Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.

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SIRT1 and other sirtuins in metabolism.

SIRT1 and other sirtuins in metabolism

Naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumour genetics, molecular targets, biological behaviour and response to conventional therapies. Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone. The value of this opportunity has been increasingly recognized in the field of cancer research for the identification of cancer-associated genes, the study of environmental risk factors, understanding tumour biology and progression, and, perhaps most importantly, the evaluation and development of novel cancer therapeutics.

Translation of new cancer treatments from pet dogs to humans.

Tumors of the Skin and Soft Tissues

Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics.

/pdf/histone-modifications-and-cancer-w2boj1xl6t.pdf

Histone Modifications and Cancer.

The aim of this investigation was to study by scanning electron microscopy the structure of several swine lymphoid organs (lymph nodes, Peyer's patches, and tonsil). Two groups of animals were used: six-month-old pigs and six- to nine-day-old piglets. Samples were jet-washed to eliminate most free cells in order to observe the reticular framework of these organs more clearly. Peyer's patches in piglets showed two types of villi. In one of them the cellular types were absorptive cells and goblet cells. The second type of villi were shorter and wider, with M cells characterized by presenting long, thick microvilli over their surfaces. Peyer's patches of pigs did not show this second type of villi but were usually covered by absorptive villi. The soft palate tonsil was similar in both groups of animals with its surface epithelial cells full of microfolds, partially and frequently obscured by microorganisms. The appearance of the surface epithelium in the same crypt was different depending on the area. There was a large number of holes through which cells apparently passed towards the crypt lumen. The medulla in the lymph nodes was at the periphery and showed a dense reticular framework. Cortex-like lymphoid tissue was formed by lymphoid follides and diffuse lymphoid tissue with high endothelid venules and lymphatic sinuses. The serosal surface of lymphoid organs was formed either by a typical mesothelial cell layer (small intestine) or by loosely arranged connective fibers (lymph nodes).

https://digitum.um.es/xmlui/bitstream/10201/18195/1/Scanning%20electron%20microscopy%20of%20swine%20lymphoid%20organs.pdf

Scanning electron microscopy of swine lymphoid organs

Immunoreactivity of canine and feline mast cell tumours.

Autologous skin grafts are effective for the repair of large skin wounds, but the availability of large amounts of skin is often limited. Through bioengineering, several autologous skin substitutes have been developed for use in human clinical practice. However, few skin substitutes are available for use in animals. The aim of this study was to develop and assess an engineered autologous skin substitute for the treatment of deep wounds in veterinary medicine. Canine keratinocytes and fibroblasts were isolated after double enzyme digestion from 8mm punch biopsies from four healthy Beagle dogs. Skin substitutes were constructed on a fibrin-based matrix and grafting capacity was assessed by xenografting in six athymic mice. Bioengineered autologous skin was assessed clinically in two dogs with large deep skin wounds. The canine skin construct was ready for use within 12-14days after the initial biopsy specimens were obtained. Grafting capacity in this model was confirmed by successful grafting of the construct in athymic mice. In both dogs, grafts were established and permanent epithelialisation occurred. Histological studies confirmed successful grafting. This full thickness skin substitute developed for the management of large skin defects in dogs appears to be a safe and useful tool for clinical veterinary practice. Further studies are needed to validate its efficacy for the treatment of deep wounds.

Proof of concept of a new autologous skin substitute for the treatment of deep wounds in dogs

ABSTRACT The mechanism of action of intravesical Mycobacterium bovis BCG immunotherapy treatment for bladder cancer is not completely known, leading to misinterpretation of BCG-unresponsive patients, who have scarce further therapeutic options. BCG is grown under diverse culture conditions worldwide, which can impact the antitumor effect of BCG strains and could be a key parameter of treatment success. Here, BCG and the nonpathogenic Mycobacterium brumae were grown in four culture media currently used by research laboratories and BCG manufacturers: Sauton-A60, -G15 and -G60 and Middlebrook 7H10, and used as therapies in the orthotopic murine BC model. Our data reveal that each mycobacterium requires specific culture conditions to induce an effective antitumor response. since higher survival rates of tumor-bearing mice were achieved using M. brumae-A60 and BCG-G15 than the rest of the treatments. M. brumae-A60 was the most efficacious among all tested treatments in terms of mouse survival, cytotoxic activity of splenocytes against tumor cells, higher systemic production of IL-17 and IFN-ɣ, and bladder infiltration of selected immune cells such as ILCs and CD4TEM. BCG-G15 triggered an antitumor activity based on a massive infiltration of immune cells, mainly CD3+ (CD4+ and CD8+) T cells, together with high systemic IFN-ɣ release. Finally, a reduced variety of lipids was strikingly observed in the outermost layer of M. brumae-A60 and BCG-G15 compared to the rest of the cultures, suggesting an influence on the antitumor immune response triggered. These findings contribute to understand how mycobacteria create an adequate niche to help the host subvert immunosuppressive tumor actions. Graphical abstract

Mycobacterial surface characters remodeled by growth conditions drive different tumor-infiltrating cells and systemic IFN-γ/IL-17 release in bladder cancer treatment

EBV-specific T cells have been recently described to be involved in fatal encephalitis and myocarditis in cancer patients after immune checkpoint therapies. Here we report the study of a human triple negative breast cancer tumor (TNBC) and EBV-transformed B cells obtained from a Patient-Derived Xenograft (PDX) that progressed into a lymphocytic neoplasm named Xenograft-Associated B Cell Lymphoma (XABCL). TCR high-throughput sequencing was performed to monitor the T cell clonotypes present in the different samples. Forty-three T cell clonotypes were found infiltrating the XABCL tissue after three passes in mice along 6 months. Eighteen of these (42%) were also found in the TNBC biopsy. TCR infiltrating the XABCL tissue showed a very restricted T cell repertoire as compared with the biopsy infiltrating T cells. Consequently, T cells derived from the TNBC biopsy were expanded in the presence of the B cell line obtained from the XABCL (XABCL-LCL), after which the TCR repertoire obtained was again very restricted, i.e., only certain clonotypes were selected by the B cells. A number of these TCR had previously been reported as sequences involved in infection, cancer and/or autoimmunity. We then analyzed the immunopeptidome from the XABCL-LCL, to identify putative B cell associated peptides that might have been expanding these T cells. The HLA class I and class II-associated peptides from XABCL-LCL were then compared with published repertoires from LCL of different HLA typing. Proteins from the antigen processing and presentation pathway remained significantly enriched in the XABCL-LCL repertoire. Interestingly, some class II-presented peptides derived from cancer-related proteins. These results suggest that bystander tumor-infiltrating EBV+ B cells acting as APC may be able to interact with tumor-infiltrating T cells and influence the TCR repertoire in the tumor site.

R.M. Rabanal

Papers

Scanning electron microscopy of swine lymphoid organs

Immunoreactivity of canine and feline mast cell tumours.

Proof of concept of a new autologous skin substitute for the treatment of deep wounds in dogs

Mycobacterial surface characters remodeled by growth conditions drive different tumor-infiltrating cells and systemic IFN-γ/IL-17 release in bladder cancer treatment

Epstein–Barr Virus+ B Cells in Breast Cancer Immune Response: A Case Report