Melanoma-associated antigen A11 reduces erlotinib and afatinib efficacy in head and neck cancer

Melanoma-associated antigen A (MAGE-A) proteins are members of the cancer/testis antigens (CTA), and the expression of these proteins is almost exclusively limited to malignant cells, making them an attractive treatment target. MAGE-A expression is correlated with poor overall survival in several cancers, including head and neck squamous cell carcinoma (HNSCC). Among others, MAGE-A11 was found to be associated with resistance to different antineoplastic and targeted compounds, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We searched The Cancer Genome Atlas (TCGA) database with a focus on MAGE-A and found that MAGE-A overexpression is a common event in HNSCC (27.5%). Furthermore, MAGE-A overexpression was correlated with significantly reduced overall survival (35.45 months vs. 64.78 months, P = 0.0173). In particular, MAGE-A11 overexpression was found in 9% of specimens. We then examined MAGE-A11 expression, the efficacy of EGFR and the EGFR mutational status and the effects of the pan-HER (human EGFR) TKIs erlotinib and afatinib in HNSCC cell lines. Next, we used a model of stable MAGE-A11 overexpression to demonstrate that MAGE-A11 impaired the efficacy of erlotinib and afatinib. In summary, our study provides evidence that MAGE-A11 contributes to erlotinib and afatinib resistance in head and neck cancer cell lines.     

91例胃粘膜EB病毒感染的检测

ＥＢ病毒是一种肿瘤病毒，与人类鼻咽癌、淋巴瘤关系密切。近年来ＥＢ病毒相关性胃癌在国外已有报道。本文通过胃镜活检，对９１例胃粘膜行ＰＣＲ方法检测ＥＢ病毒感染。一、材料与方法：９１例患者均为我院１９９６年３月～６月门诊及住院胃镜检查者。男５８例，女３３例...     

A technique for the flow cytometric analysis of lymphocytes bearing histamine receptors

Histamine receptors have been demonstrated on lymphocyte membranes by a variety of techniques. We now report a method that allows for the flow cytometric analysis of histamine receptors on human peripheral T cells. Histamine is conjugated to fluoresceinated human albumin by the coupling agent ECDI. This conjugated histamine compound (FHA-his) binds to approximately 45% of T cells. Fluoresceinated human albumin alone (FHA), not conjugated to histamine, does not bind to T cells. In addition, unconjugated histamine can inhibit completely the binding seen with FHA-his. We conclude that this technique demonstrates specific FHA-his binding to histamine receptors on T cells and can be used to determine the number of cells bearing such receptors. In addition, the reagent could be used with a cell sorter to isolate distinct histamine-receptor-bearing (HR+) cells for further immunologic study.     

Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease

Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.     

Differential effect of Serratia protease on platelet surface glycoproteins Ib and V

The effect of a zinc metalloprotease from Serratia marcescens on platelet surface glycoproteins (GP) Ib and V was analyzed. Increasing protease treatments caused progressive loss of GP Ib with appearance of the major fragment, glycocalicin, in the supernatant solution. No GP V was detected in the supernatant solution, and protease-pretreated platelets had the same capacity as control platelets to release fragment 1 of GP V in response to thrombin. The Serratia protease- pretreated platelets did show the lag before thrombin-induced dense granule secretion, characteristic of platelets modified by pretreatment with other nonstimulating proteases. Treatment with Serratia protease gives the only demonstrated selective loss of GP Ib without apparent effect on GP V. It suggests that GP V (1) does not depend on GP Ib for its association with platelets and (2) is not the substrate for protease modification of platelet function.     

Mechanical load on the inspiratory muscles during exercise hyperpnea in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary The aim of this study was to evaluate the difference between Type 1 (insulin-dependent) diabetic patients and healthy control subjects regarding inspiratory muscle load during exercise hyperpnea. For this purpose an incremental progressive exercise test on a cycle ergometer was performed by 36 Type 1 diabetic patients and 40 healthy subjects. In order to determine the mechanical load on the inspiratory muscles breath by breath, we selected the following two parameters, which represent the pressure generated by the inspiratory muscles as well as the duration and velocity of their contraction: (1) the oesophageal tension time index, which is the product of the duty cycle (ratio of inspiratory time to total breath cycle duration) and the mean oesophageal pressure expressed as a percentage of the maximal oesophageal pressure and (2) the mean oesophageal pressure change per time unit during the inspiratory phase of each breathing manoeuver, which is expressed as a fraction of the subject's maximal oesophageal pressure. Comparison of the two groups revealed that at similar levels of ventilation the mechanical load on the inspiratory muscles was significantly higher in the Type 1 diabetic patients than in the control subjects. When the loading was stopped the maximal ventilation was lower in the patients. Nevertheless, they reported a degree of respiratory effort sensation comparable to the control group, which seems to have been caused by an increase of the mechanical load on the ventilatory muscles.     

Prediction of interstitial lung involvement in rheumatoid arthritis. The value of clinical data, chest roentgenogram, lung function, and serologic parameters.

