A novel Tn antigen epitope-recognizing antibody for MUC1 predicts clinical outcome in patients with primary lung adenocarcinoma.

Mucin 1 (MUC1) expression is upregulated in multiple types of cancer, including lung cancer. However, the conventional anti-MUC1 antibody is not useful for the differentiation of malignant lung tumors and benign lesions due to its limited specificity. Our previous study screened a novel epitope-defined antibody against cancer-associated sugar chain structures that specifically recognizes the MUC1 Tn antigen (MUC1-Tn ED Ab). In the present study, its potential utility as a diagnostic marker and therapeutic tool for lung adenocarcinoma (ADC) was examined. Immunohistochemical analysis of a lung ADC tissue microarray was performed using the MUC1-Tn ED Ab (clone SN-102), and the results were compared with those of another clone and commercially available MUC1 antibodies. The association between positive immunoreactivity of SN-102 and clinicopathologic factors was analyzed. Furthermore, the association between MUC1-Tn expression and epithelial-mesenchymal transition markers and radiological characteristics was analyzed. Moderate or high MUC1-Tn expression (MUC1-Tn-H) was observed in 138 (78.9%) of the 175 lung ADC cases. MUC1-Tn-H was associated with male sex, cigarette smoking, tumor extension, pleural invasion, and higher preoperative serum carcinoembryonic antigen and cytokeratin 19 fragment levels. Tumors with MUC1-Tn-H had higher consolidation/tumor ratios according to computed tomography and greater uptakes of 18F-fluorodeoxyglucose. A total of 46 (26.9%) of the tumors had mesenchymal features, and MUC1-Tn positivity was higher in the mesenchymal group than in the epithelial and intermediate groups (P<0.01 and P<0.01, respectively). Patients with tumors exhibiting MUC1-Tn-H had significantly shorter 5-year overall and disease-free survival times (P=0.011 and P<0.001, respectively). Additionally, MUC1-Tn-H was identified as an independent prognostic factor in multivariate analysis (P=0.024). MUC1-Tn is specific for lung cancer cells and can improve diagnostic capabilities. Additionally, it may be a potential therapeutic target in lung ADC.

Evaluation of the characteristics of the neutron beam of a linac-based neutron source for boron neutron capture therapy.

The linac-base neutron source "iBNCT" developed by the Tsukuba team has begun to generate a large intensity of neutrons. To confirm the applicability of the device to BNCT, several characteristic measurements have been implemented. In a water phantom experiment, when the accelerator was operated with an average current of 1.4 mA, the maximum thermal neutron flux was approximately 7.8 × 108 (n/cm2/s). Results demonstrate the stability of the linac over time, showing its promising potential for future patient treatment.

A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes.

Aberrantly truncated immature O-glycosylation in proteins occurs in essentially all types of epithelial cancer cells, which was demonstrated to be a common feature of most adenocarcinomas and strongly associated with cancer proliferation and metastasis. Although extensive efforts have been made toward the development of anticancer antibodies targeting MUC1, one of the most studied mucins having cancer-relevant immature O-glycans, no anti-MUC1 antibody recognises carbohydrates and the proximal MUC1 peptide region, concurrently. Here we present a general strategy that allows for the creation of antibodies interacting specifically with glycopeptidic neoepitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional structure analysis, epitope mapping and biochemical analysis. The X-ray crystal structure of the anti-MUC1 monoclonal antibody SN-101 complexed with the antigenic glycopeptide provides for the first time evidence that SN-101 recognises specifically the essential epitope by forming multiple hydrogen bonds both with the proximal peptide and GalNAc linked to the threonine residue, concurrently. Remarkably, the structure of the MUC1 glycopeptide in complex with SN-101 is identical to its solution NMR structure, an extended conformation induced by site-specific glycosylation. We demonstrate that this method accelerates dramatically the development of a new class of designated antibodies targeting a variety of "dynamic neoepitopes" elaborated by disease-specific O-glycosylation in the immunodominant mucin domains and mucin-like sequences found in intrinsically disordered regions of many proteins.

Correction: A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes.

[This corrects the article DOI: 10.1039/D0SC00317D.].

[Retrograde cavernous sinus air embolism after central venous catheter removal].

