Aim : To study the correlation between lymph node metastatic disease and various pathological parameters. Lymph node metastasis is the most important factor in determining the prognosis of patients ...with early gastric cancer and is significantly associated with the submucosal invasion of neoplastic cells. However, the depth of submucosal layer as well as the depth of submucosal tumour invasion varies among different cases.
Methods and results : We studied various pathological parameters including the macroscopic appearance, location, size, area, differentiation, invasion depth, vascularity and fibrosis of submucosal gastric carcinomas (SMGC), using 248 age‐ and sex‐matched tissue samples. The presence of lymphatic emboli, a larger area, greater size, a non‐flat gross type and an increased vascularity of the tumour were significantly associated with node‐positive SMGC. Among the three depth‐related parameters, the ocular scale measurement, the sm3 method and the sm2 method, only the ocular scale measurement showed a significant correlation with node‐positive SMGC. Using multivariate analysis, the incidence of lymph node metastasis increased in the lymphatic tumour emboli and in the tumours that invaded more than half of the submucosal layer.
Conclusions : These histological indicators seem to be a feasible and easy way to predict lymph node metastatic disease from limited surgery specimens. Pathologists should carefully investigate the lymphatic invasion of tumour cells and measure the invasion depth of the tumour.
A method for protein and cell patterning on polyelectrolyte-coated surfaces using simple micromolding in capillaries (MIMIC) is described. MIMIC produced two distinctive regions. One contained ...polyethylene glycol (PEG) microstructures fabricated using photopolymerization that provided physical, chemical, and biological barriers to the nonspecific binding of proteins, bacteria, and fibroblast cells. The second region was the polyelectrolyte (PEL) coated surface that promoted protein and cell immobilization.
The difference in surface functionality between the PEL region and background PEG microstructures resulted in simple patterning of biomolecules. Fluorescein isothiocyanate-tagged bovine serum albumin, E. coli expressing green fluorescence protein (GFP), and fibroblast cells were successfully bound to the exposed PEL surfaces at micron scale. Compared with the simple adsorption of protein, fluorescence intensity was dramatically improved (by about six-fold) on the PEL-modified surfaces. Although animal cell patterning is prerequisite for adhesive protein layer to survive on desired area, the PEL surface without adhesive proteins provides affordable microenvironment for cells.
The simple preparation of functionalized surface but universal platform can be applied to various biomolecules such as proteins, bacteria, and cells.
Idiopathic multicentric Castleman disease (iMCD) is a polyclonal lymphoproliferative disorder involving cytokine-induced multiple organ dysfunction. Unlike Human Herpesvirus-8 (HHV-8)-associated MCD, ...which is caused by HHV-8, the etiology of iMCD is unknown. While excessive IL-6 drives systemic symptoms and pathogenesis in some iMCD patients and IL-6 inhibition with siltuximab is approved for treating iMCD, approximately one-half of patients do not improve with IL-6 inhibition. The pathological cell types, dysregulated signaling pathways, and cytokine cascade in these anti-IL-6 refractory cases are unknown. As such, mechanistic approaches for treating anti-IL-6 refractory patients are much needed, particularly given that second line, off-label treatment options comprise corticosteroids, rituximab and cytotoxic chemotherapy, which have varying efficacies and significant toxicities.
We report successful treatment with a novel, targeted regimen for a 25-year-old male with relapsing iMCD. The patient presented with generalized lymphadenopathy, right upper quadrant abdominal pain, diffuse eruption of cherry hemangiomas, thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO Syndrome). A lymph node biopsy revealed atrophic germinal centers, expanded mantle zones with ‘onion-skin’ appearance, vascular proliferation, interfollicular plasmacytosis, and paracortical hyperplasia. Combination chemotherapy with velcade-dexamethasone-thalidomide-adriamycin-cyclophosphamide-etoposide-rituximab (VDT-ACE-R) induced 15 month and 16 month remissions, but all attempted maintenance therapies (corticosteroids, rituximab, siltuximab, and velcade-dexamethasone-thalidomide (VDT)) failed to prevent relapse, and the patient experienced five disease flares requiring more than seven months of hospitalizations and intensive care in the first 3.5 years after diagnosis.
