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Constitutive activation of Wnt/β-catenin inhibits oligodendrocyte myelination. Tcf7l2/Tcf4, a β-catenin transcriptional partner, is required for oligodendrocyte differentiation. How Tcf7l2 modifies β-catenin signalling and controls myelination remains elusive. Here we define a stage-specific Tcf7l2-regulated transcriptional circuitry in initiating and sustaining oligodendrocyte differentiation. Multistage genome occupancy analyses reveal that Tcf7l2 serially cooperates with distinct co-regulators to control oligodendrocyte lineage progression. At the differentiation onset, Tcf7l2 interacts with a transcriptional co-repressor Kaiso/Zbtb33 to block β-catenin signalling. During oligodendrocyte maturation, Tcf7l2 recruits and cooperates with Sox10 to promote myelination. In that context, Tcf7l2 directly activates cholesterol biosynthesis genes and cholesterol supplementation partially rescues oligodendrocyte differentiation defects in Tcf712 mutants. Together, we identify stage-specific co-regulators Kaiso and Sox10 that sequentially interact with Tcf7l2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development, and point to a previously unrecognized role of Tcf7l2 in control of cholesterol biosynthesis for CNS myelinogenesis. Wnt/β-catenin signaling regulates oligodendrocyte (OL) development. Here the authors show that Tcf7l2, a β-catenin transcriptional partner,sequentially interacts with stage-specific partners to coordinate the transitions of differentiation initiation and maturation during OL development.

Health Impact Assessment (HIA) and Health in All Policies (HiAP) are policy tools used to include health considerations in decision-making processes across sectors such as transportation, education, and criminal justice that can play a role in improving health and equity. This article summarizes proceedings from an international convening of HIA and HiAP experts held in July 2019 in Barcelona, Spain. The presentations and panel discussions included different models, best practices, and lessons learned, including from government, international banks, think tanks, and academia. Participants discussed ideas from around the world for cross-sector collaboration to advance health. The convening covered the following topics: community engagement, building greater understanding of and support for HiAP, and exploring how mandates for HIA and HiAP approaches may advance health and equity.

In addition to smoking and UV exposure, lifestyle factors, such as diet, nutrition, and physical activity, have been shown to play a significant role for many cancers. It is estimated that up to 50% of some cancer types are preventable; many through lifestyle and dietary changes with the presence or absence of certain dietary components strongly associated with an increased or decreased risk. Here we summarize the work that has been performed with polyphenols, with a focus on those derived from black raspberries. These have been extensively studied for the prevention and treatment of a variety of conditions and diseases. Here we focus on their use for the prevention or treatment of specific cancer types and the impact they have on biological systems. The aim is to highlight the need to improve our understanding of how the environment impacts upon the normal biological processes that affect health and disease, thereby, enabling us to implement smarter prevention and treatment measures. A summary of the tumours and “hallmarks of cancer” that black raspberry polyphenols impact upon to elicit tumour suppressive effects.

The links between diet, microbiome, immunity, and colorectal cancer are well established. The metabolite output of the microbiome, which has a large influence over host health and disease, is related to the composition of the diet. These metabolites subsequently impact on immune and intestinal epithelial either directly or indirectly via production of secondary metabolites. Here we summarize the latest findings and briefly discuss their potential for managing disease risk. Image illustrating the impact of microbial metabolites, derived from dietary components, on the intestinal stem cells and relationship to colorectal cancer risk.

SEE PDF] HFD AND INCREASED CRC RISK Obesity is an epidemic, leading to a 30%–70% elevated CRC risk (Mantovani et al., 2018). [...]understanding the link between a pro-obesity HFD and CRC is of particular interest. (2008)'s study running further and for longer periods of time. [...]higher intensity of exercise may be crucial to prevent polyp formation in an HFD context. Future research should focus on this complicated and variable relationship between diet, exercise, and energy production on ISCs and CRC initiation, rather than individualistic studies. What effect would fluctuations in exercise have on the ISC pool? DIET AND REDUCED CRC RISK Numerous dietary components, such as fiber and fruit, are associated with reducing CRC risk (World Cancer Research Fund, 2018), including black raspberries (BRBs; May et al., 2022).

