New anticancer agents.
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Angiogenesis Inhibitors↗
Biomedical subjects
S Sharma
Publications and source records attributed to S Sharma.
Ophthaproblem. Retinal arterial macroaneurysm.
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Aged↗
AgNORs in endometrial lesions.
Silver nucleolar organizer region (AgNOR) staining was employed in one hundred specimens of endometrium. These included fifteen normal controls (Proliferative + Secretory endometrium) and eighty five lesions. Endometrial lesions comprised of endometritis (15), endometrial hyperplasia (25) and endometrial carcinoma (45). Three micron thick sections of paraffin embedded tissue were subjected to AgNOR staining as described by Crocker and Smith with a little modification of 0.01% safranin counterstain--The mean AgNOR scores were found to increase steadily from normal to endometritis to endometrial hyperplasia and carcinoma--The observations revealed statistically significant differences in values between atypical hyperplasia and carcinoma also. AgNOR staining and scoring is simple, inexpensive and a useful adjunct to routine histopathology to evaluate endometrial lesions especially to differentiate borderline lesions. Though scores cannot be standardized and fixed for a particular lesion as there are intralaboratory variations.
Endometrial Hyperplasia↗
QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy.
This study examines the relation of QT dispersion (QTd) on a surface electrocardiogram (ECG) to clinical features and established risk factors of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HC). One hundred fifty-six consecutive patients with HC (91 men, mean age 41+/-15 years, range 7 to 79) and 72 normal subjects (41 men, mean age 39+/-9 years, range 20 to 60) were studied. Standard 12-lead ECGs were recorded from each subject using a MAC VU electrocardiograph. Patients with nonsinus rhythm, atrioventricular conduction block, QRS duration > 120 ms, age < 15 years, and low amplitude T waves were excluded from the analysis (n=51). Another 22 patients who were receiving amiodarone and/or sotalol therapy were also excluded. QT interval and QTd were measured using automated analysis in the remaining 83 patients (46 men, age 40+/-14 years, range 16 to 76). QT interval (406+/-38 ms), QTc interval (432+/-27 ms), and QTd (43+/-25 ms) were significantly greater in patients with HC than in normal controls (386+/-31 ms, 404+/-16 ms, 26+/-16 ms, respectively) (p <0.0001). QTd was significantly greater in patients with HC with chest pain compared with asymptomatic or mildly symptomatic patients (50+/-28 ms vs 37+/-20 ms, p=0.02). Increased QTd was found in patients with dyspnea New York Heart Association functional classes II/III than in those with dyspnea New York Heart Association functional class I (50+/-27 ms vs 38+/-22 ms, p=0.04). QTd was weakly correlated with maximum left ventricular wall thickness (r=0.228, p=0.038). No significant association was found between QTd and any risk factors for SCD. Thus, patients with HC have increased QTd. The QTd correlates with symptomatic status. Assessment of QTd might provide complementary clinical characterization of patients with HC but its relation to SCD remains uncertain.
Adolescent↗
Crystal structure of a complex formed between proteolytically-generated lactoferrin fragment and proteinase K.
Lactoferrin is an iron binding glycoprotein with a molecular weight of 80 kDa. The molecule is divided into two lobes representing the N-terminal and C-terminal halves of the polypeptide chain, each containing an iron binding site. The serine proteinases such as trypsin, chymotrypsin, and pepsin hydrolyze lactoferrin into two unequal halves while proteinase K divides this protein into two equal halves. In the first step of hydrolysis by proteinase K, the C- and N-lobes, each having a molecular weight of approximately 40 kDa, are generated. In the next step, the lobes are further hydrolyzed into small molecular weight peptides. The proteinase K isolated from the hydrolyzed product does not show enzymatic activity suggesting that the enzyme is inhibited. Furthermore, the hydrolysis experiments on N-lobe and C-lobe showed that the inhibitory fragment came from the C-lobe. The purified lactoferrin fragment was found to be a decapeptide with an amino acid sequence of H2N-Val-Ala-Gln-Gly-Ala-Ala-Gly-Leu-Ala-COOH. The complex formed between proteinase K and lactoferrin fragment was crystallized by microdialysis. The crystals belonged to the monoclinic space group P2(1) with cell dimensions a = 44.4 A, b = 38.6 A, c = 79.2 A, beta = 105.8 degrees and Z = 2. The crystal structure has been determined at 2.4 A resolution. It has been refined to an R factor of 0.163 for 9044 reflections. The Lf-fragment forms several intermolecular interactions with proteinase K. The Ser-224 Ogamma and His-57 N epsilon2 move away to a distance of 3.68 A in the complex. In the crystal structure, Gln-3I (I indicates inhibitor i.e., lactoferrin fragment) is involved in a direct intermolecular interaction with a symmetry related proteinase K molecule through a strong hydrogen bond with Asp-254. The mode of intermolecular interactions in the complex conformational features of the enzyme and placement of the fragment with respect to the enzyme resemble with the molecular complex of proteinase K with its natural inhibitor PKI3 from wheat.