Following the fifth disease flare, clinical data were reviewed and flow cytometry, proteomics, and immunohistochemistry studies were performed to identify a novel and rational treatment option. Retrospective analyses of thirteen serum inflammatory markers revealed that two markers rose before the onset of symptoms and tracked with disease activity. Serum soluble IL-2 receptor (sIL-2R), a marker of T cell activation, rose above the upper limits of normal 20 weeks before onset of the flare and peaked at 10-fold above the upper limits of normal during flare. Vascular endothelial growth factor (VEGF), an angiogenic factor, levels approached the upper limits of normal eight weeks before flare and peaked at three-fold above the upper limits of normal during flare. Flow cytometry confirmed the presence of increased activated CD38+CD8+ T cells during disease flare, compared to healthy controls. Quantification of 315 serum analytes revealed that VEGF was the most up-regulated cytokine between flare and remission. Striking VEGF-related clinical features observed during disease flares, such as eruptive cherry hemangiomatosis, capillary leak syndrome, and hypervascularized lymph nodes, further supported an important role of VEGF in pathogenesis. Considering targetable, central signaling pathways involved in T cell activation, lymphoproliferation, and VEGF expression, we hypothesized that increased PI3K/Akt/mTOR signaling could be involved in pathogenesis. Immunostaining for phosphorylated ribosomal protein S6 (pS6), a read-out for mTOR activity, was performed on the patient's lymph node, which revealed intense staining compared to control tissues. Therefore, we initiated treatment with the mTOR inhibitor, sirolimus, along with once monthly low dose IVIg, to replete treatment-induced low immunoglobulin levels.
As of August 2017, this patient has been in a complete remission for 43 months, five times longer than the patient's previous average remission duration, with pre-disease quality of life, no clinical symptoms, and no significant complications of therapy. VEGF, sIL2R, and 11 other inflammatory marker levels remain within normal limits. Previously observed T cell activation markers are absent on flow cytometry. The results of this study suggest that sirolimus is an effective maintenance treatment for this patient and that it should be further investigated as a potential treatment for similar relapsing iMCD patients.
Fajgenbaum:Janssen Pharmaceuticals: Research Funding. Cohen:Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Uldrick:Celgene: Research Funding; Merck: Research Funding; National Institutes of Health: Patents & Royalties: immunomodulatory compound for KSHV malignancies (Inst); Roche: Research Funding.
Reduced sulfur gases and optical properties were measured in the upper ocean during an Atlantic Meridional Transect cruise of the RRS James Clark Ross from England to the Falkland Islands in 1998. ...Sea surface concentrations of carbonyl sulfide (COS) exhibited a pronounced diel variation at low latitudes but no diel cycle at mid and high latitudes possibly because of oceanic fronts and the longer hydrolysis time constant in cold water. The highest COS concentrations were observed in coastal and upwelling areas. CS2 concentrations varied less than those of COS, and the highest concentrations were found in the North African upwelling area with decreasing concentrations both northward and southward of this maximum. Dimethylsulfide (DMS) had the largest concentrations in the upper ocean, but methyl mercaptan (CH3SH) was an important reduced sulfur species in some coastal and upwelling areas. This may be associated with high bacterial growth rates. Colored dissolved organic matter (CDOM) fluorescence and absorbance also exhibit the highest values in coastal and upwelling areas and the lowest values in the southern subtropical gyre. The results suggest that carbon disulfide (CS2) outgassed from the oceans and oxidized in the atmosphere may represent a larger source of COS to the atmosphere than the direct flux of COS across the sea‐air interface.
