Objective: Hairy cell leukemia (HCL) is a rare and indolent lymphoproliferative disease characterized by the infiltration of hairy shaped leukemic B cells with specific immunophenotypic features in the bone marrow, spleen and liver resulting in progressive pancytopenia and splenomegaly. Purine analogs are preferred as the first-line treatment for HCL. This study investigates the significance of BRAF V600E mutations in HCL diagnosis and prognosis, focusing on their baseline and post-cladribine treatment incidences and impacts on patient survival. Material and Methods: This retrospective, case-control study comprises HCL patients diagnosed and treated between July 2012 and June 2014. The study group includes 22 HCL patients (newly diagnosed n=10, remission n=12). The control group comprises B-cell chronic lymphoproliferative disease patients (n=10). All HCL patients underwent cladribine treatment. Patient demographics, clinical characteristics, and survival outcomes were recorded. Results: The mean age of the predominantly male (81.8%) study group was 51.1±10.2 years. No significant differences in demographic and clinical features existed between the groups (p>0.05). The incidence of BRAF V600E mutation among HCL patients, initially 69.2%, fell to 20% post-treatment. Yet, no significant disparity in overall survival and mortality rates was found between HCL patients with/without BRAF V600E mutation (p=0.256 and p=0.999). Conclusion: The proportion of HCL patients with BRAF V600E mutations decreased from 69.2% to 20% postcladribine. However, persistence of the mutation didn't significantly affect HCL patient survival and mortality.

Objective: Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of CD5+CD19+ B cells in the bone marrow and peripheral blood. Recent studies indicated that expression of IL-10, AID and mir-155 which are regulated by STAT3 are increased in CLL patients. CD5+CD19+ regulator B (Breg) cells secrete IL-10 and suppress the immune system. While the CLL cells show similar immunophenotypic properties to Breg cells, they are also thought to be functionally similar. In this study, STAT3 and IL-10 levels of CLL patients were investigated. Methods: Peripheral blood samples obtained from patients (n:24) and healthy controls (n:14). Peripheral blood mononuclear cells were cultured for 48 hours in the presence and absence of CpG for IL-10 expression and cultured with and without PMA for STAT3 expression. IL-10 and STAT3 expression were analyzed with anti-CD5, anti-CD19, anti-CD38, anti-STAT3 and anti-IL-10 monoclonal antibodies by using flow cytometry. Results: Compared to healthy subjects, increased IL-10+, IL-10+CD19+, STAT3+CD19+ were obtained in lymphocyte population of patients. Increased IL-10 was showed CD19+ B cells of CLL patients. Our results showed that IL-10 levels had no significant difference between CD5+CD19+ cells, whereas STAT3 levels were found lower in patient compared to healthy controls. Conclusion: These results made us thought that the levels of IL-10 and STAT3 expression in CLL B cells is clearly different from normal B lymphocytes might have a role in the biology of CLL. It is believed that the presented data will contribute to the studies that scrutinize the similarity of CLL cells to Breg cells.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the elderly. T follicular helper (TFH) and follicular cytotoxic T (TFC) cells are a subset of CD4+ and CD8+ T cells expressing CXCR5, respectively. OX-40, ICOS, and PD-L1 are secondary immune checkpoint molecules and have a role in the maintenance of an immune response. The literature about the role of ICOS, OX-40, and PD-L1 receptors of TFH and, especially TFC cells, in CLL is limited. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood samples by density gradient centrifugation using Ficoll-Paque from 34 CLL patients and 19 healthy subjects. The expression of ICOS, OX-40, and PD-L1 of TFC and TFH cells in CLL patients was investigated by flow cytometry. According to healthy subjects, TFH and TFC cell levels were increased in CLL patients. High-ICOS and low-PD-L1 expression in TFH cells and high OX-40 and ICOS, low-PD-L1 expression in TFC cells of CLL patients compared to healthy subjects. OX-40 expression was positively correlated with TFH and TFC cells levels [R = 0.504, (p = 0.002) and R = 0.316, (p = 0.05)]. Additionally, OX-40 expression of TFH was positively correlated with ICOS expression [R = 0.660, (p < 0.001)] and PD-L1 expression [R = 0.649, (p < 0.001)]. OX-40L, ICOSL, and PD-L1 expression of B cells were elevated in CLL patients compared to healthy subjects. OX-40L expression of B cells was positively correlated with ICOSL expression [R = 0.568, (p = 0.0004)] and PD-L1 expression. Elevated CD4+CXCR5+ TFH and CD8+CXCR5+ TFC cells with high OX-40 and ICOS activator and low-PD-1L inhibitor receptor expression in CLL patients might have a role in the pathogenesis of CLL.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disease due to high serum low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol-lowering interventions are fundamental for patients with HoFH. OBJECTIVE: It was aimed to investigate the association between the mental status of patients with HoFH and healthy lifestyle behaviors. METHODS: This subgroup analysis of the A-HIT1 population included the data of patients aged >= 18 years with a clinical diagnosis of HoFH undergoing therapeutic LDL apheresis. Besides the demographic and clinical characteristics of patients, healthy lifestyle behaviors were assessed, and psychiatric symptoms were screened by Symptom Check List (SCL-90-R). RESULTS: The highest percentage for pathology was observed in dimensions of obsessive-compulsive, somatization, interpersonal sensitivity, and depression in SCL-90-R. Patients with any cardiovascular condition have more psychiatric symptoms in different fields of SCL-90-R. The outcomes of the correlative analysis indicated that lower the age of the first coronary event better the psychiatric status, probably denoting a better adaptation to disease and its treatment. Among 68 patients, 36 patients were not exercising regularly. Patients with regular physical activity had significantly lower scores in most dimensions of SCL-90-R and there was no association between regular physical activity and other investigated variables. The strongest predictor of regular exercising was global severity index of SCL-90-R. CONCLUSION: In the HoFH population, there was a high prevalence of mental disturbances. Better psychiatric status was associated with regular exercising. Therefore, assessing the mental status of patients with HoFH and referring patients in need, to a psychiatrist, may improve the outcome of patients. (C) 2020 National Lipid Association. All rights reserved.

