected members are all heterozygotes mutations.
L'articolo Study of candidate gene cHRNA4 for familial epilepsy syndrome sembra essere il primo su European Review.
https://ift.tt/2GmQcOR
Effects of sevoflurane post-conditioning in cerebral ischemia-reperfusion injury via TLR4/NF-κB pathway in rats
OBJECTIVE: The aim of the study was to investigate the anti-inflammatory effect of sevoflurane post-conditioning on cerebral ischemia-reperfusion injury in rats.
MATERIALS AND METHODS: Thirty Sprague Dawley (SD) rats were randomly divided into 3 groups: sham operation group (Sham), ischemia/reperfusion injury (I/R) group and sevoflurane post-conditioning group (Se). Hematoxylin-eosin (HE) staining was used to observe the inflammatory response in the brain tissue. The levels of TNF-α, IL-1β, IL-6 in serum were measured by ELISA. The mRNA and protein expression of TLR4 and NF-κB p65 were detected by RT-PCR and Western blot in the brain tissue.
RESULTS: The post-conditioning of sevoflurane decreased the level of inflammatory reaction in ischemic-reperfusion rat cerebral infarction area and reduced the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 in rats with ischemia-reperfusion injury. In addition, after treatment with sevoflurane, the mRNA and protein expression of TLR4 and NF-κBp65 in TLR4/NF-κB pathway was inhibited.
CONCLUSIONS: Sevoflurane post-conditioning can decrease the inflammatory reaction in cerebral infarct area induced by cerebral ischemia-reperfusion injury in rats. The neuroprotective effect mechanism of sevoflurane may be related to TLR4/NF-κB signaling pathway.
L'articolo Effects of sevoflurane post-conditioning in cerebral ischemia-reperfusion injury via TLR4/NF-κB pathway in rats sembra essere il primo su European Review.
https://ift.tt/2uvLGIg
miR-424 protects PC-12 cells from OGD-induced injury by negatively regulating MKP-1
OBJECTIVE: It's of great significance to investigate the novel targets of drugs for the treatment of stroke. In this study, we explored the neuroprotective role of miR-424 in oxygen glucose deprivation (OGD)-induced injuries in PC-12 cells.
MATERIALS AND METHODS: PC-12 cells were subjected to OGD stimulation to mimic ischemic injury. The expressions of miR-424 and mitogen-activated protein kinase phosphatase-1 (MKP-1) were altered by transient transfection with miR-424 mimic, miR-424 inhibitor, pEX-MKP-1, or sh-MKP-1. Cell counting kit-8 (CCK-8) assay, flow cytometry, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), were conducted to respectively detect cell viability, apoptotic cells, and the expression of miR-424 and MKP-1. The protein expressions of several factors were determined by Western blot. Meanwhile, relative luciferase activity assay was done to verify the predicted targets association.
RESULTS: OGD induced injury in PC-12 cells by suppressing cell viability and inducing apoptosis. OGD also induced the expression of miR-424 in PC-12 cells. Overexpression of miR-424 protected PC-12 cells from OGD-induced injury by increasing cell viability and decreasing apoptosis. MKP-1 was a direct target of miR-424, and its expression was negatively regulated by miR-424. Up-regulation of expression of MKP-1 aggravated OGD-induced cell injury by inhibiting the expression of hypoxia-inducible factor 1α (HIF-1α), thus inhibiting the PI3K/AKT/mTOR pathways.
CONCLUSIONS: miR-424 protected PC-12 cells from OGD-induced injury through direct suppression of MKP-1 expression, as MKP-1 promoted OGD-induced cell injury by inhibiting the expression of HIF-1α and PI3K/AKT/mTOR pathways.
L'articolo miR-424 protects PC-12 cells from OGD-induced injury by negatively regulating MKP-1 sembra essere il primo su European Review.
https://ift.tt/2GmQ4Pn
Changes in cerebrovascular reactivity in healthy adults after acute exposure to high altitude
OBJECTIVE: To study changes in the cerebrovascular reactivity (CVR) at different altitude area in healthy adults.
SUBJECTS AND METHODS: CVR was tested using transcranial Doppler combined with CO2 inhalation, near-infrared spectroscopy (NIRS) was used to detect the regional cerebral oxygen saturation (rScO2). Blood samples were collected, and the vasoactive substances in serum were detected using the enzyme-linked immunosorbent assay. In this study, 59 healthy adults were divided into 3 groups: low altitude group, medium altitude group and high altitude group. All the indicators in low altitude group were tested at 24h before departure and after arrival from Beijing (at an altitude of 44.4 m) to Xining (at a medium altitude of 2200 m). Then, after resting for 48h, all the indicators were tested at 24h and 48h after arrival from Xining (at a medium altitude of 2200 m) to Yushu Jiegu town (at a high altitude of 3700 m) together with those at the medium altitude. Intergroup comparisons were made for the subjects in the three altitudes.
