Up-regulation of TNF-alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma.

Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor-alpha (TNF-alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF-alpha/NFkB signaling pathway, and RNA-Seq confirmed the upregulation of TNF-alpha/NFkB signaling in cisplatin-resistant cell lines. NFkB was accumulated in cisplatin-resistant cell lines and in cancer stem cells (CSC), and the administration of TNF-alpha increased the CSC, suggesting that TNF-alpha/NFkB signaling is involved in the accumulation of CSC. TNF-alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin-resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin-resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin-resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF-alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin-resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.

Emetine, a small molecule natural product, displays potent anti-gastric cancer activity via regulation of multiple signaling pathways.

BACKGROUND: Gastric cancer (GC) is a life-threatening malignant tumor with high incidence rate. Despite great progress, there are still many GC sufferers that cannot benefit from the existing anti-GC treatments. Therefore, it is still necessary to develop novel medicines against GC. Emetine, a natural small molecule isolated from Psychotria ipecacuanha, has been broadly used for medicinal purposes including cancer treatment. Here, we conducted a comprehensive study on the anti-GC effects of emetine and the related mechanisms of action. METHODS: The cell viability was evaluated by MTT and colony formation assay. Cellular proliferation and apoptosis were analyzed by edu incorporation assay and Annexin V-PI staining, respectively. Moreover, wound healing assay and transwell invasion assay were conducted to detect cell migration and invasion after treatment with emetine. To elucidate the molecular mechanism involved in the anti-GC effects of emetine, RNA sequencing and functional enrichment analysis were carried out on MGC803 cells. Then, the western blot analysis was performed to further verify the anti-GC mechanism of emetine. In vivo anti-tumor efficacy of emetine was evaluated in the MGC803 xenograft model. RESULTS: MTT and colony formation assay exhibited a strong potency of emetine against GC cell growth, with IC50 values of 0.0497 µM and 0.0244 µM on MGC803 and HGC-27 cells, respectively. Further pharmacodynamic studies revealed that emetine restrained the growth of GC cells mainly via proliferation inhibition and apoptosis induction. Meanwhile, emetine also had the ability to block GC cell migration and invasion. The results of RNA sequencing and western blot showed that emetine acted through regulating multiple signaling pathways, including not only MAPKs and Wnt/ß-catenin signaling axes, but also PI3K/AKT and Hippo/YAP signaling cascades that were not found in other tumor types. Notably, the antitumor efficacy of emetine could also be observed in MGC803 xenograft models. CONCLUSION: Our data demonstrate that emetine is a promising lead compound and even a potential drug candidate for GC treatment, deserving further structural optimization and development.

Genome-wide siRNA screens identify RBBP9 function as a potential target in Fanconi anaemia-deficient head-and-neck squamous cell carcinoma.

Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity.

Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.

BACKGROUND: There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N-2' position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts. METHOD: By using an iterative structure-activity relationship strategy, several peptidyl emetine prodrug analogs (1-11) were synthesized by chemical derivatization of emetine at its N-2' position and tested for in-vitro activation by FAP. The lead prodrug 11 is made up of a DPPIV activatable prodrug precursor 10 (Ala-Pro-PABC-Emetine) coupled to FAP substrate (Ala-Ser-Gly-Pro-Ala-Gly-Pro). Activation assays of the prodrugs were performed in purified FAP, DPPIV, FBS, and human serum and were analyzed by LCMS. In vitro cytotoxicity assays of these prodrugs are carried out in prostate (LNCaP, PC3) and breast (MCF7 and MDA-MB-231) cancer cell lines. The prodrugs are also tested in normal immortalized human prostatic epithelial cell line (PrEC). RESULTS: The lead FAP activated emetine prodrug 11 is activated to emetine in tandem by FAP and DPPIV in about 70% conversion within 24 hr. In prostate and breast cancer cell lines treated with prodrug 11, it is found to be equipotent with emetine in the presence of FAP and DPPIV. However, in the PrEC cell line grown in serum free media, prodrug 11 is more than 200-fold less cytotoxic than emetine in the absence of FAP and DPPIV. CONCLUSION: This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the N-2' position of emetine in controlling its cytotoxicity. Significantly reduced toxicity observed in the PrEC cell line in the absence of FAP and DPPIV shows that prodrug 11 could be systemically delivered to regions of metastatic prostate cancer or other solid tumor for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma-associated fibroblasts. The two-step tandem enzymatic activation of prodrug 11 by FAP and DPPIV is a strategy for overcoming steric hindrance.