Chronic lymphocytic leukemia (CLL) is a neoplasm characterized by excessive accumulation of B lymphocytes in the peripheral blood, bone marrow and lymph nodes. We assessed the expressions of 22 genes in the p53 pathway in 30 CLL patients and 15 healthy subjects by a RT2 Profiler PCR (polymerase chain reaction) Array technique and their relation to cytogenetic aberrations detected by fluorescent in situ hybridization (FISH). Our Student's t-test results indicated that ATM, ATR, BAX, CASP9, CDK4, CDKN2A, CHEK1, CHEK2, E2F3, MCL1, MDM2, MDM4, PCNA, RB1, P53 and BCL2 genes were statistically significant (p <0.001). For six genes (APAF1, CDKN1A, E2F1, GADD45A, PTEN and PTX3) were not statistically significant. The ATM, ATR, BAX, CASP9, CDK4, CDKN1A, CDKN2A, CHEK1, CHEK2, MDM2, MDM4, PCNA, RB1, P53, E2F1, GADD45A and BCL2 genes were found to be upregulated by the 2-ᐃᐃCt (relative fold change in gene expression) method. The highest up-regulation was detected in CDKN2A and BCL2 genes, 10.22- and 8.51-fold, respectively. On the other hand, the PTX3 gene with a fold regulation of 1.84 was found to the highest downregulation. Overall, the CDNK2A BCL2 and PTX3 genes are related to the mechanism of the disease in the p53 pathway and may be an important predictor of the prognosis of the disease. The BCL2 gene may be associated with increased risk of developing CLL. We suggest that the PTX3 gene may be considered as a marker associated with CLL disease. The CDKN2A gene expression seems to play a protective role in CLL.

