Search

Changes in the mechanical microenvironment and mechanical signals are observed during tumor progression, malignant transformation, and metastasis.In this context, understanding the molecular details of mechanotransduction signaling may provide unique therapeutic targets. Here, we report that normal breast epithelial cells are mechanically sensitive, responding to transient mechanical stimuli through a two-part calcium signaling mechanism. We observed an immediate, robust rise in intracellular calcium (within seconds) followed by a persistent extracellular calcium influx (up to 30 min). This persistent calcium was sustainedvia microtubule-dependent mechano activation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species (ROS), which acted on transient receptor potential cation channel subfamily M member 8 (TRPM8) channels to prolong calcium signaling. In contrast, the introduction of a constitutively active oncogenic KRas mutation inhibited the magnitude of initial calcium signaling and severely blunted persistent calcium influx. The identification that oncogenic KRas suppresses mechanically-induced calcium at the level of ROS provides a mechanism for how KRas could alter cell responses to tumor microenvironment mechanics and may reveal chemotherapeutic targets for cancer. Moreover, we find that expression changes in both NOX2 and TRPM8 mRNA predict poor clinical outcome in estrogen receptor (ER)-negative breast cancer patients, a population with limited available treatment options. The clinical and mechanistic data demonstrating disruption of this mechanically-activated calcium pathway in breast cancer patients and by KRas activation reveal signaling alterations that could influence cancer cell responses to the tumor mechanical microenvironment and impact patient survival. [ABSTRACT FROM AUTHOR]

The article focuses the preventing family based-asylum claims in the U.S. Topics discussed include enactment of Immigration and Nationality Act which addresses asylum law; role of Board of Immigration Appeals in resolving the ambiguity and clarifying the nexus requirement in asylum seeker; and U.S. Court of Appeals court case Flores-Rios v. Lynch on same.

The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here we report its role and importance in breast epithelial cell signaling and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular Ca 2+ in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca 2+ responses. The non-tumorigenic cells respond to increased Ca 2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca 2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca 2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca 2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.

Background: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes., Methods: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared., Results: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma., Conclusions: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated., (© 2020 American Cancer Society.)

