A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.     

T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis.      

Relationship between Pollen Counts and Weather Variables in East-Mediterranean Coast of Turkey

BACKGROUND: Aeroallergen sampling provides information regarding the onset, duration and severity of the pollen season that clinicians use to guide allergen selection for skin testing and treatment. OBJECTIVES: This atmospheric survey reports (1) airborne pollen contributions in Adana in one-year period (2) pollen onset, duration and peak level (3) the relationship between airborne pollen and selected meteorological variables and; (4) effects on symptoms in pollen allergic children. METHODS: Pollen sampling was performed with a volumetric Burkard Spore Trap. Meteorological data were measured daily from April 2001 to April 2002. Asthma symptom scores were investigated in 186 pollen allergic children that were on follow up in pediatric allergy outpatient clinics during same period. RESULTS: Average measurements included 82.5% tree pollen, 7.7% grass pollen and 9.8% herb pollen 54 taxa were identified during one year. The most prominent tree pollens were Cupressaceae, Eucalyptus and Pinus. The most common herb was Chenopodiaceae pollen family. When airborne pollen levels were examined in relation to single meteorological conditions; daily variations in total pollen counts were not significantly correlated with any variable studied (humidity, rainfall, temperature and wind) (p > 0.05). On the other hand, statistically significant relationship between pollen concentration and symptom scores were found (p > 0.05). Positive correlations were seen between both Gramineae and Herb pollen, and humidity and rainfall from March to July. However, positive correlations were detected between tree pollen counts and temperature and humidity in May and June. CONCLUSION: This survey is the first volumetric airborne pollen analysis conducted in the survey area in Adana. This study suggested that the effects of weather on pollen count and symptom scores in this population could not be clearly identified with the evaluation of one-year data. However, pollen counts had effect on allergic symptoms in pollen allergic children. Examination of the complex interaction of multiple whether parameters would perhaps more fully elucidate the relationship between meteorology and aerobiology and provide the clinician with information necessary to forecast pollen prevalence. An awareness of the ever chancing, local aeroallergen patterns requires regular monitoring. Such awareness serves as a useful guide in the effective testing and treatment of atopic patients.     

Nasal mucosal expression of nitric oxide synthases in patients with allergic rhinitis and its relation to asthma.

BACKGROUND: Nitric oxide (NO) has contradictory roles in the pathophysiology of allergic inflammation in both allergic rhinitis (AR) and asthma. Small amounts of NO produced by constitutive NO synthase (NOS) is anti-inflammatory, whereas large amounts produced by inducible NOS (iNOS) are proinflammatory. OBJECTIVE: To investigate the difference in constitutive endothelial NOS (eNOS) and iNOS expression in nonallergic and allergic mucosa and the possible relation of this to the coexistence of asthma in seasonal AR. METHODS: Seventeen patients (10 women and 7 men) with seasonal AR and 9 nonallergic patients (5 women and 4 men) with nasal septum deviation were enrolled. Inferior turbinate nasal biopsy specimens were obtained in all. Levels of eNOS and iNOS expressed as immunohistochemical scores (HSCOREs) were determined immunohistochemically from the specimens. RESULTS: The mean +/- SD HSCOREs for eNOS in patients with seasonal AR were not significantly different from those of the nonallergic controls (1.85 +/- 0.78 vs 1.63 +/- 0.54; P = .12). On the other hand, the mean +/- SD HSCOREs for iNOS were significantly higher in patients with seasonal AR (1.75 +/- 0.75 vs 0.71 +/- 0.6; P = .004). Furthermore, although eNOS expression was not different between seasonal AR patients with and without asthma, the mean +/- SD HSCOREs for iNOS were significantly higher in the patients with asthma (1.93 +/- 0.78 vs 1.65 +/- 0.55; P = .01). CONCLUSION: Increased expression of iNOS might have a role in the development of allergic inflammation in upper and lower airways and in comorbidity of AR and asthma.     