Emetine dihydrochloride: a novel therapy for bladder cancer.

PURPOSE: Current cisplatin based therapies for stage IV bladder cancer show 4% to 20% 5-year survival, underscoring the need to develop novel therapies for these patients. In the 1970s the natural alkaloid emetine dihydrochloride demonstrated modest anticancer efficacy as a single agent in clinical trials but this was not pursued. Groups recently reported that emetine induced apoptosis in leukemia cell lines, which was enhanced by cisplatin. We determined the antiproliferative effects of emetine with and without cisplatin in bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cell lines and normal human urothelial cell cultures were treated with emetine and/or cisplatin. We measured cell proliferation and evaluated synergy using the Chou-Talalay method. The combination index was calculated. Cell cycle analysis was done and caspase activation was evaluated to assess growth arrest and apoptosis. RESULTS: Emetine and cisplatin individually inhibited bladder cancer cell proliferation. When combined, emetine and cisplatin acted synergistically to inhibit tumor cell proliferation with combination index values reflecting moderate to strong synergy. Normal urothelial cells were relatively resistant to this treatment. Emetine alone and combined with cisplatin appeared to primarily induce tumor cell growth arrest and not apoptosis. CONCLUSIONS: To our knowledge this study demonstrates for the first time that emetine has in vitro antiproliferative activity against bladder cancer cell lines at nanomolar concentrations but little effect on normal urothelial cells. Moreover, emetine and cisplatin worked synergistically to inhibit tumor cell proliferation. Results suggest that combined emetine and cisplatin based chemotherapy may benefit patients with bladder cancer.

Design, synthesis, and evaluation of pH-dependent hydrolyzable emetine analogues as treatment for prostate cancer.

The N-2' position of the natural product emetine has been derivatized to thiourea, urea, sulfonamide, dithiocarbamate, carbamate, and pH responsive hydrolyzable amide analogues. In vitro studies of these analogues in PC3 and LNCaP prostate cancer cell lines showed that the analogues are generally less cytotoxic (average IC(50) ranging from 0.079 to 10 µM) than emetine (IC(50) ranging from 0.0237 to 0.0329 µM). The pH sensitive sodium dithiocarbamate salt 13 and the amide analogues 21, 22, 26 (obtained from maleic and citraconic anhydrides) showed the most promise as acid-activatable prodrugs under mildly acidic conditions found in the cancer microenvironment. These prodrugs released 12-83% of emetine at pH 6.5 and 41-95% emetine at pH 5.5. Compounds 13 and 26 were further shown to exhibit increased cytotoxicity in PC3 cell culture medium that was already below pH 7.0 at the time of treatment.

Comportamiento clínico-terapéutico de Fasciola hepatica en una serie de 87 pacientes / Clinical and therapeutic behaviour of Fasciola hepatica in a series of 87 patients

Introducción: la fasciolosis, por Fasciola hepatica, muestra a escala mundial un incremento en la incidencia de enfermos en los últimos años. Cuba se encuentra entre aquellos países donde se reportan casos esporádicos y algunos brotes epidémicos. Objetivo: describir el comportamiento clínico-terapéutico de esta trematodiosis de trasmisión digestiva en una serie de 87 pacientes ingresados en el Instituto de Medicina Tropical "Pedro Kourí" desde enero de 1996 a diciembre de 2005. Método: los pacientes se dividieron en 2 grupos atendiendo al fármaco prescrito, dihidroemetina o triclabendazol. Se recogieron las variables clínicas al inicio del diagnóstico y 90 d después del tratamiento; se hallaron las medias y la desviación estándar. Resultados: el sexo masculino predominó discretamente con 54 por ciento en nuestra serie de pacientes ingresados en el servicio de medicina tropical del instituto. La ingestión de berro (Nasturtium officinale) estuvo presente en casi la mitad de los pacientes. El dolor abdominal, fiebre y astenia resultaron los síntomas de mayor frecuencia. El triclabendazol y la dihidroemetina fueron útiles en el tratamiento. Conclusiones: se comprobó la utilidad de los exámenes de laboratorio en el diagnóstico y seguimiento de los enfermos. Los antiparasitarios dihidroemetina y triclabendazol resultaron efectivos a las dosis utilizadas con efectos adversos menores.

