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Summary:CD19- and B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T cells have enabled unprecedented responses in a subset of refractory patients with B-cell and plasma cell malignancies, leading to their approval by the FDA for the treatment of leukemia, lymphoma, and myeloma. These “living drugs” can become part of a synthetic immune system, persisting at least a decade in some patients. However, despite this tremendous impact, significant unmet treatment needs remain for patients with hematologic malignancies and solid cancers. In this perspective, we highlight recent innovations that advance the field toward production of a more potent and universal cellular immunotherapy of the future. Next-generation CAR T cells will incorporate advances in gene engineering and synthetic biology to enhance functionality and persistence, and reduce treatment-associated toxicities. The combination of autologous CAR T cells with various allogeneic cell treatment strategies designed to target the immunosuppressive tumor microenvironment will broaden the impact of future CAR T-cell therapies.

Incomplete surgery of solid tumors is a risk factor for primary treatment failure. Here, we have investigated whether chimeric antigen receptor T cells (CARTs) could be used as an adjuvant therapy to clear residual cancer cells. We tested the feasibility of this approach in two partial resection xenograft models using mesothelin-specific CARTs. In addition, we developed a previously unexplored in vivo toxicity model to evaluate safety and effects on wound healing in immunocompetent C57BL/6 mice. We found that the local delivery of CARTs in a fibrin glue–based carrier was effective in clearing residual cancer cells following incomplete surgery. This resulted in significantly longer overall survival when compared to mice treated with surgery and CARTs without fibrin glue. On-target off-tumor toxicity was diminished, and wound healing complications were not seen in any of the mice. On the basis of these observations, a clinical trial in patients with locally advanced breast cancer is planned.

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028].Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.

Bu çalışma Konya ilinde 2-6 aylık 121 adet yavru sokak köpeğinin gastro-intestinal helmint ve protozoon enfeksiyonlarının yaygınlığını belirlemek amacıyla yapılmıştır. Bu amaçla toplanan gaita örnekleri Fulleborn flotasyon ve sedimantasyon yöntemleri ile incelenmiştir. Mikroskobik muayenede tespit edilen helmint yumurtası ile protozoon kist, ookist ve sporokistleri ilgilili teratürler yardımıyla teşhis edilmiştir. Toplamda 121 adet gaita numunesinin 92’si (%76.03) helmint ve protozoon enfeksiyonları açısından pozitif bulunmuştur. Gaita örneklerinde protozon parazitlerden Giardia spp. kistleri (%2.48), Sarcocystis spp. sporokistleri (%2.48) ve Isospora spp. ookistlerine (%26.45) rastlanmıştır. Gastrointestinal helmintlerden ise cestod ve nematode enfeksiyonlarına rastlanmış, ancak herhangi bir trematod enfeksiyonu belirlenmemiştir. Çalışmada helmintlerden Joyeuxiella spp. (%1.65), Dipylidium caninum (%10.74), Taenia/Echinococcus spp. (%0.83), Toxascaris leonina (%33.06), Toxacara canis (%38.84) ve Physaloptera spp. (%6,61) yumurtalarının varlığı tespitedilmiştir. Bu çalışmada ayrıca bazı köpeklerde tekli ve miks parazit enfeksiyonlarının varlığı tespit edilmiştir. Çalışmada %47.82 tekli, %43.48 ikili ve %7.61 üçlü miks enfeksiyonlar tespit edilmiştir. Bir dışkı örneğinde ise biri protozoon kisti ve üçü de farklı helmint yumurtası olmak üzere (Isospora spp., T. leonina, T. cati ve D. caninum) dört farklı parasite rastlanmıştır. Bu çalışma Türkiye’de köpeklerde Physaloptera spp. enfeksiyonunun bildirildiği ilk çalışmadır.

Maggot debridement therapy (MDT), which lost its importance after discovering antibiotics, has recently come to the fore with the increase of antibiotic resistance. MDT, widely used in human medicine, has had limited use in veterinary medicine. The material of this case report was a 5-month-old Doberman dog that was bandaged due to a fracture of the left hind toe. It was got information that the bandage in the leg area was wet and remained on the wound for five days. As a result, the foot turned into a macerated tissue and gas gangrene was formed. The gangrenous foot area was amputated from the upper 1/3 of the femur. After surgery the amputated area became an infected wound and did not respond to antibiotic therapy. The research was planned to investigate the efficacy of MDT on an infected wound. For this purpose, the sterile first and second instar larvae of Lucilia sericata were used. The first MDT administration was done six days after the amputation procedure. The second maggot application was repeated after 24 hours, and the other two applications were repeated 48 hours intervals. After the first application, it was observed that the amount of discharge gradually decreased in the wound, and rapid healing was detected in the amputation area. The infected wound that did not respond to antibiotic treatment was successfully treated through the sterile L. sericata larvae’ characteristics, promoting wound healing. This suggests that MDT may be widely used in the future, as it is a cheap, effective, natural and easy-to-apply method.

