The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the ...underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment.
Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by IHC and the genetic and epigenetic alterations of KLF4 in and KLF4's impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3'-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal models.
Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. In addition, DIM treatment caused significant inhibition of cell growth
and tumorigenesis in animal models of pancreatic cancer.
This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers.
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The roles of chance, contingency, and necessity in evolution are unresolved because they have never been assessed in a single system or on timescales relevant to historical evolution. We combined ...ancestral protein reconstruction and a new continuous evolution technology to mutate and select proteins in the B-cell lymphoma-2 (BCL-2) family to acquire protein–protein interaction specificities that occurred during animal evolution. By replicating evolutionary trajectories from multiple ancestral proteins, we found that contingency generated over long historical timescales steadily erased necessity and overwhelmed chance as the primary cause of acquired sequence variation; trajectories launched from phylogenetically distant proteins yielded virtually no common mutations, even under strong and identical selection pressures. Chance arose because many sets of mutations could alter specificity at any timepoint; contingency arose because historical substitutions changed these sets. Our results suggest that patterns of variation in BCL-2 sequences – and likely other proteins, too – are idiosyncratic products of a particular and unpredictable course of historical events.
One of the most fundamental and unresolved questions in evolutionary biology is whether the outcomes of evolution are predictable. Is the diversity of life we see today the expected result of organisms adapting to their environment throughout history (also known as natural selection) or the product of random chance? Or did chance events early in history shape the paths that evolution could take next, determining the biological forms that emerged under natural selection much later?
These questions are hard to study because evolution happened only once, long ago. To overcome this barrier, Xie, Pu, Metzger et al. developed an experimental approach that can evolve reconstructed ancestral proteins that existed deep in the past. Using this method, it is possible to replay evolution multiple times, from various historical starting points, under conditions similar to those that existed long ago. The end products of the evolutionary trajectories can then be compared to determine how predictable evolution actually is.
Xie, Pu, Metzger et al. studied proteins belonging to the BCL-2 family, which originated some 800 million years ago. These proteins have diversified greatly over time in both their genetic sequences and their ability to bind to specific partner proteins called co-regulators. Xie, Pu, Metzger et al. synthesized BCL-2 proteins that existed at various times in the past. Each ancestral protein was then allowed to evolve repeatedly under natural selection to acquire the same co-regulator binding functions that evolved during history.
At the end of each evolutionary trajectory, the genetic sequence of the resulting BCL-2 proteins was recorded. This revealed that the outcomes of evolution were almost completely unpredictable: trajectories initiated from the same ancestral protein produced proteins with very different sequences, and proteins launched from different ancestral starting points were even more dissimilar.
Further experiments identified the mutations in each trajectory that caused changes in coregulator binding. When these mutations were introduced into other ancestral proteins, they did not yield the same change in function. This suggests that early chance events influenced each protein’s evolution in an unpredictable way by opening and closing the paths available to it in the future.
This research expands our understanding of evolution on a molecular level whilst providing a new experimental approach for studying evolutionary drivers in more detail. The results suggest that BCL-2 proteins, in all their various forms, are unique products of a particular, unpredictable course of history set in motion by ancient chance events.
Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) ...editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression.
Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate ...embryos and emerge from the neural plate borders into multiple cell lineages that differentiate into bone, cartilage, neurons and glial cells. We have previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we have investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicate that TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural tube closure, and Irf6 is involved in defining neural fold borders by restricting AP2α expression. Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs. Disruption of TWIST1 phosphorylation in vivo leads to epidermal blebbing, edema, neural tube defects and CNCC-derived structural abnormalities. Altogether, this study describes a previously uncharacterized function of mammalian Twist1 and Irf6 in the neural tube and CNCCs, and provides new target genes for Twist1 that are involved in cytoskeletal remodeling.
