Biological basis of extensive pleiotropy between blood traits and cancer risk.

BACKGROUND: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Reconstrução palpebral dinâmica com transferência do músculo temporal: relato de caso / Dynamic eyelid reconstruction with temporal muscle transfer: a case report

■ RESUMO Os defeitos na região palpebral são causados principalmente por excisões cirúrgicas de neoplasias cutâneas. Os objetivos da reconstrução palpebral estão fundamentados na restauração da funcionalidade desta unidade anatômica para manter a proteção ocular e a recuperação de uma aparência normal devido à importância crítica da região periocular na estética facial. O reparo dos defeitos palpebrais começa com uma cuidadosa avaliação dos componentes anatômicos que têm sido ressecados e precisam ser reconstruídos; a extensão e a localização do defeito guiarão a reconstrução. Grandes defeitos comprometendo a totalidade da espessura palpebral são um desafio para os cirurgiões plásticos. Milhares de técnicas cirúrgicas têm sido descritas para a reconstrução de defeitos palpebrais de espessura total; apresentamos neste artigo a descrição de um caso de reconstrução dinâmica da pálpebra com associação de um retalho frontal com transposição do músculo temporal após ressecção de um carcinoma basocelular infiltrativo recidivado.

■ ABSTRACT Surgical excisions of skin neoplasms mainly cause defects in the eyelid region. The objectives of eyelid reconstruction are based on the restoration of this anatomical unit's functionality to maintain eye protection and recovery from a normal appearance due to the critical importance of the periocular region in facial aesthetics. Repair of eyelid defects begins with a careful evaluation of the anatomical components that have been resected and need to be reconstructed; the extent and location of the defect will guide the reconstruction. Large defects compromising the entire body thickness are a challenge for plastic surgeons. Thousands of surgical techniques have been described for the reconstruction of total thickness eyelid defects; we present in this article the description of a case of dynamic eyelid reconstruction with an association of a frontal flap with temporal muscle transposition after resection of a recurrent infiltrative basal cell carcinoma.

Francisella noatunensis subsp. noatunensis triggers calcium metabolism gene modulation in Eleginops maclovinus.

Francisella noatunensis subsp. noatunensis is the responsible agent of Francisellosis, a bacterial disease that affects an important amount of aquatic farmed species. Eleginops maclovinus is a fish that cohabits with salmonids cages in Chile and can also act as a vector of this bacterial disease. In the present study, we evaluated calcium metabolism in the liver of E. maclovinus injected intraperitoneally with different doses of F. noatunensis subsp. noatunensis (low 1.5 × 101, medium 1.5 × 105 and high doses 1.5 × 1010 cells/µL). Fish were sampled at 1, 3, 7, 14, 21 and 28 days post injection (dpi). No mortalities nor clinical signs were observed. Plasma calcium levels were higher in the high doses group of F. noatunensis subsp. noatunensis at day 7 and 14 compared to the control group (fish injected with bacterial medium alone). Hypercalcemic factors increased at day 14 and 21 for the medium and low dose (parathyroid hormone-related protein precursor), while vitamin D3 receptor increased its expression at times 1, 3 and 7 for the low dose. On the other hand, hypocalcemic factors such as calcitonin receptor and stanniocalcin increased its expression at time 7 and 14, respectively. Calmodulin involved in calcium storage decreased its expression during all experimental days in fish subjected to high bacterial dose. Proteins involved in calcium transport, such as L-type voltage-gated calcium channel and trpv5 increased their transcription at day 1 and 14, compared to calcium sensing-receptor and plasma membrane Ca2 +- ATPase that showed peak expression at times 14 and 28. The results suggest a clear alteration of calcium metabolism, mainly in high bacterial doses. This study provides new knowledge about the calcium metabolism in fish infected with bacteria.

Recombinant viruses delivering the necroptosis mediator MLKL induce a potent antitumor immunity in mice.