Bacterial cancer therapy (BCT) is emerging as an important option for the treatment of solid tumours, with promising outcomes in preclinical trials. Further progress is hampered by an incomplete understanding of how oncotropic bacteria, such as attenuated strains of Salmonella enterica serovar Typhimurium, colonise tumours and the responses of both the bacteria and tumour cells to this colonisation. To model this, we developed organoids that are permissive for bacterial colonisation, replacing the conventional commercially available extracellular matrix (e.g., Matrigel) with a type I collagen matrix scaffold. A comparison of the two extracellular matrices indicated that type 1 collagen permitted an initial infection efficiency more than 5-times greater than with Matrigel. In addition, subsequent growth within type 1 collagen expanded bacterial cell numbers by over 10-fold within 4 days of infection. These organoids allow for the visualisation of bacterial chemoattraction, cell invasion and subsequent population of the interior lumen, and will permit the future optimisation of BCT. In addition, by establishing patient-derived organoids, we demonstrate a platform for developing future personalised treatments exploiting BCT.

Background Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo. Results The attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc . In vivo therapeutic efficacy was demonstrated using the Lgr5creER T2 Apc flx/flx and BlgCreBrca2 flx/fl p53 flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% ( P  < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 10 6 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals. Conclusions In summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation.

Background Cancer/testis (CT) genes have expression normally restricted to the testis, but become activated during oncogenesis, so they have excellent potential as cancer-specific biomarkers. Evidence is starting to emerge to indicate that they also provide function(s) in the oncogenic programme. Human TEX19 is a recently identified CT gene, but a functional role for TEX19 in cancer has not yet been defined. Methods siRNA was used to deplete TEX19 levels in various cancer cell lines. This was extended using shRNA to deplete TEX19 in vivo. Western blotting, fluorescence activated cell sorting and immunofluorescence were used to study the effect of TEX19 depletion in cancer cells and to localize TEX19 in normal testis and cancer cells/tissues. RT-qPCR and RNA sequencing were employed to determine the changes to the transcriptome of cancer cells depleted for TEX19 and Kaplan-Meier plots were generated to explore the relationship between TEX19 expression and prognosis for a range of cancer types. Results Depletion of TEX19 levels in a range of cancer cell lines in vitro and in vivo restricts cellular proliferation/self-renewal/reduces tumour volume, indicating TEX19 is required for cancer cell proliferative/self-renewal potential. Analysis of cells depleted for TEX19 indicates they enter a quiescent-like state and have subtle defects in S-phase progression. TEX19 is present in both the nucleus and cytoplasm in both cancerous cells and normal testis. In cancer cells, localization switches in a context-dependent fashion. Transcriptome analysis of TEX19 depleted cells reveals altered transcript levels of a number of cancer-/proliferation-associated genes, suggesting that TEX19 could control oncogenic proliferation via a transcript/transcription regulation pathway. Finally, overall survival analysis of high verses low TEX19 expressing tumours indicates that TEX19 expression is linked to prognostic outcomes in different tumour types. Conclusions TEX19 is required to drive cell proliferation in a range of cancer cell types, possibly mediated via an oncogenic transcript regulation mechanism. TEX19 expression is linked to a poor prognosis for some cancers and collectively these findings indicate that not only can TEX19 expression serve as a novel cancer biomarker, but may also offer a cancer-specific therapeutic target with broad spectrum potential.

Jaboticaba (Myrciaria jaboticaba) is a recognizable and unique crop from Brazil. The fruit’s byproducts are currently being studied, given their bioactive composition and promising anti-cancer potential. It is not evident, however, if different harvesting seasons can modify the chemical profile and antioxidant capacity of jaboticaba fruit fractions. Furthermore, as there is limited data for jaboticaba’s anti-proliferative effects, additional assessments are required to improve the robustness of these findings. Therefore, this study aimed to determine the composition of the peel of jaboticaba collected in two periods (May—off-season, sample 1—and August–October—peak season, sample 2) and test the peel’s richest anthocyanin sample against colorectal cancer (CRC) cell lines. To accomplish this, proximate, spectrophotometric, and chromatographic analyses were performed in two freeze-dried samples; and anti-proliferative and/or colony-forming assays were carried out in Caco-2, HT29, and HT29-MTX cells. As a result, sample 2 showed the highest levels of polyphenols overall, including flavonoids and anthocyanins. This sample displayed significative higher contents of cyanidin-3-O-glucoside (48%) and delphinidin-3-O-glucoside (105%), in addition to a superior antioxidant capacity (23% higher). Sample 1 showed higher amounts of total protein, gallic acid (20% higher), and specific carotenoids. An aqueous extract from sample 2 was tested against CRC, showing anti-proliferative effects for Caco-2 cells at 1 and 2 mg/mL concentrations, with IC50 values of 1.2–1.3 mg/mL. Additionally, the extract was able to inhibit cell colony formation when tested at both low and high concentrations. In conclusion, jaboticaba collected in the main season stands out regarding its polyphenol composition and holds potential against cancer cell growth.