After the recent success and approvals of chimeric antigen receptor (CAR) T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities including melanoma. However, severe and potentially life-threatening side effects like cytokine release syndrome, neurologic toxicities, and the competing risk of morbidity and mortality from the treatment itself are still a major limiting factor in the current CAR T-cell landscape. In addition, especially in solid tumors, the lack of ideal target antigens to avoid on-target/off-tumor toxicities also restricts its use. While various groups are working on strategies to boost CAR T-cell efficacy, mechanisms to increase engineered T-cell safety should not move out of focus. Thus, the aim of this article is to summarize and to discuss current and potential future strategies and mechanisms to increase CAR T-cell safety in order to enable the wide use of this promising approach in melanoma and other tumor entities.

Objectives: Non-alcoholic fatty liver disease (NAFLD) may affect many organs and systems, especially the kidney as well as the liver. While NAFLD’s renal impacts can be evaluated via the estimated glomerular filtration rate (eGFR), its effects on renal hemodynamic changes can be monitored with the renal resistive index (RRI). Our aim in this study is to evaluate RRI and eGFR in NAFLD patients. Materials and methods: In this study, a total of 69 patients with NAFLD and 50 age- and gendermatched healthy controls were included. The basic clinical and laboratory parameters of patient and control groups were assessed and recorded. Results: In the patient group, the RRI was observed as 0.64±0.06 and eGFR value as 86±52 (mL/min/1.73m2), while in the control group, the RRI was 0.61±0.05 and eGFR was 95.40±20.21 (mL/min/1.73m2). Compared to the control group, the RRI and eGFR values were significantly different in the patient group (PRRI=0.003 and PeGFR=0.025). There was a negative correlation observed between the RRI and eGFR (r=-0.347, P=0.003). Receiver-operating characteristic curve analysis suggested that the optimum RRI cut-off value for patients with NAFLD is 0.62, with 65% sensitivity and 60% specificity (p=0.002). There was an independent relationship found between the RRI and eGFR according to the linear regression analysis (β=-0.301, P=0.015). Conclusion: This study shows that RRI may be an indicator of renal functions, such as eGFR in patients with NAFLD.

Introduction: The disease caused by the novel coronavirus (COVID -19) is a vital public health problem that has now affected approximately 68,037,473 people and caused 1,552,802 deaths around the world. We aimed to correlate the frequency of the lung involvement patterns, the segmental distribution of lung infiltration, and TLSS in COVID-19 pneumonia patients with and without splenomegaly. Material and Methods: This retrospective study included patients admitted to Yunus Emre State Hospital Emergency, Internal Medicine and Infectious Disease Departments between March 11, 2020, and June 10, 2020, and diagnosed with COVID-19 by PCR test with a throat and nasal swab. The thoracic and upper abdomen CTs and the clinical and demographic features of the patients were analyzed at the time of initial diagnosis. Results: Consolidation (group 1 - 18 (47%), group 2 - 69 (28.2%); P = 0017), crazy pavement pattern (15 (39.5%), 42 (17.1%); p = 0.001), pleural band formations (24 (63.2%), 87 (35.5%); p = 0.001), interlobular septal thickening (23 (60.5%), 79 (32.2%); p = 0.001), and sequelae of secondary tuberculosis (4 (10.5%), 8 (3.3%); p = 0.039) were more frequent in the patient with splemomegaly. The total lung severity score was high in the group with splenomegaly (7.32 ± 6.15, 3.69 ± 5.16; p = 0.001). Conclusion: Consolidation, interlobular septal thickening, tuberculosis sequela, pleural band, and crazy pavement patterns were frequent in the COVID-19 pneumonia patients with splenomegaly. The most frequently affected segment was the superior segment of the right lower lobe. TLSS was higher in the COVID-19 pneumonia patients with splenomegaly.