Animals↗
Mini-Mental State Examination (MMSE) performance of partially remitted community-dwelling patients with schizophrenia.
Patients with schizophrenia perform worse than healthy controls on many neuro-psychological tests. However, previous studies of neuro-cognitive function have mostly been carried out on acutely ill or institutionalized patients. The objective of this study was to generate norms for performance of partially remitted community-dwelling patients with schizophrenia on the Mini-Mental State Examination (MMSE). Partially remitted outpatients attending a depot antipsychotic clinic or a clozapine clinic (n = 272) were tested using the MMSE. Demographic and clinical characteristics associated with MMSE performance, as well as the performance of specific items, were examined. MMSE score was significantly associated with educational status and race. Patients in our sample performed approximately 2-3 points below the population norms at all ages, but the mean score for the group was not in the impaired range. There was no apparent widening of this gap with advancing age. Patients who did poorly most frequently had difficulty with memory, attention and construction tasks. The MMSE is easy to administer to outpatients with schizophrenia and most patients score in the un-impaired range. The MMSE may be used to identify a subgroup of patients who score in the impaired range, for further investigations.
Acute Disease↗
Evaluation of the stoichiometry and energetics of carbohydrate binding to Ricinus communis agglutinin: a calorimetric study.
High-sensitivity isothermal titration calorimetry has been used to investigate the thermodynamics of binding of Ricinus communis agglutinin to galactose, lactose and their derivatives in the temperature range 280.5-298 K. The present study unequivocally establishes the carbohydrate-binding stoichiometry of the tetrameric agglutinin from castor bean as two, i.e. the (As-sB)2-type tetramer of the agglutinin has two equivalent sites that are non-interacting and independent. The site binding constants range from 2.2x10(3) M-1 at 282 K for galactose to 4.84x10(4) M-1 at 281 K for N-acetyl-lactosamine. The binding enthalpies range from -21.9 kJ. mol-1 at 293 K for 4-methylumbelliferyl-beta-galactoside to -50.2 kJ. mol-1 at 292.9 K for thiodigalactoside. The observation of limited entropy-enthalpy compensation for binding of the sugars to the lectin indicates that reorganization of water molecules plays an important role in binding. As the slope of the compensation plot is greater than unity, the reactions are largely enthalpically driven. These studies show that the stronger binding of N-acetyl-lactosamine than lactose is due to a favourable interaction between the acetamido group of the reducing-end N-acetylglucosamine of the former and the corresponding loci in the agglutinin molecule. Preferential binding of methyl-beta-galactoside over methyl-alpha-galactoside also indicates the apolar nature of the interaction with the methyl group of the former sugar.
Calorimetry↗
A pivotal role of cyclin D3 and cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-mediated human B cell proliferation.
The functional differences between IgDhighCD38- naive and IgD-CD38- memory (M) or IgDlowCD38+ germinal center (GC) B cells may stem from their variable response to signals that regulate activation, proliferation, and differentiation. In this report, we provide evidence for differential induction of cell cycle regulators in tonsillar human B cell subpopulations that were activated with anti-IgM and anti-CD40 in the presence or absence of IL-2, IL-4, or IL-10. Naive (IgDhigh) B cells exhibited a significant proliferative response to IL-4, but not to IL-2 or IL-10, whereas these cytokines triggered variable levels of growth in the combined GC/M subpopulation (referred to as IgDlow), as measured by [3H]thymidine incorporation. Induction of growth by cytokines in B cell subpopulations strictly correlated with the increased levels of cyclin D3 and cyclin-dependent protein kinase (cdk) 6. Moreover, only cyclin D3/cdk6 complexes were functional as observed in both naive and GC/M B cells stimulated in the presence of IL-4. In addition, active growth was associated with cytokine-mediated elimination of the cell cycle inhibitor p27. The significance of p27 in human B cell cycle was further demonstrated by rapamycin-mediated growth inhibition of IL-4-dependent proliferation, which resulted in strikingly increased p27 levels. Taken together, our findings suggest that cyclin D3, cdk6, and p27 play key roles in IL-2-, IL-4-, and IL-10-mediated human B cell proliferation. Furthermore, these results may provide a molecular basis for different cycling characteristics of naive and GC/M B cell subpopulations.
