Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer

Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. Although it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically engineered mouse line lacking functional Muc4 (Muc4 ko), and then crossed these animals with the NDL (Neu DeLetion mutant) model of ErbB2-induced mammary tumorigenesis. We observed that Muc4 ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4 ko /NDL female mice exhibit similar latencies and growth rates as Muc4 wt /NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4 ko /NDL mice. Interestingly, histological analysis of lung lesions from Muc4 ko /NDL mice revealed a reduced association of disseminated cells with platelets and white blood cells. Moreover, isolated cells derived from Muc4 ko /NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4 wt /NDL cells than Muc4 ko /NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation

CKD in disadvantaged populations

Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline within the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age ( 5 years), gender and NIHSS ( 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analyses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this observational study, citicoline use was associated with a better functional status and lower rates of short-term mortality, possibly due to fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a randomized, controlled clinical trial. " 2010 Prous Science, S.A.U. or its licensors.",,,,,,"10.1358/mf.2010.32.5.1465004",,,"http://hdl.handle.net/20.500.12104/40081","http://www.scopus.com/inward/record.url?eid=2-s2.0-79952113397&partnerID=40&md5=3d5e6fd790ee6322dcc55aac4da37495",,,,,,"5",,"Methods and Findings in Experimental and Clinical Pharmacology",,"32

Citicoline for acute ischemic stroke in mexican hospitals: A retrospective postmarketing analysis

Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline within the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age (± 5 years), gender and NIHSS (± 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analyses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this observational study, citicoline use was associated with a better functional status and lower rates of short-term mortality, possibly due to fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a randomized, controlled clinical trial. © 2010 Prous Science, S.A.U. or its licensors

CKD in disadvantaged populations

Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline within the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age ( 5 years), gender and NIHSS ( 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analyses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this observational study, citicoline use was associated with a better functional status and lower rates of short-term mortality, possibly due to fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a randomized, controlled clinical trial. " 2010 Prous Science, S.A.U. or its licensors.",,,,,,"10.1358/mf.2010.32.5.1465004",,,"http://hdl.handle.net/20.500.12104/40081","http://www.scopus.com/inward/record.url?eid=2-s2.0-79952113397&partnerID=40&md5=3d5e6fd790ee6322dcc55aac4da37495",,,,,,"5",,"Methods and Findings in Experimental and Clinical Pharmacology",,"32

Recent striking changes in histological differentiation and rate of human papillomavirus infection in squamous cell carcinoma of the lung in Okinawa, a subtropical island in southern Japan

Aims—The incidence of lung cancer in Okinawa has been the highest in Japan since 1975, and squamous cell carcinoma (SCC), especially the well differentiated form, is the most prevalent form in Okinawa, although well differentiated SCC is relatively rare in mainland Japan. Furthermore, a high proportion of SCC of the lung in Okinawa was positive for human papillomavirus (HPV). In this study, we report recent striking changes in histological features and in the incidence of HPV infection. Methods—In Okinawa between 1986 and 1998, 1109 surgically resected lung tumours were examined histopathologically. In addition, human papillomavirus infection was detected by the polymerase chain reaction and Southern blot analysis in SCC cases reported in 1993 and 1995–8. Non-isotopic in situ hybridisation of HPV DNA was also carried out. Results—Up until 1994 SCC, especially the well differentiated form, was the most prevalent type of tumour. However, since 1995 the number of such cases has diminished steadily, accompanied by a slight rise in the incidence of adenocarcinoma. Although most present and past patients are heavy smokers, the incidence of SCC, especially the well differentiated form, continues to decrease steadily. Furthermore, in 1993, HPV was detected in 79% of all cases, and was particularly prevalent in the well differentiated form, but the rate fell to 68% in 1995, 35% in 1996, 23% in 1997, and 24% in 1998. The age distribution of patients, the male to female ratio, and the number of tumours overexpressing p53 protein did not change significantly over the study period, and thus did not correlate with changes in the differentiation of SCC. Conclusions—The decreasing incidence of viral infection correlates strongly with the falling numbers of SCC cases, especially well differentiated cases. These findings suggest that HPV might be involved in the development of SCC of the lung, affecting the histological differentiation of SCC in particular, at least in Okinawa, a subtropical island in southern Japan. Key Words: squamous cell carcinoma of the lung • histological differentiation • human papillomaviru