Introduction: in the last few years, the Incidence rate of fascioliosis caused by Fasciola hepatica has increased worldwide. Cuba is one of the countries that have reported sporadic cases and also some outbreaks of fasciolosis. Objective: to describe clinical and therapeutic features of this trematodiasis of digestive transmission found in 87 patients, who had been admitted to "Pedro Kourí" Institute of Tropical Medicine from January 1996 to December 2005. Methods: patients were divided into 2 groups according to the prescribed drug, that is, triclabendazole and dihydroemetine. The clinical variables were collected at the time of diagnosis and 90 days after treatment; the means and the standard deviation were estimated. Results: males was slightly predominant (54) in our series of patients admitted to the institute service. Consumption of watercress (Nasturtium officinale) was found in almost half of the patients. Abdominal pain, fever and malaise were the most frequent symptoms. Both drugs were useful to treat F. hepatica. Conclusions: this study showed the usefulness of lab tests for diagnosis and follow-up of patients after treatment. The anti-parasitic drugs dihydroemetine and triclabendazole proved to be effective at the prescribed doses in this research with minor adverse effects.

Characteristics of apoptosis induction by the alkaloid emetine in human tumour cell lines.

Cytotoxic and apoptosis-inducing effects of the alkaloid emetine from Psychotria ipecacuanha (Rubiaceae) were studied in human cell lines. In Jurkat T-cells emetine leads to phosphatidylserine exposure, mitochondrial depolarisation, and DNA fragmentation. Furthermore, activation of several caspases (caspase-3, -9/6, and -8) was demonstrated in a fluorescent caspase assay. Bcl-2 over-expressing cells are less sensitive to emetine while caspase-8-deficient Jurkat T-cells react similarly to wild-type cells. This indicates that apoptosis induction is mediated via the mitochondrial pathway. By using hepatoma cell lines with differing p53 expression, it was concluded that p53 does not seem to play a role in apoptosis induction by emetine. Alterations of protein profiles during emetine-induced apoptosis were analysed by 2D-PAGE and MALDI-TOF-MS. A new protein spot was apparent after treatment with emetine: It could be identified as the N-terminal fragment lamin B1, which is released after cleavage by caspase-6.

[Fascioliasis: diagnosis, epidemiology and treatment]. / Fascioliasis. Diagnóstico, epidemiología y tratamientos.

Fascioliasis is a trematode, disease of liver and bile ducts of sheep, cattle, and other ruminants throughout the world that is caused by the fluke, Fasciola hepatica. Human infection has been reported in Mexico, Cuba, Puerto Rico, Chile, Peru, Uruguay, Brazil, Argentina, the US, Europe, eastern Africa, Japan and Australia. The parasite's miracidium invades one of the various Lymnaea water snail hosts. Infection results from ingestion of encysted metacercariae attached to raw watercress (Nasturtium officinale). Symptoms recorded from human cases included irregular fever, epigastric pain and abdominal tenderness, obstructive jaundice and leucocytosis with eosinophilea up to 60%. Specific diagnosis is based on recovery of the eggs in the patient's stool or from biliary tract drainage. Treatment is with emetine hydrochloride given intramusculary. Bithionol is given orally at a dosage of 30-50 mg/kg but on alternate days from 10 to 15 doses. Praziquantel is probably effective. Preventive measures include education of the public on mode of transmission of life cycle of the parasite, and dipping fresh watercress into boiling water for a few sec, or drying suspected watercress.

[Effect of intralesional treatment with emetine hydrochloride on Leishmania (Viannia) braziliensis in hamsters]. / Efecto del tratamiento intralesional con clorhidrato de emetina sobre Leishmania (Viannia) braziliensis en hámsteres.