Antibodies, Anti-Idiotypic↗
Nutrient intakes among UK African-Caribbeans: changing risk of coronary heart disease.
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Female↗
Intravaginal misoprostol for medical evacuation of first trimester missed abortion.
Objective: To evaluate the safety and efficacy of intravaginal misoprostol for medical evacuation of first trimester missed abortions.Methods: Seven women with a transvaginal ultrasound diagnosis of a first trimester missed abortion were treated with 800 µg of misoprostol. Four 200 µg misoprostol tablets were placed intravaginally, and a repeat dose of 800 µg was repeated if products of conception were not expelled in 12 hours.Results: Five of seven of the medical evacuations were successful. The average gestational age for the patients was 9 weeks with a range of 8 3/7 to 9 3/7 weeks. The average time from insertion to complete passage of products of conception was 18 hours with a range from 5 hours 10 minutes to 50 hours. Only one patient in the successful group required the second dose of misoprostol. One patient completely passed products of conception 2 weeks after the 2 doses of misoprostol and was considered a treatment failure. Another patient passed products of conception within 12 hours following insertion of the misoprostol but required a dilatation and curettage 3 days later and was also considered a treatment failure. Side effects included cramping in all patients, which was noted to be moderate in six and mild in one. One patient also had mild nausea, mild headache, and one episode of diarrhea. The average blood loss was estimated at 434 mL with a range from 171 to 871 mL.Conclusion: Intravaginal misoprostol for medical evacuation of first trimester missed abortions appears to be safe and effective and may be an alternative to dilatation and curettage.
Journal Article↗
Interleukin-6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway.
The mechanism by which interleukin-6 (IL-6) protects multiple myeloma (MM) plasma cells from apoptosis induced by anti-fas antibodies and dexamethasone was studied. Anti-apoptotic concentrations of IL-6 had no effect on cell-cycle distribution or activation of RAF-1 or ERK in dexamethasone- or anti-fas-treated 8226 and UCLA #1 MM cell lines. However, IL-6-dependent protection of viability correlated with an inhibition of dexamethasone- and anti-fas-induced activation of jun kinase (JNK) and AP-1 transactivation. To test the hypothesis that cytokine-induced protection was mediated through inhibition of JNK/c-jun, we also inhibited c-jun function in 8226 cells via introduction of a mutant dominant negative c-jun construct. Mutant c-jun-containing MM cells were also resistant to anti-fas-induced apoptosis but were significantly more sensitive to dexamethasone-induced apoptosis. These results support the notion that IL-6 protects MM cells against anti-fas through its inhibitory effects on JNK/c-jun but indicate protection against dexamethasone occurs through separate, yet unknown pathways.
Apoptosis↗
Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat.
The mothers of infant rats show individual differences in the frequency of licking/grooming and arched-back nursing (LG-ABN) of pups that contribute to the development of individual differences in behavioral responses to stress. As adults, the offspring of mothers that exhibited high levels of LG-ABN showed substantially reduced behavioral fearfulness in response to novelty compared with the offspring of low LG-ABN mothers. In addition, the adult offspring of the high LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor density in the central, lateral, and basolateral nuclei of the amygdala as well as in the locus ceruleus, (ii) increased alpha2 adrenoreceptor density in the locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH) receptor density in the locus ceruleus. The expression of fear and anxiety is regulated by a neural circuitry that includes the activation of ascending noradrenergic projections from the locus ceruleus to the forebrain structures. Considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, as well as the anxiolytic actions of benzodiazepines, for the expression of behavioral responses to stress, these findings suggest that maternal care during infancy serves to "program" behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.