The influence of bilateral sagittal split ramus osteotomy on submental‐cervical aesthetics

The effect of orthodontic‐surgical treatment on submental‐cervical region was evaluated in a very limited number of studies. The aim of this study was to evaluate submental‐cervical soft tissue contour changes following mandibular advancement and set‐back procedures via bilateral sagittal split ramus osteotomy. Sixty‐seven patients were included in this study. Group 1 consisted of 27 skeletal Class II patients who underwent mandibular advancement surgery, whereas Group 2 consisted of 40 skeletal Class III patients who underwent mandibular set‐back surgery. Various linear and angular measurements were performed on pre‐operative and sixth month post‐operative cephalometric radiographs. A new method was used to evaluate the amount of sagging at submental region. The submental length did not change in Group 1; however, it decreased significantly in Group 2 (P < 0·05). The angle between submental plane and facial plane decreased to 95·9° from 98·8° in Group 1(P < 0·05), whereas it increased to 93·1° from 88·2° in Group2 (P < 0·05). The change of submental soft tissue sag was almost stable in Group 1, while 0·34 mm increase of sag was observed in Group 2. This increase was not statistically significant (P > 0·05). Mandibular set‐back and advancement procedures do not remarkably change the submental sag following approximately 6 mm jaw movement. Although mandibular advancement did not significantly effect submental length, soft tissue followed mandibular set‐back with a ratio of 1:1 at C‐point to projection of soft tissue pogonion and 1:0·7 at C‐point to soft tissue menton distances.     

The Effects of the Enriched Environment on Sympathetic Skin Response in Pentylenetetrazol-Kindled Rats

Epilepsy is a neurodegenerative disease that interrupts the normal electrical activity of the brain and promotes abnormal wiring in this organ.Epileptic seizures are often associated with significant changes in the functioning of the autonomic nervous system(ANS).     

Cytokines,adipocytokines and inflammatory markers in patients on continuous ambulatory peritoneal dialysis and hemodialysis

Background: Cytokines are essential mediators of immune response. Chronic renal failure patients suffer from chronic inflammation that results from factors such as impaired renal function, accumulation of uremic toxins and bio incompatibility of dialyzer membranes. These patients are also at increased risk of cardiovascular diseases. We have evaluated cytokines, adipocytokines and inflammatory markers in patients with chronic renal failure undergoing hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD).

Material and methods: We have determined serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), leptin and ghrelin levels of chronic renal failure patients treated with either HD (n?=?20) or CAPD (n?=?20). TNF-α, IL-6, ghrelin and leptin measurements were performed by commercially available kits based on enzyme-linked immunosorbent assay (ELISA) method. hsCRP levels were determined by turbidimetric methods.

Results: Serum TNF-α and IL-6 levels of patients on HD were significantly higher than those of the ones on CAPD (p?<?0.05). Ghrelin, leptin and hsCRP concentrations were similar in both groups.

Conclusions: We can conclude that cytokine production is more obvious in HD process.     

Blastic Plasmacytoid Dendritic Cell Neoplasm: Single Center Experience on a Rare Hematological Malignancy

PurposeBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poor prognostic hematological malignancy. There is still no standard treatment established for BPDCN patients. We aim to summarize the main clinical, biological features and treatment of 9 BPDCN patients.MethodsNine patients with BPDCN who had been diagnosed between July 2008 and December 2018 in Ankara University School of Medicine, were retrospectively evaluated.ResultsAll patients (n = 9) were male, median age was 64 (21–80). Five patients (55.6%) had bone marrow infiltration, 5 patients (55.6%) cutaneous lesions, 6 patients (66.7%) lymph node involvement, 2 patients (22.2%) central nervous system involvement and 2 patients (22.2%) spleen involvement at time of diagnosis. Complex karyotype was observed in 2 patients. CHOP was given to 5 patients (55.6%), hyper-CVAD to 2 patients (22.2%), fludarabine, cyclophosphamide and mitoxantrone to 1 patient (11.1%) and cyclophosphamide, etoposide, methylprednisolone to 1 patient (11.1%) as first line chemotherapy. Four patients (44.4%) underwent allogeneic hematopoietic stem cell transplantation (AHSCT) in complete remission (CR) 1. Venetoclax was given to a transplant ineligible patient who had skin and lymph node involvement, with the off-label use. The median follow-up time was 15.9 months (3–48.6 months). Estimated median overall survival was 15.9 + 1.6 (95% CI 12.7–19.1) months.ConclusionIntensive induction therapies followed by AHSCT in CR seems to be best approaches for patients with BPDCN. Thus, more effective treatment strategies particularly targeted therapies should be warranted to improve the survival of patients with this rare disease.