RESULTS: There was an increase in the CVR in low altitude group after acute exposure to high altitude, and the difference was significant (CVR: 1.94re was vs. 0.91±0.53, p<0.001); the CVR index was increased, and the difference was significant [cerebrovascular reserve index (CVRI): 3.65he CVR vs. 1.37e CVR, p<0.001]; the rScO2 level was decreased with the increase of altitude, and the difference was significant [(66.78±4.61)% vs. (70.29±4.52)%, p<0.001]. The levels of vasoactive substances in low altitude group were decreased after acute exposure to high altitude compared with those before exposure: NO: [(79.14±9.54) μmol/L vs. (58.01±9.93) μmol/L, p<0.001]; serum eNOS level was increased, and the difference was significant [(77.23±6.20) pg/ml vs. (65.07±9.82) pg/ml, p<0.001]; EPO: [(84.68±13.16) pg/ml vs. (65.01±5.92) pg/ml, p<0.001]; VEGF: [(71.91±11.62) pg/ml vs. (54.92±11.86) pg/ml, p<0.001]; sFlt: [(384.18±42.73) pg/ml vs. (320.62±78.96) pg/ml, p<0.001].
There was also an increase in CVR in medium altitude group after acute exposure to high altitude, and the difference was significant [CVR: 2.00±0.79 vs. 0.91±0.66, p<0.001]; the difference of CVRI was significant [3.83±0.67 vs. 1.67±0.87, p<0.001]; rScO2 was slightly decreased with the increase of altitude, and the difference was not statistically significant [(67.53±4.61) % vs. (69.63±5.59) %, p<0.001]. Before exposure to high altitude area, the levels of NO, NOS, EPO, VEGF, and sFlt in low and medium altitude groups were higher than those in high altitude group. CVR level of subjects at different altitudes was negatively related to the ScO2 (r=-0.91) but positively related to NO and NOS levels (rs=0.89, r=0.75); CVR was moderately related to VEGF and EPO (rs=0.45, r=0.42). rScO2 was positively related to RBC, HB and VEGF levels (r=0.89, r=0.75, rs=0.86), but had a moderately negative correlation with NO and NOS levels (rs=-0.52, r=-0.57).
CONCLUSIONS: After subjects at a low altitude are exposed to high altitude rapidly, CVR is increased, RBC and vasoactive substances in serum, such as NO, eNOS, and EPO, are dramatically increased, VEGF is increased first and then decreased, sFlt-1 level is increased gradually, and rScO2 level is gradually decreased with the increase of altitude, indicating the local brain anoxia of subjects at a high altitude.
L'articolo Changes in cerebrovascular reactivity in healthy adults after acute exposure to high altitude sembra essere il primo su European Review.
https://ift.tt/2uCL6s6
Endothelial progenitor cell miR-126 promotes homing of endothelial progenitor cells within arterial thrombus in patients with cerebral infarction and its molecular mechanism
OBJECTIVE: The present study was designed to investigate the effect of microRNA-126 (miR-126) on the migration and homing of endothelial progenitor cells (EPCs) within arterial thrombus of cerebral infarction patients.
MATERIALS AND METHODS: EPCs from rat bone marrow were isolated, and miR-126 overexpressed EPCs were constructed by lentiviral transfection. Then, the middle cerebral artery occlusion (MCAO) model was established by the method of thread ligation. Successfully established model rats were randomly divided into miR-126 overexpression EPC group, miR-126 wild type EPC group, and normal saline group. One day after the infarction, the miR-126 overexpression EPCs, miR-126 wild type EPCs, and normal saline, were injected into the lateral ventricle of the corresponding groups. Also, the transplanted cells were tracked by cell dye SPDiIC18. The expression of tight junction proteins ZO-1 and Claudin-5 in brain tissue was detected by Western blotting.
RESULTS: Transplanted cells were detected in the cerebral infarction area 3 days after transplantation by cell dye SP-DiIC18. The number of homing EPCs in miR-126 overexpression group was significantly higher than that of miR-126 wild type EPC group (p < 0.05). Also, the protein expression of ZO-1 and Claudin-5 in the miR- 126 overexpression EPC group was significantly higher compared with that of the miR-126 wild type EPC group and the normal saline group.
