Search

Time series of TEM images observed in the motion of a MoC nanomotor encapsulated in a carbon nanotube during in situ laser irradiation.

The moving components of combustion engines are operated under harsh conditions of high pressures and temperatures. Extreme-pressure anti-wear additives, such as tricresyl phosphate (TCP), are mixed with base oil to prevent wear through the formation of a lubricant film on the substrate. We studied the effect of liquid pressure on the decomposition pathway of TCP in base oil molecules (2,5-dimethylhexane) using hybrid quantum-classical simulations with density functional theory for electrons. At a temperature of 300 K, we found that: (i) bond-breaking barrier energies of both the OC and PO bonds of TCP decrease monotonically as the liquid pressure increases; (ii) the bond-breaking barrier energy of PO is lower than that of OC at pressures of 0 and 2.0 GPa, but is higher at a pressure of 5.0 GPa; and (iii) the applied pressure significantly lowers the bond-breaking barrier energies of both OC and PO when the PO bond of TCP is directed upward from the substrate. These findings are explained by the inhomogeneous distribution of base oil molecules around TCP and the steric repulsion of the PO bond of TCP. These results indicate that the internal structures of the lubricant films are pressure-dependent.

This is the first reported case of follicular T-cell lymphoma (FTCL) that primarily developed in the extranodal site of the right submandibular gland. An 86-year-old man was detected with a right cervical mass suspected to be malignant lymphoma during his physical examination. Imaging studies revealed that the mass was a submandibular gland tumor. The tumor was excised for diagnosis and treatment. Pathologically, the tumor was composed of densely aggregated lymphocytes with a follicular growth pattern. The immunohistochemical investigation showed that the lymphoma cells expressed CD3, CD4, programmed cell death protein 1, BCL6, chemokine (C-X-C motif) ligand 13, and BCL2. Staining of the follicular dendritic cell revealed its meshwork structure limited in the germinal center. Monoclonal rearrangement of the T-cell receptor was detected using polymerase chain reaction. These findings are consistent with the characteristics of FTCL. Here, we describe the first reported case of extranodal counterpart of FTCL of the submandibular gland. Accumulation and investigation of such extranodal cases is essential.

We developed high temperature in situ transmission electron microscopy using a high-density laser irradiation device (nominal maximum laser density ~9.4 GW/m

A series of alkylated indigos were synthesized. Alkylated indigos were characterized by NMR, mass spectrometry, absorption spectra, cyclic voltammetry, and density functional theory (DFT) calculations. Propyl and butyl group substituted indigo was most soluble in chloroform and 1,2-dicrolobenzene, and these solubility were 65–89 times increased as compared to the parent indigo. DFT calculations suggested that the presence of the alkyl chains at the 5.5′-position increases the energy of the highest occupied molecular orbital, while reducing the energy of the lowest unoccupied molecular orbital. This theoretical finding was in good agreement with the experimental results. Crystal structures obtained by X-ray diffraction showed one-dimensional pi–pi stacking. Alkylated molecules were converted to leuco structure, and these structures were then converted to the corresponding indigos in the film state. After deposition of the films on TiO2/FTO substrate, oxidative photocurrents were observed.

Recently, a new boron allotrope B52 with orthorhombic structure was theoretically predicted to be more stable than α-tetragonal boron B50. In experiments however, only tetragonal boron phases have been obtained so far. Here, we report for the first time on the preparation of orthorhombic boron phase of B52-type, space group Pnnn, a = 8.894 A, b = 8.784 A, c = 5.019 A, by normal-pressure annealing of α-tetragonal boron, synthesized at high pressures by pyrolysis of decaborane, B10H14. We have investigated temperature-induced structure evolution and thermal desorption of boron samples, which allowed us to regard the structure of mother “α-tetragonal boron” as a boron-rich hydride with composition close to B51.5H7.7. In accordance with density-functional theory calculations, the most preferable sites of hydrogen placement in tetragonal unit cell are 8j and 4g; the tetragonal-to-orthorhombic transition takes place spontaneously upon complete dehydrogenation.