The therapeutic effect of the emetine hydrochloride alkaloid administered intralesionally was compared with that of standard parenteral treatment with Glucantime in outbred male hamsters experimentally infected with 4 x 10(3) amastigotes of Leishmania (Viannia) braziliensis. Both chemotherapeutic agents reduced significantly (P < 0.01) the average lesion sizes in experimental animals in comparison with those untreated. The alkaloid infiltration was found to be as effective as the antimonial injection for clinical resolution. The ultrastructural effects on the Leishmania parasites exposed to emetine were observed mainly in the inner cytoplasm, which appeared disorganized, pycnotic and with loss of morphological definition; however, any known emetine hydrochloride action mechanism factor could not be directly related with ultrastructure effects detected on leishmanial parasites. Smears, conventional histopathology, culture in NNN medium and indirect immunoperoxidase method showed viable amastigotes in nodules and/or scars of all the evaluated hamsters 75 to 230 days after the end of treatment. These findings suggest that measurement of the size of cutaneous leishmania lesions does not appear to be a valid criterion for evaluating the efficiency of chemotherapy in experimental LT. Detection of leishmania parasites in the lesion scars, supports the hypothesis that man could be considered as an domestic reservoir.

[Amebic abscess of the liver: ultrasound guided puncture]. / Abcés amibiens du foie: ponction écho-guidée.

The aim of this study is to present the results of ultrasound-guided needle aspiration in amoebic abscess of the liver in 1289 patients. Out of 1512 patients hospitalized from 1990 to 1995 for an amoebic abscess of the liver, 1289 (83.6%) were treated by this approach. The abscesses of less than 40 mm (8.9%) were treated medically, and those of more than 170 mm (0.6%) were operated on. The abscesses with peritonitis (5.2%) were also operated on. A treatment with metronidazole or dehydroemetin was associated with the surgical treatment or with the aspiration of the abscess. There was no death. A second aspiration was necessary in 24.9% of the patients, and a third one in 9.4%. Three complications were observed, two hemorrhages and one fistula. Nine patients had a recurrent abscess after their discharge from hospital. Four failures were observed in patients with abscesses of more than 170 mm in diameter. Results were considered as good in 1273 patients (98.7%). These results suggest that in amoebic abscess of the liver with a diameter between 40 and 170 mm, aspiration associated with amoebic treatment may be the standard treatment. Smaller abscesses usually recover with medical treatment alone, and greater abscesses need surgical drainage.

Amebic hepatic abscess in children.

The authors retrospectively reviewed all case histories of children with amebic hepatic abscess treated from 1975 to 1993 at their hospital. Twenty boys and 12 girls were diagnosed. Their ages ranged from 10 months to 12 years, with a mode of 1 and 2 years. In 17 (53%) of the patients, the abscess remained confined to the liver and was treated medically with dehydroemetine and metronidazole. Imminence of complication was present in 9 patients (52%), and required percutaneous needle aspiration. Imminence of complication was evidenced by: (1) clinical worsening of the patient despite adequate medical treatment, (2) presence of an abscess of 6 cm or more in a septic patient, or (3) clinical or ultrasonographic findings of an abscess on the verge of rupture. All 9 patients did satisfactorily. Fifteen cases (47%) were complicated by rupture and required surgical treatment. One of these patients died of sepsis. Medical treatment alone was excellent for small abscesses. Percutaneous needle aspiration was a successful approach in patients with imminence of complication. Surgery was reserved for ruptured abscesses.

Tratamiento del absceso hepático amibiano en niños: revisión de 20 casos / Treatment of hepatic amebic abscess on children: review of 20 cases

