bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the Antiviral Mechanism of Different MARCH Factors
Authors: Umthong Supawadee , Lynch Brian , Timilsina Uddhav , Waxman Brandon , Ivey Emily B. , Stavrou Spyridon
Published: March 2021

This study examines the mechanism utilized by different MARCH proteins to restrict retrovirus infection. MARCH proteins block the incorporation of envelope glycoproteins to the budding virions.
What factors shape surgical access in West Africa? A qualitative study exploring patient and provider experiences of managing injuries in Sierra Leone
Authors: Virk Amrit , Bella Jalloh Mohamed , Koedoyoma Songor , Smalle Isaac O , Bolton William , Scott J A , Brown Julia , Jayne David , Ensor Tim , King Rebecca
Published: March 2021

Introduction

Surgical access is central to universalising health coverage, yet 5 billion people lack timely access to safe surgical services. Surgical need is particularly acute in post conflict settings like Sierra Leone. There is limited understanding of the barriers and opportunities at the service delivery and community levels. Focusing on fractures and wound care which constitute an enormous disease burden in Sierra Leone as a proxy for general surgical need, we examine provider and patient perceived factors impeding or facilitating surgical care in the post-Ebola context of a weakened health system.

Methods

Across Western Area Urban (Freetown), Bo and Tonkolili districts, 60 participants were involved in 38 semistructured interviews and 22 participants in 5 focus group discussions. Respondents included surgical providers, district-level policy-makers, traditional healers and patients. Data were thematically analysed, combining deductive and inductive techniques to generate codes.

Results

Interacting demand-side and supply-side issues affected user access to surgical services. On the demand side, high cost of care at medical facilities combined with the affordability and convenient mode of payment to the traditional health practitioners hindered access to the medical facilities. On the supply side, capacity shortages and staff motivation were challenges at facilities. Problems were compounded by patients’ delaying care mainly spurred by sociocultural beliefs in traditional practice and economic factors, thereby impeding early intervention for patients with surgical need. In the absence of formal support services, the onus of first aid and frontline trauma care is borne by lay citizens.

Conclusion

Within a resource-constrained context, supply-side strengthening need accompanying by demand-side measures involving community and traditional actors. On the supply side, non-specialists could be effectively utilised in surgical delivery. Existing human resource capacity can be enhanced through better incentives for non-physicians. Traditional provider networks can be deployed for community outreach. Developing a lay responder system for first-aid and front-line support could be a useful mechanism for prompt clinical intervention.
Effectiveness of custom-made foot orthoses in patients with systemic lupus erythaematosus: protocol for a randomised controlled trial
Authors: Reina-Bueno María , Vázquez-Bautista María del Carmen , Palomo-Toucedo Inmaculada C , Domínguez-Maldonado Gabriel , Castillo-López José Manuel , Ramos-Ortega Javier , Munuera-Martínez Pedro V
Published: March 2021

Introduction

Systemic lupus erythaematosus (SLE) is a chronic autoimmune disease of heterogeneous involvement. The disease may affect feet with a high prevalence of symptoms such as, for example, pain, forefoot and rearfoot deformities, and biomechanics dysfunctions. Custom-made foot orthoses (CMFO) have been previously reported to be effective in patients with other rheumatic diseases. However, as far as the authors know, there exist no studies about their effectiveness in SLE. This study aims at determining the effect of CMFO versus placebo flat cushioning insoles on pain, foot functionality, fatigue and quality of life in patients with SLE.

Methods and analysis

A randomised controlled trial would compare the effects of (1) CMFO and group B, which received a placebo, flat cushioning insoles, for 3 months. The main outcome measures are foot pain, foot functionality and foot-related disability. The secondary outcome measures are fatigue and quality of life.

Ethics and dissemination

The study has been approved by the Portal de Ética de la Investigación Biomédica de Andalucía ethical committee 1494-N-19. The results will be disseminated regardless of the magnitude or direction of effect.