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment.

This study aimed to retrospectively evaluate the efficacy and safety of capecitabine plus oxaliplatin(CapeOX)for heavily pretreated advanced gastric cancer(AGC)refractory to S-1, cisplatin, irinotecan, and taxanes.Twelve patients with AGC refractory to S-1, cisplatin, irinotecan, and taxanes were enrolled in this study.Treatment comprised capecitabine(1,000mg/m / 2 twice a day on days 1-14)and oxaliplatin(130mg/m2 on day 1).Cycles were repeated at 3- week intervals.The overall response rate was 16.7%, and the disease control rate at 6 weeks was 75.0%. The progression free survival was 3.1 months, and the overall survival was 8.3 months after initiation of CapeOX therapy. The most common hematological toxicity was grade 3 neutropenia(50%).Peripheral neuropathy of Grade 1 or 2 was found in 50%of cases, but no Grade 3 or 4 neuropathy was found.CapeOX showed some activities as salvage therapy for heavily pretreated AGC patients.We suggest that CapeOX therapy should be considered a treatment option for pretreated AGC with good performance status.

Many problems in various fields can be expressed as the problem of optimizing the value of a pseudo-Boolean constraint which is a linear constraint over Boolean variables. This paper proposes a new technique, called Mixed Radix Weight Totalizer Encoding (MRWTE), which encodes pseudo-Boolean constraints into clauses that can be handled by a standard SAT solver. This new technique will allow us to fully exploit the latest improvements in SAT research. Unlike other encodings, the number of auxiliary variables required for MRWTE does not depend on the magnitudes of the coefficients. Instead, it depends on the number of distinct combinations of the coefficients. Our experimental results show that MRWTE compactly encodes the constraints, and the obtained clauses are efficiently handled by a state-of-the-art SAT solver.

A 75-year-old man was admitted to our hospital in May 2016 with progressive shortness of breath. We considered him to be experiencing acute heart failure caused by atrial fibrillation. Contrast-enhanced computed tomography showed a hypodense mass involving the right atrium and left ventricle, pericardial effusion, and lymphadenopathy of the groin. Histological finding from the groin and pericardial effusion analysis showed diffuse large B-cell lymphoma(DLBCL). We thus diagnosed this patient with cardiac tamponade owing to the involvement of the heart by DLBCL. Treatment was initiated with tetrahy- dropyranyldoxorubicin/cyclophosphamide/vincristine/prednisolone(THP-COP)therapy(50% dose)and continuous pericardial drainage. We carefully added rituximab 4 days after monitoring his symptoms and vital signs. There were a few adverse effects, and after treatment, the mass and pericardial effusion disappeared. Subsequently, 8 courses of THP-COP therapy accompanied by rituximab(R-THP-COP)(full dose)were administered, resulting in a complete response.

BiRd combination therapy, which comprises clarithromycin(CAM: Biaxin®), lenalidomide(LEN: Revlimid®), and dexamethasone( DEX), is a highly effective treatment for newly diagnosed symptomatic multiple myeloma(MM). However, its efficacy against recurrent myeloma refractory to LEN and DEX combination therapy(Rd therapy)remains unclear. In this study, we retrospectively analyzed the data of 7 patients(4 men and 3 women, median age of 76 years)with MM, who had clarithromycin added to their Rd regimen. In all patients, the starting dose of clarithromycin was 400 mg daily and the median number of prior therapies was 3(range, 1-4). Patients received a median of 9 cycles of Rd(range, 6-27 cycles)for a median duration of 8 months. Then, patients received a median of 14 cycles of BiRd(range 2-36 cycles). One patient showed partial response(PR), which was the best response, while the others showed stable disease(SD). Our results demonstrated that the addition of clarithromycin to Rd could overcome resistance to Rd and lead to durable responses, without exacerbating hematological or non-hematological toxicities. Thus, BiRd therapy may represent a therapeutic option for symptomatic MM resist- ant to Rd therapy.

