Inhibition of monoamine oxidase activity by repetitive transcranial magnetic stimulation: implications for inter-train interval and frequency.

Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulation technique that stimulates cortical regions via time-varying electromagnetic fields; in several countries this technique has been approved as a treatment for major depressive disorder. One empirically established target in antidepressant pharmacotherapy is the flavin-containing monoamine oxidoreductase (MAO). The function of MAO enzymes is based on oxidation processes that may be sensitive towards strong electromagnetic fields. Therefore, we hypothesized that rTMS-induced electromagnetic fields impact the activity of this enzyme. Using crude synaptosomal cell preparations from human SH-SY5Y neuroblastoma cells and rat cortex as well as viable cells, we assessed the effects of rTMS on MAO-A and -B activity in a well-controlled in vitro set up. In short, samples were stimulated at maximal intensity with an equal number of total stimuli at frequencies of 5, 20, and 100 Hz. Sham stimulation was performed in parallel. Treatment at frequencies of 5 and 20 Hz significantly decreased mainly MAO-B activity in all tissue preparations and species, whereas 100 Hz stimulation remained without effect on any MAO activity. Our results support the hypothesis, that rTMS-induced electromagnetic fields affect MAO activity and provide further evidence for intracellular effects possibly contributing to therapeutic effects of this neuromodulatory method. On a cautionary note, however, our findings are solely based on in vitro evidence.

Maltrato institucional hacia el adulto mayor: percepciones del prestador de servicios de salud y de los ancianos / Institutional abuse toward the elderly: Perceptions of health care providers and older adults

Objetivo. Analizar la percepción que el prestador de servicios de salud y el adulto mayor (AM) tienen sobre el maltrato al AM en los servicios públicos de salud, en ciudades seleccionadas de México. Material y métodos. De 2009 a 2012 se realizó un estudio con diseño cualitativo y estrategia de triangulación de fuentes de datos; se efectuaron entrevistas semiestructuradas a 13 prestadores y a 12 ancianos para recuperar su experiencia en el tema. El análisis utilizó procedimientos de la Teoría Fundamentada. Resultados. El maltrato contra el AM es una práctica naturalizada por el personal y por el anciano, la cual se manifiesta de formas diversas. Conclusiones. La institucionalización, profesionalización histórica y falta de conciencia sobre las necesidades de los AM demandan cambios de planeación, organización y supervisión del Sistema de Salud. El personal requiere intervenciones de formación, capacitación y cambio de actitudes/comportamiento, para otorgar atención integral, digna, humana y de respeto a los Derechos Humanos de los AM.

Objective. To analyze the health care providers (HCP) and elderly patients' perceptions about abuse of the elderly by health personnel of public health services, in selected cities in Mexico. Materials and methods. A qualitative study and a strategy of data triangulation were performed during 2009 and 2012; 13 HCPs and 12 elders were interviewed, in order to obtain their experience regarding elder abuse. Grounded Theory proceedings were used for the analysis. Results. Elder abuse is a naturalized practice, from HCP and elderly people's point of view; these perceptions are showed in different ways. Conclusion. Institutionalization, historical professionalization and lack of consciousness about needs of the elderly (sociocultural and economic), require changes in planning, organization and monitoring process in the Health System; training and educational interventions on staff and exchange attitudes and behavior are necessary in order to offer a health care that is comprehensive, decent, human and with respect for the human rights.

Las obsesiones antes de Freud: historia y clínica / Obsessions before Freud: history and clinical practice

Se analiza el significado del concepto de “obsesión” en el alienismo del siglo XIX. Desde el punto de vista clínico, la descripción de Esquirol fue completada por otros autores (Jules Falret, Legrand du Saulle). En el ámbito de la reflexión psicopatológica, el alienismo francés, con el delirio emotivo de Morel o la psicastenia de Janet, defendió la teoría emocional, frente al trastorno intelectual propuesto por los médicos alemanes. Finalmente, se insiste en la importancia del marco cultural en la aparición de los síntomas obsesivos y de su interpretación. En este sentido, se estudian las relaciones de los escrúpulos religiosos con la melancolía o la aparición de categorías diagnósticas sometidas a los códigos y mentalidades fin-de-siècle.

The article analyses the significance of the concept of “obsession” in nineteenth-century alienism. From a clinical point of view, Esquirol’s description was completed by other authors (Jules Falret, Legrand du Saulle). In the area of psychopathological studies, French alienism, with Morel’s emotional delirium or Janet’s psychasthenia, defended the emotional theory, as opposed to the intellectual disorder proposed by German doctors. Lastly, the importance of the cultural framework is stressed in the appearance of obsessive symptoms and their interpretation. Along these lines, the article discusses the relationship of religious scruples to melancholy or the appearance of diagnostic categories subject to fin de siècle codes and mentalities.

