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LIN28B-S in Huh7.5 cells

Ossification of the posterior longitudinal ligament (OPLL), is a progressive disease that typically presents with mild, non-specific symptoms. Symptoms may include neck and low back pain, tingling, and numbness in the upper extremities, and as the disease advances, it may impair activities of daily living. Occasionally, OPLL can be misdiagnosed if imaging is analyzed without considering clinical findings. Therefore, the imaging results need to be correlated with a comprehensive history for diagnostic accuracy. In addition, an evaluation by a spinal specialist should be considered for persistent symptoms to further correlation between imaging and clinical presentation.

Rehabilitation experts play an important role in preventing hospital-acquired debility, increasing patients' abilities to safely perform activities of daily living, and facilitating discharge to the home setting for patients with COVID-19. Surges in COVID-19 hospitalization rates combined with increases in length of hospital stay and decreases in post-acute care placements have necessitated the opening of COVID-19 field hospitals around the country. Most field hospitals lack the resources to offer a full suite of rehabilitation services, but there are opportunities for small teams of rehabilitation experts to increase their reach by using innovative strategies. This article describes the implementation of a small team of rehabilitation experts in a COVID-19 field hospital and strategies used by this team to maximize patient activity and mobility, facilitate timely discharge, and maximize the number of patients discharged to the home setting. Strategies include training nonclinical staff to assist with activity and mobility promotion and using a rehabilitation triage system to determine needs of individual patients and facilitate efficient resource utilization. The authors reflect on successful aspects of these strategies, as well as barriers to rehabilitation implementation, and make recommendations for other field hospitals seeking to implement rehabilitation during the COVID-19 pandemic or future health crises.

The RNA-binding protein LIN28B plays an important role in development, stem cell biology, and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, colorectal cancer cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, whereas the short isoform did not. The LIN28B-long isoform–expressing cells demonstrated increased drug resistance to 5-fluorouracil and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7–dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting the maturation of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7. Coexpression of the short isoform in the LIN28B-long isoform–expressing cells rescued the phenotypes induced by the LIN28B-long isoform. Implications: This study demonstrates the differential antagonistic functions of the LIN28B-short isoform against the LIN28B-long isoform through an inability to degrade LET-7, which leads to the novel premise that the short isoform may serve to counterbalance the long isoform during normal colonic epithelial homeostasis, but its downregulation during colonic carcinogenesis may reveal the protumorigenic effects of the long isoform. Mol Cancer Res; 16(3); 403–16. ©2018 AACR.

The overarching purpose of this article is to review and synthesize the accumulated evidence that explores the causes and consequences of abusive supervision in work organizations. Our review is organized in three sections. In the first section, we discuss research trends and provide clarification regarding the pressing and not-so-pressing problems with the way that abusive supervision is ordinarily conceptualized and studied. In the second section, we highlight problems and prospects in research on the consequences of abusive supervision. In the third section, we turn our attention to the growing body of research that explores the antecedent conditions and processes that explain when abusive supervision is more or less likely to occur. Throughout the article, we offer an overview of what has been learned over the past 15-plus years and highlight unanswered questions that warrant examination in future studies.

RNA binding proteins, including IMP1/IGF2BP1, are essential regulators of intestinal development and cancer. Imp1 hypomorphic mice exhibit gastrointestinal growth defects, yet the specific role for IMP1 in colon epithelial repair is unclear. Our prior work revealed that intestinal epithelial cell‐specific Imp1 deletion ( Imp1 Δ IEC ) was associated with better regeneration in mice after irradiation. Here, we report increased IMP1 expression in patients with Crohn9s disease and ulcerative colitis. We demonstrate that Imp1 Δ IEC mice exhibit enhanced recovery following dextran sodium sulfate (DSS)‐mediated colonic injury. Imp1 Δ IEC mice exhibit Paneth cell granule changes, increased autophagy flux, and upregulation of Atg5. In silico and biochemical analyses revealed direct binding of IMP1 to MAP1LC3B , ATG3, and ATG5 transcripts. Genetic deletion of essential autophagy gene Atg7 in Imp1 Δ IEC mice revealed increased sensitivity of double‐mutant mice to colonic injury compared to control or Atg7 single mutant mice, suggesting a compensatory relationship between Imp1 and the autophagy pathway. The present study defines a novel interplay between IMP1 and autophagy, where IMP1 may be transiently induced during damage to modulate colonic epithelial cell responses to damage.

The purpose of this article is to review the current available material pertaining to atopic dermatitis, contact dermatitis, urticaria, and angioedema. This article focuses on each disease process's clinical presentation, diagnosis, and management. Although atopic dermatitis and contact dermatitis are similar, their development is different and can affect a patient's quality of life. Urticaria and angioedema are also similar, but the differentiation of the two processes is crucial in that they have significant morbidity and mortality, each with a different prognosis.

Bordetella pertussis can cause serious and potentially fatal complications, especially in very young infants. Early diagnosis and treatment of pertussis with a macrolide antibiotic, such as azithromycin, before the paroxysmal stage of disease can help mitigate complications and reduce the spread of this highly contagious disease.

RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B. In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild-type or LIN28B-overexpressing mice enhances the regenerative response to irradiation. Together, our data provide new evidence for the opposing effects of the LIN28B–IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.