A 47-year-old man presented at a local ophthalmological hospital with blurred vision. He had been diagnosed with hypertensive retinopathy and renal failure and was referred to our hospital for treatment. A renal biopsy was done to evaluate pathology of high proteinuria, hematuria, and rapidly progressive glomerulonephritis. Blood pressure remained high despite antihypertensive therapy; anemia and thrombocytopenia gradually progressed. Thrombotic microangiopathy (TMA) was suspected based on red blood cell fragmentation due to hemolytic anemia, thrombocytopenia, and renal failure. However, plasma exchange resolved neither thrombocytopenia nor renal failure, and anemia gradually progressed. Backache suddenly developed 13 days later, and CT findings indicated a retroperitoneal hematoma secondary to bleeding from the kidney. Selective renal artery embolization via angiography stopped the bleeding, but the patient went into hemorrhagic shock. Pathological findings on renal biopsy were identical to those in malignant hypertension, namely an edematous membrane lining, thickened arterioles, and stenosis. We diagnosed thrombotic microangiopathy due to malignant hypertension, without decrease in activities of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif) or its antibodies. Renal failure did not improve, and continuous hemodiafiltration was needed. This procedure stabilized blood pressure and improved the TMA.

A 71-year-old woman who had been treated with methotrexate (MTX) and prednisolone for rheumatoid arthritis since 2010 presented with hematuria. Cystitis was diagnosed. Chest and abdominal CT images revealed a bladder tumor, with lung and bilateral adrenal metastases. Transurethral resection of the bladder tumor (TUR-BT) confirmed these findings in September 2014. Histological findings of the bladder included large atypical lymphoid cells indicating diffuse large B-cell lymphoma. After TUR-BT, CT imaging showed that the tumor had shrunk. Still, MTX was continued. She was diagnosed with MTX-related lymphoproliferative disorders in November 2014 and MTX was discontinued. Fluorodeoxyglucose-positron emission tomography on March 2015 showed a complete response.

ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot. ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b. ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.

Boron bulk crystals are marked by exceptional structural complexity and unusual related physical phenomena. Recent reports of hydrogenated $\alpha$-tetragonal and a new $\delta$-orthorhombic boron B$_{52}$ phase have raised many fundamental questions. Using density functional theory calculations it is shown that hydrogenated $\alpha$-tetragonal boron has at least two stable stoichiometric compositions, B$_{51}$H$_{7}$ and B$_{51}$H$_{3}$. Thermodynamic modeling was used to qualitatively reproduce the two-step phase transition reported by Ekimov et al. [J. Mater. Res. 31, 2773 (2016)] upon annealing, which corresponds to successive transitions from B$_{51}$H$_{7}$ to B$_{51}$H$_{3}$ to pure B$_{52}$. The so obtained $\delta$-orthorhombic boron is an ordered, low-temperature phase and $\alpha$-tetragonal boron is a disordered, high-temperature phase of B$_{52}$. The two phases are connected by an order-disorder transition, that is associated with the migration of interstitial boron atoms. Atom migration is usually suppressed in strongly bound, covalent crystals. It is shown that the migration of boron atoms is likely to be assisted by the migration of hydrogen atoms upon annealing. These results are in excellent agreement with the above mentioned experiment and they represent an important step forward for the understanding of boron and hydrogenated boron crystals. They further open a new avenue to control or remove the intrinsic defects of covalently bound crystals by utilizing volatile, foreign atoms., Comment: 27 pages, 7 figures, 3 tables

Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1–14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240–416 days) and median OS was 722 days (95% CI 411 days–not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.

