Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1.

Angiogenesis is regulated by highly coordinated function of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLCγ1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCγ1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. In this study, we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLCγ1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCγ1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCγ1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis.

Electrodeposited iridium oxide for neural stimulation and recording electrodes.

Iridium oxide films formed by electrodeposition onto noniridium metal substrates are compared with activated iridium oxide films (AIROFs) as a low impedance, high charge capacity coating for neural stimulation and recording electrodes. The electrodeposited iridium oxide films (EIROFs) were deposited on Au, Pt, PtIr, and 316 LVM stainless steel substrates from a solution of IrCl4, oxalic acid, and K2CO3. A deposition protocol involving 50 potential sweeps at 50 mV/s between limits of 0.0 V and 0.55 V (versus Ag AgCl) followed by potential pulsing between the same limits produced adherent films with a charge storage capacity of >25 mC/cm2. Characterization by cyclic voltammetry and impedance spectroscopy revealed no differences in the electrochemical behavior of EIROF on non-Ir substrates and AIROF. The mechanical stability of the oxides was evaluated by ultrasonication in distilled water followed by dehydration and rehydration. Stability under charge injection was evaluated using 200 micros, 5.9 A/cm2 (1.2 mC/cm2) cathodal pulses. Loss of iridium oxide charge capacity was comparable for AIROFs and the EIROFs, ranging from 1% to 8% of the capacity immediately after activation or deposition. The EIROFs were deposited and evaluated on silicon microprobe electrodes and on metallized polyimide electrodes being developed for neural recording and stimulation applications.

Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation.

Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in vasculogenesis and angiogenesis. However, the mechanism by which VEGFR-2 activation elicits these cellular events is not fully understood. We recently constructed a chimeric receptor containing the extracellular domain of human CSF-1R/c-fms, fused with the entire transmembrane and cytoplasmic domains of murine VEGFR-2 (Rahimi, N., Dayanir, V., and Lashkari, K. (2000) J. Biol. Chem. 275, 16986-16992). In this study we used VEGFR-2 chimera (herein named CKR) to elucidate the signal transduction relay of VEGFR-2 in porcine aortic endothelial (PAE) cells. Mutation of tyrosines 799 and 1173 individually on CKR resulted in partial loss of CKR's ability to stimulate cell growth. Double mutation of these sites caused total loss of CKR's ability to stimulate cell growth. Interestingly, mutation of these sites had no effect on the ability of CKR to stimulate cell migration. Further analysis revealed that tyrosines 799 and 1173 are docking sites for p85 of phosphatidylinositol 3-kinase (PI3K). Pretreatment of cells with wortmannin, an inhibitor of PI3K, and rapamycin, a potent inhibitor of S6 kinase, abrogated CKR-mediated cell growth. However, expression of a dominant negative form of ras (N(17)ras) and inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD98059 did not attenuate CKR-stimulated cell growth. Altogether, these results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth.

Sonographic assessment of renal length in the first year of life: the problem of "spurious nephromegaly".

PURPOSE: Interest in the potential diagnostic or prognostic implications of nephromegaly as evidence for compensatory renal hypertrophy has recently been emphasized in a variety of clinical settings. This project was designed to compare the results of linear and nonlinear sonographic models in the interpretation of renal size and growth during the first year of life. MATERIALS AND METHODS: We identified all renal and abdominal ultrasound examinations that were performed between March 1994 and October 1997 in full-term infants under age 1 year during which (1) both renal lengths were measured and (2) both kidneys appeared anatomically normal. Using three different computerized algorithms based on published standards for sonographic renal length in relation to age, we calculated z-scores for the renal lengths and compared the results of the three methods: in method A the standards at birth, 1 week, 4 months, 8 months, and 1 year were all used; in method B the 1-week standard was omitted; in method C the standards at 1 week, 4 months, and 8 months were omitted. RESULTS: We evaluated 1,234 renal measurements in 617 patients (293 boys, 324 girls; mean age 0.24 year). Compared with method A, z-scores were significantly increased when either method B or C was used (P < 0. 0001). The mean increment in z-score was + 0.433 for method B and + 1.135 for method C. The prevalence of "nephromegaly" (z > + 2) was significantly increased when subannual standards were omitted (P < 0. 0001): using method A, 20 (1.6 %) kidneys were large for age compared with 74 (6.0 %) using method B, and 214 (17.3 %) using method C. All kidneys that were large for age based on method A were also large for age using both methods B and C. The rate of false-positive diagnosis of nephromegaly was 73 % (54/74 kidneys) with method B and 91 % (194/214 kidneys) with method C. CONCLUSIONS: Although the use of multiple subannual standards for renal length in infants less than 1 year of age is time consuming and mathematically more complicated, omission of these standards results in a statistically significant increase in the frequency of "spurious" nephromegaly. LEARNING OBJECTIVES: Precise application of published standards is important in the interpretation of sonographic measurements of renal length. Omission of the subannual standards for renal length in children who are less than 1 year of age can result in an incorrect impression of nephromegaly.