We present ultraviolet (UV) photometry of M31 globular clusters (GCs) found in 23 Galaxy Evolution Explorer (GALEX) images covering the entirety of M31. We detect 485 and 273 GCs (and GC candidates) ...in the near-ultraviolet (NUV) and far-ultraviolet (FUV), respectively. The UV properties of GCs have been analyzed using various combinations of UV-optical and optical-optical colors. Comparing M31 data with those of Galactic GCs in the UV with the aid of population models, we find that the age ranges of old GCs in M31 and the Galactic halo are similar. Three metal-rich (Fe/H > -1) GCs in M31 produce significant FUV flux making their FUV-V colors unusually blue for their metallicities. These are thought to be analogs of the two peculiar Galactic GCs, NGC 6388 and NGC 6441, with extended blue HB stars. Based on the models incorporating helium enriched subpopulations in addition to the majority of the population that have a normal helium abundance, we suggest that even small fraction of super-helium-rich subpopulations in GCs can reproduce the observed UV bright metal-rich GCs. Young clusters in M31 show distinct UV and optical properties from GCs in Milky Way. Population models indicate that their typical age is less than similar to 2 Gyr and is consistent with the age derived from the most recent high-quality spectroscopic observations. A large fraction of young GCs have the kinematics of the thin, rapidly rotating disk component. Most GCs with bulge kinematics show old ages. The existence of young GCs on the outskirts of M31 disk suggests the occurrence of a significant recent star formation in the thin-disk of M31. We detect 12 (10) intermediate-age GC candidates in NUV (FUV) identified by previous spectroscopic observations. On the basis of comparing our UV photometry to population models, we suggest that some of spectroscopically identified intermediate-age GCs may not be truly intermediate in age, but rather older GCs that possess developed HB stars which contribute to enhanced UV flux as well as Balmer lines.
We reviewed retrospectively seven patients with Apert acrosyndactyly and measured the size of the capitate ossification centre relative to that of the hamate and determined the relative position of ...the middle finger metacarpal relative to the ring finger metacarpal. We then compared those parameters in 197 normal children. In all patients, the middle finger metacarpal bone had migrated proximally relative to the ring finger metacarpal and the size of the capitate ossification centre was smaller than that of the hamate. After surgical release of the middle finger, relative proximal migration of the middle finger metacarpal was partially relieved and catch-up growth of the capitate was observed within several months. As fusion of the distal phalanges creates a diamond-shaped configuration, bone growth is markedly impaired in the middle finger ray. Therefore, early separation of the middle finger may be as important as early separation of the border digits.
To determine the tumor control rates and endocrinological responses after stereotactic radiosurgery for pituitary adenomas, we reviewed our experience in 65 patients (40 men, 25 women) treated in the ...Gamma Knife during the last 4 years. The mean age was 41.6 years (range 19-69 years). 43 patients had endocrinologically active tumors (20 growth hormone-secreting, 19 prolactin-secreting and 4 ACTH-secreting adenomas). 22 had nonfunctioning adenomas. 39 patients had a macroadenoma and 26 patients had a microadenoma. 33 patients underwent Gamma Knife radiosurgery for recurrent or residual tumors after microsurgery. 50 patients have had follow-up neuroimaging studies and/or hormonal evaluation. The follow-up period was 25.5 months (range 3 to 54 months). The margin of the tumor was incorporated within the 50 to 90% isodose. The mean number of isocenters was 3.8 and the mean marginal dose was 25.4 Gy (range 15 to 36 Gy). 27 out of 40 patients (65.7%) showed decreased tumor volume to less than 50% of the initial volume. In 17 out of 38 patients (44.7%) with endocrinologically active tumors, the hormonal level fell to within the normal range. Two patients had delayed complications: in one case there was pituitary insufficiency and in the other a visual disturbance. Gamma Knife radiosurgery seems to be effective adjuvant therapy for pituitary adenoma in selected cases. More long-term follow-up is required to evaluate the efficacy and side effects further.
