The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells.

We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.

Trichinella britovi etiological agent of sylvatic trichinellosis in the Republic of Guinea (West Africa) and a re-evaluation of geographical distribution for encapsulated species in Africa.

In West Africa, Trichinella infection was documented in humans and animals from Senegal in the 1960s, and the biological characters of one isolate showed a lower infectivity to domestic pigs and rodents when compared with that of a Trichinella spiralis pig isolate from Europe. To identify the Trichinella species present in West Africa, a survey was conducted in a total of 160 wild animals in the Republic of Guinea. Three Viverridae, one true civet (Viverra civetta) and two African palm civets (Nandinia binotata) from the Fouta Djallon Massif, Pilimini Subprefecture, were found positive by artificial digestion of muscle samples. Trichinella larvae from these three viverrids were identified as Trichinella britovi and no difference was detected in three examined sequences from these African isolates and the reference strain of T. britovi from Europe, indicating common ancestry, an historically continuous geographic distribution, and recent isolation for African and European populations. The detection of T. britovi in West Africa modifies our knowledge about the distribution of encapsulated species of Trichinella in Africa. Thus, Trichinella nelsoni is now considered to have a distribution limited to the Eastern part of the Afrotropical region from Kenya to South Africa. This provides a plausible explanation for the presence of Trichinella T8 in Namibia and South Africa, and further suggests that T. britovi could be the Trichinella species circulating among wild animals of Northern Africa.

Detection of Babesia caballi in Amblyomma variegatum ticks (Acari: Ixodidae) collected from cattle in the Republic of Guinea.

A reverse line blot hybridisation (RLB) assay was applied to screen Amblyomma variegatum adult ticks (n = 504) collected from N'Dama cattle in the Republic of Guinea. In a PCR, the V1 hypervariable region of the 16S ribosomal RNA (rRNA) gene was amplified with a set of primers unique for species of the genera Anaplasma and Ehrlichia, and the V4 hypervariable region of the 18S rRNA gene was amplified with primers specific for members of the genera Theileria and Babesia. Amplified PCR products from A. variegatum ticks were hybridised onto a membrane, to which oligonucleotide probes species-specific for Ehrlichia/Anaplasma and Theileria/Babesia parasites were covalently linked. No pathogens belonging to Ehrlichia/Anaplasma species were found, while 10 DNA samples resulted positive for Babesia caballi and 5 samples for Theileria velifera. This is the first report of B. caballi in A. variegatum ticks. One of the B. caballi positive samples was sequenced. This new strain (BcabGuinea) showed a 97% similarity to the Z15104 B. caballi GenBank sequence.

O6-Alkylguanine-DNA alkyltransferase content in synchronised human cancer cells.

The DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT) was analysed in the human ovarian-cancer SW626 cell line and in the human promonocytic leukemia U937 cell line following their synchronisation with low non-toxic concentrations of methotrexate. In SW626, AT increased in the early S phase of the cell cycle and then declined during progression of the S phase to levels found in the G1 phase of unsynchronised cells. In contrast, at the G1/S-phase boundary and in the S phase, U937 cells showed a lower AT content than did exponentially growing unsynchronised cells. In addition, AT activity was greatly reduced in resting U937 cells but was not reduced appreciably in resting SW937 cells but was not reduced appreciably in resting SW626 cells. The results of these studies indicate that AT fluctuations do not follow a constant pattern during the cell cycle of different cell lines.

An automated system for animal exposure to nitrogen dioxide.

We have designed an automated system for controlled exposure of rodents to nitrogen dioxide (NO2). The system consists of 1) two stainless-steel exposure chambers (3.96 m3), for control and treated animals, in which temperature, humidity, and air changes are consistent with current guidelines for rodent housing; 2) a cylinder containing 1% NO2 in N2; 3) a detector connected with a personal computer system that monitors the NO2 concentration, and regulates the NO2 influx, using a closed-loop feedback; and 4) a fan system to distribute the gas uniformly within the chambers. In a typical experiment rats were exposed to 15 ppm of NO2, and changes in the differential count of polymorphonuclear leukocytes, macrophages, and lymphocytes in bronchoalveolar lavage fluid were investigated.

HIV/HCV co-infection: natural history.

