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Biomedical subjects

P Chu

Publications and source records attributed to P Chu.

At least 19 recordsLinked to original sources

Localization and physical property experiments conducted by Opportunity at Meridiani Planum.

The location of the Opportunity landing site was determined to better than 10-m absolute accuracy from analyses of radio tracking data. We determined Rover locations during traverses with an error as small as several centimeters using engineering telemetry and overlapping images. Topographic profiles generated from rover data show that the plains are very smooth from meter- to centimeter-length scales, consistent with analyses of orbital observations. Solar cell output decreased because of the deposition of airborne dust on the panels. The lack of dust-covered surfaces on Meridiani Planum indicates that high velocity winds must remove this material on a continuing basis. The low mechanical strength of the evaporitic rocks as determined from grinding experiments, and the abundance of coarse-grained surface particles argue for differential erosion of Meridiani Planum.

Extraterrestrial Environment↗

Localization and physical properties experiments conducted by Spirit at Gusev Crater.

The precise location and relative elevation of Spirit during its traverses from the Columbia Memorial station to Bonneville crater were determined with bundle-adjusted retrievals from rover wheel turns, suspension and tilt angles, and overlapping images. Physical properties experiments show a decrease of 0.2% per Mars solar day in solar cell output resulting from deposition of airborne dust, cohesive soil-like deposits in plains and hollows, bright and dark rock coatings, and relatively weak volcanic rocks of basaltic composition. Volcanic, impact, aeolian, and water-related processes produced the encountered landforms and materials.

Extraterrestrial Environment↗

Antirecipient helper and cytotoxic T-cell frequencies in bone marrow transplantation.

We assayed helper T-lymphocyte precursor frequencies (HTLPf), interferon (IFN)-gamma-producing cell frequencies (IFN-gammaPf) and CTL precursor frequencies (CTLPf) to see if they could predict the severity of acute graft-versus-host disease (aGVHD) and disease relapse after transplantation. In all, 48 bone marrow transplantation (BMT) patients and their HLA-identical sibling (n=29) or matched unrelated donors (MUD) (n=19) were recruited. HTLPf, IFN-gammaPf and CTLPf were measured using a limiting dilution assay (LDA). Patients were followed prospectively to assess the severity of aGVHD and the status of the primary disease after BMT. High (>5 x 10(-6)) HTLPf, CTLPf and IFN-gammaPf were significantly associated with the occurrence and severity of aGVHD in patients who received transplants from HLA-identical sibling. Among patients receiving BMT from MUD, HTLPf and CTLPf, but not IFN-gammaPf, were associated with aGVHD. Five patients had disease relapse post-BMT and the risk was not significantly associated with HTLPf, CTLPf or IFN-gammaPf. Patients with high (>5 x 10(-6)) HTLPf, IFN-gammaPf or CTLPf before BMT are at higher risk of developing aGVHD after transplantation from both matched sibling donors and MUD. Whether these parameters can predict disease relapse would have to be investigated with a larger cohort of patients.

Adult↗

Usefulness of immunohistochemistry in delineating renal spindle cell tumours. A retrospective study of 31 cases.

AIMS: To assess the usefulness of immunohistochemistry in delineating tumour diagnoses on a series of morphologically diagnosed renal spindle cell tumours (RSCTs). METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues from 31 morphologically diagnosed tumours were reinterpreted in light of newly obtained immunohistochemical information. By morphology, six had originally been classified as sarcomatoid carcinoma, five as spindle cell tumour (NOS), four as sarcoma (NOS), three as leiomyoma, three as leiomyosarcoma, and one each as fibrous polyp, hamartoma, neurilemmoma, mesoblastic nephroma, medullary fibroma, angiomyolipoma, haemangiopericytoma, malignant rhabdoid tumour, malignant Triton tumour, and carcinosarcoma. The application of immunohistochemistry verified the original diagnosis in 18 cases (18/31, 58%), confirming the diagnosis of sarcomatoid renal carcinoma (4/6), leiomyoma (2/3), leiomyosarcoma (3/3), sarcoma (NOS) (2/4), carcinosarcoma (1/1), malignant rhabdoid tumour (1/1), malignant Triton tumour (1/1), fibrous polyp (1/1), mesoblastic nephroma (1/1), hamartoma (1/1), and angiomyolipoma (1/1). Different tumour designations were suggested in 13 cases (13/31, 42%), including carcinosarcoma, sarcoma (NOS), leiomyosarcoma, solitary fibrous tumour, monomorphic/biphasic angiomyolipoma, endometrial stromal tumour, and congenital mesoblastic nephroma. CONCLUSIONS: Our data indicate that although morphology is most important in formulating the initial differential diagnosis, the addition of immunohistochemistry is vital in arriving at the correct classification of RSCTs.