Vaccinia viruses (VACV) are a novel class of immune-oncolytic therapeutics and their mechanism of action is based both on their capacity to replicate selectively in cancer cells and to elicit danger signals that can boost anti-tumor immunity. We recently reported that the intratumor expression of MLKL, a necroptosis inducing factor, generates a protective anti-tumor immunity. Here, we combined both approaches to test the use of VACV to deliver MLKL into the tumor. We generated VACV vectors expressing MLKL and evaluated the effects of MLKL on antitumor efficacy. In vitro infection of cancer cells with MLKL-expressing vectors led to cell death with necroptotic hallmarks. In syngeneic mouse tumor models, VACV expressing MLKL induced an outstanding antitumor activity, which was associated with a robust immunity directed against neo-epitopes. In conclusion, delivery of MLKL by VACV vectors boosts the intrinsic anti-tumor properties of these viral vectors by promoting in situ immunogenic cell death of infected cancer cells.

[Surgical-pathologic correlation to assess the margin status in wide local excision for early-stages breast cancer]. / Correlación quirúrgico-patológica para evaluar el estado de los bordes en las escisiones locales amplias de cáncer mamario en etapas clínicas tempranas.

OBJETIVE: To know the surgical-pathologic correlation to assess the state of the edges in wide local excisions of breast cancer in clinical stages. MATERIAL AND METHODS: retrospective and descriptive study, conducted in Breast Tumors Unit from Oncology Service of the General Hospital of Mexico, in the period from January 2009 to December 2011, with follow-up in December2012. Were included patients with breast cancer in early clinical stages, subject wide local excisions histopalogic report of a second surgery. RESULTS: From wide local excisions, 119 (28.5%) were due to breast cancer and included. Positive margins after initial surgery were diagnosed in 63 patients (52.9%). The residual tumor found in the second surgery was 39.7%. The variables associated with the presence of positive margins and statistically significant (p≤ 0.05) were: multicentricity, tumor size clinical and pathological, histological subtypes, and tumor grade. The age and clinical stage were not statistically significant. The variables associated with the presence of residual tumor and are statistical relevance (p≤ 0.05) were clinical stage, tumor size, clinical and pathological, histological variant and histological grade. Age and multicentricity were not associated with the presence of residual tumor. CONCLUSION: Although each case must be individualized, these results demonstrate the analyzed factors must be taken into account during the planning of breast conservative procedures, and despite an histopalogical report of margin after an initial surgery, even seconds procedures can be performed to conserve the organ.

Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth.

Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof of concept, we demonstrated that intratumoral coadministration of hyaluronidase in mice-bearing tumor xenografts improves the antitumor activity of an oncolytic adenovirus. Next, we constructed a replication-competent adenovirus expressing a soluble form of the human sperm hyaluronidase (PH20) under the control of the major late promoter (MLP) (AdwtRGD-PH20). Intratumoral treatment of human melanoma xenografts with AdwtRGD-PH20 resulted in degradation of hyaluronan (HA), enhanced viral distribution, and induced tumor regression in all treated tumors. Finally, the PH20 cDNA was inserted in an oncolytic adenovirus that selectively kills pRb pathway-defective tumor cells. The antitumoral activity of the novel oncolytic adenovirus expressing PH20 (ICOVIR17) was compared to that of the parental virus ICOVIR15. ICOVIR17 showed more antitumor efficacy following intratumoral and systemic administration in mice with prestablished tumors, along with an improved spread of the virus within the tumor. Importantly, a single intravenous dose of ICOVIR17 induced tumor regression in 60% of treated tumors. These results indicate that ICOVIR17 is a promising candidate for clinical testing.

Verapamil enhances the antitumoral efficacy of oncolytic adenoviruses.

The therapeutic potential of oncolytic adenoviruses is limited by the rate of adenovirus release. Based on the observation that several viruses induce cell death and progeny release by disrupting intracellular calcium homeostasis, we hypothesized that the alteration in intracellular calcium concentration induced by verapamil could improve the rate of virus release and spread, eventually enhancing the antitumoral activity of oncolytic adenoviruses. Our results indicate that verapamil substantially enhanced the release of adenovirus from a variety of cell types resulting in an improved cell-to-cell spread and cytotoxicity. Furthermore, the combination of the systemic administration of an oncolytic adenovirus (ICOVIR-5) with verapamil in vivo greatly improved its antitumoral activity in two different tumor xenograft models without affecting the selectivity of this virus. Overall, our findings indicate that verapamil provides a new, safe, and versatile way to improve the antitumoral potency of oncolytic adenoviruses in the clinical setting.