HIV and HCV share common transmission pathways, but HCV is more efficiently transmitted through blood than with sexual exposure. Thus HCV coinfection is frequent in HIV seropositives, mainly in those with history of injection drug use and/or transfusion. HIV coinfection increases HCV replication rate, the rate of HCV vertical transmission and accelerates the course of hepatitis C towards cirrhosis and hepatocellular carcinoma. The evidence of an effect of HCV on HIV disease progression is less convincing. The results of several studies suggest that HCV coinfection does not hasten the progression of HIV infection towards AIDS. However two recent studies showed that HCV coinfection is independently associated with a lower restoration of CD4 counts during combination antiretroviral treatment. However this finding should be confirmed by additional studies.

Adjuvant chemotherapy in the treatment of clinically localised Ewing's sarcoma.

The results are presented of thirty-seven patients with Ewing's sarcoma; ten were treated by a combination of operation, radiotherapy and cyclic chemotherapy, the remainder by radiotherapy and chemotherapy but without operation. The drugs, vincristine, cyclophosphamide and adriamycin were used in combination and were continued for two years. The follow-up ranged from twelve to sixty-two months. The mortality rate and the incidence of metastases were both markedly lower than in a comparable previous series treated by radiotherapy alone, or by operation plus radiotherapy, but all without chemotherapy. The percentage of local recurrences and of metastases was much higher in the twenty-seven patients who had radiotherapy and adjuvant chemotherapy, than in the ten in whom operation was also performed. It is suggested that on the basis of these results (and on theoretical grounds) treatment should consist of radiotherapy combined with chemotherapy plus, whenever feasible, operative excision of the primary tumour.

Multiple-drug chemotherapy for the primary treatment of osteosarcoma of the extremities.

Fifty-five cases of osteosarcoma of the extremities were treated between 1972 and 1976 by combined surgery and chemotherapy (vincristine, adriamycin and methotrexate in medium doses) for 18 months. The follow-up ranges from 30 to 80 months (mean = 48 months). Twenty-six patients remained free from any evidence of disease, two had local recurrences but no metastases and 27 had metastases (four of these also had local recurrences). In 12 patients, the metastases appeared after the end of chemotherapy. Both metastases and local recurrences were more frequent in patients who had segmental bone resection (7/8) than in those treated by more radical surgery (22/47). Comparison with an "historical" group (94 osteosarcoma patients treated by operation alone in our Institute between 1960 and 1971) showed that the percentage of patients free from evidence of disease was higher in the group who receiving chemotherapy. In addition, the appearance of metastases in this group was delayed (mean = 16 months) as compared with the historical controls (mean = 8 months). On the other hand, after the same kind of operative treatment, the rate of local recurrences and the time of their appearance was almost identical in both groups.

Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity: a 6 year report.

Fifty-five cases of osteosarcoma of the extremities were treated between 1972 and 1976 with combination surgery and polychemotherapy (vincristine, adriamycin and methotrexate at medium doses) for 18 months. Their follow-up presently ranges between 30 and 80 months (mean = 48 months). Twenty-six patients remained free from disease signs, 2 showed local recurrence but no metastases, and 27 exhibited metastases (4 of these also had local recurrences). In 12 patients, the metastases appeared after the end of chemotherapy. Both metastases and local recurrences were more frequent in those patients submitted to segmental bone resection (7/8) than in those treated by more radical surgery (22/47). Comparison with a historical group (94 osteosarcoma patients treated with surgery alone at our Institute between 1960 and 1971) revealed that, during the follow-up period considered, the percentage of patients free from disease signs was higher in the group that also received chemotherapy. In addition, in this group metastatic appearance was delayed (mean = 15 months) as compared to historical controls (mean = 8 months). On the other hand, after the same kind of surgery, the rate of local recurrences and the time of their appearance was practically the same in both groups.

[The association of local radiation therapy and systemic chemotherapy in the treatment of clinically localized Ewing's sarcoma]. / L'associazione terapia radiante locale - chemioterapia sistemica nel trattamento del sarcoma di Ewing clinicamente localizzato

The results obtained in 12 cases of still clinically localized Ewing's sarcoma by associating radiation therapy of the primary focus with intermittent systematic chemotherapy are reported. Two of these patients presented pulmonary and bone metastases 12 and 14 months respectively after bioptic diagnosis while the remaining ten were in good health and free from metastasis at between 6 and 28 months (average 16 months) after biopsy. Although it is considered necessary to make further observations before the association's validity is certain, it is considered that on this basis and on the basis of the few cases reported in the literature than the association of rationally conducted systematic chemotherapy with local radiation therapy will extend the onset time of metastasis and so increase average survival in Ewing's sarcoma.