Objectives: To investigate the relationship of the neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) with lung involvement and total lung severity score (TLSS) in computed tomography (CT) of patients with coronavirus disease -19 (COVID-19) and to evaluate their clinical usability. Methods: Basic laboratory, clinical features and imaging data of patients was obtained by examining the file and archive records of our hospital. According to the findings of lung CT scan at the time of diagnosis among COVID-19 patients, 2 groups were formed. Results: The NLR was 2.22±11.15 and the PLR was 142.77±387.10 in patients with COVID-19 pneumonia. The NLR was 1.88±7.47 and the PLR was 130.65±203.6 8 in patients without COVID-19 pneumonia. The differences in the NLR and the PLR were determined to be statistically significant between the 2 groups. A positive correlation was observed between NLR and PLR (r=0.225, p=0.010) and TLSS (r=0.244, p=0.005). Conclusion: This study showed that the NLR and PLR values can be 2 inflammatory markers that can be used to evaluate lung involvement and disease severity in COVID-19 patients. At the time of initial diagnosis and during follow-up, these markers can give an idea in terms of prognosis, together with other clinical findings and markers.

Background Although dendritic cell (DC)–based cancer vaccines represent a promising treatment strategy, its exploration in the clinic is hampered due to the need for Good Manufacturing Practice (GMP) facilities and associated trained staff for the generation of large numbers of DCs. The Quantum bioreactor system offered by Terumo BCT represents a hollow-fiber platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. In the respective established protocols, the hollow fibers are coated with fibronectin and trypsin is used to harvest the final cell product, which in the case of DCs allows processing of only one tenth of an apheresis product. Materials and Results We successfully developed a new protocol that circumvents the need for fibronectin coating and trypsin digestion, and makes the Quantum bioreactor system now suitable for generating large numbers of mature human monocyte-derived DCs (Mo-DCs) by processing a complete apheresis product at once. To achieve that, it needed a step-by-step optimization of DC-differentiation, e.g., the varying of media exchange rates and cytokine concentration until the total yield (% of input CD14+ monocytes), as well as the phenotype and functionality of mature Mo-DCs, became equivalent to those generated by our established standard production of Mo-DCs in cell culture bags. Conclusions By using this new protocol for the Food and Drug Administration–approved Quantum system, it is now possible for the first time to process one complete apheresis to automatically generate large numbers of human Mo-DCs, making it much more feasible to exploit the potential of individualized DC-based immunotherapy.

Introduction of a tumor antigen-specific T cell receptor (TCR) into patient-derived lymphocytes has already exhibited promising results for the treatment of melanoma and other malignancies in clinical trials. However, insufficient or unsuccessful ex vivo manufacturing of engineered T cells due to low expansion and/or transduction rate can still be observed in some patients. Thus, we isolated human CD8+ T cells from healthy donors and equipped them with a gp100-specific TCR using a lentiviral construct in combination with a novel chemical lentiviral transduction enhancer (Lentiboost) to increase the rate of transduced cells. Following experiments to determine the ideal multiplicity of infection (MOI) and to analyze the efficacy of the transduction enhancer using a GFP-encoding lentivirus, we analyzed in the next step the transduction rate, cell count, and functionality of gp100 TCR-transduced T cells, i.e. antigen-specific cytokine secretion and lytic capacity. In order to increase the number of transduced cells, antigen-specific stimulation was performed, either once for 1 week (1st activation) or twice for another week (2nd activation). In general, each cycle of antigen-specific stimulation resulted in expansion of TCR-positive cells, while no further significant increase of transduced cells was observed after 2nd activation. Cytokine production pattern of transduced cells after antigen encounter, however, revealed significant antigen-specific secretion of TNF and IFNγ after the 1st as well as the 2nd activation. Furthermore, TCR T cells, either activated once or twice, showed significant cytotoxicity towards antigen-positive tumor cells. Taken together, these results show that it is feasible to transduce human T cells using a lentiviral construct in combination with this novel lentiviral transduction enhancer, which shows potential in the growing field of cancer immunotherapy.

Purpose: Demodex folliculorum and Demodex brevis are common ectoparasites on skin that also can lead to blepharitis and chalazion. The aim of our study is to determine the prevalence of Demodex spp. in eyelashes of patients diagnosed with chronic blepharitis and chalazion. Methods: This study included 330 patients diagnosed with chronic blepharitis, 70 patients diagnosed with chalazion and 130 volunteers without any ocular problems. Patient eyelashes were examined under a light microscope at magnifications of × 40, × 100 and × 400. Demodex spp. were determined. Results: Parasite prevalence was significantly higher in blepharitis (75.5%) and chalazion groups (70%) compared to the control group (16.2%) (p D. folliculorum in the blepharitis group and D. brevis in the chalazion group was found to be significantly higher compared to other groups (p Conclusion: The results of the study show that Demodex acari infestations should be considered in chronic blepharitis and chalazion.