Amygdala↗
HIV-1 Tat elongates the G1 phase and indirectly promotes HIV-1 gene expression in cells of glial origin.
Human immunodeficiency virus type-1 (HIV-1) infection of the central nervous system (CNS) gives rise to many of the neurological complications in patients with AIDS. Infection of microglial cells and astrocytes in the brain promotes the release of HIV-1 Tat and other candidate neurotoxins that may be associated with the widespread neuropathology. To examine the contribution of HIV-1 Tat to the interplay between virus and CNS cells, the human astrocytic cell line, U-87MG, was treated with recombinant Tat protein. Fluorescence-activated cell sorting analysis indicated that Tat induces a G1 arrest in these cells. Consistent with this observation, lower levels of cyclin E-Cdk2 kinase activity and phosphorylated Rb were detected in the Tat-treated cells compared with the control cells. Interestingly, our observations indicate that the underphosphorylated form of Rb that is prevalent in Tat-treated cells promotes HIV-1 transcription by a mechanism involving the NF-kappaB enhancer region. Taken together, the data presented here provide the first evidence that the HIV-1 regulatory protein, Tat, may manipulate the host cell cycle to promote viral gene expression. The significance of these findings relates to the current hypothesis that indirect effects of HIV-1 infection of the CNS may contribute to the neurological complications associated with AIDS dementia complex.
Astrocytes↗
Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.
Tumor-derived prostaglandin E2 (PGE2) modifies cytokine balance and inhibits host immunity. We hypothesized that a high level of PGE2 production by lung tumor cells is dependent on tumor cyclooxygenase (COX)-2 expression. We found that PGE2 production by A549 non-small cell lung cancer (NSCLC) cells was elevated up to 50-fold in response to interleukin (IL)-1beta. Reversal of IL-1beta-induced PGE2 production in A549 cells was achieved by specific pharmacological or antisense oligonucleotide inhibition of COX-2 activity or expression. In contrast, specific COX-1 inhibition was not effective. Consistent with these findings, IL-1beta induced COX-2 mRNA expression and protein production in A549 cells. Specific inhibition of COX-2 abrogated the capacity of IL-1beta-stimulated A549 cells to induce IL-10 in lymphocytes and macrophages. Furthermore, specific inhibition of A549 COX-2 reversed the tumor-derived PGE2-dependent inhibition of macrophage IL-12 production when whole blood was cultured in tumor supernatants. Our results indicate that lung tumor-derived PGE2 plays a pivotal role in promoting lymphocyte and macrophage IL-10 induction while simultaneously inhibiting macrophage IL-12 production. Immunohistochemistry of human NSCLC tissues obtained from lung cancer resection specimens revealed cytoplasmic staining for COX-2 within tumor cells. This is the first description of functional COX-2 expression by NSCLC cells and the definition of a pathway whereby tumor COX-2 expression and a high level of PGE2 production mediate profound alteration in cytokine balance in the lung cancer microenvironment.
Adenocarcinoma↗
Gene transfer of CD40-ligand induces autologous immune recognition of chronic lymphocytic leukemia B cells.
CD40-CD40-ligand (CD154) interactions play a critical role in immune activation. Using replication defective adenovirus encoding mouse CD154 (Ad-CD154), we modified human chronic lymphocytic leukemia B cells to express a functional ligand for CD40. This not only induces expression of immune accessory molecules on the infected cell, but also allows it to trans-activate noninfected bystander leukemia B cells. Also, factors that impair the antigen-presenting capacity of leukemia B cells are downmodulated. Ad-CD154- infected leukemia cells are highly effective stimulators in mixed lymphocyte reactions and can induce generation of cytotoxic T lymphocytes specific for autologous nonmodified leukemia cells. As such, Ad-CD154 can induce a host antileukemia response that may have therapeutic potential.
Adenoviridae↗
Malignant intracerebral nerve sheath tumor: a case report and review of the literature.