Trial registartion number

Clinicaltrials.gov identifierNCT04098055.
Psychoeducational and rehabilitative intervention to manage cancer cachexia (PRICC) for patients and their caregivers: protocol for a single-arm feasibility trial
Authors: Buonaccorso Loredana , Bertocchi Elisabetta , Autelitano Cristina , Allisen Accogli Monia , Denti Monica , Fugazzaro Stefania , Martucci Gianfranco , Costi Stefania , Tanzi Silvia
Published: March 2021

Introduction

Half of all patients with cancer experience cachexia, with the prevalence rising above 80% in the last weeks of life. Cancer cachexia (CC) is a complex relational experience that involves the patient–family dyad. There are no studies on the association between the psychoeducational component and the rehabilitative component of dyads for supporting more functional relationships in the management of CC.

The primary objective of this study is to evaluate the feasibility of a psychoeducational intervention combined with a rehabilitative intervention on dyads.

The secondary objective is to improve the quality of life (QoL) and acceptability of the intervention.

Methods and analysis

This mixed-methods study with a nonpharmacological interventional prospective includes 30 consecutive cancer patients with cachexia and refractory cachexia and their caregivers, assisted by the Specialised Palliative Care Team. The recruitment will last 1 year. The intervention involves two components: (1) psychoeducational intervention: 3 weekly face-to-face consultations between dyads and trained nurses to help the dyads cope with involuntary weight loss and strengthening dyadic coping resources and (2) rehabilitation intervention: 3 biweekly educational sessions between dyads and trained physiotherapists focused on self-management, goal-setting, physical activity with three home exercise sessions per week.

The primary endpoint will be in adherence to the intervention, indicated by a level of completion greater than or equal to 50% in both components. The secondary endpoints will be QoL (Functional Assessment of Anorexia-Cachexia Therapy), caregiver burden (Zarit Burden), physical performance (Hand-Grip strength and 30 seconds sit-to-stand test), and the acceptability of the intervention (ad hoc semi-structured interviews with the dyads and the healthcare professionals).

Ethics and dissemination

The study was approved by the Ethics Committee Area Vasta Emilia Nord, Azienda USL-IRCSS Reggio Emilia, Italy, number: 73/2019/SPER/IRCCSRE. The authors will provide the dissemination of the results through publication in international scientific journals.

Trial registration number

NCT04153019.
Failure phenomena in metallic and metal-lined polymer composite pressure vessels for aerospace applications
Authors: Goldin Priscilla C.P. , Selwin Rajadurai J.
Published: March 2021

Metallic and metal-lined polymer composite pressure vessels are extensively used in industries, including the aerospace industry. In the absence of unique failure criteria for the structural elements, phenomenological or empirical methodologies are used by researchers. This paper discusses comprehensive methodologies for predicting burst pressure of metallic and metal-lined polymer composite pressure vessels for aerospace applications. Metallic pressure vessels were analysed using Ansys software, considering the elastic-plastic nature of the materials. The progressive analysis was performed in metal-lined composite pressure vessels in an explicit mode using Ansys software. The problem of solution convergence is discussed in detail. The extent of degradation in static analysis is suggested after multiple analysis trials. In the unit pressure extrapolation technique, the stress components were evaluated using Ansys software and transformed into a local coordinate system, and hence, the failure pressure of the first-ply was identified by the maximum stress criterion. The analysis then continues with the degradation of the failed layers using Ansys software, and successive failures of layers were identified in steps. The results of burst pressure, evaluated through the present analyses, showed good agreement with the published test results. The procedures described in the paper would be of interest to the designers of pressure vessels.
INVESTIGATION OF RESIDUAL STRESS FIELD IN THE CURVED SURFACE OF ROUND ROD SUBJECTED TO MULTIPLE LASER SHOCK PEENING
Authors: ZHANG XINGQUAN , NIU WENWU , YIN YUANDE , FANG JINXIU , SHAH SYED SOHAIL AHMAD , YU YUANCHAO
Published: March 2021

Laser shock peening (LSP) was employed to squeeze compressive residual stress (CRS) into the curved surface of the round rod with diameter of 16[Formula: see text]mm. The residual stress field was induced by nine laser shots irradiating at different locations along the specified path. The developing process of the residual stress field was investigated with finite element analysis, and the corresponding experiments were also carried out to validate the calculated results. Results demonstrate that multiple LSP with 50% overlapping rate can result in residual stress field with the maximum CRS varying from 155.2[Formula: see text]MPa to 198.8[Formula: see text]MPa along the direction of the rod axis. The peened surface appears wavy in shape and the maximum depth of plastic deformation in the curved surface is 13.41[Formula: see text][Formula: see text]m. The value of surface roughness increases from 3.87[Formula: see text][Formula: see text]m to 4.65[Formula: see text][Formula: see text]m.
On the generalization of moyal equation for an arbitrary linear quantization
Authors: Borisov Leonid A. , Orlov Yuriy N.
Published: March 2021