Introduction: Chronic lymphocytic leukemia (CLL) that arises by malignant transformation of mature B cell is the most common leukemia in elderly. CLL is characterized by accumulation of CD5(+)CD19(+) cells in the peripheral blood and lymphoid organs. While CD8(+) T lymphocytes response intracellular pathogen and tumor, CD4(+) T lymphocytes regulate immune response. T follicular (Tfol) cells stimulate affinity maturation and class-switch recombination in B lymphocytes due to cytokine and surface molecules. In this study, we aimed to investigate CD4(+)T, CD8(+)T and CD3(+)CD4(+)CXCR5(+) follicular T (Tfol) cells in the peripheral blood of the CLL patients compared to healthy controls. Materials and Methods: Peripheral blood samples were collected from 37 patients with CLL and 16 healthy subjects. CD4(+) T, CD8(+) T and Tfol cells in peripheral blood samples were analyzed by flow cytometry. Results: CD4(+) T, CD8(+) T and Tfol cells were decreased in all lymphocyte population, CD4(+)T cells are decreased, and CD8(+) T and Tfol cells are increased but in T cell population. There was no differences T cell subgroups and clinical outcome. Conclusions: Although the high CD8(+) T lymphocyte and Tfol cell ratios observed in patients may not be a prognostic marker for the clinical course of the disease, the increased Tfol cell ratio as a result of the disease may be the source of the cytokines required for the survival and proliferation of leukemic B cells and the induction of enzymes that were though to be associated with chromosomal deletions in these cells.

Hereditary spherocytosis (HS) is characterized by the morphological transformation of erythrocytes into a spherical shape due to a hereditary defect in cell membrane proteins (ghosts) associated with disruption of erythrocyte skeletal structures. Contrary to the literature, pores were detected in the erythrocytes of a patient with HS. The aim of the present study was to determine the affected proteins and genes that were responsible for the pores. Ghost isolation was performed to determine the proteins responsible for the pores observed on the erythrocytes of the patient. Erythrocyte membrane proteins were visualized using SDS‑PAGE. Exome and matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI TOF MS) analyses were used to identify the genes and proteins responsible for the observed defect. Quantitative protein assessments were performed using MALDI TOF MS. A difference was detected in the components of the erythrocyte membrane proteins. Band 3 and protein 4.2, which serve a particular role in membrane structure, decreased 4.573 and 4.106 fold, respectively. Through proteomic analyses, a non‑synonymous exonic mutation region was identified in the Golgi membrane protein 1 (GOLM1) gene (Chr9 rs142242230). Sorting Intolerant From Tolerant and Polymorphism Phenotyping Scores, Likelihood Ratio Tests and MutationTaster revealed that the mutation was deleterious. The pores observed in the morphology of the erythrocytes may have developed due to the decrease in these proteins, which reside in the erythrocyte membrane structure. Furthermore, genetic profiling of the patient with HS and her family was conducted in the present study. Next‑generation sequencing was used, and the genetic source of HS was identified as a GOLM1 gene mutation. The assessment of specific molecular defects is often not performed as the majority of mutations are unique to a family. However, molecular analyses should be performed in severe cases where prenatal diagnosis is required, or for unique HS phenotypes to aid scientific investigation.

C. difficile is responsible for antibiotic associated diarrheas with various clinical presentations.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening inherited disease leading to early-onset atherosclerosis and associated morbidity. Because of its rarity, longitudinal data on the management of HoFH in the real world are lacking, particularly on the impact the condition has on quality of life (QoL), including the impact of the extracorporeal lipid removal procedure apheresis (LA). METHODS: The A-HIT1 study included 88 patients with HoFH aged >= 12 years receiving regular LA in 19 centers in Turkey. Demographic and disease characteristics data were obtained. For patients aged >= 18 years, additional data on psychosocial status were obtained via the SF-36 score, the Hospital Anxiety and Depression Scale, and a HoFH-specific questionnaire. RESULTS: There was no standardized approach to therapy between centers. Mean (+/-SD) frequency of LA sessions was every 19.9 (+/-14) days, with only 11.6% receiving LA weekly, and 85% of patients were not willing to increase LA frequency. The most common concerns of patients were disease prognosis (31%), and physical, aesthetic, and psychological problems (27.5%, 15.9%, and 11.6%, respectively). Lower age at diagnosis was associated with better QoL, lower anxiety, improved functioning, and greater emotional well-being compared to later diagnosis. CONCLUSIONS: These findings demonstrate that adult patients with HoFH undergoing LA, experience significant impairment of QoL with an increased risk of depression. From patients' point of view, LA is time-consuming, uncomfortable, and difficult to cope with. The speed of diagnosis and referral has a considerable impact on patient well-being. (C) 2019 National Lipid Association. All rights reserved.