BACKGROUND: Intraparenchymal nerve sheath tumors of the central nervous system are rare, usually benign tumors. Three cases with tumor recurrences have previously been reported in the literature. The authors report a case of a malignant intracerebral nerve sheath tumor in a girl age 8 years and analyze the biologic characteristics of this tumor. METHODS: The tumor was analyzed by histologic, immunohistochemical, and ultrastructural techniques. RESULTS: Magnetic resonance imaging revealed a mixed, attenuating, contrast-enhancing mass in the right posterior temporal lobe. Histopathology of the resected specimen revealed a uniformly S-100 positive and reticulin rich biphasic tumor with a characteristic distribution of spindle and epithelioid cells, with the latter almost entirely confined to the invading edge of the tumor. There was extensive brain infiltration in the form of lobules and fingerlike processes with a targetoid appearance. The spindle cells showed palisading and had elongated, wavy nuclei. Electron microscopy demonstrated basal lamina around both cell types with scattered Luse bodies in between. The patient is perfectly healthy and recurrence free 17 months after surgery. CONCLUSIONS: This represents the fourth and the youngest case in the literature of a malignant intracerebral nerve sheath tumor and highlights the distinctive clinicopathologic features of these tumors. First, these tumors have very great infiltrative potential, as observed histopathologically and reflected in their frequent recurrences. Second, epithelioid cells confined to the infiltrative edge suggest their aggressive role. Epithelioid cells have been shown to represent a malignant component of systemic schwannomas with malignant transformation; however, this case does not have any evidence of origin from a preexisting benign schwannoma. Third, despite histologic similarities to neuraxial desmoplastic neuroepithelial tumors, none of the malignant schwannomas had any evidence of divergent differentiation towards astrocytic or neuronal lineage, and had a much worse prognosis. Fourth, the event free survival after initial resection appears to be an important predictor of overall survival in the reviewed cases. Chemotherapy and radiation therapy have not been successful in the treatment of this rare entity. Hence, an accurate diagnosis and planned extensive resection appear to be the key elements in its management.
Brain Neoplasms↗
Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects.
The molecular basis of the immunomodulatory properties of 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) remains elusive. We demonstrate here that 1alpha,25(OH)2D3-mediated suppressive effects on the inducible expression of cytokine genes in human T cells may, in part, be due to diminished activity of the transcription factor NFAT. The vitamin D3 receptor (VDR) and its heterodimeric partner retinoid X receptor alpha (RXR alpha) specifically bound to the distal NFAT site in the human IL-2 promoter, and this binding was abolished by mutating unique regions in the NFAT oligonucleotide. In vitro inhibition of NFAT complex formation was noted when VDR-RXR alpha heterodimers were added to DNA binding reactions containing nuclear extracts from activated B or T cells, whereas in vitro NFkappaB complex formation was not significantly influenced. Furthermore, 1alpha,25(OH)2D3 treatment of activated T cells resulted in decreased formation of NFAT complexes detected upon incubation of nuclear extracts from these cells with 32P-labeled probe. Transient expression of both VDR and RXR alpha, but not of a single component, was capable of inhibiting expression of a NFAT-driven reporter gene in stimulated jurkat cells in a ligand-dependent manner. These results suggest that NFAT plays a crucial role in 1alpha,25(OH)2D3-mediated immunosuppressive activity.
Base Sequence↗
Does a visible retinal embolus increase the likelihood of hemodynamically significant carotid artery stenosis in patients with acute retinal arterial occlusion?
OBJECTIVE: To determine the value of visible retinal emboli as a diagnostic "test" for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion. METHODS: A cross-sectional diagnostic accuracy study was performed in a tertiary North American center, with the results of the dichotomous diagnostic test (the presence or absence of visible retinal emboli) being placed against the dichotomous outcome of the presence or absence of hemodynamically significant carotid artery stenosis (defined as > or = 60%, or < 60%, carotid artery stenosis on either side). RESULTS: Forty-eight (18.7%) of our 256 patients had hemodynamically significant carotid artery stenosis. The sensitivity and specificity of retinal emboli for the detection of hemodynamically significant carotid artery stenosis were 39% and 68%, respectively. The presence of a visible retinal embolus generated a likelihood ratio of 1.24 (95% confidence interval, 0.84-1.86). This value corresponds to a patient with a pretest probability of 50% having a posttest probability of 55.3%. The absence of a visible retinal embolus generated a likelihood ratio of 0.88 (95% confidence interval, 0.68-1.15). CONCLUSIONS: The presence of a visible retinal embolus is a poor diagnostic test for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion. Accordingly, the presence of an embolus should not influence the decision to perform carotid Doppler ultrasonography in patients with acute retinal arterial occlusion.
Adult↗