Whereas approximately half of metastatic melanoma patients benefit from combined immune checkpoint inhibition targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1), for those who do not respond, further strategies and treatment options need to be developed. Thus, focus is turning to the use of chimeric antigen receptor (CAR) T cells, a novel therapy that has not yet achieved a major breakthrough in solid tumors despite the impressive response rates reported for their use in hematologic malignancies. In melanoma and other solid tumor entities, different problems still need to be addressed to improve this therapy, with mechanisms to counteract tumor escape being one of them. In this context, we could show the feasibility of combining two different transfection methods - lentiviral transduction and RNA-electroporation - for equipping the same T lymphocyte with two different tumor antigen-specific receptors. While further analysis is required to transfer this novel strategy from bench to bedside, appropriate target antigens that avoid on-target/off-tumor toxicities and additional optimization to increase CAR T cell power are also needed to maximize their potential use in dermatologic oncology.

Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a systemic inflammatory marker, and recently, it has been used quite commonly for the assessment of inflammation in cardiovascular disorders. The aim of the present study is to investigate the relevance of MHR as a marker to assess metabolic syndrome (MetS) and MetS severity in clinical practice. A total of 147 patients with MetS who were diagnosed according to National Cholesterol Education Program Adult Treatment Panel III criteria and 134 healthy controls, matched for age and gender, were included in our retrospective study. MHR values were 13.15 ± 6.07 for patients with MetS and 9.74 ± 5.24 for the control group. MHR values of the patients were found to be statistically significantly higher than the control group ( P < .0001). MHR showed a significantly positive correlation with the severity of MetS ( r = .429; P < .0001). When patients with MetS were assessed with MHR in the study population, receiver–operating characteristic curve analysis yielded a cutoff value of 9.36 with a sensitivity of 72%, a specificity of 61%, and a P value

Objective Is there any influence of a therapy with TNF alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in psoriasis patients?. Methods In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF alpha inhibitors or fumaric acid esters for moderate to severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every three months under therapy. Sperm parameters were assessed according to the current WHO definitions. Results In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters like mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient. Conclusion At baseline, many psoriasis patients showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed. This article is protected by copyright. All rights reserved.

PubMed ID: 27436495, Familial Mediterranean fever (FMF) is a disease characterized by chronic inflammation. Atherogenic index of plasma (AIP) is a logarithmic value of the triglyceride to high-density lipoprotein cholesterol ratio and it is a good marker for atherosclerotic heart disease and cardiac risk. In this study, we investigated subclinical atherosclerosis and cardiac risks in patients with FMF. Patients with FMF (78 men and 84 women) and healthy controls (74 men and 82 women) were included in this study. The AIP values of the patients were calculated and carotid intima-media thicknesses (cIMTs) were measured. The cIMT (P

cure, erkan/0000-0001-7807-135X; Cure, Medine Cumhur/0000-0001-9253-6459; Aydogan Baykara, Rabia/0000-0003-0542-266X WOS: 000399025700011 PubMed: 27431747 Behcet's disease (BD) is a systemic vasculitis characterized by cardiovascular complications. Early diagnosis of these complications can reduce morbidity and mortality. Carotid artery intima-media thickness (cIMT) and the logarithmic value of triglyceride to high density lipoprotein ratio (atherogenic index of plasma, AIP) are good markers of atherosclerosis. the purpose of this study was to investigate whether AIP is a predictive marker of subclinical atherosclerosis in BD patients. A total of 84 BD patients (60 male, 24 female) and 84 healthy control individuals (58 male, 26 female) were included in this study. cIMT measurements were made, and AIP values were calculated. cIMT (p < 0.001) and AIP (p < 0.001) values of the BD patients were higher than those of the control group. A strong independent relationship was found between the AIP value and cIMT (beta = 0.232, p = 0.018). in the subgroup analysis, the cIMT and AIP values of male BD patients were higher than those of female BD patients. Increased AIP and cIMT values can be a good marker for subclinical atherosclerosis in BD patients, especially in male BD patients.

