Notes

Kinetics associated with charged polymer-bonded failure inside bad chemicals.
Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1. Selleck ARV-110 Autoamplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell epithelial-mesenchymal transition and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis. SIGNIFICANCE This study provided potential therapeutic targets and robust preclinical evidence for PDAC treatment by interrupting feedback signaling between cancer cells and macrophages with targeted inhibitors.Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka-Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost-turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. SIGNIFICANCE Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.See related commentary by Strobl et al., p. 811.Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse. SIGNIFICANCE These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
Large (≥20 mm) sessile serrated lesions (L-SSL) are premalignant lesions that require endoscopic removal. Endoscopic mucosal resection (EMR) is the existing standard of care but carries some risk of adverse events including clinically significant post-EMR bleeding and deep mural injury (DMI). The respective risk-effectiveness ratio of piecemeal cold snare polypectomy (p-CSP) in L-SSL management is not fully known.

Consecutive patients referred for L-SSL management were treated by p-CSP from April 2016 to January 2020 or by conventional EMR in the preceding period between July 2008 and March 2016 at four Australian tertiary centres. Surveillance colonoscopies were conducted at 6 months (SC1) and 18 months (SC2). Outcomes on technical success, adverse events and recurrence were documented prospectively and then compared retrospectively between the subsequent time periods.

A total of 562 L-SSL in 474 patients were evaluated of which 156 L-SSL in 121 patients were treated by p-CSP and 406 L-SSL in 353 patients by EMR. Technical success was equal in both periods (100.0% (n=156) vs 99.0% (n=402)). No adverse events occurred in p-CSP, whereas delayed bleeding and DMI were encountered in 5.1% (n=18) and 3.4% (n=12) of L-SSL treated by EMR, respectively. Recurrence rates following p-CSP were similar to EMR at 4.3% (n=4) versus 4.6% (n=14) and 2.0% (n=1) versus 1.2% (n=3) for surveillance colonoscopy (SC)1 and SC2, respectively.

In a historical comparison on the endoscopic management of L-SSL, p-CSP is technically equally efficacious to EMR but virtually eliminates the risk of delayed bleeding and perforation. p-CSP should therefore be considered as the new standard of care for L-SSL treatment.
In a historical comparison on the endoscopic management of L-SSL, p-CSP is technically equally efficacious to EMR but virtually eliminates the risk of delayed bleeding and perforation. p-CSP should therefore be considered as the new standard of care for L-SSL treatment.
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