Visualization of data.

Data visualization has developed in several directions: theoretical; methodological; and in new application areas. Advances include the development of a grammar of graphics, deeper understanding of human perception and implications for graphical layout, and better approaches to visualizing multi-dimensional data and large data sets. Gene expression is a notable new application area for visualization of large data sets.

Whitening of endodontically untreated calcified anterior teeth.

Definitive treatment for whitening endodontically untreated anterior teeth with dystrophic calcification is provided by removing the coronal sclerotic dentin and utilizing internal and external bleaching as necessary.

Accessory innervation of the mandible: identification and anesthesia options.

The nerves commonly associated with accessory innervation of the mandible are identified and alternative techniques to gain their anesthesia are recommended, based on sound anesthetic principles and the current understanding of nerve anatomy.

Entrapment neuropathies of the tibial (posterior tibial) nerve.

Entrapment neuropathies of the tibial nerve are relatively rare. They are often misdiagnosed largely because of the clinician's low index of suspicion. The clinical features, diagnostic studies, and treatment of these disorders are reviewed in detail in this article. Almost all of these disorders can now be confirmed through nerve conduction and other image studies.

Single appointment amalgam crown procedure for posterior teeth.

When faced with the restoration of severely broken-down posterior teeth, many treatment options exist. Expense, time constraints, and periodontal health, as well as the needs and desires of the patient, all play a role in the selection of treatment modality. In many instances, a well-fabricated amalgam crown can provide a highly acceptable functional restoration in the posterior region. Here, the amalgam crown is discussed in relation to other options and several case reports are presented.

One-appointment composite crown: an alternative to conventional crown and bridge.

When presented with little coronal tooth structure remaining, four options exist: (1) extraction only, (2) extraction and restoration, (3) root canal therapy and a cast restoration (which may involve crown lengthening and/or orthodontic extrusion), or (4) root canal therapy and a composite/amalgam crown. A technique for the composite crown option is described with case presentations.

Anatomical basis for inferior alveolar nerve block.

This article discusses a scientific approach to customize the inferior alveolar nerve block technique, by focusing on individual anatomy and neurophysiology.

Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS.

The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B (AmB) lipid complex (ABLC) in the treatment of AIDS-associated cryptococcal meningitis. Of 55 patients randomly assigned to 6 weeks of therapy with ABLC (1.2-5.0 mg/[kg.d], with ascending doses for three sequential cohorts) or AmB (0.7-1.2 mg/[kg.d]), 46 received > or = 12 doses. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with AmB than with ABLC. The total number of adverse events, infusion-related events, and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar. Among 21 recipients of ABLC at a dosage of 5 mg/kg (daily for 2 weeks and then thrice weekly for 4 weeks), symptoms and signs resolved for 18 (86%). Of those receiving > or = 12 doses of ABLC, cultures converted to negative for 8 (42%), were undeterminable for 3 (16%), and remained positive for 8 (42%) despite resolution of symptoms. Although preliminary, these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis. Because this formulation has less hematologic and renal toxicity than does AmB, further evaluation of ABLC is warranted.

Imported echinococcosis in southern California.

A retrospective chart review conducted at two teaching hospitals in Los Angeles County identified 28 patients with infection due to Echinococcus granulosus diagnosed by positive echinococcal serology and/or tissue biopsy between January 1981 and December 1990. Of these patients, 25 (89%) were foreign born and 19 (68%) were immigrants from the Middle East or central Asia. Only 12 of 22 immigrants questioned about epidemiologic risk factors described a history of rural residence or direct exposure to dogs in their native country. Single cysts of liver, lung, and soft tissue were present in six of 28 patients; multiple cysts in the 22 remaining patients were exclusively hepatic in 13 patients, exclusively pulmonary in two patients, and involved mixed sites including liver, lung, abdomen, central nervous system, and bone in seven patients. Natives of middle eastern countries currently constitute a major risk group for imported infection due to E. granulosus in the United States. Since their epidemiologic risk factors may be absent and clinical presentations varied, a high index of suspicion for echinococcosis is warranted in this population based solely on the presence of a cystic mass in liver, lung, or another organ site.

A comparison of grip strength and selected psychomotor performance measures in healthy and frail elderly females.