Background/objective: Natural history and outcomes for truncal/extremity (TE) soft tissue sarcoma (STS) is derived primarily from studies investigating all histiotypes as one homogenous cohort. We aimed to define the recurrence rate (RR), recurrence patterns, and response to radiation of TE leiomyosarcomas (LMS)., Methods: Patients from the US Sarcoma Collaborative database with primary, high-grade TE STS were identified. Patients were grouped into LMS or other histology (non-LMS). Primary endpoints were locoregional recurrence-free survival (LR-RFS), distant-RFS (D-RFS), and disease specific survival (DSS)., Results: Of 1215 patients, 93 had LMS and 1122 non-LMS. In LMS patients, median age was 63 and median tumor size was 6 cm. In non-LMS patients, median age was 58 and median tumor size was 8 cm. In LMS patients, overall RR was 42% with 15% LR-RR and 29% D-RR. The 3yr LR-RFS, D-RFS, and DSS were 84%, 65%, and 76%, respectively. When considering high-risk (>5 cm and high-grade, n = 49) LMS patients, the overall RR was 45% with 12% LR-RR and 35% D-RR. 61% received radiation. The 3yr LR-RFS (78vs93%, p = 0.39), D-RFS (53vs63%, p = 0.27), and DSS (67vs91%, p = 0.17) were similar in those who did and did not receive radiation. High-risk, non-LMS patients had a similar overall RR of 42% with 15% LR-RR and 30% D-RR. 60% of non-LMS patients received radiation. There was an improved 3yr LR-RFS (82vs75%, p = 0.030) and DSS (77vs65%,p = 0.007) in non-LMS patients who received radiation., Conclusions: In our cohort, patients with LMS have a low local recurrence rate (12-15%) and modest distant recurrence rate (29-35%). However, LMS patients had no improvement in local control or long-term outcomes with radiation. The value of radiation in these patients merits further investigation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Both minimally invasive surgery (MIS) and open approaches for distal pancreatectomy are acceptable. MIS options include total laparoscopic/robotic (TLR) and hand-assist laparoscopy (HAL). When considering safety profile and specimen quality, the optimal approach is unknown., Methods: Patients who underwent distal pancreatectomy from 2010-2018 at two major academic institutions were included. Converted procedures were categorized into final approach. Ninety-day perioperative/pathologic outcomes of MIS and open were compared. Subset analyses between TLR vs HAL and HAL vs open were performed. Intent-to-treat analysis was performed., Results: Among 1006 patients, resection was performed by MIS in 35% (n = 352), open in 65% (n = 654). MIS had similar patient comorbidity profile as open but had increased operative time (183 vs 162 min; p < 0.01), lower estimated-blood-loss (EBL; 131 vs 341 mL; p < 0.01), fewer intraoperative blood transfusions (1.4 vs 5%; p < 0.01), shorter LOS (5.2 vs 7.2 days; p < 0.01). Tumor size was smaller (3.2 vs 4.4 cm; p < 0.01) with lower lymph node (LN) yield (14 vs 16; p < 0.01). When comparing HAL (n = 109) to TLR (n = 243), despite increased prior abdominal operations (60 vs 43%; p = 0.008), HAL had shorter operative time (167 vs 191 min; p < 0.01), similar length-of-stay (LOS; 5.4 vs 5.1 days; p = 0.27), and readmission rate (15 vs 13%; p = 0.47). When comparing HAL to open, the advantages of TLR approach persisted including lower EBL (171 vs 342 mL; p < 0.01), and shorter LOS (5.4 vs 7.2 days; p < 0.01). Although HAL had smaller tumors, it had a similar LN yield (16 vs 16; p = 0.80), and higher R0-rate (97 vs 83%; p < 0.01)., Conclusion: Hand-assist laparoscopy is safe and feasible for distal pancreatectomy as operative time, complication profile, lymph node yield, and R0-rates are similar to open procedures, while maintaining the associated the advantages of a total laparoscopic/robotic approach with reduced blood loss and shorter length-of-stay., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Radiographic prediction of peritoneal carcinomatosis index (PCI) can improve patient selection for cytoreductive surgery. We aimed to determine the correlation of computed tomography (CT)-predicted PCI (CT-PCI) and magnetic resonance imaging (MRI)-predicted PCI (MRI-PCI) with intraoperative-PCI, and if a preoperative-PCI cutoff is associated with incomplete cytoreduction., Patients and Methods: Patients from the US HIPEC Collaborative (2000-2017) with appendiceal, colorectal, or peritoneal mesothelioma (PM) histology who underwent cytoreductive surgery were included. Pearson correlation coefficients were used to determine correlation between preoperative and intraoperative-PCI values. Fisher r-to-z transformation was used to compare correlations., Results: A total of 488 patients were included. Of these, 34% had noninvasive appendiceal, 30% invasive appendiceal, 28% colorectal, and 8% PM histology. CT-PCI was correlated with intraoperative-PCI for patients with noninvasive and invasive appendiceal and colorectal histologies (r = 0.689, 0.554, and 0.571; all P < .001), but not PM (r = 0.188; P = .295). MRI-PCI was correlated with intraoperative-PCI for all histologies (non-invasive appendiceal: r = 0.591; P = .002; invasive appendiceal: r = 0.848; P < .001; colorectal: r = 0.729; P < .001; PM: r = 0.890; P = .007). Comparing CT and MRI, correlations were similar in noninvasive appendiceal and colorectal histologies; MRI was better for invasive appendiceal and PM (P = .005 and P = .021, respectively). Twenty-eight (6%) patients underwent an incomplete cytoreduction (cytoreduction score, 2-3). PCI greater than 15 was associated with cytoreduction score of 2 to 3 for both CT and MRI (CT-PCI: odds ratio, 3.0; P = .033; MRI-PCI: odds ratio, 7.6; P = .071)., Conclusions: In this multi-institutional cohort, CT and MRI-PCI correlate well with intraoperative-PCI. MRI appears to be superior for invasive appendiceal and peritoneal mesothelioma. External validation in a larger population is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique-Particle Image Velocimetry (PIV)-we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell sheet, while the increase in cell migration speed is maintained only at the leading edge. The overall directionality steadily increases with time as cells migrate into the cell-free space, but migration speed remains largely the same. A particle-based compass (PBC) model suggests cellular interplay (which depends on cell-cell distance) and migration speed are sufficient to capture the dynamics of migration directionality revealed experimentally. Extracellular Ca 2+ regulated both migration speed and directionality, but in a significantly different way, suggested by the correlation between directionality and speed only in some dynamic ranges. Our experimental and modeling results reveal distinct directionality and speed dynamics in collective migration, and these factors can be regulated by extracellular Ca 2+ through cellular interplay. Quantitative visualization using PIV and our PBC model thus provide a powerful approach to dissect the mechanisms of collective cell migration.