Recent discoveries of supposedly pure alpha-tetragonal boron require to revisit its structure. The system is also interesting with respect to a new type of geometrical frustration in elemental crystals, which was found in beta-rhombohedral boron. Based on density functional theory calculations, the present study has resolved the structural and thermodynamic characteristics of pure alpha-tetragonal boron. Different from beta-rhombohedral boron, the conditions for stable covalent bonding (a band gap and completely filled valence bands) are almost fulfilled at a composition B_52 with two 4c interstitial sites occupied. This indicates that the ground state of pure alpha-tetragonal boron is stoichiometric. However, the covalent condition is not perfectly fulfilled because non-bonding in-gap states exist that cannot be eliminated. The half occupation of the 4c sites yields a macroscopic amount of residual entropy, which is as large as that of beta-rhombohedral boron. Therefore, alpha-tetragonal boron can be classified as an elemental crystal with geometrical frustration. Deviations from stoichiometry can occur only at finite temperatures. Thermodynamic considerations show that deviations delta from the stoichiometric composition B_(52+delta) are small and positive. For reported high-pressure syntheses conditions delta is predicted to be about 0.1 to 0.2. An important difference between pure and C- or N-containing alpha-tetragonal boron is found in the occupation of interstitial sites: the pure form prefers to occupy the 4c sites, whereas in C- or N-containing forms a mixture of 2a, 8h, and 8i sites are occupied. The present article provides relations of site occupation, delta values, and lattice parameters, which enable us to identify pure alpha-tetragonal and distinguish the pure form from other ones., Comment: 31 pages, 8 figures, 5 tables, accepted by Phys. Rev. B

A longstanding issue why boron crystals such as β-rhombohedral boron are insulator, while band calculations predict metals, has been solved. The issue is intimately related to another property of the crystal, namely breaking of stoichiometry. The presence of unfilled bands requires reconstruction of chemical bonds. Usually, for simple structures, the energy barrier is so high that the bond reconstruction rarely occurs. For large unit cells, the degree of internal freedom increases, and accordingly the chance to meet other energy minima in the atomic configuration increases. Such reconstructions of bonds take place when the valence requirement is fulfilled. This often occurs for boron crystals by breaking the stoichometry. This mechanism is described for various boron crystals in a step-by-step approach.

The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE.The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE.Seven of the mutations found were novel, including 4 missense mutations (8728TG, 8831CA, 16661TG and 16885CA), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations.The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

We report a case of gastrointestinal manifestation of hereditary angioedema. Computed tomography (CT) revealed wall thickening of the gastric antrum, duodenum, and jejunum. Dilatation of the third part of the duodenum, thickening of the small bowel mesentery and omentum, and retroperitoneal edema were present. The importance of considering this condition in patients presenting such CT findings correlated with the appropriate history is discussed.

Objectives Osteopontin (OPN) is associated with several human malignancies, but the role of OPN in head and neck cancer (HNC) remains unclear. We investigated the clinicopathologic relevance of serum OPN levels in HNC patients. Methods Serum OPN levels in HNC patients were determined by quantitative sandwich enzyme immunoassay (EIA). OPN levels and their correlation with clinical features were examined. In addition, serum squamous cell carcinoma (SCC) antigen was examined simultaneously. Results The mean OPN level was significantly higher in HNC patients (99.5 ng/ml) than in control subjects (55.3 ng/ml). OPN levels were significantly higher in patients with advanced stage HNC than in patients with early stage HNC. OPN levels did not correlate with SCC antigen levels. Conclusions OPN may play a role in the pathogenesis of head and neck cancer (HNC), and serum OPN may be a potential biomarker of HNC.

