Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation

AIMS: Chromosomal gains and losses were surveyed by comparative genomic hybridisation (CGH) in a series of colorectal adenomas and carcinomas, in search of high risk genomic changes involved in colorectal carcinogenesis. METHODS: Nine colorectal adenomas and 14 carcinomas were analysed by CGH, and DNA ploidy was assessed with both flow and image cytometry. RESULTS: In the nine adenomas analysed, an average of 6.6 (range 1 to 11) chromosomal aberrations were identified. In the 14 carcinomas an average of 11.9 (range 5 to 17) events were found per tumour. In the adenomas the number of gains and losses was in balance (3.6 v 3.0) while in carcinomas gains occurred more often than losses (8.2 v 3.7). Frequent gains involved 13q, 7p, 8q, and 20q, whereas losses most often occurred at 18q, 4q, and 8p. Gains of 13q, 8q, and 20q, and loss of 18q occurred more often in carcinomas than in adenomas (p = 0.005, p = 0.05, p = 0.05, and p = 0.02, respectively). Aneuploid tumours showed more gains than losses (mean 9.3 v 4.9, p = 0.02), in contrast to diploid tumours where gains and losses were nearly balanced (mean 3.1 v 4.1, p = 0.5). CONCLUSIONS: The most striking difference between chromosomal aberrations in colorectal adenomas and carcinomas, as detected by CGH, is an increased number of chromosomal gains that show a nonrandom distribution. Gains of 13q and also of 20q and 8q seem especially to be involved in the progression of adenomas to carcinomas, possibly owing to low level overexpression of oncogenes at these loci.     

Targeting JNK-interacting protein 1 (JIP1) sensitises osteosarcoma to doxorubicin

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite aggressive therapy, survival outcomes remain unsatisfactory, especially for patients with metastatic disease or patients with a poor chemotherapy response. Chemoresistance contributes to treatment failure. To increase the efficacy of conventional chemotherapy, essential survival pathways should be targeted concomitantly. Here, we performed a loss-of-function siRNA screen of the human kinome in SaOS-2 cells to identify critical survival kinases after doxorubicin treatment. Gene silencing of JNK-interacting-protein-1 (JIP1) elicited the most potent sensitisation to doxorubicin. This candidate was further explored as potential target for chemosensitisation in OS. A panel of OS cell lines and human primary osteoblasts was examined for sensitisation to doxorubicin using small molecule JIP1-inhibitor BI-78D3. JIP1 expression and JIP1-inhibitor effects on JNK-signalling were investigated by Western blot analysis. JIP1 expression in human OS tumours was assessed by immunohistochemistry on tissue micro arrays. BI-78D3 blocked JNK-signalling and sensitised three out of four tested OS cell lines, but not healthy osteoblasts, to treatment with doxorubicin. Combination treatment increased the induction of apoptosis. JIP1 was found to be expressed in two-thirds of human primary OS tissue samples. Patients with JIP1 positive tumours showed a trend to inferior overall survival. Collectively, JIP1 appears a clinically relevant novel target in OS to enhance the efficacy of doxorubicin treatment by means of RNA interference or pharmacological inhibition.     

The vascular response induced by transmyocardial laser revascularization is determined by the size of the channel scar: Results of CO2, holmium and excimer lasers

BACKGROUND AND OBJECTIVES: To investigate the angiogenic effect of CO2, Ho:YSGG, and XeCl excimer TMLR in a rat model with morphologic characteristics of chronic myocardial ischemia. STUDY DESIGN/MATERIALS AND METHODS: Two channels (200-320 microm) were created per rat heart. After 14 days, vessel numbers and densities in and around laser scars were assessed. RESULTS: Capillary densities in the laser scars were equal between the three lasers ( approximately 130 vessels/mm2) but much lower than in control areas ( approximately 2,100 vessels/mm2). Vessel densities excluding capillaries were significantly higher in Ho:YSGG and CO2 scars compared to excimer scars, while only Ho:YSGG scars contained significantly more large vessels (diameter > or = 20 microm) than control areas. Only rarely, extension of vascular growth into adjacent myocardium was observed in any of the three groups. CONCLUSIONS: These results indicate that the angiogenic response following TMLR is limited to the channel scar and related to the scar size rather than the specific laser type.     

Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence

Aim of the study

Loss of the nuclear lamina protein lamin A/C (LMNA) has been observed in several human malignancies. The present study aimed to investigate associations between LMNA expression and clinical outcome in colon cancer patients.

Patients and methods

Clinicopathological data and formalin-fixed paraffin embedded tissues were collected from 370 stage II and III colon cancer patients. Tissue microarrays were constructed, stained for lamin A/C and evaluated microscopically. Microsatellite instability status was determined for 318 tumours.

Results

Low levels of LMNA expression were observed in 17.8% of colon tumours, with disease recurrence occurring in 45.5% of stage II and III colon cancer patients with LMNA-low expressing tumours compared to 29.6% of patients with LMNA-high expressing tumours (p = 0.01). For stage II patients, disease recurrence was observed for 35.7% of LMNA-low compared to 20.3% of LMNA-high expressing tumours (p = 0.03). Microsatellite stable (MSS) tumours exhibited more frequently low LMNA expression than microsatellite instable (MSI) tumours (21% versus 9.8%; p = 0.05). Interestingly, disease recurrence among LMNA-low and LMNA-high expressing MSS tumours varied significantly for stage III patients who had not received adjuvant chemotherapy (100% versus 37.8%; p < 0.01) while no such difference was observed for patients who received adjuvant chemotherapy (46.7% versus 46.0%; p = 0.96).

Conclusion

These data indicate that low expression of LMNA is associated with an increased disease recurrence in stage II and III colon cancer patients, and suggest that these patients in particular may benefit from adjuvant chemotherapy.     

Serum platelet-activating factor acetylhydrolase and paraoxonase-1 activity in horses infected with Leptospira spp

Chagas disease is a tropical parasitic disease endemic to Latin America which affects more than 10 million people, and kills more than 15,000 people each year. This condition, caused by the protozoan parasite Trypanosoma cruzi, is principally transmitted by kissing bugs (Triatominae). In Bolivia, recent reports by the Departmental Health Service showed the presence of Panstrongylus rufotuberculatus in dwellings located in the Charazani Valley (La Paz). A study was then carried out in the area to evaluate the degree of domiciliation of this species, and its possible role in the transmission of Chagas disease. In seven communities, 108 dwellings were visited to actively search for the bugs and 217 people participated in a serological study to determine the prevalence of Chagas disease in the population. Nymphs and adults belonging to two species: Panstrongylus geniculatus (5 insects, 1.5%) and P. rufotuberculatus (344 insects, 98.5%) were collected. One P. rufotuberculatus was captured in a bed, while all the other specimens of this species were found in kitchens in which guinea pigs were being reared. A large bug colony has been encountered in a kitchen environment, with more than 300 specimens of all stages. None of the 201 analyzed bugs was positive for T. cruzi. The seroprevalence of Chagas disease in the human population was low (1.3%); no evidence of a local vectorial transmission was found. In conclusion, for the time being there is no evidence of vectorial transmission of Chagas disease in the region. The possible association between reared guinea pigs and the bugs is discussed. The presence of infected people, the migratory movement of the human population and the relatively high colonization process demonstrate that the region needs to be regularly controlled to prevent the area from becoming a local source of Chagas transmission.