Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin

In order to investigate the molecular mechanisms implicated in the induction of chemo sensitivity by adenovirus E1a gene expression, we decided to investigate which signal transduction pathways could be affected by the E1a gene in Human Normal Fibroblast (IMR90). No effect was observed in SAPK pathways (p38MAPK and JNK), but E1a was able to affect the Akt activation mediated by insulin. This result was confirmed by transient transfection experiments performed in Cos-7 cells and also observed in other transformed cell lines such as A431. Furthermore, E1a expression induces a decrease in the basal status of Akt activity. Finally we demonstrated that E1a is able to block the Akt activation mediated by cisplatin and correlates with a sensitive phenotype. In summary, our data demonstrate that specific inhibition of the PI3K/Akt pathway mediates some of the biological properties of E1a such as induction of chemosensitivity.     

Magnetic resonance imaging of prostate cancer

Management of carcinoma of the prostate has traditionally been guided by digital rectal examination, and by laboratory data such as serum prostate-specific antigen (PSA) level and histopathologic tumor grade. The introduction of the endorectal coil has improved the ability of magnetic resonance imaging (MRI) to contribute to staging and treatment planning of prostate cancer, especially in cases of confined or locally invasive disease. Exciting research in the fields of magnetic resonance spectroscopy (MRS) and MR-guided intervention of the prostate may soon expand the role of MRI in the diagnosis and treatment of prostate cancer. This article reviews current MRI techniques, the MRI features of prostate cancer, the role and efficacy of MRI in prostate carcinoma staging, and the current and future uses of MR spectroscopy and MR-guided prostate brachytherapy.     

The epidemiology of oral and pharynx cancer in Brazil

A study was carried out on the occurrence of oral and pharynx cancer among populations living in five Brazilian geographic regions, by using incidence and mortality rates and trends. Information on survival was also analyzed. Complementary information regarding prevalence of the disease risk factors has been supplied in the attempt to establish some etiological connections with the incidence and mortality observed. Two clear patterns for the occurrence of oral and pharyngeal cancer have been detected: a pattern for the north (including the northern, northeastern and midwestern regions, which are the poorest ones) and a pattern for the south (including the southern and southeastern regions). The southern pattern revealed incidence rates higher than 15 per 100,000 among males, and the northern pattern displayed lower rate levels. Similarly, mortality rates in the south were higher than three per 100,000 and the northern pattern was characterized by lower rates. Other cancers linked to tobacco smoking, such as esophagus, larynx, lung and bladder cancer kept the same pattern of incidence and mortality rates related to oral and pharyngeal cancer in males per region. Information on survival of patients with oral and pharyngeal cancer was very restricted in Brazil, thus hindering the survival analysis per region, but the studies conducted allowed to conclude that the majority of diagnoses were conducted in advanced stages of the disease and implied the low 5-year survival rate observed in Brazil. Tongue tumors displayed the worst survival rates. The southern region shares specific risk factors involved in the oral and pharyngeal cancer present in the Argentinean and Uruguayan populations, namely heavy tobacco smoking and alcohol consumption, as well as high intake of charcoal-grilled red meat and mate. In addition to these risks, part of the oral and pharyngeal cancer registered in Brazil might be linked to a few factors present among people with low life standards, including poor oral hygiene and nutrition.     

National Cancer Institute workshop on chemopreventive properties of nonsteroidal anti-inflammatory drugs: role of COX-dependent and -independent mechanisms

A workshop, "Chemopreventive properties of nonsteroidal anti-inflammatory drugs (NSAIDs): Role of COX-dependent and -independent mechanisms," sponsored by the Chemical and Physical Carcinogenesis Branch, Division of Cancer Biology of the National Cancer Institute, was held in Rockville, Maryland, on January 8, 2001. The workshop was composed of two parts: oral presentations by a series of speakers, and a group discussion of preselected topics.     

Implications of lymphatic drainage to unusual sentinel lymph node sites in patients with primary cutaneous melanoma

BACKGROUND: Sentinel lymphadenectomy reliably identifies the first site(s) of regional lymphatic drainage and, therefore, the most likely lymph nodes to contain occult metastasis in patients with primary cutaneous melanoma. Although in most patients lymphatic drainage from the primary melanoma first reaches a standard lymph node basin, a sentinel lymph node (SLN) may be identified in an unusual location. The objective of this study was to determine the frequency and significance of unusual sentinel lymph node drainage patterns in a large cohort of patients with primary melanoma. METHODS: The records of 1145 consecutive primary melanoma patients who underwent SLN biopsy were reviewed. Preoperative lymphoscintigraphy was performed in all patients with truncal melanoma and in many patients with distal extremity lesions. Unusual lymph node sites were defined as epitrochlear, popliteal, or ectopic/interval (in-transit or any other nonstandard lymph node-bearing area). RESULTS: At least one SLN was harvested in 1117 patients (98%). SLN biopsy of an unusual lymph node site was attempted in 59 patients (5%). Successful intraoperative localization and biopsy was performed in 54 (92%) of 59 patients for a total of 56 unusual sites. Of these, 7 (13%) were popliteal, 8 (14%) were epitrochlear, and 41 (73%) were ectopic/interval. Preoperative lymphoscintigraphy was performed in 41 of these 54 patients and correctly identified unusual SLN locations in 12 (29%); the majority of unusual SLNs were identified only with the assistance of the intraoperative gamma probe. In four patients (7%), the unusual lymph node site was the only site from which SLNs were harvested. In the remaining 50 patients (93%), biopsies were performed on SLNs from both unusual sites and from a standard lymph node basin. Among the 54 patients who underwent a SLN biopsy of an unusual nodal site, 7 (13%) had lymph node metastases in that location. In four of the seven patients, the only positive SLN was from the unusual site. CONCLUSIONS: Sentinel lymphatic drainage patterns include lymph node-bearing areas that may be outside established standard lymph node basins and may represent the only site of regional lymph node metastases. Although preoperative lymphoscintigraphy may assist in the identification of unusual SLN drainage patterns, intraoperative use of the gamma probe is recommended to identify accurately and completely all sites of regional lymph node drainage.     

Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency

Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents. Their potency depends on their replication efficiency in cancer cells and their capacity to destroy these cells by oncolysis. In this regard, a critical determinant is the capacity of CRAds to induce cell death at late stages of infection to release their progeny. One of the cell death pathways that are exploited by adenoviruses involves the tumor suppressor protein p53. Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not effectively support CRAd-induced cell death. We hypothesized that restoration of the p53-dependent cell death pathway in cancer cells would promote CRAd-induced cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus replication accelerated cell death by several days and augmented early virus progeny release. The p53-enhanced oncolysis occurred independent of E1A binding to pRb and independent of E3 functions. On the basis of these findings, we constructed a new CRAd, AdDelta24-p53. This virus expressed functional p53 while replicating in cancer cells. Most importantly, AdDelta24-p53 exhibited enhanced oncolytic potency on 80% of tested human cancer cell lines of various tissue origins and with different p53 status. CRAd potency was increased up to >100-fold by p53 expression. We conclude that CRAds expressing p53 are promising new agents for more effective treatment of many human cancers.     

Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin

BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer.     

Hypophysiotropic neurons of the paraventricular nucleus respond in spatially, temporally, and phenotypically differentiated manners to acute vs. repeated restraint stress: rapid publication

The antennules of decapod crustaceans are covered with thousands of chemosensilla that mediate odor discrimination and orientation behaviors. Most studies on chemoreception in decapods have focused on the prominent aesthetasc sensilla. However, previous behavioral studies on lobsters following selective sensillar ablation have revealed that input from nonaesthetasc antennular chemosensilla is sufficient for many odor-mediated behaviors. Our earlier examination of the setal types on the antennules of the Caribbean spiny lobster Panulirus argus revealed three types of nonaesthetasc chemosensilla. The most abundant and widely distributed of these is the hooded sensillum. The present study describes the detailed ultrastructure of antennular hooded sensilla and the physiological response properties of their receptor neurons. Light and scanning and transmission electron microscopy were used to examine structural characteristics, and electrophysiology was used to examine single-unit responses elicited by focal chemical and mechanical stimulation of antennular hooded sensilla. Hooded sensilla have a porous cuticle and are innervated by 9-10 chemosensory and 3 mechanosensory neurons whose dendrites project to the distal end of the sensillum. Hooded sensillar chemosensory neurons responded to waterborne chemicals, were responsive to only one of the six tested single compounds, and had different specificities. Hooded sensillar mechanosensory neurons were not spontaneously active. They had low sensitivity in that they responded to tactile but not waterborne vibrations, and they responded to sensillar deflection with phasic bursts of activity. These results support the idea that hooded sensilla are bimodal chemo-mechanosensilla and are receptors in an antennular chemosensory pathway that parallels the well-described aesthetasc chemosensory pathway.     

Ethnicity and treatment response in schizophrenia: a comparison of 3 ethnic groups

BACKGROUND: Numerous cultural and ethnic factors may directly and indirectly influence treatment outcome in schizophrenia. The present study compared the response to antipsychotic treatment in 3 ethnic groups of patients with schizophrenia. METHOD: Fifty black, 63 mixed descent, and 79 white patients with DSM-IV-diagnosed schizophrenia or schizophreniform disorder who were participants in multinational clinical drug trials were assessed by means of the Positive and Negative Syndrome Scale (PANSS). Treatment response was measured by the change in PANSS total scores and the change in positive, negative, and general psychopathology subscale scores from baseline to 6 weeks. Also, the percentage of responders (defined as > or = 40% reduction in PANSS total scores) was calculated for each group. RESULTS: Baseline PANSS scores differed significantly, being higher for black and mixed descent patients. Mixed descent patients showed the greatest mean +/- SD percentage reduction in PANSS total score (29.4 +/- 21.6) followed by black (28.4 +/- 14.7) and white (11.4 +/- 27.6) patients. Analysis of covariance revealed a significant effect of ethnicity on the reduction in PANSS total scores (p < .0001). The numbers of responders were 20 mixed descent (32%), 12 black (24%), and 7 white (9%) patients (p = .002). CONCLUSION: Significant ethnic differences in acute antipsychotic treatment response are demonstrated by this study. Factors such as diet, nutritional status, body mass, and substance use could be important, as well as genetically determined ethnospecific pharmacokinetic and pharmacodynamic differences. Delayed help-seeking may account for the higher baseline scores in the black and mixed descent patients.     

Management of urethral catheter knot in a neonate

To accommodate the small size of the infant urethra, finer, more flexible tubes are often used for urinary catheterization in the pediatric intensive care units. These tubes have the ability to knot in the bladder, occasionally requiring surgical removal. The mechanism of knotting appears to result from excessive intravesical catheter coiling, and as the bladder decompresses the catheter tip can migrate through a coil thereby creating a knot. Review of the literature from 1975 to 2000 identified 19 cases of urethral catheter knotting in the pediatric bladder with two reports of prostatic urethral involvement. Herein, we describe the first reported instance of catheter knotting within the penile urethra and describe the surgical technique employed for its removal.