上気道閉塞性病変に対して，気管切開術は基本的な手技であり，耳鼻咽喉科医にとって非常に重要な手術手技の1つである。今回，われわれはCiaglia法の一種である，Blue Rhino法（NEO PERC®：タイコ ヘルスケア社）を用いた，経皮的気管切開術による気道確保を行った4症例について報告し，当科での外科的気管切開術と経皮的気管切開術との比較検討を行った。外科的気管切開術を施行した症例は19例であり，経皮的気管切開術を施行した症例は4例であった。外科的気管切開術と比較して経皮的気管切開術では明らかに，手術時間の短縮を認め，術後出血や皮下気腫，創部感染といった術後合併症を認めなかった。気管切開部の創処置においても，外科的気管切開術では全例において，気管孔閉鎖術が必要であった。しかし，経皮的気管切開術では半数の2例であり，気管孔閉鎖術の有無にかかわらず，切開創痕はどちらも相違はなく目立たなかった。気管切開手技に精通している耳鼻咽喉科医において，本方法は気管切開術の有用な1つの手技として考慮しうるものと考えられた。

BACKGROUND Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-s-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. METHODS In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. RESULTS We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P ≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). CONCLUSIONS Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

Pseudo-cubic tetragonal boron, which may be another form of boron allotropes, has recently been discovered under high pressure and high temperature conditions. In this paper, the structure of pseudo-cubic tetragonal boron is studied by density-functional-theory (DFT) calculation. The structure is abnormal compared with other boron allotropes in many respects, making it difficult to comprehend. The lattice is very close to a cubic lattice, such that the icosahedra are largely distorted along the c-axis. Such distortions are normally not favorable for boron crystals; in fact, the present calculations supported this. The reported positions of partially occupied interstitial sites render the intericosahedral bonds unusually long or short, which were again not supported by the present calculations. Furthermore, the potential of involving impurities is unlikely in terms of the formation energy and lattice parameters. Therefore, the structure of pseudo-cubic tetragonal boron was not proven by calculation, despite this extensive study. Something may be overlooked in the present structural model, or something unusual may have happened in this structure, the solution of which is left as an open question.

We have resolved long-standing discrepancies between the theoretical and experimental crystal structures of boron carbide ${\mathrm{B}}_{13}{\mathrm{C}}_{2}$. Theoretical studies predict that ${\mathrm{B}}_{13}{\mathrm{C}}_{2}$ should be stoichiometric and have the highest symmetry of the boron carbides. Experimentally, ${\mathrm{B}}_{13}{\mathrm{C}}_{2}$ is a semiconductor and many defect states have been reported, particularly in the CBC chain. Reconciling the disordered states of the chain, the chemical composition, and the lowest-energy state is problematic. We have solved this problem by constructing a structural model where approximately three-quarters of the unit cells contain $({\mathrm{B}}_{11}\mathrm{C})$(CBC) and one-quarter of them contain $({\mathrm{B}}_{12})({\mathrm{B}}_{4})$. This structural model explains many experimental results, such as the large thermal factors in x-ray diffraction and the broadening of the Raman spectra, without introducing unstable CBB chains. The model also solves the energy-gap problem. We show that there are many arrangements of these two types of unit cells, which are energetically almost degenerate. This demonstrates that boron carbides are well described by a geometrically frustrated system, similar to that proposed for $\ensuremath{\beta}$-rhombohedral boron.

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.

CRKL, an SH2-SH3-SH3 adapter protein, is one of the major tyrosine phosphoproteins detected in primary leukemic neutrophils from patients with CML. CRKL binds directly to BCR/ABL through its N-terminal SH3 domain, suggesting it may be involved in BCR/ABL signal transduction. However, the biological function of CRKL in either normal or leukemic cells is still largely unknown. In this study, we have examined the effects of overexpressing full length or deletion mutants of CRKL in hematopoietic cell lines. Full length, SH2- and SH3(N)-domain deletion mutants of CRKL were transfected into an interleukin-3-dependent hematopoietic cell line, Ba/F3, and 3-5 individual sublines which stably overexpressed each transgene were obtained [Ba/F-CRKL, Ba/F-CRKL deltaSH2, and Ba/F-CRKL deltaSH3(N)]. The growth properties of these transfected cells in the presence or absence of IL-3 were not different from mock transfected or untransfected Ba/F3 cells. However, Ba/F3 cells overexpressing full length CRKL, but not deletion mutants of CRKL, were found to have an increase in their ability to bind to fibronectin-coated surfaces. Further, expression of full length, but not deltaSH2- or deltaSH3-CRKL deletion mutants, was found to alter cell morphology on fibronectin-coated plates, an effect which was further enhanced by certain kinds of stress stimuli, such as ionizing radiation. Similar results were obtained when CRKL was transiently overexpressed in Ba/F3 cells, and were also obtained in a second IL-3 dependent hematopoietic cell line, 32Dcl3. Adhesion to fibronectin was blocked by anti-beta1 integrin monoclonal antibody, but overexpression of CRKL did not affect surface expression of beta1 integrins, nor did it spontaneously induce expression of the beta1 integrin 'activation' epitope recognized by the 9EG7 monoclonal antibody. These data suggest a role for CRKL in signaling pathways which regulate adhesion to fibronectin.