Background Serum amyloid A (SAA), which is produced in the liver, acts as an apoprotein of high-density lipoprotein (HDL) accumulation in extracellular matrix of tissues and organs. SAA elevations play a significant role in the development of amyloidosis. Microalbuminuria (MAU) is the early period of amyloidosis in patients with familial Mediterranean fever (FMF). We assessed the association between SAA as an important factor for the development of amyloidosis in patients with FMF and cytokines, HDL, and MAU. Methods A total of 40 FMF patients diagnosed with Tel-Hashomer criteria and making regular follow-up visits at the tertiary referral center from 2012 to 2013 were included in this study, besides 40 age- and sex-matched individuals as controls. Results Compared with controls, FMF patients had higher SAA (25.20 ± 45.78 vs. 1.68 ± 0.63 ng/ml; P = 0.002). Also, FMF patients had higher MAU than controls (23.20 ± 39.86 vs. 9.40 ± 5.32 mg/day; P = 0.036). HDL was significantly lower in the patient group than in controls (39.35 ± 10.45 vs. 47.82 ± 15.31 mg/dl; P = 0.023). Interleukin-1 beta (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) levels were higher in the FMF group than in controls (P < 0.0001, P = 0.009, P = 0.003, respectively). Conclusions Our results suggest that IL-1, IL-6, TNF-α, SAA, and HDL may serve as markers of subclinical inflammation in FMF patients. Due to increased plasma HDL levels, antiinflammatory and antioxidant effects may elevate in FMF patients.

WOS: 000376445200008, PubMed ID: 27185605, Systematic inflammation, enhanced oxidative stress, and endothelial dysfunction are important for evolution and progression of renal damage, and they cause an increase in red cell distribution width (RDW). Familial Mediterranean fever (FMF) patients who are in the attack-free period and its relation with albuminuria and performance on assessment of microalbuminuria. One hundred and seventy-seven patients who had been diagnosed in accordance with Tel-hoshmer criteria and were in the attack-free period, and 143 age-and sex-matched healthy individuals were enrolled in our study. RDW values of FMF patients were higher compared with those of the controls (13.85 +/- 1.07 and 13.15 +/- 0.91, respectively; p < 0.0001). RDW values of FMF patients with microalbuminuria were higher compared with those of FMF patients with normoalbuminuria and the control group (p = 0.002 and p < 0.0001, respectively). RDW values of FMF patients with normoalbuminuria were higher compared with those of the control group (p < 0.0001). We have showed RDW levels are positively correlated with albuminuria (r = 0.185, p = 0.014). When assessing microalbuminuria with RDW in the patients, a cutoff value of 13.85 with sensitivity of 60%, specificity of 62%, and p = 0.002 (area under curve: 0.651, 95% confidence interval 0.563-0.738), was observed according to receiver-operating characteristic curve analysis. Among the various variables associated with albuminuria in multivariate logistic regression analyses, RDW remained an independent predictor of albuminuria (95% confidence interval 0.479-0.942, p = 0.021). RDW may be associated with albuminuria in FMF patients and it can be a predictor of microalbuminuria. Copyright (C) 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC.

Background Cardiovascular diseases, among which atherosclerotic heart disease, are known to be one of the most important mortality and morbidity causes in patients with rheumatoid arthritis (RA). Ischemia modified albumin (IMA) is a potential marker that can be used to assess atherosclerosis-related myocardial ischemia. Another frequently used marker for the assessment of atherosclerotic lesions is the carotid intima media thickness (CIMT). Aim To evaluate the role that IMA has on atherosclerosis development and its clinical usability in patients with RA, by assessing the values of IMA and CIMT. Methods and materials Our prospective study was conducted between June 2012 and March 2013 at the Rheumatology Department of Necmettin Erbakan Meram Medical School, Turkey. Fifty-two RA patients, diagnosed according to the 1987 criteria of the American College of Rheumatology, and an age- and sex-matched control group of 46 healthy subjects were included in this study. Results No significant difference was detected between the groups with respect to age, sex and body mass index. In the patient group the IMA and CIMT values were found to be 0.37 ± 0.12 absorbance units (ABSU) and 0.80 ± 0.22 mm, respectively, while in the control group they were 0.31 ± 0.11 ABSU and 0.51 ± 0.18 mm, respectively. The IMA and CIMT values were significantly higher in the patient group (P = 0.022 and P < 0.0001, respectively). A positive correlation was found between IMA, CIMT and Disease Activity Score of 28 joints (P = 0.016 and P = 0.002, respectively). Conclusion Since the values of IMA were higher in the patient group compared to controls and because of its correlation with CIMT, we suggest the use of IMA as an early marker of atherosclerosis in RA patients.