Adolescent↗

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats.

AIMS/HYPOTHESIS: Advanced glycation and lipoxidation endproducts have been implicated in the pathogenesis of diabetic complications, including diabetic nephropathy. LR-90, a new advanced glycation endproduct inhibitor, was investigated for its effects on the development of renal disease in diabetic rats. METHODS: Diabetic animals were randomly allocated into groups receiving LR-90 or vehicle (untreated). Age- and weight-matched non-diabetic rats were studied concurrently. Body weight, plasma glucose, glycated haemoglobin, urinary albumin and creatine excretions were measured serially. Kidney histopathology, AGE accumulation in cells and tissues, protein oxidation, were also examined. In vitro assays were used to assess the possible mechanism of action of LR-90. RESULTS: LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced cross-linking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine. CONCLUSION/INTERPRETATION: LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

Animals↗

Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling.

In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor-stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems.

Adaptor Proteins, Signal Transducing↗

Heterologous inhibition of G protein-coupled receptor endocytosis mediated by receptor-specific trafficking of beta-arrestins.

We have observed an unexpected type of nonreciprocal "cross-regulation" of the agonist-induced endocytosis of G protein-coupled receptors by clathrin-coated pits. Isoproterenol-dependent internalization of beta2-adrenergic receptors in stably transfected HEK293 cells was specifically blocked (>65% inhibition) by vasopressin-induced activation of V2 vasopressin receptors co-expressed at similar levels. In contrast, activation of beta2 receptors caused no detectable effect on V2 receptor internalization in the same cells. Several pieces of evidence suggest that this nonreciprocal inhibition of endocytosis is mediated by receptor-specific intracellular trafficking of beta-arrestins. First, previous studies showed that the activation of V2 but not beta2 receptors caused pronounced recruitment of beta-arrestins to endocytic membranes (Oakley, R. H., Laporte, S. A., Holt, J. A., Barak, L. S., and Caron, M. G. (1999) J. Biol. Chem. 274, 32248-32257). Second, overexpression of arrestin 2 or 3 (beta-arrestin 1 or 2) abolished the V2 receptor-mediated inhibition of beta2 receptor internalization. Third, mutations of the V2 receptor that block endomembrane recruitment of beta-arrestins eliminated the V2 receptor-dependent blockade of beta2 receptor internalization. These results identify a novel type of heterologous regulation of G protein-coupled receptors, define a new functional role of receptor-specific intracellular trafficking of beta-arrestins, and suggest an experimental method to rapidly modulate the functional activity of beta-arrestins in intact cells.

Arginine Vasopressin↗

Pathobiologic findings in DCIS of the breast: morphologic features, angiogenesis, HER-2/neu and hormone receptors.

With the increasing incidence of ductal carcinoma in situ (DCIS) of the breast and its relationship to invasive breast carcinoma, it is important to understand the biology of this entity. We report on a hospital-based survey of 219 case subjects with DCIS of the breast without associated invasive carcinoma diagnosed between 1982 and 1994. The cases of DCIS were analyzed for architectural type, size, nuclear grade, necrosis, calcification, periductal fibrosis, neovascularization, estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu expression. Periductal neovascularization was associated with tumor size, microcalcifications, periductal fibrosis, and HER-2/neu overexpression. Expression of ER and PR was observed in 60 and 62% of the cases, respectively, and HER-2/neu overexpression in 28% of the cases. ER and PR expression were both inversely associated with comedo histology and nuclear grade. HER-2/neu overexpression was positively associated with comedo histology, high nuclear grade, and periductal neovascularization and was inversely correlated with both ER and PR expression. High nuclear grade was positively associated with comedocarcinoma, necrosis, microcalcification, and periductal fibrosis. The role of these molecular/pathologic markers in the biology of DCIS and their potential clinical implications are discussed.

Breast Neoplasms↗

Development of perfluorocarbon (PFC) primary standards for monitoring of emissions from aluminum production.

An EPA Voluntary Aluminum Industrial Partnership (VAIP) program has been formed to help US primary producers focus on reducing the emissions of two perfluorocarbons (PFCs), tetrafluoromethane (CF4) and hexafluoroethane (C2F6), during the production of aluminum. To ensure comparability of measurements over space and time, traceability to national sources was desirable. Hence, the EPA approached the NIST to develop a suite of primary standards to cover a mole fraction (concentration) range of 0.1 to 1400 micromol mol(-1) for CF4 and 0.01 to 150 micromol mol(-1) of C2F6. A total of eight gravimetric PFC gas standards were prepared with relative expanded uncertainties of < or = 0.52% (approximately 95% confidence level). These primary standards were ultimately used to assign values to a series of secondary gas standards at three mole-fraction levels with relative expanded uncertainties ranging from +/- 0.7% to 5.3% (approximately 95% confidence level). This series of secondary standards was used within the aluminum industry to calibrate instruments used to make emission measurements. Assignment of values to the secondary standards was performed by use of gas chromatography with flame-ionization detection (GC-FID) and Fourier transform infrared spectrometry (FTIR). Real time pot-line and stack samples from a local aluminum plant were also obtained and sub-samples sent to each participating facility for analysis. The data generated from each facility were sent to NIST for analysis. The maximum difference between the NIST and individual facilities' values for the same sub-sample was +/- 26%.