CRKL is an SH2-SH3-SH3 adapter protein that is a major substrate of the BCR/ABL oncogene. The function of CRKL in normal cells is unknown. In cells transformed by BCR/ABL we have previously shown that CRKL is associated with two focal adhesion proteins, tensin and paxillin, suggesting that CRKL could be involved in integrin signaling. In two hematopoietic cell lines, MO7e and H9, we found that CRKL rapidly associates with tyrosine-phosphorylated proteins after cross-linking of β1 integrins with fibronectin or anti-β1 integrin monoclonal antibodies. The major tyrosine-phosphorylated CRKL-binding protein in the megakaryocytic MO7e cells was identified as p120CBL, the cellular homolog of the v-Cbl oncoprotein. However, in the lymphoid H9 cell line, the major tyrosine-phosphorylated CRKL-binding protein was p110HEF1. In both cases, this binding was mediated by the CRKL SH2 domain. Interestingly, although both MO7e and H9 cells express p120CBLand p110HEF1, β1 integrin cross-linking induces tyrosine phosphorylation of p120CBL (but not p110HEF1) in MO7e cells and of p110HEF1 (but not p120CBL) in H9 cells. In both cell types, CRKL is constitutively complexed to C3G, SOS, and c-ABL through its SH3 domains, and the stoichiometry of these complexes does not change upon integrin ligation. Thus, in different cell types CRKL and its SH3-associated proteins may form different multimeric complexes depending on whether p120CBL or p110HEF1 is tyrosine-phosphorylated after integrin ligation. The shift in association of CRKL and its SH3-associated proteins from p120CBL to p110HEF1 could contribute to different functional outcomes of “outside-in” integrin signaling in different cells.

Primary malignant lymphoma of the uterine cervix is a rare disease, and the therapeutic strategy has not been clearly established. A 45-year old woman presented with vaginal bleeding and hypermenorrhea in January 2012. Physical examination revealed a mass in the pelvic cavity approximately the size of a neonate's head. Pelvic magnetic resonance imaging(MRI) showed a solid mass 11 cm in size in the uterine cervix with homogeneous low intensity on T1-weighted images, iso-high intensity on T2-weighted images, and heterogeneous iso-high intensity on gadolinium-diethylenetriaminepentaacetate(Gd- DTPA)-enhanced images. Multiple lymphadenopathy were also detected in the pelvis. The Papanicolaou smear indicated class 5 cervical cytology, and a subsequent histological examination by a punch biopsy of the cervix showed diffuse infiltration of medium- to large-sized mononuclear cells that stained positive for CD20 and CD79a and negative for CD3, CD5, and EBER. Bone marrow biopsy revealed no abnormality. Positron emission tomography-computed tomography(PET-CT)showed strong fluorodeoxyglucose(FDG)accumulation in the uterine cervix mass, and in the pelvic and right inguinal lymphadenopathy. The patient was diagnosed with diffuse large B-cell lymphoma of the uterine cervix, Ann Arbor stage II AE. She was successfully treated with 8 courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP) chemotherapy, and maintains a complete remission.

Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare disorder characterized by severe thrombocytopenia associated with total absence or a selective decrease in bone marrow megakaryocytes. A 67-year-old male presented with a 2-month bleeding tendency. He was referred to our hospital because of severe thrombocytopenia. Bone marrow biopsy showed complete absence of megakaryocytes without dysplasia in cells of the myeloid and erythroid lineages. AATP was diagnosed. In addition, mild normocytic normochromic anemia and reticulocytosis were also observed and haptoglobin was below the detectable level. Coombs-negative autoimmune hemolytic anemia (AIHA) was diagnosed based on the high titer of RBC-bound IgG and negative direct and indirect coombs test results. He was first treated with cyclosporine 200 mg per day and subsequently with prednisolone but only slight temporary improvement was achieved. Administration of eight doses of rituximab 375 mg/m(2) per week ameliorated both thrombocytopenia and anemia. AATP should be considered in the differential diagnosis of thrombocytopenia, and immunosuppressive therapy is a potential first-line treatment. This is the first case report of AATP accompanied by AIHA successfully treated with rituximab.

A 69-year-old male was referred to our hospital because of anemia, renal insufficiency, and a positive urine test for Bence-Jones protein. A bone marrow examination showed 73.7% of myeloma cells with lymphoplasmacytic morphology, the strong expressions of CD20 and CD23 by flow cytometry, and the chromosomal aberration of CCND1/IGH by FISH analysis. He was diagnosed with multiple myeloma, IgG-λ type. The initial treatment with bortezomib plus dexamethasone (BD) provided a rapid decrease in the level of IgG; however, he developed bortezomib-induced recurrent paralytic ileus accompanied by aspiration pneumonia during the second course. Interestingly, CD23 expression on myeloma cells decreased from 87.7% to 2.2% after 2 courses of BD. Negative CD23 expression was maintained following lenalidomide plus dexamethasone therapy. There are extremely few reports on CD23 expression on myeloma cells, and this is the first case report of multiple myeloma in which CD23 expression was lost after BD therapy.

We report a case of anal variceal bleeding successfully treated with endoscopic injection sclerotherapy (EIS). A 64-year-old man with alcoholic liver cirrhosis was hospitalized because of repeated anal bleeding. Colonoscopy revealed external anal varices connecting with rectal varices. Three days after admission, external anal variceal bleeding was observed. Angiography revealed that the anorectal varices formed by hepatofugal inferior mesenteric vein drained into the internal iliac vein. On angiography, the variceal blood flow rate was extremely low, therefore we performed EIS. Seven days after therapy, thrombosis of anorectal varices was observed.

The Philadelphia chromosome (Ph) translocation generates a chimeric tyrosine kinase oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML) and a type of acute lymphoblastic leukemia (ALL). In primary samples from virtually all patients with CML or Ph+ALL, the CRKL adapter protein is tyrosine phosphorylated and physically associated with p210(BCR/ABL). CRKL has one SH2 domain and two SH3 domains and is structurally related to c-CRK-II (CRK) and the v-Crk oncoprotein. We have previously shown that CRKL, but not the related adapter protein c-CRK, is tyrosine phosphorylated in cell lines transformed by BCR/ABL, and that CRKL binds to BCR/ABL through the CRKL-SH3 domains. Furthermore, the CRKL-SH2 domain has been shown to bind one or more cellular proteins, one of which is p120(CBL). Here we demonstrate that another cellular protein linked to BCR/ABL through the CRKL-SH2 domain is p130(CAS). p130(CAS) was found to be tyrosine phosphorylated and associated with CRKL in BCR/ABL expressing cell lines and in samples obtained from CML and ALL patients, but not in samples from controls. In both normal and BCR/ABL transformed cells, p130(CAS) was detected in focal adhesion-like structures, as was BCR/ABL. In normal cells, the focal adhesion proteins tensin, p125(FAK), and paxillin constitutively associated with p130(CAS). However, in BCR/ABL transformed cells, the interaction between p130(CAS) and tensin was disrupted, while the associations between p130(CAS), p125(FAK), and paxillin were unaffected. These results suggest that the BCR/ABL oncogene could alter the function of p130(CAS) in at least three ways: tyrosine phosphorylation, inducing constitutive binding of CRKL to a domain in p130(CAS) containing Tyr-X-X-Pro motifs (substrate domain), and disrupting the normal interaction of p130(CAS) with the focal adhesion protein tensin. These alterations in the structure of signaling proteins in focal adhesion like structures could contribute to the known adhesion abnormalities in CML cells.