CONCLUSIONS: miR-126 overexpression EPCs, which were transplanted in the lateral ventricle, can home to the cerebral infarction areas via increasing increase
L'articolo Endothelial progenitor cell miR-126 promotes homing of endothelial progenitor cells within arterial thrombus in patients with cerebral infarction and its molecular mechanism sembra essere il primo su European Review.
https://ift.tt/2GmPYHv
The role of AMPK/mTOR signal pathway in brain injury following chronic intermittent hypoxia in growing rats
OBJECTIVE: To investigate the role of AMPK-mTOR signal pathway in brain injury induced by chronic intermittent hypoxia (CIH) in young rats.
MATERIALS AND METHODS: Forty healthy male Sprague-Dawley rats (3-4 weeks old, weighing 80-100 g) were randomly assigned to four groups: 2-week-CIH group (2IH), 4-week-CIH group (4IH), 2-week-simulated air control group (2AC) and 4-week-simulated air control group (4AC). TUNEL staining was used to detect the cell apoptosis in the hippocampus and pre-frontal cortexes, respectively. The Western blot was conducted to analysis the P-AMPK (Phospho-AMP-activated protein kinase) and P-mTOR (phosphorylated mammalian target of rapamycin) protein expression.
RESULTS: The neurons apoptosis in the hippocampus and pre-frontal cortex in 2IH and 4IH groups increased significantly, compared with that of in 2AC and 4AC groups, (p<0.05, respectively). Moreover, 4IH group exhibited significantly increased apoptosis rates than 2IH group (p<0.05). 2IH and 4IH groups exhibited increased protein expression levels of P-AMPK in the hippocampus and prefrontal cortexes compared with 2AC and 4AC groups (p<0.05, respectively), whereas the protein expression of P-mTOR decreased after CIH treatment (p<0.05, respectively). Higher expression levels of P-AMPK and lower levels of P-mTOR were observed in 4IH group compared to 2IH group. No difference of apoptotic cells and protein expression of P-AMPK and P-mTOR was exhibited between 2AC and 4AC groups.
CONCLUSIONS: CIH induces neural apoptosis in a time-dependent manner by activating AMPK and inhibiting mTOR phosphorylation in young rats.
L'articolo The role of AMPK/mTOR signal pathway in brain injury following chronic intermittent hypoxia in growing rats sembra essere il primo su European Review.
https://ift.tt/2uvMahk
Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression
Cancer Medicine, EarlyView.
https://ift.tt/2pRhhiE
Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies
Abstract
Purpose
The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.
Methods
In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.
Results
A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.
Conclusions
Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.
Registration
The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.
https://ift.tt/2pUJaFJ
Evaluation of Stem Cell Therapies in a Bilateral Patellar Tendon Injury Model in Rats
https://ift.tt/2J5hnLw
Lower Energy Consumption for South Asian Migrants With T2DM
FRIDAY, March 30, 2018 -- Among South Asian (SA) migrants in the United States, those with type 2 diabetes mellitus (T2DM) consume less total energy and have lower consumption of many nutrients than those without T2DM, according to a study published...
https://ift.tt/2uzaWNt
Early Age-Related Macular Degeneration Linked to High HDL
FRIDAY, March 30, 2018 -- There is a higher risk for early age-related macular degeneration (AMD) in individuals with high plasma high-density lipoprotein cholesterol levels, according to a study published online March 29 in JAMA...
https://ift.tt/2Gp0uxO
Aortic Valve Replacement in Elderly Tied to High Mortality
FRIDAY, March 30, 2018 -- The 10-year mortality rate in elderly patients who receive surgical aortic valve replacement (SAVR) is considerable, according to a study published in the April 3 issue of the Journal of the American College of...
https://ift.tt/2pOaIgY
ACA Has Provided Better Access to Care for Cancer Survivors
FRIDAY, March 30, 2018 -- Cancer survivors are more likely to have difficulty accessing and affording health care, but the proportion reporting these issues is decreasing, according to a study published online March 29 in JAMA Oncology. Ryan D....
https://ift.tt/2uB4wO4
Montreal Parkinson Risk of Dementia Scale Deemed Accurate
FRIDAY, March 30, 2018 -- The office-based, eight-item Montreal Parkinson Risk of Dementia Scale is a valid predictor of development of dementia, according to a study published online March 26 in JAMA Neurology. Benjamin K. Dawson, from McGill...