Journal Article↗

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation.

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Acute Disease↗

Histological and immunohistochemical characterization of extranodal diffuse large-cell lymphomas with prominent spindle cell features.

AIMS: To describe five cases of diffuse large-cell lymphoma with prominent spindle cell components involving skin, nasal-ocular mucosa, and soft tissue. Because of the spindle cell morphology, such cases must be differentiated from true sarcomas arising in or metastasizing to soft tissue, skin, bone, lymph node, or other organs and sites. METHODS AND RESULTS: Formalin-fixed paraffin-embedded archival tissue from five consultation cases of diffuse large-cell lymphoma with prominent spindle cell features involving the skin, nasal-ocular mucosa, and soft tissue in three male and two female patients was studied by histology and immunohistochemistry. Clinicopathological findings were also reviewed for all the patients. By morphology, initial evaluation of the cases suggested spindle cell sarcoma in two cases, inflammatory pseudotumour in one case, large-cell lymphoma in another case, and one case was considered suspicious for malignant lymphoma. Immunohistochemistry demonstrated a B-cell lineage in four of the spindle cell lesions, with a diagnosis of primary cutaneous CD30+ anaplastic large cell lymphoma made for the fifth case. Four of five cases also showed actin reactivity. CONCLUSIONS: Although extremely rare, lymphomas with prominent spindle cell morphology can be encountered in daily surgical pathology practice, and should be included in the differential diagnosis of spindle cell lesions in skin and soft tissue. The observed actin reactivity in four of the five spindle cell lymphomas may lead to a misdiagnosis of leiomyosarcoma if lymphoid markers are not included in the immunohistochemical panel.

Adult↗

Acute correction of metabolic acidosis increases serum procollagen type I carboxyterminal propeptide in patients with chronic renal failure.

BACKGROUND AND PURPOSE: Previous in vitro study has shown that an acidic medium increases osteoclastic and inhibits osteoblastic activity. The present study sought to determine the role of alkali therapy in osteoblast function in patients with chronic renal failure by assessing the serum concentration of procollagen type I carboxyterminal propeptide (PICP), a marker of bone formation, before and after bicarbonate infusion. PATIENTS AND METHODS: Eighteen patients with chronic renal failure (creatinine clearance 12 +/- 6.6 mL/min) associated with mild to moderate metabolic acidosis were enrolled in this study. None had undergone dialysis. Metabolic acidosis was corrected by continuous bicarbonate infusion while plasma ionized calcium was clamped at the preinfusion level by calcium gluconate infusion throughout the procedure. RESULTS: After bicarbonate infusion, there were significant increases in plasma pH (7.31 +/- 0.04 to 7.40 +/- 0.03, p < 0.001), bicarbonate concentration (18.46 +/- 2.49 to 23.66 +/- 2.72, p < 0.001), serum total calcium concentration (2.01 +/- 0.24 to 2.12 +/- 0.24 mmol/L, p < 0.001), and PICP concentration (137.3 +/- 56.25 to 159.6 +/- 57.30 micrograms/L, p < 0.05), whereas serum parathyroid hormone concentrations assessed by radioimmunoassay decreased significantly (153.7 +/- 88.6 to 111.5 +/- 78.7, p < 0.001). Serum ionized calcium concentrations showed no significant difference before and after bicarbonate infusion. CONCLUSION: These results suggest that acute correction of metabolic acidosis improves osteoblast function and appear to underline the importance of maintaining normal acid-base homeostasis in chronic renal failure.

Acidosis↗

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I-restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis. (Blood. 2000;95:3853-3858)

Anti-Bacterial Agents↗

Multiple infundibulocystic basal cell carcinomas in association with human immunodeficiency virus.

Infundibulocystic basal cell carcinoma (IBCC) is a relatively recently described variant of basal cell carcinoma that is controversial and not universally accepted. Excluding cases of nevoid basal cell carcinoma syndrome, IBCC usually presents as a small, solitary, superficial lesion on the face of older persons. There have been previous reports of diffusely distributed, multiple similar lesions, but there is disagreement about the diagnosis in these cases. We present a case of a 43-year-old man with multiple papular lesions which we believe represent IBCC in the setting of infection with the human immunodeficiency virus (HIV).