Researchers have examined the relationships between strength and psychomotor skills among healthy male subjects far more thoroughly than among female subjects, especially elderly females. The purpose of the present investigation was to compare healthy and frail elderly females on grip strength and psychomotor performance measures. Nineteen healthy elderly females (M = 75.7 years of age) and 20 frail elderly females (M = 80.5 years of age) performed simple aiming movements in order for the investigators to obtain psychomotor measures (e.g., reaction time, movement time, kinematic movement characteristics). In addition, strength measures were obtained in the dominant and nondominant hands. Significant differences were found between elderly females on grip strength and psychomotor performance measures. In general, healthy subjects were stronger and exhibited superior control of movements (e.g., greater impulse, fewer movement adjustments).

Persistence of Pneumocystis carinii in patients with AIDS receiving chemoprophylaxis.

Pneumocystis carinii organisms have been shown to persist throughout therapy in the majority of patients with Pneumocystis carinii pneumonia (PCP). This study evaluated the relationship between persistence of organisms and recurrence of disease, and the effect of chemoprophylaxis on bronchoalveolar lavage specimens. Seven patients receiving PCP chemoprophylaxis underwent serial bronchoalveolar lavage (BAL) examinations at 1, 4, and 7 mo after recovery from a first episode of PCP. Specimens were examined for persistent organisms with Gomori's methenamine silver stain and immunofluorescent antibody staining. There were no persistent organisms 1 mo after completion of antimicrobial treatment in six of the seven patients. The one patient with persistent organisms demonstrated clearance of organisms by 4 mo and had no recurrence of PCP. One patient had a recurrence of PCP at 4 mo, after a negative 1-mo BAL. We conclude that a positive BAL result by silver stain or immunofluorescent antibody staining more than a month after ending treatment may indicate clinical recurrence of PCP and not just persistence of nonpathologic cysts. These findings suggest that recurrences of PCP are more likely due to new infection than to relapse of prior disease.

Herpes simplex chronic laryngitis and vocal cord lesions in a patient with acquired immunodeficiency syndrome.

Chronic laryngitis in patients with acquired immunodeficiency syndrome may be due to infections or tumors, such as Kaposi's sarcoma and non-Hodgkin's lymphoma. We present what we believe to be the first proven case of herpes simplex virus chronic laryngitis in a man positive for human immunodeficiency virus. Direct laryngoscopy showed leukoplakic lesions on both vocal cords. Biopsy of the lesions showed squamous epithelial cells with the characteristic features of herpes simplex virus, which was confirmed by immunohistochemical stains. We discuss the differential diagnosis of chronic laryngitis in a human immunodeficiency virus infection. Herpes simplex viral infection of the vocal cords should be considered in patients with acquired immunodeficiency syndrome presenting with chronic hoarseness and leukoplakic lesions on direct laryngoscopy, especially with no evidence of Kaposi's sarcoma, tumor, or cytomegaloviral or fungal infection elsewhere. Treatment should be acyclovir, except in the face of acyclovir resistance.

Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group.

OBJECTIVE: To test the hypothesis that the therapeutic success rate of oral atovaquone is not worse than that of intravenous pentamidine in the primary treatment of mild and moderate Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome and to detect differences in the toxicity rates of the two treatments. DESIGN: Patients were randomly assigned to receive 21 days of open-label therapy with either atovaquone, 750 mg orally with meals three times daily, or intravenous pentamidine, 3 to 4 mg per kg body weight once daily. SETTING: Multicenter study including university and community treatment facilities. PATIENTS: Patients with human immunodeficiency virus infection and clinical presentations consistent with mild or moderate P. carinii pneumonia were eligible. For efficacy and safety analyses, patients with histologically confirmed P. carinii pneumonia were emphasized. MEASUREMENTS: Patients were monitored by clinical and laboratory evaluations for therapeutic efficacy and adverse events during the acute treatment phase and for 8 weeks after therapy was discontinued. RESULTS: As initial therapy for a histologically confirmed episode of P. carinii pneumonia, 56 patients received atovaquone and 53 received pentamidine. More patients were successfully treated with atovaquone (57%) than with pentamidine (40%), a difference of 17% (95% CI, -3% to 38%; P = 0.085), but more patients failed to respond to atovaquone (29%) than to pentamidine (17%), a difference of 12% (CI, -6% to 29%; P = 0.18). Discontinuation of original therapy because of treatment-limiting adverse events was more frequent in the pentamidine group (36%) than in the atovaquone group (4%) (difference, -32%; CI, -48% to -17%; P < 0.001). Nine patients in each treatment group died during the study. CONCLUSIONS: Oral atovaquone and intravenous pentamidine have similar rates for successful treatment of mild and moderate P. carinii pneumonia, but atovaquone has significantly fewer treatment-limiting adverse events.