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
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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...