Air embolism is a rare, but occasionally fatal complication of peripheral and central venous catheterization. We present a case of an 89-year-old female, who had a central venous catheter placed in her right jugular vein during the perioperative period for right femoral subtrochanteric fracture. On the day following her operation, level of consciousness worsened a few minutes after the catheter was removed. CT scan showed air bubbles in bilateral cavernous sinuses and brachiocephalic vein. Administration of 100% oxygen was started, and she regained consciousness a few hours later, finally air bubbles disappeared on a CT scan performed 10 hours after onset. Air embolism should be taken into consideration when treating venous catheters, and appropriate O2 administration and radiological examinations must be performed immediately if level of consciousness or vital signs deteriorate.

The effect of atmospheric pressure on ventricular assist device output.

The effect of cabin pressure change on the respiratory system during flight is well documented in the literature, but how the change in atmospheric pressure affects ventricular assist device (VAD) output flow has not been studied yet. The purpose of our study was to evaluate the change in VAD output using a mock circulatory system in a low-pressure chamber mimicking high altitude. Changes in output and driving pressure were measured during decompression from 1.0 to 0.7 atm and pressurization from 0.7 to 1.0 atm. Two driving systems were evaluated: the VCT system and the Mobart system. In the VCT system, output and driving pressure remained the same during decompression and pressurization. In the Mobart system, the output decreased as the atmospheric pressure dropped and recovered during pressurization. The lowest output was observed at 0.7 atm, which was 80% of the baseline driven by the Mobart system. Under a practical cabin pressure of 0.8 atm, the output driven by the Mobart system was 90% of the baseline. In the Mobart system, the output decreased as the atmospheric pressure dropped, and recovered during pressurization. However, the decrease in output was slight. In an environment where the atmospheric pressure changes, it is necessary to monitor the diaphragmatic motion of the blood pump and the driving air pressure, and to adjust the systolic:diastolic ratio as well as the positive and negative pressures in a VAD system.

Rechargeable batteries driven by redox reactions of Mn12 clusters with structural changes: XAFS analyses of the charging/discharging processes in molecular cluster batteries.

Molecular clusters such as the Mn12 cluster (Mn12) can be used as a cathode-active material in Li batteries. X-ray absorption fine structure studies on the cathode materials in Mn12 molecular cluster batteries demonstrated that the charging/discharging processes include four-electron-redox reaction of Mn12 with a significant change in its molecular structure.

Discovery of spontaneous deformation of Pd metal during hydrogen absorption/desorption cycles.

A drastic deformation was observed in Pd metal of various shapes after hydrogen absorption and desorption cycles at 150 degrees C at a gas pressure of 1-5 MPa. All of the phenomena observed indicate that some strong internal force is induced spontaneously during hydrogen absorption/desorption cycles to produce a collective deformation so as to minimize the surface.

Skull metastases from atypical pulmonary carcinoid tumor in a 19-year-old man.

A 19-year-old man presented with a rare skull metastasis from atypical pulmonary carcinoid tumor (APCT) manifesting as headache, diplopia, and cough. Head magnetic resonance imaging showed a skull base tumor extending from the posterior clinoid process to the clivus, and calvarial tumors in the right temporal and occipital bones. Chest and abdominal computed tomography showed a round tumor, 4 cm in diameter, in the lower lobe of the right lung and multiple small tumors in the liver. Surgery for the calvarial tumor in the right temporal bone was performed on June 27, 2003. The histological diagnosis was skull metastasis of neuroendocrine tumor. Gamma knife radiosurgery was performed for the residual skull metastases. Partial resection of the right lower lobe was performed for the lung tumor on August 22, 2003. The histological diagnosis was atypical carcinoid tumor. Subsequent adjuvant systematic chemotherapy was performed. The patient died of progression of the tumors in the lung and liver on April 19, 2004. We must consider APCT in the differential diagnosis of pulmonary tumors in adolescents, and perform follow-up observation or treatment, including surgery, if APCT is suspected.

Characterization and expression analysis of the chicken interleukin-11 receptor alpha chain.