Specific antioxidant compounds differentially modulate cytotoxic activity of doxorubicin and cisplatin: in vitro and in vivo study.

AIM: To use the antioxidant compounds (sodium selenite, selenomethionine, D-pantethine) for modulation of cytotoxic effect of doxorubicin and cisplatin toward wild type and drug-resistant mutants of several human tumor cells. Similar treatments were applied in vivo toward adult male Wistar rats. METHODS: Human tumor cells of different lines (HCT-116, Jurkat and HL-60) with various mechanisms of drug-resistance were treated with doxorubicin or cisplatin, alone or in combination with sodium selenite, selenomethionine, or D-pantethine. Cell viability, induction of apoptosis, and production of O2- radicals were measured. Activity of redox potential modulating enzymes was measured in the liver and blood plasma of adult male Wistar rats subjected to similar treatments. RESULTS: All antioxidants used in physiologically harmless concentration inhibited cytotoxic action of doxorubicin toward tumor cells sensitive to chemotherapy treatment by 15%-30%, and slightly enhanced cytotoxic effect of this medicine toward drug-resistant malignant cells. At the same time, there was no significant effect of these antioxidants on cisplatin action. Such effects were accompanied by a complete inhibition of production of superoxide radicals induced by doxorubicin. The results of in vivo study in adult male Wistar rats were in agreement with the results of in vitro study of human tumor cells. CONCLUSION: Protective effect of specific antioxidant agents during cytotoxic action of doxorubicin was demonstrated in vitro in drug-sensitive human tumor cells and in adult male Wistar rats, while there was no protective effect in drug-resistant sub-lines of these tumor cells during action of doxorubicin and cisplatin.

Impact of PLK-1 silencing on endothelial cells and cancer cells of diverse histological origin.

The main goal of this work was to assess in vitro the potential of Polo-like kinase gene (PLK-1) as a molecular target within the tumor microenvironment, namely in both cancer cells of tumors of different histological origin and endothelial cells from angiogenic blood vessels, upon silencing with anti-PLK-1 siRNA. In addition, the effect of Plk-1 downregulation on the cancer cells chemosensitization to paclitaxel was further assessed. Downregulation of Plk-1 reduced cancer cells viability from 40 to 85% and up to 59% in endothelial cells. Regarding the latter, it compromised their ability to form new tube-like structures, decreasing the formation of network projections up to 46%. This suggested for the first time, PLK-1 as a valuable angiogenic molecular target. In combination with paclitaxel, anti-PLK-1 siRNA chemosensitized non-small cell lung cancer (NSCLC) and prostate carcinoma cell lines, leading up to a 2-fold increase in the drug cytotoxic effect. Moreover, the sequential incubation of anti-PLK-1 siRNA and paclitaxel led to a decrease in the IC50 of the latter up to 2.7- and 4.1-fold, in A-549 and PC-3 cells, respectively. The combination of anti-PLK-1 siRNA with paclitaxel led to cell cycle arrest, increasing the number of cells at the G2/M and S phases to 1.5 and 1.3-fold in PC-3 cells, and to 1.6 and 1.4-fold in A-549 cells, respectively. Overall, it has been demonstrated that PLK-1 silencing with siRNA can impact multiple cellular players of tumor aggressiveness, thus enabling the opportunity to interfere with different hallmarks of cancer, in tumors with diverse histological origin.

Black tea polyphenols inhibit tumor proteasome activity.

Tea is a widely consumed beverage and its constituent polyphenols have been associated with potential health benefits. Although black tea polyphenols have been reported to possess potent anticancer activities, the effect of its polyphenols, theaflavins on the tumor's cellular proteasome function, an important biological target in cancer prevention, has not been carefully studied. Here black tea extract (T5550) enriched in theaflavins inhibited the chymotrypsin-like (CT) activity of the proteasome and proliferation of human multiple myeloma cells in a dose-dependent manner. Also an isolated theaflavin (TF-1) can bind to, and inhibit the purified 20S proteasome, accompanied by suppression of tumor cell proliferation, suggesting that the tumor proteasome is an important target whose inhibition is at least partially responsible for the anticancer effects of black tea.

Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer.