We initiated the present study to predict interstitial lung involvement in rheumatoid arthritis (RA) by means of logistic regression analysis of clinical data, lung function, chest roentgenogram, and serologic parameters. Fifty-eight nonsmoking patients with RA were randomized from the rheumatologic unit and sent for investigation to the pulmonary department. Bronchoalveolar lavage (BAL) was performed in the middle lobe and the BAL fluid was considered abnormal in case of increased cell count per milliliter and/or lymphocytosis and/or neutrophil granulocytosis; these findings or combinations thereof were found in 42 (72.4 percent) of 58 cases. The patients' data that had an impact on the normality of BAL were the sex (p = 0.001), vital capacity (p = 0.028), peripheral blood T-helper cells (OKT4+) (p = 0.025), DR(+)-lymphocytes (p = 0.002), and antinuclear antibodies (p = 0.025). By means of the logistic regression analysis, it was possible to reach high significance in the prediction of interstitial lung involvement, with a sensitivity of 92.9 percent and a specificity of 75.0 percent (p less than 10(-6)). The efficiency of prediction was 87.9 percent. From these results, we conclude that interstitial lung involvement in RA is predictable from laboratory findings that have been yielded by noninvasive diagnostic techniques. These data should be used in clinical routine monitoring and they may help to facilitate the assessment of whether bronchoscopy is indicated.     

Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis

Programmed cell death, also known as apoptosis, is frequently initiated when cells are deprived of specific trophic factors. To investigate if accelerated apoptosis contributes to the pathogenesis of Diamond- Blackfan anemia (DBA), a rare pure red blood cell aplasia of childhood, we studied the effect of erythropoietin (epo) deprivation on erythroid progenitors and precursors from the bone marrow of DBA patients as compared with hematologically normal controls. Apoptosis in response to epo deprivation was evaluated by enumeration of colony-forming unit- erythroid (CFU-E)- and burst-forming unit-erythroid (BFU-E)-derived colonies in plasma clot semisolid culture and by the identification of typical DNA oligosomes by gel electrophoresis from marrow mononuclear cells in liquid culture. In all DBA patients there was a marked decrease in CFU-E- and BFU-E-derived colony formation compared with normal controls at comparable time points of epo deprivation, with a complete loss of CFU-E-derived colonies in semisolid culture by 9 hours of epo deprivation versus 48 hours in controls. The BFU-E-derived colony response to epo deprivation displayed a similar pattern of decrement. Apoptotic changes assessed by the presence of characteristic DNA fragmentation began in the absence of epo deprivation and were readily detected within 3 hours of epo deprivation in DBA cultures versus 9 hours in controls. We conclude that DBA is characterized by accelerated apoptosis as measured by the loss of erythroid progenitor clonogenicity and increased progenitor and precursor DNA fragmentation leading to the formation of characteristic oligosomes, consistent with an intrinsic erythroid-progenitor defect in which increased sensitivity to epo deprivation results in erythroid failure.     

A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells

BACKGROUND & AIMS: Constitutive expression of cyclooxygenase 2 (COX-2) has been found in 85% of colorectal cancers. Ras mutations are found in 50% of colorectal adenocarcinomas. The aim of this study was to determine the role of COX-2 in ras-induced transformation in rat intestinal epithelial (RIE) cells. METHODS: Cell growth was determined by cell counts. The expression of COX-2 was examined by Northern and Western analyses. For tumorigenicity assays, cells were inoculated into dorsal subcutaneous tissue of athymic nude mice. DNA-fragmentation assays were performed to detect apoptosis. RESULTS: The expression of COX-2 was increased in RIE-Ras cells at both messenger RNA (9-fold) and protein (12-fold) levels. Prostaglandin I2 levels were elevated 2.15-fold in RIE-Ras cells. Serum deprivation further increased COX-2 expression 3.8-fold in RIE-Ras cells. Treatment with a selective COX-2 antagonist (SC58125) inhibited the growth of RIE-Ras cells through inhibition of cell proliferation and by induction of apoptosis. SC-58125 treatment reduced the colony formation in Matrigel by 83.0%. Intraperitoneal administration of SC-58125 suppressed RIE-Ras tumor growth in nude mice by 60.3% in 4 weeks. SC-58125 treatment also induced apoptosis in RIE-Ras cells as indicated by increased DNA fragmentation. CONCLUSIONS: Overexpression of COX-2 may contribute to tumorigenicity of ras-transformed intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits growth of ras-transformed intestinal epithelial cells and induces apoptosis. (Gastroenterology 1997 Dec;113(6):1883-91)     

Dental MRI: Imaging of soft and solid components without ionizing radiation

Purpose:

To evaluate the ability of conventional and ultra‐short or zero echo time MRI for imaging of soft and solid dental components in and ex vivo.

Materials and Methods:

Turbo spin echo (TSE), ultra‐short echo time (UTE), and zero echo time (ZTE) MRI were performed on extracted (human and equine) teeth and in vivo using whole‐body and small‐bore MR systems at 3 T, 7T, and 9.4T, respectively.

Results:

At an isotropic resolution of (600 μm)³, strong signal of soft‐tissue, e.g., mucosa and nerves with excellent contrast was achieved using TSE at 3T in vivo. No signal, though, was obtained from solid components, e.g., teeth (due to short T₂). In contrast, dentin, cementum as well as enamel of extracted teeth were readily depicted using UTE and ZTE at a resolution of ≈ (150 μm)³ at 7T and 9.4T. In particular, ZTE provided higher signal in enamel.

Conclusion:

As an alternative to X‐ray based methods like cone‐beam computed tomography (CT) or conventional CT, the presented results demonstrate the potential of ZTE and UTE MRI as a radiation‐free imaging modality, delivering contrast of soft and solid components at the same time. J. Magn. Reson. Imaging 2012;36:841–846. © 2012 Wiley Periodicals, Inc.