https://ift.tt/2GlJMiX
Lag in Progress Against Lung CA Mortality in Midwest, Appalachia
FRIDAY, March 30, 2018 -- In the Midwest and Appalachia there are areas where progress against lung cancer mortality among women is lagging compared with the rest of the nation, according to a study published March 30 in Cancer Epidemiology,...
https://ift.tt/2uDDW78
3, 6 Month Adjuvant CAPOX Equally Effective for Colon Cancer
THURSDAY, March 29, 2018 -- For patients with stage III colon cancer, three months of capecitabine and oxaliplatin (CAPOX) therapy is not noninferior to six months of therapy overall, according to a study published in the March 20 issue the New...
https://ift.tt/2E7e4A1
Pectoralis Major Tears Described in Deployed Military Personnel
FRIDAY, March 30, 2018 -- Deployed military personnel may be at high risk for pectoralis major tears, according to a study published online in the Journal of Orthopedics & Rheumatology. Dane Salazar, M.D., from the Saint Louis University School...
https://ift.tt/2Gp0r56
Rate of MI, Stroke Higher After Respiratory Infection
FRIDAY, March 30, 2018 -- The risk for myocardial infarction (MI) or stroke remains higher after laboratory-confirmed Streptococcus pneumoniae or influenza, according to a study published March 21 in the European Respiratory Journal. Charlotte...
https://ift.tt/2Gl4q2y
Childhood Irritability, Depressive Mood Linked to Suicidality Later
FRIDAY, March 30, 2018 -- Children with high irritability and depressive/anxious mood have increased suicidality risk during adolescence, according to a study published online March 28 in JAMA Psychiatry. Massimiliano Orri, Ph.D., from the Institut...
https://ift.tt/2E6cdLN
Hearing What You See
A recent gif image has been circulating where individual can report hearing a "thud" sound
https://ift.tt/2GmIFzt
Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy
Objective
As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.
DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg–/– (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.
ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.
ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
https://ift.tt/2pUAWgP
Effect of cultivation mode on the production of docosahexaenoic acid by Tisochrysis lutea
In this study, Tisochrysis lutea was cultivated in mixotrophic and heterotrophic cultures with glycerol as a carbon source and with glucose and acetate for comparison; autotrophic cultivation was the control grou...
https://ift.tt/2uvwtqq
Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond
Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond
Cancers doi: 10.3390/cancers10040099
Authors: Nina Prokoph Hugo Larose Megan Lim G. Burke Suzanne Turner
Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.
https://ift.tt/2pSTBd4
Measuring Gene Expression in Bombarded Barley Aleurone Layers with Increased Throughput
An improved protocol is presented for the measurement of transient gene expression from reporter constructs in barley aleurone cells after particle bombardment. The combination of automated grain grinding with 96-well plate enzyme assays provides high throughput for the procedure.
https://ift.tt/2GLl3DM
An Efficient and Simple Method to Establish NK and T Cell Lines from Patients with Chronic Active Epstein-Barr Virus Infection
A simple method for obtaining NK and T cell clones from CAEBV patients was developed with high efficiency, a small amount of peripheral blood, and a low-dose of IL-2.
https://ift.tt/2IdAXEb
The significance of interfamilial relationships on birth preparedness and complication readiness in Pakistan
Publication date: Available online 30 March 2018
Source:Women and Birth
Author(s): Usman Ghani, Susan Crowther, Yasir Kamal, Muhammad Wahab
BackgroundIn the interests of improving maternal health care and survival, the issue of birth preparedness and complication readiness has been much debated and has remained a priority for the international health community. The provision of birth preparedness and complications readiness is determined by a range of different factors.AimThe main aim of this study is to identify and measure the influence of husbands and other family relationships on birth preparedness and complications readiness in the Khyber Pakhtunkhwa province of Pakistan.MethodsThis study is a cross-sectional exploratory study. Data was collected through a survey questionnaire. Logistic regression and descriptive analysis was used.FindingsAnalysis indicated that the mother-in-law's role, men's and women's level of education and interfamilial relationships are still the most significant factors influencing birth preparedness and complications readiness. Of the respondents, 86% were receiving antenatal care and 76.5% were planning for the birth to take place in state-run hospitals or private obstetric and gynae clinics.ConclusionThe tendency to take up antenatal care in Khyber Pakhtunkhwa can mainly be credited to a mutual understanding between husband and wife and a good relationship between the woman and her mother-in-law. Highlighting the significance of these relationships has implications for ensuring birth preparedness and complications readiness.
https://ift.tt/2pUyFlN
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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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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