Metastasis and thrombosis are serious threats to cancer patients and generally associated with poor prognosis. The elusive mechanisms underlying the pathogenesis of metastasis and thrombosis have ...been subjects of extensive investigations. The presence of circulating tumor cells (CTCs) is closely related to tumor metastasis, and these cells play an important role in thrombosis in cancer patients. In this review, we describe the latest findings on the role of CTCs in tumor metastasis and cancer-related thrombosis and the regulatory role of microRNAs in CTCs and thrombosis. Additionally, we discuss anticoagulant-based strategies for the prevention of thrombosis and reduction of cancer metastasis and the potential to translate current knowledge on these strategies to the treatment of cancer.
We report a case of tibial osteochondroma in a 25-year-old female who presented with a palpable calf mass. This mass was associated with a thick cartilaginous cap on cross-sectional imaging, ...suggesting chondrosarcoma. A CT-guided biopsy was performed, and histology, however, was consistent with osteochondroma. Orthopedic oncology recommended surgical excision due to the potential high sampling error with chondroid lesions. The patient underwent surgical resection, resulting in a final diagnosis of osteochondroma. No post-surgical complications occurred, and a 12-month follow-up showed no evidence of local recurrence. This case highlights the atypical imaging feature of a thick cartilaginous cap in a benign etiology without malignant transformation.
Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of m6A reader YTHDF3 in human diseases. ...Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients. YTHDF3 promotes cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of m6A-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to m6A residues within its own 5′ UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence.
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•YTHDF3 overexpression clinically correlates with breast cancer brain metastases•Breast cancer brain metastases have YTHDF3 gene copy gain and autoregulation•YTHDF3 plays critical roles in multiple steps of brain metastasis cascade•YTHDF3 promotes translation of the key brain metastatic genes ST6GALNAC5 and GJA1
Chang et al. report that YTHDF3 overexpression associates with breast cancer brain metastasis and confers poor survival. Mechanistically, YTHDF3 enhances the expression of m6A-enriched transcripts that promote cancer cell-brain microenvironment interactions and brain metastasis.
Despite ample evidence on the labor productivity impact of heat shocks, little is known about how heat shocks affect labor adjustment over time. This paper uses administrative employer–employee ...linked data from Brazil to examine margins of labor market adjustment to extreme heat. Tracking workers over time and across job spells, I find that quarterly heat shocks increase the probability of formal manufacturing layoffs. In the medium run, there is limited intersectoral and interregional reallocation, as well as a significant failure rate to reallocate back to formal sectors, indicating job transitional costs. Finally, the employment impact of heat shocks is larger for workers in more routine manual task intensive, less abstract occupations.
Background
In multidisciplinary education, different perspectives from more than one discipline are used to illustrate a certain topic. The aim of this study was to evaluate the effectiveness of an ...online, multidisciplinary radiology curriculum to teach radiology to medical students in Egypt. A multidisciplinary team of radiologists, surgeons, and internists taught a series of 5 case-based radiology sessions on a web conference platform. Topics included common clinical case scenarios for various body systems. Undergraduate medical students across Egypt were enrolled in the course. A pre-test–post-test design was used to evaluate the efficacy of each session. Upon course completion, students filled out a subjective survey to assess the radiology education series.
Results
On average, 1000 students attended each session. For each session, an average of 734 students completed both the pre-test and post-test. There was a statistically significant increase in post-test scores compared to pre-test scores across all 5 sessions (
p
< 0.001) with an overall average score improvement of 63%. A subjective survey at the end of the course was completed by 1027 students. Over 96% of students found the lecture series to be a worthwhile experience that increased their imaging knowledge and interest in radiology, and that the use of a multidisciplinary approach added educational value. About 66% of students also reported that the session topics were “excellent and clinically important.” There was a marked increase in reported confidence levels in radiology competencies before and after attendance of the sessions.
Conclusions
An online radiology curriculum with a multidisciplinary approach can be implemented successfully to reach a large group of medical students and meet their educational objectives.
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