The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b(+)Gr-1(+) myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b(+) cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific interest over the past 10 years. This is largely due to the development of bacterial strains that maintain good anti-tumor efficacy, but with reduced potential to cause toxicities to the host. Because of its ability to replicate in viable as well as necrotic tissue, cancer therapy using attenuated strains of facultative anaerobic bacteria, such as Salmonella, has several advantages over standard treatment modalities, including chemotherapy and radiotherapy. Despite some findings suggesting that it may operate through a direct cytotoxic effect against cancer cells, there is accumulating evidence demonstrating that bacterial therapy acts by modulating cells of the immune system to counter the growth of the tumor. Herein, we review the experimental evidence underlying the success of bacterial immunotherapy against cancer and highlight the cellular and molecular alterations in the peripheral immune system and within the tumor microenvironment that have been reported following different forms of bacterial therapy. Our improved understanding of these mechanisms should greatly aid in the translational application of bacterial therapy to cancer patients.

T2DM is linked to an increase in the fracture rate as compared to the nondiabetic population even with normal or raised bone mineral density (BMD). Hence, bone quality plays an important role in the pathogenesis of skeletal fragility due to T2DM. This study analyzed the changes in the trabecular bone microstructure due to T2DM at various time points in ovariectomized and nonovariectomized rats. Animals were divided into four groups: (I) control (sham), (II) diabetic (sham), (III) ovariectomized, and (IV) ovariectomized with diabetes. The trabecular microarchitecture of the femoral head was characterized using a micro-CT. The differences between the groups were analyzed at 8, 10, and 14 weeks of the onset of T2DM using a two-way analysis of variance and by post hoc multiple comparisons. The diabetic group with and without ovariectomies demonstrated a significant increase in trabecular separation and a decrease in bone volume fraction, trabecular number, and thickness. BMD decreased in ovariectomized diabetic animals at 14 weeks of the onset of T2DM. No significant change was found in connectivity density and degree of anisotropy among groups. The structural model index suggested a change towards a weaker rod-like microstructure in diabetic animals. The data obtained suggested that T2DM affects the trabecular structure within a rat's femoral heads negatively and changes are most significant at a longer duration of T2DM, increasing the risk to hip fractures.

The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational

Mammary gland stem cells (MaSC) have not been identified in spite of extensive research spanning over several decades. This has been primarily due to the complexity of mammary gland structure and its development, cell heterogeneity in the mammary gland and the insufficient knowledge about MaSC markers. At present, Lin (-) CD29 (i) CD49f (i) CD24 (+/mod) Sca- 1 (-) cells of the mammary gland have been reported to be enriched with MaSCs. We suggest that the inclusion of stem cell markers like Oct4, Sox2, Nanog and the mammary gland differentiation marker BRCA-1 may further narrow down the search for MaSCs. In addition, we have discussed some of the other unresolved puzzles on the mammary gland stem cells, such as their similarities and/or differences with mammary cancer stem cells, use of milk as source of mammary stem cells and the possibility of in vitro differentiation of embryonic stem (ES) cells into functional mammary gland structures in this review. Nevertheless, it is the lack of identity for a MaSC that is curtailing the advances in some of the above and other related areas.

BackgroundDiabetes mellitus (DM) is associated with osteoporosis and increase fracture risk1. Increase fractures in type 1 DM are linked to decrease bone mineral density (BMD) but BMD alone does not explain the increase fracture rate seen in diabetics. Alterations in bone quality which entails bone microarchitecture, material and composition of bone tissue also contributes to diabetic osteopathy2. Chronic state of hyperglycaemia, hypoinsulinemia, inflammation, low levels of insulin growth factor-1 (IGF-1), increased marrow adiposity, altered adipokine and endocrine factors, increased cell death and accumulation of advanced glycation products that compromise matrix properties impairs normal bone metabolism in type 1 DM1. While BMD is detected clinically using a dual-energy X-ray absorptiometry (DEXA) scan, methods to detect changes in bone quality are limited. Estimating bone markers in serum and urine are used in assessing bone quality. An imbalance in bone remodelling as measured by various bone markers is observed in type I DM. But due to discrepancy in results of various studies the exact mechanisms is still elusive.ObjectivesTo investigate the underlying mechanism of altered bone quality in type 1diabetes:1. By measuring the bone formations and resorption markers.2. By measuring the advanced glycation end products.3. By analysing the changes at cellular level in type I diabetesMethodsExperimental diabetes mellitus was induced in 24 Wistar rats by injecting streptozotocin 60 mg/kg body weight intraperitoneally. Rats were sacrificed at 6th, 8th and 12th week of developing diabetes. Blood and bone specimens were collected. Serum levels of osteocalcin, bone alkaline phosphatase, C-terminal cross-linked telopeptide of type-I collagen (CTX) and pentosidine were measured using ELISA to investigate bone turnover in type I DM. The bone specimens were fixed, processed, sectioned and stained for bone histomorphometry3. Histological analysis was carried out using an ‘Olympus Research Inverted Microscope Model IX53’ complete with fluorescent attachment equipped with a DP73 camera (Olympus). Statistical analysis was carried out using sigmastat 4.0.ResultsLow levels of osteocalcin and bone alkaline phosphatase and increased levels of pentosidine and CTx levels in serum were found in 6th and 12th week duration of diabetes. Additionally increase number of mast cells p<0.05 were observed in diabetic bones as compared to control specimensConclusionsChronic hyperglycaemic state in type I DM impairs bone remodelling by decreasing bone formation and increasing bone resorption. Increase in advanced glycation end products and mast cells also contribute to diabetic osteopathy.References[1] Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL & On behalf of the IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nature Reviews Endocrinology2017;13:208–219.[2] Motyl K, McCabe LR. Streptozotocin, type I diabetes severity and bone. Biol Proced Online2009;11:296–315.[3] Mohsin S, ...

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