Nasal swabs were collected to isolate S. aureus in 296 children, who visited the pediatrics department with a variety of symptoms. Staphylococcus aureus was isolated from 95 children (32.1%). Of the ...isolates, 18 were methicillin-resistant S. aureus (MRSA) (18.9%). Antimicrobial susceptibility testing was performed for all S. aureus cultured and the molecular characteristics were investigated. Forty-nine spa types were identified among the S. aureus isolates, and were classified into 13 spa groups (A-L). The most prevalent clone (34 isolates, 35.8%) belonged to the spa group B (spa repeat motif, WG/FKAOMQ), which corresponded to sequence type 30 (ST30) and its variants. Sixteen different spa types, within the spa group B, suggested that this group has evolved over a long period of time. In addition, all S. aureus isolates belonging to the spa group B were methicillin-susceptible, indicating that this group might represent successful adaptation of this clone in the community setting with low antibiotic pressure. The most frequently found clone in the MRSA group was spa group C (spa repeat motif, DMGGM) and SCCmec type IVA, which represented half of the MRSA isolates and corresponded to ST72. ST5-MRSA-II, the most prevalent MRSA clone in Korean hospitals, was found in only two isolates. These findings suggest that strains of S. aureus nasal carriage in Korean children visiting an outpatient pediatric department were different from the strains identified in hospital infections.
Using the CARIBIC Boeing 767 aircraft, a suite of trace gases and aerosols was measured between Germany and the Maldives in June 2000 at altitudes between 9.4 and 10 km. In the extratropics, the ...flight track was located in the tropopause region. A large variability of trace gases and ultrafine aerosol concentrations was observed while the aircraft intercepted air masses from the upper troposphere and the lowermost stratosphere, as well as outflow of deep convection. The correlations of alkanes (C2–C5) observed in the nonconvective areas point to relatively rapid mixing across the tropopause within about a day. Unusually high mixing ratios of short‐lived alkanes (C4–C6) in the convective areas indicate rapid transport of boundary layer air masses to cruising altitude. Using the ratios of the mixing ratios of alkanes (C3–C5) observed in the convective and nonconvective areas, we estimate the age of air masses in the tropopause region to be 24(±6) days for this event. This timescale is similar to that of vertical transport within the troposphere. Altogether our observations provide further evidence that the extratropical tropopause is often not a very effective mixing barrier.
An airfreight container with automated instruments for measurement of atmospheric gases and trace compounds was operated on a monthly basis onboard a Boeing 767-300 ER of LTU International Airways ...during long-distance flights from 1997 to 2002 (CARIBIC, Civil Aircraft for Regular Investigation of the Atmosphere Based on an Instrument Container, http://www.caribic-atmospheric.com). Subsequently a more advanced system has been developed, using a larger capacity container with additional equipment and an improved inlet system. CARIBIC phase #2 was implemented on a new long-range aircraft type Airbus A340-600 of the Lufthansa German Airlines (Star Alliance) in December 2004, creating a powerful flying observatory. The instrument package comprises detectors for the measurement of O3, total and gaseous H2O, NO and NOy, CO, CO2, O2, Hg, and number concentrations of sub-micrometer particles (>4 nm, >12 nm, and >18 nm diameter). Furthermore, an optical particle counter (OPC) and a proton transfer mass spectrometer (PTR-MS) are incorporated. Aerosol samples are collected for analysis of elemental composition and particle morphology after flight. Air samples are taken in glass containers for laboratory analyses of hydrocarbons, halocarbons and greenhouse gases (including isotopic composition of CO2) in several laboratories. Absorption tubes collect oxygenated volatile organic compounds. Three differential optical absorption spectrometers (DOAS) with their telescopes mounted in the inlet system measure atmospheric trace gases such as BrO, HONO, and NO2. A video camera mounted in the inlet provides information about clouds along the flight track. The flying observatory, its equipment and examples of measurement results are reported.
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