RNA binding proteins, such as IMP1, are emerging as essential regulators of intestinal development and cancer. IMP1 hypomorphic mice exhibit severe intestinal growth defects, yet it’s role in adult intestinal epithelium is unclear. We employed ribosome profiling to test the effect of IMP1 loss on the “translatome” in colon cancer cell lines. In parallel, we evaluated mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following irradiation or colitis models. Ribosome-profiling revealed translation efficiency changes for multiple pathways important for intestinal homeostasis, including autophagy, in IMP1 knockout cells. We found increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts MAP1LC3B and ATG3. We found that Imp1ΔIEC mice exhibit enhanced recovery following irradiation, which is attenuated with genetic deletion of autophagy gene Atg7. Finally, we demonstrated that IMP1 is upregulated in Crohn’s disease patients and Imp1 loss lessened colitis severity in mice. These studies demonstrate that IMP1 acts as a posttranscriptional regulator of gut epithelial repair post-irradiation and colitis, in part through modulation of autophagy.

Summary The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin ( p120ctn )-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras G12D -driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi-allelic p120ctn loss demonstrate marked lung organotropism; however, rescue with p120ctn isoform 1A restores liver metastasis. In a p120ctn -independent PDAC model, mosaic loss of E-CADHERIN expression reveals selective pressure for E-CADHERIN-positive liver metastasis and E-CADHERIN-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn -deficient versus p120ctn -wild-type cells. Taken together, P120CTN and E-CADHERIN mediated epithelial plasticity is an addition to the conceptual framework underlying metastatic organotropism in pancreatic cancer.

The RNA binding protein LIN28B plays an important role in development, stem cell biology and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers (CRCs) and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, CRC cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, while, the short isoform did not. The LIN28B-long isoform expressing cells demonstrated increased drug-resistance to 5-FU and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7 dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting the maturation of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7. Co-expression of the short isoform in the LIN28B-long isoform expressing cells rescued the phenotypes induced by the LIN28B-long isoform.

Purpose: We have generated a mouse model to delete the gene Ctnnd1, whose gene product p120 catenin (p120ctn) is necessary for E-CADHERIN stability, resulting in enhanced metastasis in the conventional KPC pancreatic tumor mouse model. An unbiased screen of tumor cells isolated from these mice identified misregulated calcium signaling as a previously unappreciated contributor to epithelial-to-mesenchymal transition (EMT) and metastasis. Thus, our overarching hypothesis is that p120ctn loss in pancreatic cancer drives EMT and metastasis through functional upregulation of the calcium signaling component PTHLH. Background: Pancreatic ductal adenocarcinoma (PDAC) is a major health issue, with only 7% of patients surviving beyond 5 years, and increases in PDAC-associated deaths project this disease to be the second leading cause of cancer deaths by 2020. An unbiased approach to discover candidate cancer genes in PDAC identified the p120 catenin gene as one of the top 20 PDAC cancer genes, and further analysis revealed that p120ctn loss was associated with reduced PDAC patient survival. Recent work from our lab further demonstrated that conditional p120ctn/Ctnnd1 deletion in the esophagus was sufficient to drive invasive squamous cell carcinoma, establishing p120ctn/Ctnnd1 as a bona fide tumor-suppressor gene. Results presented herein determined the in vivo role of p120ctn loss in PDAC tumorigenesis and metastasis through genetic mouse models and unbiased RNA-seq analysis. Methods: A PDAC mouse model was established to study the role of p120ctn in pancreatic carcinogenesis and metastasis. Specifically, LSL-KrasG12D/+; p53fl/+; Pdx1cre; Rosa26LSL-YFP; Ctnnd1fl/wt mice (herein KPCY-p120CKO) were generated to determine the effect of conditional p120ctn loss on pancreatic cancer. Furthermore, RNA-seq was performed on p120-intact or p120-null pancreatic tumor cells isolated from these mice to identify novel mechanisms of pancreatic tumorigenesis and metastasis. Results: We demonstrate p120ctn loss as a catastrophic event for tumor epithelial cell identity in vivo, leading to enhanced EMT and metastasis. Specifically, we show that KPCY-p120CKO mice have an enhanced metastatic phenotype relative to KPCY controls. Our data therefore suggest that p120ctn is a critical factor in metastatic cell dissemination, and that p120ctn loss results in tumor cells being “locked” in a mesenchymal phenotype by failing to stabilize E-cadherin at the metastatic site. To determine the mechanism of enhanced EMT and metastasis, RNA-seq analysis of p120ctn-null tumor cells was performed, which surprisingly revealed aberrant activation of calcium signaling. Unexpectedly, two of the top five most upregulated genes in p120ctn-null cells were the secreted factor Pthlh and the kinase Camk2b, both of which are key signaling molecules involved in calcium signaling. We demonstrate that PTHLH binding to its cognate receptor leads to cytosolic calcium ion (Ca2+) release, resulting in phosphorylation and activation of CaMKII. We further establish that genetic deletion or pharmacologic inhibition of Pthlh results in proliferation and migration defects. Moreover, orthotopic implantation of KPC-PthlhNULL tumor cell lines reduced tumor growth and metastasis in vivo. Finally, we show that PDAC patients with high expression of Pthlh have significantly decreased survival, suggesting that calcium signaling may be a potent oncogenic pathway in pancreatic cancer and that blocking this pathway may be of therapeutic benefit. Conclusions: This work has demonstrated the importance of the previously unappreciated role of calcium signaling in pancreatic cancer progression and metastasis, and future studies will look to determine the efficacy of calcium-modulating therapeutics in preclinical models of pancreatic cancer. This abstract is also being presented as Poster A42. Citation Format: Jason R. Pitarresi, Maximilian Reichert, Basil Bakir, Leticia Moreira, Lauren Simon, Anil K. Rustgi. p120 catenin loss drives pancreatic cancer EMT and metastasis through activation of calcium signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR04.