CDK4 is a probable target gene in a novel amplicon at 12q13.3-q14.1 in lung cancer

Several chromosomal regions are recurrently amplified or deleted in lung tumors, but little is known about the underlying genes, which could be important mediators in tumor formation or progression. In lung cancer, the RB1-CCND1-CDKN2A pathway, involved in the G1-S transition, is damaged in nearly all tumors. In the present study, we localized a novel amplicon in lung tumors to a fragment of less than 0.5 Mb at 12q13.3-q14.1 by using comparative genomic hybridization (CGH) on cDNA microarrays. This approach enabled us to identify 10-15 genes with the most consistent amplifications. Semiquantitative RT-PCR analyses of 13 genes in this region showed that four of them (CDK4, CYP27B1, METTL1, and TSFM) were also highly up-regulated. Immunohistochemical (IHC) analysis of 141 tumor samples on a tissue microarray showed that CDK4 was expressed at a high level in 23% of lung tumors. Six (21.4%) of the tumors with high CDK4 expression (n = 28) were shown by fluorescence in situ hybridization (FISH) to contain the 12q13.3-q14.1 amplification. For CDK4, a positive correlation was found between gene copy number (FISH and CGH array), mRNA expression (RT-PCR), and level of protein expression (IHC). CDK4 expression did not correlate with CDKN2A methylation status. Amplification of CDK4 has been described in other tumor types, but its role in lung cancer remains to be elucidated. Although CDK4 amplification seems to be a relatively rare event (4.3%) in lung tumors, it indicates the significance of the RB1-CCND1 pathway in lung tumorigenesis.     

Effect of tumor necrosis factor on cell proliferation kinetics and sister chromatid exchange frequency in human lymphocytes

Recombinant human tumor necrosis factor (TNF) was found tocause a significant increase in cell proliferation rates andsister chromatid exchange (SCE) frequency in phytohemagglutinin-stimulatedhuman lymphocytes in vitro. The cells were treated for the entirecultivation time with 10, 50, 100, 500, 1000 and 5000 U/ml TNF.Cell proliferation rates, as measured by the replication index,increased significantly (P < 0.01) in a concentration-independentmanner. The maximal extent of SCE induction (15.18 ±0.57 versus 10.26 ± 0.45 SCEs/cell in control, P <0.001) was observed with 50 U/ml TNF.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.     

Investigating the relationship between the severity of periodontitis and rheumatoid arthritis: a cross-sectional study

Clinical Rheumatology - This paper evaluates the prevalence and severity of periodontitis (PD) in patients with rheumatoid arthritis (RA), focusing on the link between the severity of PD with RA...     

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.     

Combination of Extrusion and Fermentation with Lactobacillus plantarum and L. uvarum Strains for Improving the Safety Characteristics of Wheat Bran

Processed wheat bran (W) is of great importance for food and feed. Consequently, the biosafety of W should be evaluated and improved with valorisation strategies. This study tested a design combining extrusion (at temperature of 115 and 130 °C; screw speeds of 16, 20, and 25 rpm) and fermentation with Lactobacillus plantarum and L. uvarum strains for the valorisation of W to provide safer food and feed stock. The influence of different treatments on biogenic amine formation, mycotoxin content, and free amino acids, as well as acidity, microbiological parameters, and sugar concentration, were analysed. This research showed that a combination of extrusion and fermentation with selected strains can change several aspects of W characteristics. There was a significant effect of applied treatments on acidity and the microbiological parameters of W, as well as biogenic amines content. The lowest total mycotoxin concentration (29.8 µg/kg) was found in extruded (130 °C; 25 rpm) and fermented with L. uvarum sample. Finally, the combination of the abovementioned treatments can be confirmed as a prospective innovative pre-treatment for W, capable of potentially enhancing their safety characteristics and composition.     

Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study

Purpose  

Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2.     

Cortical dynamics subserving visual apparent motion

Motion can be perceived when static images are successively presented with a spatial shift. This type of motion is an illusion and is termed apparent motion (AM). Here we show, with a voltage sensitive dye applied to the visual cortex of the ferret, that presentation of a sequence of stationary, short duration, stimuli which are perceived to produce AM are, initially, mapped in areas 17 and 18 as separate stationary representations. But time locked to the offset of the 1st stimulus, a sequence of signals are elicited. First, an activation traverses cortical areas 19 and 21 in the direction of AM. Simultaneously, a motion dependent feedback signal from these areas activates neurons between areas 19/21 and areas 17/18. Finally, an activation is recorded, traveling always from the representation of the 1st to the representation of the next or succeeding stimuli. This activation elicits spikes from neurons situated between these stimulus representations in areas 17/18. This sequence forms a physiological mechanism of motion computation which could bind populations of neurons in the visual areas to interpret motion out of stationary stimuli.     

Experimental acute pancreatitis induces mitochondrial dysfunction in rat pancreas,kidney and lungs but not in liver

Background/aimsExcessive systemic inflammatory response syndrome during severe acute pancreatitis (AP) leads to multiple organ dysfunction syndrome, which is the main cause of death and may be associated with primary mitochondrial disturbances. The aim of our study was to evaluate the role of mitochondria during experimental AP in pancreas and vital organs like kidney, lungs and liver within the first 48 h.MethodsAP was induced in 39 male Wistar rats by intraductal application of sodium taurocholate (5%, 1.75 ml/kg). Animals were divided into groups reflecting the time from induction of the AP till collection of tissues (control and 1, 3, 6, 12, 24, 48 h). Mitochondria were isolated by differential centrifugation and mitochondrial respiration rates were measured oxygraphically.Results(1) Mitochondria in pancreas are affected within the first 6 h after onset of AP, (2) kidney mitochondria are affected 24 h after onset of AP, (3) lungs mitochondria are affected within 48 h after onset of AP whereas (4) liver mitochondria remain well preserved within the first 48 h. Severe AP–induced decrease in the oxidative phosphorylation of pancreas, kidney and lungs mitochondria was more pronounced with Complex I-linked (glutamate/malate) than with Complex II-linked (succinate) substrates and was associated with inhibition of Complex I.ConclusionOur data show that the disturbances of mitochondrial energy metabolism in pancreas, kidney and lungs may play an important role in the development and progression of AP as a systemic disease.