Adult↗

Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases.

Cytokeratin 7 (CK 7) and cytokeratin 20 (CK 20) are low molecular weight cytokeratins. Their anatomic distribution is generally restricted to epithelia and their neoplasms. We surveyed 435 epithelial neoplasms from various organ systems by immunohistochemistry using CK 7 and CK 20 monoclonal antibodies. Expression of CK 7 was seen in the majority of cases of carcinoma, with the exception of those carcinomas arising from the colon, prostate, kidney, and thymus; carcinoid tumors of the lung and gastrointestinal tract origin; and Merkel cell tumor of the skin. The majority of cases of squamous cell carcinoma of various origins were negative for CK 7, except cervical squamous cell carcinoma, in which 87% of cases were positive. Approximately two thirds of cases of malignant mesothelioma were CK 7-positive. CK 20 positivity was seen in virtually all cases of colorectal carcinomas and Merkel cell tumors. CK 20-positive staining was also observed in cases of pancreatic carcinomas (62%), gastric carcinoma (50%), cholangiocarcinomas (43%), and transitional cell carcinomas (29%). The expression of CK 20 was virtually absent in carcinomas from other organ systems and in malignant mesothelioma. CK 7- and CK 20-negative epithelial neoplasms included adrenal cortical carcinoma, germ cell tumor, prostate carcinoma, renal cell carcinoma, and hepatocellular carcinoma.

Biomarkers, Tumor↗

Pedunculated malignant melanoma.

BACKGROUND: The pedunculated melanoma is an unusual variant of nodular melanoma that presents a challenge in staging and management. OBJECTIVE: We discuss the clinical and histopathologic characteristics of a case of pedunculated melanoma and present a brief review of the literature. METHODS: Routine stain with hematoxylin and eosin was performed on tissue specimens. RESULTS: The pedunculated melanoma was excised. Sentinel lymph node dissection was performed and was negative for the presence of melanoma. CONCLUSIONS: Pedunculated melanoma is a rare type of melanoma. Conventional staging methods for melanoma may not be reliable in this type of tumor. Complete workup, possibly including sentinel lymph node dissection, should be performed in all patients with pedunculated melanomas.

Adult↗

Post-transfusion HIV infection despite donor screening: a report of three cases.

In August 1996, a blood donation was collected which subsequently infected three patients post-transfusion with HIV 1. The donation itself was originally screened as negative for anti-HIV 1/2 using a sensitive EIA method, but subsequently was shown to contain p24 Ag and HIV RNA by an amplification technique. The proposed introduction of nucleic acid testing of all blood donations in the UK for hepatitis C, hepatitis B and HIV may further reduce the remote risk of further episodes of post-transfusion infection. The infection in the index recipient was detected on routine pre-transplant virological screening but proved difficult to confirm, at a time when she had recently received myeloablative treatment for a haematological malignancy which impaired the immune response. There is a need for continued vigilance in such patients to exclude post-transfusion infection, at a time when natural immunological responses have been impaired by their disease or treatment.

Aged↗

Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma.

We tested 505 cases of nonhematopoietic neoplasms by immunohistochemistry using a newly characterized monoclonal antibody (clone 56C6) against the CD10 antigen. CD10 was expressed widely in neoplasms of the genitourinary tract, including 41 (89%) of 46 cases of renal cell carcinoma, 13 (54%) of 24 cases of transitional cell carcinoma, and 11 (61%) of 18 cases of prostatic adenocarcinoma. In addition, 5 (100%) of 5 endometrial stromal sarcomas, 3 (60%) of 5 rhabdomyosarcomas, 7 (50%) of 14 pancreatic adenocarcinomas, 5 (45%) of 11 cases of schwannoma, and 12 (40%) of 30 cases of malignant melanoma also were positive for CD10. Similar to normal tissue, CD10 positivity was restricted to the apical surface of malignant glandular cells of well-differentiated colonic, pancreatic, and prostatic adenocarcinoma, whereas in poorly differentiated adenocarcinoma and other tumors, such as melanoma, transitional cell carcinoma, renal cell carcinoma, and endometrial stromal sarcoma, the CD10 positivity showed diffuse cytoplasmic or membranous/Golgi patterns. The monoclonal antibody clone 56C6 is a reliable marker for CD10 in paraffin immunohistochemistry after heat-induced epitope retrieval. CD10 expression in renal cell carcinoma and endometrial stromal sarcoma may be a useful marker in the differential diagnoses of these tumors because both tumors otherwise lack specific markers.

Antigens, Neoplasm↗