Interleukin-11 (IL-11) is a multifunctional cytokine involved in various pathways in blood cells, their precursors and many other cell types in vitro and in vivo. The effects of IL-11 are largely mediated by the IL-11 receptor alpha-chain (IL-11Ralpha). In this study, a putative cDNA sequence encoding the 414 amino acid propeptide of chicken IL-11R (chIL-11R) was identified. The predicted 414 amino acid sequence showed 42-43% sequence identity with mammalian homologues. In a domain search of the molecule, two fibronectin (FN) type-III domains were identified in the C- terminal portion. On comparison with mammalian IL-11R, 4 conserved cysteine residues and a WSXWS motif were observed within the FN type-III domains. Expression analysis revealed that chIL-11Ralpha is strongly expressed in brain, heart, lung, liver, glandular stomach, kidney, the immature testis, ovary and chicken blastodermal cells (CBCs) after 1-day-cultivation. These findings strongly indicate that the identified chicken cDNA sequence encodes chIL-11R alpha-chain homologue.

Excision of foreign gene product with cathepsin D in chicken hepatoma cell line.

To easily and rapidly recover exogenous gene products from chicken egg yolk, we constructed pVTG-catD (VTG, vitellogenin; catD, cathepsin D), a vector cassette carrying two catD-recognition signal peptides (catD-RSPs) in addition to the cloning site. An enhanced green fluorescence protein (EGFP)-encoding DNA fragment was ligated into the pVTG-catD. When the resultant construct pVTG-EGFP-catD containing histidine- and myc-tags was transfected into the chicken hepatoma cell line LMH, EGFP-expression at 24h post-cultivation was confirmed by fluorescence microscopy. Because a signal peptide (NTVLAEF) encoded in pVTG-EGFP-catD is recognized by catD, the VTG-EGFP fusion protein digested with catD was detectable by Western blotting. Digested exogenous gene product was recovered with nickel resin. These results indicate that catD-recognition sites bearing pVTG-catD and His-tags are functional in chicken LMH cells. Therefore, the system described here may be of use in making excision exogenous gene products in the chicken and in creating homozygous knock-in chickens.

Genomic organization of the chicken T-cell receptor beta chain D-J-C region.

We examined overlapping genomic clones containing the chicken T cell receptor (TCR) Dbeta-Jbeta-Cbeta complex, which contains a single diversity segment, four joining segments and four exons that encode the constant region. This sequence comprised 18.3 kb. All four Jbeta sequences possessed typical recombination signal sequences (RSS) with intervening 12-bp spacers at their 5'-ends and splice sites at their 3'-ends. No Jbeta-pseudogenes were identified. TGTG sequences in the RSS heptamer sequences were well conserved, as is the case in mammals. A chicken repeat 1-like sequence was found in the intron region between Jbeta-1336 and Cbeta, and several small repeat sequences were identified in intron regions throughout this cloned genome. As germline sequences revealed complete Jbeta sequences, the CDR3 (complementarity-determining region) sequences of TCRbeta from non-immunized splenocytes were analyzed. Non-coding (N) and palindromic (P) nucleotides were frequently observed at the Dbeta-Jbeta recombination sites. There were differences in length of deletion at the 5'-end of each Jbeta. Deletion of the 5'-end of Jbeta-1280 was particularly short when compared with that of Jbeta-1336, but there were no changes in the length of the CDR3 using any of the four Jbeta sequences.

Brain metastasis from small-cell neuroendocrine carcinoma of the urinary bladder: a case report.

Eight months after radical surgery for small-cell neuroendocrine carcinoma (SCNC) of the urinary bladder, a 69-year-old man was admitted with a brain tumor in the left frontal lobe. The tumor, about 5 cm in diameter, was intensely but heterogeneously enhanced on computed tomography and magnetic resonance imaging. The tumor was subtotally removed, leaving only the portion adjacent to the anterior horn of the left lateral ventricle. Microscopically, the tumor was composed of diffuse sheets of small tumor cells with round to spindle-shaped nuclei, indistinct nucleoli, scant or absent cytoplasm, and indistinct cell margins. Immunohistochemically, the tumor cells were positive for synaptophysin, neuron-specific enolase, chromogranin A, and keratin. Ultrastructurally, the tumor cells showed classic neurosecretory granules and microvilli in the cytoplasm. The tumor was diagnosed as a brain metastasis from SCNC of the urinary bladder. After surgery, whole-brain radiation therapy of 40 Gy was performed, which succeeded in controlling the residual tumor. However, 4 months after surgery, the patient died of meningeal carcinomatosis. To our knowledge, this is the first report focusing on brain metastasis from SCNC of the urinary bladder. The clinicopathological features and pathological diagnosis of this tumor are discussed.