There have been only three reports in the literature of T-cell large granular lymphocyte (T-LGL) leukemia occurring after autologous peripheral stem cell transplantation (APBSCT). We describe 3 patients in whom a transient monoclonal T-LGL developed after APBSCT for malignant lymphoma. Case 1: A 58-year-old man with peripheral T-cell lymphoma in second complete remission (CR) who underwent APBSCT. Case 2: A 51-year-old man with follicular lymphoma in second CR who underwent APBSCT. Case 3: A 65-year-old man with diffuse large B-cell lymphoma in second CR who underwent tandem APBSCT. One month after transplant, fever followed by the proliferation of CD8+/CD57+ T-LGL in peripheral blood occurred in all three cases. Because clonal rearrangements of the T-cell receptor were detected in peripheral blood samples, T-LGL leukemia was diagnosed. The first patient had episodes of Epstein-Barr virus viremia. The other patients suffered from cytomegalovirus colitis after APBSCT. These data show that T-LGL leukemia can occur after viral infection followed by APBSCT.

Salivary ductcarcinoma (SDC)is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor(AR)expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.

Changes in c-kit proto-oncogene expression were examined in a human erythroleukemia cell line, HEL, during 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced megakaryocytic differentiation. When HEL cells were treated with 10(-7) M TPA, glycophorin A expression and hemoglobin synthesis were reduced, while the expression of GP IIb/IIIa was induced in association with the morphological changes. Northern blot analysis showed that, during this megakaryocytic differentiation of HEL cells, c-kit mRNA expression persisted even after there was an apparent reduction in c-myc mRNA. This finding supports the idea that the expression of c-kit, a marker of primitive hematopoietic progenitors, may persist along with differentiation toward a megakaryocytic lineage.

To explore the biologic significance of the membrane-anchored form of macrophage colony-stimulating factor (M-CSF), we examined whether interaction between membrane-bound M-CSF and its receptor mediates intercellular adhesion as well as cell proliferation and differentiation. Human M-CSF receptors were expressed on a murine interleukin-2 (IL-3)-dependent cell line, FDC-P2, by DNA transfection with the c-fms gene (FDC-P2-MCSFR). A human bone marrow-derived stromal cell line, KM102, was used in the cell adhesion assay. The expression of membrane-bound M-CSF on KM102 cells was demonstrated by flow cytometry and immunoblot analysis. After the incubation of parent and transformed FDC-P2 cells on confluent KM102 cells, nonadherent cells were removed and the cells attached to KM102 cells were examined microscopically. Almost all parent FDC-P2 cells were nonadherent, whereas a significant number of FDC-P2-MCSFR cells bound to KM102 cells. The addition of anti-M-CSF or anti-M-CSF receptor neutralizing antibodies dose-dependently inhibited the binding of [3H]-thymidine- labeled FDC-P2-MCSFR cells to KM102 cells. An excess amount of M-CSF also inhibited the binding. On the other hand, the addition of antibodies against some representative adhesion molecules (vitronectin receptor, Pgp-1/CD44, and VLA-4) did not inhibit the adhesion between FDC-P2-MCSFR cells and KM102 cells. These results support the idea that membrane-anchored M-CSF and its receptor may function as mediators of cell-cell adhesion.