La amibiasis hepática continúa siendo la complicación más frecuente y grave de la amibiasis intestinal, su tratamiento origina controversias. La presente serie analiza los métodos terapéuticos utilizados en 20 niños con absceso hepático amibiano. Tres de ellos ingresaron al Hospital de Especialidades No. 1 de Ciudad Obregón, Sonora, en condiciones críticas por ruptura peritoneal del absceso y fueron sometidos a laparotomía para lavado y drenaje de la cavidad abdominal, con lo que sobrevivieron dos de ellos; 15 fueron tratados con dehidroemetina y metronidazol parenterales durante 10 días, obteniéndose resultados satisfactorios sólo en 10, requiriendo los cinco casos fallidos el procedimiento de drenaje mediante guía ultrasonográfica, con el que todos sanaron. Se observó que los pacientes que mejoraron con manejo farmacológico fueron los niños mayores y con afección clínica menos grave. Con este antecedente se trataron los últimos dos casos, ambos menores de cinco años, con el procedimiento de drenaje guidado por ultrasonido a las pocas horas de haber ingresado al hospital, teniendo ambos mejoría inmediata y rápido egreso. Se concluye que el tratamiento médico del absceso hepático amibiano puede fallar con mayor frecuencia en los niños más pequeños y con ataques serios a sus condiciones clínicas. En ellos, el procedimiento de drenaje guiado por ultrasonido puede ser una magnífica alternativa terapéutica

Fasciolasis hepática aguda masiva: relato de un caso / Severe massive hepatic fasciolasis: a case report

La fasciolasis hepática afecta accidentalmente al Hombre, desconociéndose su real incidencia. Describimos un caso de fasciolasis aguda masiva, en una niña de 9 años, que presenta dolor abdominal decahimiento, fiebre y hepatomegalia. Hemograma con leucocitosis e hipereosinofilia, anemia y VHS alta, fosfatasas alcalinas altas, PT bajo, IgE elevadda. Mielograma de cresta iliaca con abundantes eosinófilos, desviación a izquierda y ausencia de blastos. Biopsia diferida: alteraciones de maduración, serie granulocítica con predominio de eosinófilos. Se plantea probable fasciolasis hepática y se obtiene, dirigidamente, antecedente de ingestión de berros. Ecografía abdominal describe hígado con áreas hipoecogénicas. TAC abdominal informa defectos focales hepáticos vascularizados y destrucción localizada del parénquima tipo microcavitaria. Biopsia hepática: hepatitis aguda necrótica con intensa infiltración eosinofílica. Parasitológico seriado de deposición (método Teleman modificado) y aspirado duodenal, negativas pafa fasciolasis hepática. El diagnóstico se confirmó por serología, reacción de ELISA y Doble Difusión, positivas para Fasciola. Se trató con dihidroemetina con muy buena respuesta

Interferon alfa activates a lytic mechanism in ovarian and cervical carcinoma cells.

OBJECTIVE: Our purpose was to examine the in vitro cytolytic potential of interferon alfa for human cervical and ovarian carcinoma cell lines. STUDY DESIGN: The lytic potential of interferon alfa alone and in the presence the protein synthesis inhibitors actinomycin D and emetine was determined in the human cervical carcinoma cell lines ME-180, MS751, SiHa, HT-3, and C-33A and the ovarian carcinoma cell lines Caov-3, NIH:OVCAR-3, SK-OV-3 carcinoma cell lines by means of an 18-hour chromium 51 release assay. RESULTS: Exposure of these cell lines to interferon alfa alone did not result in lysis. Similarly, when cells were simultaneously exposed to interferon alfa and either actinomycin D or emetine there was no additional increase in lysis above that seen with actinomycin D or emetine alone. Pretreatment of cells with interferon alfa (10(3), 10(4), or 10(5) U/ml) followed by protein synthesis inhibition by actinomycin D or emetine resulted in a synergistic increase in lysis. CONCLUSION: The ability to reveal the lytic potential of interferon alfa when protein synthesis is subsequently inhibited could have practical applications for the treatment of gynecologic malignancies.

Eficacia del triclabendazole en paragonimiasis pulmonar humana refractaria a la emetina, bithionol y praziquantel / Efficacy of triclabendazole in human pulmonary paragonimiasis refractary to emetine, bithionol and praziquantel

Dentro del estudio clínico-terapéutico para determinar la posología efectiva de triclabendazole contra Paragonimus recibieron tratamiento con esta droga tres pacientes ecuatorianos con paragonimiasis pulmonar que fracasaron al tratamiento con emetina más cloroquina, bithienol y praziquantel individualmente. En todos los síntomas de tos, expectoración herrumbrosa y la presencia de huevos de Paragonimus mexicanus en esputo estaban presentes antes del tratamiento. Dos pacientes recibieron tricabendazole a 10mg/kg en dosis única, y el tercero a 5mg/kg una vez al día por tres días . El seguimiento hasta el año 1 postratamiento demostró la desaparición de la sintomatología y cura parasitológica. Los pacientes no presentaron efectos secundarios al fármaco.

