Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.

Galectin-1 (Gal-1) is involved in tumoral angiogenesis, hypoxia and metastases. Actually the Gal-1 expression profile in multiple myeloma (MM) patients and its pathophysiological role in MM-induced angiogenesis and tumoral growth are unknown. In this study, we found that Gal-1 expression by MM cells was upregulated in hypoxic conditions and that stable knockdown of hypoxia inducible factor-1α significantly downregulated its expression. Therefore, we performed Gal-1 inhibition using lentivirus transfection of shRNA anti-Gal-1 in human myeloma cell lines (HMCLs), and showed that its suppression modified transcriptional profiles in both hypoxic and normoxic conditions. Interestingly, Gal-1 inhibition in MM cells downregulated proangiogenic genes, including MMP9 and CCL2, and upregulated the antiangiogenic ones SEMA3A and CXCL10. Consistently, Gal-1 suppression in MM cells significantly decreased their proangiogenic properties in vitro. This was confirmed in vivo, in two different mouse models injected with HMCLs transfected with anti-Gal-1 shRNA or the control vector. Gal-1 suppression in both models significantly reduced tumor burden and microvascular density as compared with the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on X-ray in the intratibial model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM blocking angiogenesis.

Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo.

We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.

Reproductive costs of heat shock protein in transgenic Drosophila melanogaster.

Senescence may evolve when genes have antagonistic effects between early reproduction and later age-specific mortality. Although widely consistent with data of quantitative genetics, this model has yet to be validated with the identification of a specific locus presenting such trade-offs. The molecular chaperone hsp70 may be a candidate for such a gene. Heat induced expression of the Hsp70 protein in adults decreases rates of age-specific mortality during normal aging, while maternally experienced heat shock depresses the production of mature progeny. Here we show that maternal heat shock reduces the proportion of egg hatch but not the viability of successfully hatched offspring. To assess whether heat induced maternal expression of hsp70 causes reduced egg hatch, we measured the proportion of eggs that hatch from females engineered to overexpress hsp70 transgenes. We used the same transgenic strains that extend longevity upon hsp70 expression and found that Hsp70 is sufficient to suppress egg hatch. The proportion of egg hatch as a function of hsp70 expression was not reduced in the first eggs laid after maternal heat shock, but appears in later laid eggs, which were at preoogenic and early vitellogenic stages during the maternal expression of hsp70. The contervailing effects of hsp70 upon fecundity and subsequent age-specific mortality exemplify antagonistic pleiotropy, and this trade-off could contribute to the evolution of Drosophila senescence.

[Cockayne syndrome. Case report]. / Síndrome de Cockayne. Relato de caso.

We describe a girl with Cockayne syndrome (CS), the diagnostic criteria and the complications of this syndrome. The required criteria for the diagnosis include: prenatal poor growth failure, congenital structural eye anomalies, cataracts, pigmentary retinopathy, severe neurologic dysfunction from birth, sensorineural hearing loss, cutaneous photosensitivity and dental caries. CS is a rare autosomal recessive and biochemical disorder.

Clinical treatment of post partum delirium with perfenazine and lithium carbonate.

Despite the development of psychopharmaceutical therapy, post partum delirium was difficult to treat. The patients remained psychotic for long periods and the course was of the disease capricious due to the many relapses. A comparative study of two groups, one consisting of 6 patients and the other of 13, all with a typical post partum delirium was carried out. The symptomatic treatment of this syndrome with a combination of perfenazine and lithium carbonate produced relatively favorable results in our clinic. For the time being, at any rate, it seems to be the medication of choice.

The principle of separate responsibility and the therapeutic community.

Within a psychiatric hospital it has been attempted to realize a maximum number of the elements of the therapeutic community. Problems here are the short median stays of patients and the rapid turnover of both patients and staff. What is more, a basic problem of the therapeutic community was encountered, namely that the interests of the individual patient and of the patients as a group are considered as identical. Thus there came about the development of the principle of separate responsibility, whereby a division of responsibility is made between the individual patient and the unit. Work is carried out by multidsiciplinary and largely democratized teams.