Salinomycin is a novel identified cancer stem cells (CSCs) killer. Higher ALDH activity represents CSCs characterization. Here, we screened ALDH activities on several gastric cancer cell lines and divided them into ALDH(high) and ALDH(low) gastric cancer groups. ALDH(high) cancer cells (NCI-N87 and SNU-1) disclosed more CSCs characteristics, such as higher levels of Sox2, Nanog and Nestin, more floating spheroid bodies, more colony formation and more resistance to conventional chemotherapeutic drugs 5-Fu and CDDP, compared to these parameters observed in ALDH(low) cancer cells (P<0.01). Importantly, ALDH(high) cancer cells are relatively sensitive to salinomycin when compared to ALDH(low) cancer cells (P<0.01). Our results confirmed ALDH as functional marker of CSCs population on gastric cancer. Salinomycin might be selective therapy for CSCs fraction, which is resistant to conventional anticancer drugs 5-Fu and CDDP.

Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice.

Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

ATM-dependent phosphorylation of 53BP1 in response to genomic stress in oxic and hypoxic cells.

The ATM kinase is activated by chromatin modification following exogenous and endogenous DSBs or cell stress, including acute anoxia. The p53 binding protein 1 (53BP1) contains multiple ATM-consensus phosphorylation sites in its N- and C-termini and may therefore be a distal read-out of ATM function. We have examined the cellular activation of these phosphorylation sites for the first time in situ following anoxic/hypoxic stress and IR-induced exogenous DSBs. We show that multiple residues of 53BP1 are phosphorylated and that these phosphoforms form discrete nuclear foci following IR or during DNA replication as exogenous or endogenous DNA double strand breaks (DSBs), respectively. Novel data pertaining to the phosphorylation of 53BP1(Ser25)in situ supports its dependency on the ATM kinase; but this occurs independently of p53 function. We show that 53BP1(Ser25) is activated specifically in S-phase cells during anoxia in an ATM-dependent manner. Exogenous DSBs form discrete IR-induced foci whereas oxygen stress induced non-localized 53BP1(Ser25) activation. Our in vitro data are supported by irradiated xenograft studies in vivo whereby 53BP1(Ser25) phosphorylation does not occur in sub-regions positive for the hypoxia marker EF5. We propose a model whereby DSBs induce chromatin modification at sites of DNA damage which are tracked by the ATM substrates γ H2AX and 53BP1(Ser25) in a mechanism distinct from p53-mediated cell cycle arrest. Together this work indicates 53BP1(Ser25), and possibly other 53BP1 phosphoforms, as a bona fide DSB-biomarkers for surveying ongoing DNA-damage related signaling in oxic and hypoxic cells during clinical radiotherapy.

The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.

The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.

Knockdown of the DNA-dependent protein kinase catalytic subunit radiosensitizes glioma-initiating cells by inducing autophagy.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. A growing body of evidence suggests that only a small subpopulation of malignant glioma cells, called glioma stem cells or glioma-initiating cells (GICs), have true tumorigenic potential and confer glioma radioresistance. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in the repair of DNA double-strand breaks induced by ionizing radiation (IR). Suppression of one of these components of the DNA-PK complex can inhibit the DNA double-strand break repair and radiosensitize the cells. In general, the cell death induced by IR is considered to be apoptotic. Recently, autophagy, an alternative form of programmed cell death, has been shown to contribute significantly to anti-neoplastic effects of radiation therapy. Autophagy is independent of phagocytes and differs from apoptosis by the presence of autophagosomes, autolysosomes, and an intact nucleus in the cell. Little is known, however, regarding the relationship between DNA-PKcs and IR-induced autophagy in GICs. In the present study, we constructed plasmids encoding short hairpin RNA (shRNA) targeting DNA-PKcs, which were then transfected into GICs. Then, we used GICs and DNA-PKcs-RNAi transfected cells to investigate the role of DNA-PKcs in IR-induced apoptotic and autophagic cell death. IR induced massive autophagic cell death in DNA-PKcs-RNAi transfected cells, but only occasional apoptotic cells were detected among GICs. Specific inhibition of DNA-PKcs in GICs induced autophagy and radiosensitized the cells. Our results suggest that such radiation-induced autophagy may enhance the effect of glioma therapies.

Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation.

OBJECTIVES: Angiogenesis seems important for both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Angiogenesis is regulated by the balance between pro- and antiangiogenic cytokines, which also indicates an important role of matrix metalloproteases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteases (TIMPs). We investigated the constitutive release of MMPs and TIMPs for a large group of consecutive AML patients. METHODS: AML cells were cultured in vitro either alone or together with microvascular endothelial cells, and levels of MMPs and TIMPs were determined in culture supernatants. RESULTS: AML cells showed constitutive release of several MMPs and TIMPs. For all patients, detectable MMP-10 release was observed, and most patients showed detectable release of at least one additional MMP, usually MMP-9 or MMP-2. A significant correlation was found between MMP-9 and TIMP-1 release and the release of several CCL and CXCL chemokines. MMP-9 release was higher for AML cells with monocytic differentiation corresponding to the FAB-subtype M4/M5 AML; it was mainly released in its inactive form, but endogenously active MMP-9 could be detected even in the presence of the constitutively released TIMP-1/2. Endothelial cells released relatively high levels of MMP-10, and these levels were further increased by coculture with AML cells. Patients achieving complete hematological remission after only one induction cycle showed relatively low constitutive MMP-2 release. CONCLUSION: We conclude that primary human AML cells show constitutive release of both MMPs and TIMPs, and this release may be important for leukemogenesis and possibly also for chemosensitivity.

Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma.

Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2Dimensional (2D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3Dimensional (3D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 cell migration ability in a dose-dependent manner. Our further study revealed that X-ray irradiation and VX-680 upregulated p53 expression level as well as arrested cell cycle in G(2)/M, sensitized NPC CNE-2 cells to radiation and effectively resulted in cell death. In summary, our data indicated that Aurora-A small molecule inhibitor VX-680, potently destructed tumor formation and induced apoptosis, reduced cell migration and enhanced radiosensitivity, offering a promising therapeutic agent for human NPC.

Role of the proteolytic hierarchy between cathepsin L, cathepsin D and caspase-3 in regulation of cellular susceptibility to apoptosis and autophagy.

The present investigation was undertaken to measure the relative abilities of pro-death versus pro-survival proteases in degrading each other and to determine how this might influence cellular susceptibility to death. For this, we first carried out in vitro experiments in which recombinant pro-death proteases (caspase-3 or cathepsin D) were incubated with the pro-survival protease (cathepsin L) in their respective optimal conditions and determined the effects of these reactions on enzyme integrity and activity. The results indicated that cathepsin L was able to degrade cathepsin D, which in turn cleaves caspase-3, however the later enzyme was unable to degrade any of the cathepsins. The consequences of this proteolytic sequence on cellular ability to undergo apoptosis or other types of cell death were studied in cells subjected to treatment with a specific inhibitor of cathepsin L or the corresponding siRNA. Both treatments resulted in suppression of cellular proliferation and the induction of a cell death with no detectable caspase-3 activation or DNA fragmentation, however, it was associated with increased accumulation of cathepsin D, cellular vaculolization, expression of the mannose-6-phosphate receptor, and the autophagy marker LC3-II, all of which are believed to be associated with autophagy. Genetic manipulations leading either to the gain or loss of cathepsin D expression implicated this enzyme as a key player in the switch from apoptosis to autophagy. Overall, these findings suggest that a hierarchy between pro-survival and pro-death proteases may have important consequences on cell fate.

New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check.

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl(T315I) mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl(T315I) and discuss the potential of combined Abl kinase inhibitor therapy to preempt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells.

Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5+ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5+ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n=26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a half-maximal dose (IC(50)) of 2.35 microM. In healthy B cells a significantly higher mean IC(50) of 148.5 microM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; P<0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P=0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.

GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT-I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT-I mRNA as well as GM3 in 40 tumor tissues surgically removed from non-small cell lung cancer patients. Adenocarcinoma tissues expressed SAT-I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT-I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT-I mRNA and epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR-TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC(50) values for gefitinib and AG1478 decreased dramatically with increasing SAT-I mRNA levels (R(2) = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR-TK inhibitors, the SAT-I gene was introduced stably into a GM3-negative clone of murine 3LL lung cancer cells to produce GM3-reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3-reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT-I mRNA in lung biopsy samples from non-small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR-TK inhibitors.

Influences of cyclooxygenase-1 and -2 expression on the radiosensitivities of human cervical cancer cell lines.

We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2 activity, were found to be significantly higher than that of the C33A cell line which had neither COX-1 nor COX-2 activity. Moreover, the acquisition of COX-1 in C33A cell line significantly reduced its radiosensitivity, but COX-2 transfection increased radiosensitivity in this cell line. In addition, the inhibition of COX-1 activity in HT-3 cell line using siRNA resulted in an increased radiosensitivity, but this phenomenon was not observed for COX-2 inhibition. The same experiment in HeLa cells using siRNA also showed no significant change in radiosensitivity. The results obtained during this study suggest that COX expression is associated with the radiosensitivity in uterine cervical cancer cell lines and COX-1 might have more important role than COX-2.

[Telomerase activity: a molecular marker for early diagnosis of bladder tumor]. / Attività telomerasica: un efficiente marcatore molecolare per la diagnosi precoce del tumore della vescica.

Quantitative evaluation of telomerase activity in voided urine represents a molecular test for early diagnosis of bladder tumor. This test shows a high accuracy, mainly in males bladder tumor, and could be an important non invasive diagnostic tool for bladder cancer detection in high-risk groups screening programs.