Amibiasis cutánea: presentación de dos casos / Cotaneous amebiasis: two cases report

La localización en la piel de la amiba no es tan frecuente como sus localizaciones intraintestinal o el abceso hepático amibiano. Es una enfermedad grave si el diagnóstico y el tratamiento no son realizados en forma oportuna. Se presentan dos casos de amibiasis cutánea con buena respuesta al tratamiento.

[3 cases of hematogenous lung abscess of amebic origin]. / Tres casos de absceso pulmonar hematógeno de origen amibiano.

Invasive amebiasis is a very serious health problem in Mexico as it is presumably related to the presence of virulent strains of Entamoeba histolytica and poor hygienic and sanitary conditions; other factors related to invasive amebiasis are undernutrition, alcoholism, and homosexuality. We present three patients with pulmonary amebic hematogenous abscess. Clinically all patients had the typical "chocolate" exudate. The three patients had pulmonary consolidations by chest roentgenogram; one of them had multiple opacities with air fluid level, and the others had an isolated opacity with air fluid level. The ultrasound and hepatogammagram were negative for diaphragmatic communication in all; in one of them the pneumoperitoneum was negative for diaphragmatic communication. The transthoracic needle biopsy of the lesions was positive to ameba in two patients. The serologic tests were positive in all. We treated the patients with metronidazole and emetine during 10 days; since the clinical picture and the radiologic findings did not remit completely, we gave a second course of metronidazole during 10 days more and achieved complete resolution.

Inhibition of protein synthesis enhances the lytic effects of tumor necrosis factor alpha and interferon gamma in cell lines derived from gynecological malignancies.

Few clinical responses have occurred in preliminary studies using the cytokines tumor necrosis factor alpha (TNF alpha) or interferon gamma (IFN gamma) in cancer patients. This may be related to the observation that many malignant cell lines are resistant to lysis by these cytokines in vitro. Resistance to lysis by TNF alpha or IFN gamma in many cells is controlled by a protein-synthesis-dependent mechanism, such that when protein synthesis is inhibited cells become sensitive to lysis by these cytokines. Because there is some evidence that TNF alpha and IFN gamma act through different lytic mechanisms and are opposed by different resistance mechanisms, we treated a panel of eight cell lines, five derived from human cervical carcinomas (ME-180, MS751, SiHa, HT-3, and C-33A) and three derived from ovarian carcinomas (Caov-3, SK-OV-3, and NIH: OVCAR-3) with both TNF alpha and IFN gamma to determine whether such combination treatment might maximize in vitro cell lysis. Our results showed that pretreatment with IFN gamma followed by exposure to TNF alpha in the presence of protein synthesis inhibitors increased lysis of seven of the eight cell lines above that seen with either TNF alpha or IFN gamma and inhibitors of protein synthesis. Only the cell line C-33A was resistant to lysis by TNF alpha and IFN gamma, when exposed to these agents both alone and in combination with protein synthesis inhibitors. Clinically, combining the cytokines TNF alpha and IFN gamma with protein synthesis inhibitors may maximize the in vivo lytic effects of these cytokines.

Fasciolasis humana epidémica. Cuba 1983. VI. Estudio clínico de 40 niños del Hospital provincial de Sagua la Grande / Epidemic human fascioliasis. Cuba 1983. VI. Clinical study of 40 children in the Hospital Provincial de Sagua la Grande

Se estudiaron 40 niños con "Síndrome Eosinofílico Febril" en los cuales se confirmó la infección por Fasciola Hepática por presentar la triada clásica: fiebre, eosinofilia y dolor abdominal; tener antecedentes de ingestión de berro (82%), laparoscopia y biopsias positivas (100%) y pruebas de intradermoreacción inmediata (100%) y electrocinéresis (100%) positivas a antígenos de Fasciola. Este trabajo demuestra la afectación de los niños durante el brote epidémico de Cuba en 1983