WOS: 000372174600020, PubMed ID: 26864298, Background/Aims: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by attacks of fever and diffuse abdominal pain. The primary concern with this presentation is to distinguish it from acute appendicitis promptly. Thus, we aimed to evaluate the role of neutrophil lymphocyte ratio (NLR) to leverage the differential diagnosis of acute FMF attack with histologically proven appendicitis. Methods: Twenty-three patients with histologically confirmed acute appendicitis and 88 patients with acute attack of FMF were included in the study. NLR, C-reactive protein and other hematologic parameters were compared between the groups. Results: Neutrophil to lymphocyte ratio was significantly higher in patients with acute appendicitis compared to the FMF attack group (8.24 +/- 6.31 vs. 4.16 +/- 2.44, p = 0.007). The performance of NLR in diagnosing acute appendicitis with receiver operating characteristic analysis with a cut-off value of 4.03 were; 78% sensitivity, 62% specificity, and area under the curve 0.760 (95% confidence interval, 0.655 to 0.8655; p < 0.001). Conclusions: This study showed that NLR, the simple and readily available inflammatory marker may have a useful role in distinguishing acute FMF attack from acute appendicitis.

Cure, Medine Cumhur/0000-0001-9253-6459; cure, erkan/0000-0001-7807-135X; Balta, Sevket/0000-0002-6657-7334 WOS: 000374792900009 PubMed: 26941246 Behcet's disease (BD) is a vasculitic and inflammatory disease causing endothelial dysfunction. Irisin is a metabolic hormone related to insulin resistance and endothelial functions. in this study, we investigated the relationship between irisin and carotid intima-media thickness (cIMT), which is a marker of atherosclerosis in patients with BD. 48 patients with BD and 50 healthy individuals were enrolled in the study. Disease severity was evaluated by BD current activity form. Irisin, glucose, insulin, C reactive protein, erythrocyte sedimentation rate and lipid panel were examined in all patients. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to calculate insulin resistance. A simple and inexpensive cIMT test was used as indicator of atherosclerosis. cIMT was 0.62 (0.45-1.05) mm in the patients, while it was 0.38 (0.25-0.65) mm in the control group (p

WOS: 000390679600010, PubMed ID: 27713783, Introduction: Chronic hepatitis C (CHC) infection is a systemic disorder that can lead to liver inflammation, fibrosis, cirrhosis, and hepatocellular cancer. The mean platelet volume (MPV) is widely used as an inflammatory marker to evaluate the platelet function and the status of systemic inflammation. Aim: To determine the pre- and post-treatment MPV values in CHC patients who were administered a 48-week antiviral therapy based on systemic inflammation. Material and methods: We enrolled 28 patients, diagnosed with CHC genotype 1b, who received a 48-week antiviral therapy and attended regular follow-up, and 28 healthy individuals. In diagnosing CHC, a positive anti-HCV for a minimum duration of 6 months and a positive serum HCV RNA were accepted as the criteria. The patients were assigned to one of two groups based on their group 1 (pre-treatment values) and group 2 (post-treatment values) after 3 months therapy. We analysed and compared the blood samples of all of the groups. Results: The MPV value was 8.89 +/- 1.20 in group 1 and 8.00 +/- 1.07 in group 2, and 8.21 +/- 1.18 in the control group. The value in group 1 was detected to be statistically significantly different from that in group 2 and the control group (p < 0.0001, p = 0.045, respectively). No statistically significant difference was observed between group 2 and the control group (p = 0.455). Conclusions: The results of this study suggest that MPV could represent an inexpensive marker for use in assessing low-grade inflammation in patients with CHC.

BACKGROUND Sentinel lymph node status is a strong prognostic factor in melanoma. However, up to 21% of sentinel lymph node-negative patients develop locoregional and distant metastases during follow-up. AIM To analyze risk factors for locoregional and distant metastasis in patients with sentinel lymph node-negative melanoma. PATIENTS AND METHODS A total of 545 patients underwent sentinel lymph node biopsy (SNB) between 2005 and 2013 at our hospital. Data for 449 patients with a negative SNB were analyzed regarding risk factors and development of metastases. Follow-up was performed until 2016. RESULTS A total of 72 SNB-negative patients developed metastases, including 25 (34.7%) distant and 47 (63.3%) locoregional metastases. Locoregional metastases occurred earlier compared to distant metastases (with a mean of 24.2 and 23.5 months for regional lymph node and cutaneous metastases, respectively, vs. 31.4 months for distant metastases). Patients with metastases despite negative SNB had a greater tumor thickness (p=0.001), a higher rate of nodular melanoma (p=0.001), ulceration (p