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator’s choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2–6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943).

Background and aims: Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by lethally high levels of low-density lipoprotein cholesterol (LDL-C) from birth, and requires rapid and aggressive intervention to prevent death due to coronary heart disease and/or atherosclerosis. Where available, lipoprotein apheresis (LA) is the mainstay of treatment to promote survival. Methods: A-HIT1 registry was conducted with the aim of providing insight to the real-life management of HoFH patients undergoing LA in Turkey, where LA procedures are fully reimbursed and widely available. Participating centers provided patient information, including family history, treatment patterns and relevant laboratory values, via a standard questionnaire. Results: The study evaluated 88 patients (mean age: 27 +/- 11 years, 41 women) in 19 centers. All patients were receiving regular LA with a clinical diagnosis of HoFH. Mean age at first symptom disease was 10 +/- 10 years, and at diagnosis it was 12 +/- 11 years; 74.7% were diagnosed before age 15 years; and only 31% before the age of 7. First referral of most patients was to pediatricians. Early onset coronary artery disease was present in 57.8% of patients. Mean age at first LA was 21 +/- 12 years. Only 11 (12.5%) patients were undergoing LA weekly. Mean frequency of apheresis sessions was 19 +/- 13 days. For the last four LA sessions, LDL-C levels reached the target in only in 5.7% of patients. Conclusions: Diagnosis of HoFH is delayed, and LDL targets are not reached. LA frequencies are not optimal. Urgent attention is needed to support the survival of patients with HoFH. (c) 2018 Elsevier B.V. All rights reserved.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of the malign lymphocytes in the bone marrow and blood. LATS2 (Large Tumor Suppressor Homolog 2) is an important component of the Hippo pathway, which plays a crucial role in regulation of apoptosis, proliferation and cell growth. The present study was designed to determine the interactions between LATS2 (Large Tumor Suppressor Homolog-2) expression on risk of Chronic lymphocytic leukemia (CLL). In 28 patients with CLL and 20 controls, LATS2-mRNA and LATS2-protein expressions were measured by quantitative reverse-transcription-PCR and Western blotting techniques, respectively. The LATS2 expressions were down-regulated in the CLL group compared to the controls. We observed that the percentage of CD20 was higher in CLL subjects with the LATS2-mRNA Fold change (FC) of ≤ 0.1 than those with the LATSmRNA FC of > 0.1 (p= 0.057), while interestingly, the percentage of CD3, CD8, and CD56 T-cell markers was lower in CLL subjects with the FC of ≤ 0.1 than those with the LATS2-mRNA FC of > 0.1 (p= 0.004, p= 0.008 and p= 0.058, respectively). The relationships among between the immunophenotypically determined B-cell marker-CD20, T cell markers-CD3, CD8 and CD56 and LATS2-mRNA levels may suggest possible diagnostic/ prognostic value of LATS2 in CLL. We suppose that these markers may be significant indicators of the severity or advanced stages of the CLL.

Background and aims: Familial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of largescale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). Methods: A-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. Results: A-HIT1 evaluated 88 patients (27 +/- 11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37 +/- 7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19 +/- 13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19 +/- 13 (7-90) days. Only 2 centers were aware of the target LDL levels. A-HIT2 enrolled 1071 FH patients (53 +/- 8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. Conclusions: The first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.