SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

First-time mothers’ experiences of pregnancy and birth following assisted reproductive technology treatment in Taiwan

Background Assisted Reproductive Technology (ART) treatment tends to involve significant physical and emotional commitments that can impact maternal, infant and family health and well-being. An in-depth understanding of experiences is necessary to provide adequate support for women and their families during pregnancy and transition to parenthood following ART treatment. The aim of this study was to explore first-time mothers’ experiences of pregnancy and transition to parenthood following successful ART treatment in Taiwan. Method Twelve first-time mothers who conceived and gave live birth using ART treatment were purposively selected from a fertility centre in Taipei, Taiwan. Women’s experiences in pregnancy and in their transition to motherhood were explored using semi-structured in-depth interviews. All interviews were recorded, transcribed, and analysed using the Colaizzi strategy. Results The mothers’ accounts reflected three main themes: ‘being different from mothers who became pregnant naturally’; ‘ensuring health and safety of the foetus’; and ‘welcoming new lives with excitement’. The difference mothers felt about themselves was evident in four subthemes: becoming pregnant after a long wait, feeling vulnerable during pregnancy, relying on family’s assistance and support, and worrying about the impact of ART on health. The theme on ‘ensuring health and safety of the foetus’ encompassed three subthemes: activities to protect the unborn baby, monitoring foetal movement constantly to maintain peace of mind, and receiving foetal reduction for the sake of the pregnancy. Narratives around ‘welcoming new lives with excitement’ reflected four subthemes: overcoming hardship for worthwhile results, realising one’s life and dreams, proving to be fertile enough to give birth, and return to normal life track. Conclusion Findings indicate the need for educational and psychosocial interventions to support women and their families physically and psychologically during ART treatment. The stigma related to infertility and the psychosocial support from family are aspects to consider while planning intervention programmes

mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses

Differential Impact of Tumor Suppressor Pathways on DNA Damage Response and Therapy-Induced Transformation in a Mouse Primary Cell Model

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes

Evaluating mechanical properties of silica-coated alginate beads for immobilized biocatalysis.

For continuous reactions in biochemical engineering, enzymes or whole cells are usually immobilized for structural stabilization and retention in order to ensure repetitive use. One of the most frequently used encapsulation methods is immobilization of biocatalysts in silica-coated alginate beads. The mechanical properties of these beads are of great relevance for biochemical engineering approaches where these beads are applied in stirred tanks or packed bed reactors. In this report, alginate beads prepared in gelation media of different composition and ionic strength were subsequently coated with silica shells of varying chemical composition. The resistance of these coated beads against mechanical stress was then quantitatively compared by measuring the minimal absolute static force necessary to induce breakage of the silica shell. It was found that this force and therefore the structural integrity of the coated beads highly depended not only on the composition of the coating material, but also on the method by which the alginate core was prepared

Could nasal septal deformities type 5 and 6 be a predictive factor of the individual genetic predilection for the onset of an acute coronary syndrome?

WOS: 000387634400010PubMed: 29727128Objectives: the possible impact of nasal septal deformities (SD) on cardiac pathology has not been well studied, despite growing evidence among data showing that upper airway obstruction has a negative effect on cardiac function in general and a "deviated nasal septum" being considered one of the most frequent factors responsible for impaired nasal breathing. Methods: a retrospective, case-control, double-blind study was performed on 249 patients who survived an acute coronary syndrome (ACS) attack. All patients underwent coronary angiography and were divided into coronary angiography positive (123 pts) and coronary angiography negative (126 pts) groups. The quality of nasal breathing was not considered in this study, but morphological aspects of the nasal septum (nasal septal deformities) were observed by anterior native rhinoscopy and endoscopic examination of the nose following the application of superficial anaesthesia. Mladina classification of nasal septal deformities was used. Results: there was a statistically significant difference between coronary angiography negative and positive patients in Mladina type 1 to Mladina type 7 groups (p=0.000, X-2=54.605). The incidence of nasal SD types 5 and 6 was higher in the group of ACS patients with the positive coronary angiography, whereas general distribution of the particular types of nasal septal deformities as they appear in the general population was found in the coronary angiography negative group. Conclusion: the fact that types 5 and 6 are inherited deformities and not related to trauma against the nose suggests the possible genetic predisposition for the onset of ACS with positive coronary angiography