Dendritic cell (DC)-based vaccines have been successfully used for immunotherapy of cancer and infections. A major obstacle is the need for high-level class A cleanroom cGMP facilities for DC generation. The CliniMACS Prodigy® (Prodigy) represents a new platform integrating all GMP-compliant manufacturing steps in a closed system for automated production of various cellular products, notably T cells, NK cells and CD34+ cells. We now systematically tested its suitability for producing human mature monocyte-derived DCs (Mo-DCs), and optimized it by directly comparing the Prodigy approach to our established standard production of Mo-DCs from elutriated monocytes in dishes or bags. Upon step-by-step identification of an optimal cell concentration for the Prodigy's CentriCult culture chamber, the total yield (% of input CD14+ monocytes), phenotype, and functionality of mature Mo-DCs were equivalent to those generated by the standard protocol. Technician's labor time was comparable for both methods, but the Prodigy approach significantly reduced hands-on time and high-level clean room resources. In summary, using our optimized conditions for the CliniMACS Prodigy, human Mo-DCs for clinical application can be generated almost automatically in a fully closed system. A significant drawback of the Prodigy approach was, however, that due to the limited size of the CentriCult culture chamber, in contrast to our standard semi-closed elutriation approach, only one fourth of an apheresis could be processed at once.

Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR-T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR-T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on-target/off-tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR-T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR-T cell therapy, particularly for its use in melanoma.

Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that plays an important role in the blood vessels of heart and peripheral circulation, a lack of which may cause vasculopathies. In this study, the clinical course of disease, as well as the efficacy, side effects, and patient satisfaction of systemic calcitonin therapy in patients with systemic sclerosis (SSc), was evaluated. Forty-nine patients received repetitive intravenous calcitonin infusions as first-line treatment. The average number of cycles was 12.2 ± 10.3 over a period of 30 months (each cycle: 100 U/day over 10 days). Clinical examinations, laboratory tests, and organ imaging were performed before the start of, and at regular intervals during therapy in order to evaluate organ manifestations and the clinical course of the disease. In addition, patients’ own experiences of the therapy, side effects, and therapy success were evaluated with standardized questionnaires. Over the course of the treatment, seven patients experienced improvements in their condition with a considerable reduction in digital ulceration and improved movement (14.3%). Pulmonary function in seven patients improved during the therapy (14.3%). With regards to side effects, nausea (41.7%), headaches (33.3%), fluctuations in blood pressure (29.2%), and flushing (29.2%) were observed. Overall, 45.8% of patients evaluated the therapy as good and 58.3% would undergo further courses of therapy with calcitonin. Systemic calcitonin treatment seems to have positive clinical effects on SSc and contributes to relieving symptoms, especially in patients with cutaneous manifestations. No severe side effects were reported during this study.

Background/aim: Human endothelial cell-specific molecule-1 (endocan) is a marker of vascular endothelial dysfunction that may be used in the evaluation of inflammatory-associated atherosclerotic lesions. Endocan may be a marker for the evaluation of atherosclerosis and disease activity in rheumatoid arthritis (RA) patients.Materials and methods: We included 39 RA patients assessed according to the American College of Rheumatology/European League Against Rheumatology 2010 diagnostic criteria and recruited 30 age- and sex-matching healthy subjects for the control group.Results: Endocan values were 14.11 ± 3.27 for the RA patients and 12.10 ± 2.92 for the controls. The endocan values of the patients were significantly higher than those of the control group (P = 0.009). In the correlation analysis, endocan showed a significantly positive correlation with disease activity score-28 (r = 0.386, P = 0.029) and carotid intima-media thickness (cIMT) (r = 0.419, P = 0.008). Linear regression analysis revealed that there was an independent relationship between endocan and cIMT (P = 0.029).Conclusion: Endocan can be a marker for early atherosclerosis and disease activity in RA patients.

Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with unknown etiology. Accelerated atherosclerosis (AS) and AS with heart disease are among the major causes of morbidity and/or mortality in RA. Endothelial-specific molecule 1 (endocan) is a potential indicator of vascular events and is expressed in response to inflammatory mediators in endothelial cells. Carotid intima media thickness (cIMT) is used to detect early signs of AS but also progression in cardiovascular diseases related to AS. Objectives The aim of the present study is to evaluate the relationship of serum endocan levels with RA and cIMT as a candidate marker of diseases to be used in clinical practice. Methods The study was conducted between June 2012 and March 2013 at the Rheumatology Clinics of Necmettin Erbakan Meram Medical School, Turkey. Thirty nine39 RA patients, diagnosed according to the 1987 criteria of the American College of Rheumatology, and 30 age-and sex-matched healthy subjects as the control group were included in this study. Results No significant difference was detected between groups with respect to age, sex and body mass index. In the patient group the Endocan and cIMT values were found to be 14.11±3.27 ng/mL and 0.63±0.17 mm, while in the control group they were 12.10±2.92 ng/mL and 0.51±0.12 mm, the Endocan and cIMT values were significantly higher in the patient group (p=0.009 and p=0.001, respectively). Positive correlations was found between Endocan, cIMT and Disease Activity Score of 28 joints (p=0.008 and p=0.029, respectively). When assessing the endocan levels of RA patients in the study population, cut off value of 12.21 with sensitivity of 71%, specificity of 57% and p=0.012 (area under curve: 0.678, 95% confidence interval (CI) 0.555–0.805) were observed according to ROC curve analysis. Conclusions Endocan might be a useful marker to evaluate atherosclerotic lesions in patients with RA and also to assess disease severity. Disclosure of Interest None declared

Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), leading to an impaired antitumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA-4). Flow cytometry revealed that activation-induced upregulation of both PD-1 and CTLA-4 was suppressed when compared to CAR-T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD-L1- and CD80-transfected melanoma cells endogenously expressing CSPG4. CAR-T cells transfected with siPD-1 alone showed improvement in cytokine secretion. Additionally, CAR-T cells transfected with either siPD-1 alone or together with siCTLA-4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR-T cells were co-transfected with siCTLA-4 only. Taken together, it is feasible to optimize CAR-T cells by co-transfection of CAR-encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR-T cells, suggesting that this strategy could represent a novel method to enhance CAR-T-cell immunotherapy of cancer.

Bu calismanin amaci, dahiliye kliniklerine tedavi edilmek uzere yatirilan 60 yas ustu hastalarin hastane disi ilac kullanim tutumlarinin ve eksik yonlerinin belirlenmesidir. Calisma Nisan–Kasim 2017 tarihleri arasinda Yunus Emre Devlet Hastanesinin Dahiliye Kliniginde tedavi goren 60 yas ustu 110 hasta uzerinde yapilmistir. Verilerin toplanmasinda anket formu kullanilmistir. Verilerin degerlendirilmesinde ise yuzdelik, ortalama, Ki-kare testi ve lojistik regresyon analizi kullanilmistir. Tum katilimcilarin yas ortalamasi 70,3 ± 10,7 yil, %65’i kadin, %85’i okur-yazar, %63,6’si sehir merkezinde yasayan, %73,6’si 1000-2000 TL gelire sahip ve %96,4’unun bir saglik guvencesine sahip oldugu saptanmistir. Katilimcilarin %46,4’u evde hic kullanilmamis veya arta kalan ilac bulundurduklarini ve bunlari yeniden kullanmak istediklerinde ise %65’inin hekim veya eczaciya danistigi saptanmistir. Katilimcilarin %72,7’si evde bulundurduklari ilaclari hastaliklarinda kullanilip kullanilmadigina ve %67,3’u son kullanma tarihine dikkat ettiklerini belirtmislerdir. Hastalarin egitim duzeyleri ile ilaclarin atilmasi, saklanma kosullari, tavsiye edilen ilac kullanimi, ilaclarla birlikte tuketilmemesi gereken yiyecekler ve muadil ilac kullanimi gibi degiskenler arasindaki iliski degerlendirildiginde istatistiksel olarak anlamli sonuclar elde edilmistir (p

The constriction of vessels due to atherosclerotic lesions causes hypoxia/ischemia and oxidative changes resulting in transformation of free albumin to ischemia-modified albumin (IMA) in the circulation and increased carotid intima–media thickness (cIMT). We investigated the reliability of IMA increase in evaluating atherosclerosis in patients with familial Mediterranean fever (FMF) compared with cIMT. Patients with FMF (n = 58) diagnosed by the Tel-Hashomer criteria in attack-free period and 38 healthy people were included in the study. Patient demographics as well as the clinical and laboratory characteristics of the healthy controls and patients with FMF were noted. The IMA levels and cIMT in patients with FMF were 0.30 ± 0.09 absorbance units (ABSUs) and 1.12 ± 0.27 mm, respectively, and in the control group, IMA levels and cIMT were 0.25 ± 0.07 ABSU and 0.74 ± 0.26 mm, respectively. The IMA levels and cIMT were significantly higher in patients with FMF than in controls ( P = .020 and P < .0001, respectively). The IMA values showed positive correlation with cIMT in patients with FMF( r = .302, P = .041). Our results reveal that IMA—an oxidative stress marker—may be an indicator of atherosclerosis in patients with FMF. This finding deserves further investigation.