Clonal dominance defines metastatic dissemination in pancreatic cancer.

Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination. This model revealed the multifaceted nature of tumor growth, with rapid changes in clonal fitness leading to continuous reshuffling of tumor architecture and alternating clonal dominance as a distinct feature of cancer growth. Regarding dissemination, a large fraction of tumor lineages could be found at secondary sites each having distinctive organ growth patterns as well as numerous undescribed behaviors such as abortive colonization. Paired analysis of primary and secondary sites revealed fitness as major contributor to dissemination. From the analysis of pro- and nonmetastatic isogenic subclones, we identified a transcriptomic signature able to identify metastatic cells in human tumors and predict patients' survival.

Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer.

While pancreatic ductal adenocarcinomas (PDACs) are addicted to KRAS-activating mutations, inhibitors of downstream KRAS effectors, such as the MEK1/2 kinase inhibitor trametinib, are devoid of therapeutic effects. However, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway may induce vulnerabilities of therapeutic relevance. An in-depth molecular analysis of the transcriptional and epigenomic alterations occurring in PDAC cells in the initial hours after MEK1/2 inhibition by trametinib unveiled the induction of endogenous retroviruses (ERVs) escaping epigenetic silencing, leading to the production of double-stranded RNAs and the increased expression of interferon (IFN) genes. We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

Screen time usage among preschoolers aged 2-6 in rural Western India: A cross-sectional study.

AIMS: We have evaluated screen time usage among preschool-aged (≤6 years) children in rural Western India. In addition, we have evaluated various lifestyle factors and their impact on the screen time of these children. MATERIALS AND METHODS: English-medium schools in the locality were chosen based on convenience. A self-report survey requesting family information and screen usage information was distributed to the parents. Daily screen time was categorized as a three-category variable. Ordered logistic regression with multivariable regression was performed to examine the association of risk factors with screen time. RESULTS: Average screen time among the 379 (208 males, 171 female) children amounted to 2.7 hours (SD: 1.7), with average daily television screen time of 1.6 hours (SD: 1.1). Most children (87.2%) started screen use by the age of 3. Only 65 (17.2%) participants met AAP recommendation. Households with three devices and smartphone usage by mothers increased the odds of screen time by 60% and two-folds, respectively. Compared to weekdays, children had increased screen time exposure (3.5 vs 2.7 hours, P < 0.001), outdoor activity time (2.3 vs 1.6, P < 0.001), and reading hours (1.2 vs 1.1, P = 0.03) on weekends. No association was observed between screen time and mother's occupation. CONCLUSIONS: More than 80% of children exceeded the advised screen time with television and smartphone being the major contributors. This issue has to be dealt with at both individual and societal levels. Increased awareness about the high prevalence of inappropriate use of screen time use within the Indian context is needed to inspire attention and interventions for this emerging public health problem in India.

Video Surveillance Audit of Hand-washing Practices in a Neonatal Intensive Care Unit.

OBJECTIVE: To audit hand-washing practices by video-surveillance. METHODS: Six main steps (step 2 to step 7) of World Health Organizations hand hygiene technique with soap and water were used for evaluation. Handwashing was categorized as excellent, acceptable and unacceptable. RESULTS: Of 1081 recordings, 403 (37.3%) were excellent, 521 (48.2%) were acceptable and 157 (14.5%) were unacceptable handwash. Unacceptable handwashing was more prevalent in the night in comparison to daytime (17.5% vs 12.5%). Thirteen people washed their face after washing their hands. CONCLUSIONS: Innovative interventions are required to improve handwashing during night shifts.