For an arbitrary linear combination of quantizations, the kernel of the inverse operator is constructed. An equation for the evolution of the Wigner function for an arbitrary linear quantization is derived and it is shown that only for Weyl quantization this equation does not contain a source of quasi-probability. Stationary solutions for the Wigner function of a harmonic oscillator are constructed, depending on the characteristic function of the quantization rule. In the general case of Hermitian linear quantization these solutions are real but not positive. We found the representation of Weyl quantization in the form of the limit of a sequence of linear Hermitian quantizations, such that for each element of this sequence the stationary solution of the Moyal equation is positive.
Generalized Bernoulli Wick differential equation
Authors: Altoum Sami H. , Ettaieb Aymen , Rguigui Hafedh
Published: March 2021

Based on the distributions space on [Formula: see text] (denoted by [Formula: see text]) which is the topological dual space of the space of entire functions with exponential growth of order [Formula: see text] and of minimal type, we introduce a new type of differential equations using the Wick derivation operator and the Wick product of elements in [Formula: see text]. These equations are called generalized Bernoulli Wick differential equations which are the analogue of the classical Bernoulli differential equations. We solve these generalized Wick differential equations. The present method is exemplified by several examples.
The connected p-median problem on complete multi-layered graphs
Authors: Nguyen Kien Trung , Nhan Tran Hoai Ngoc , Teh Wen Chean , Hung Nguyen Thanh
Published: March 2021

We address in this paper the connected [Formula: see text]-median problem on complete multi-layered graphs. We first solve the corresponding 1-median problem on the underlying graph in linear time based on the structure of the induced path. For [Formula: see text], we prove that the connected [Formula: see text]-median contains at least one vertex in the layered set corresponding to the 1-median or its adjacent vertices in the induced path. Then, we develop an [Formula: see text] algorithm that solves the problem on a complete multi-layered graph with [Formula: see text] vertices.
Unusual Case of Gallbladder Adenocarcinoma Metastasis to the Abdominal Wall 11 Years Later: Synchronous Presentation with Two Malignant Colon Tumors, Coincidence or Not?
Authors: Matías-García Belén , Mendoza-Moreno Fernando , Díez-Alonso Manuel , Quiroga-Valcárcel Ana , Aguirregoicoa-García Elena , Vera-Mansilla Cristina , Ovejero-Merino Enrique , Mínguez-García Javier , Córdova-García Diego , Gutiérrez-Calvo Alberto
Published: March 2021

Introduction. Abdominal wall masses are a common finding in clinical practice. A high percentage of these masses are malignant. We present the case of a patient operated for a gallbladder adenocarcinoma, who consulted eleven years later for a malignant mass of the abdominal wall in synchrony with two adenocarcinomas of the left colon and sigmoid. Case Report. A 75-year-old male underwent a laparoscopic cholecystectomy with an incidental diagnosis of adenocarcinoma in situ (TisN0M0 according to AJCC 8th edition). The operative report mentioned that the removal of the gallbladder was difficult due to the inflammatory process, and the gallbladder was accidentally opened during the operation. It was not clear from the operative report whether an extraction bag was utilized to remove the specimen, but the histopathological study confirmed an open gallbladder. He presented 11 years later with an asymptomatic heterogeneous complex cystic mass involving the anterior rectus abdominis muscle. Colonoscopy showed synchronous tumors in the descending and sigmoid colon with pathology confirming adenocarcinoma. The patient underwent an elective laparotomy with resection of the anterior abdominal wall mass, left hemicolectomy, and sigmoidectomy. The histopathological results of the abdominal mass (CK7, CK20, EMA, CEA positive) were described as metastasis of adenocarcinoma of biliary origin. Discussion. Port site recurrences are rare complications following laparoscopic surgery when malignancy is unsuspected. Possible factors related to local implantation include direct seeding of spilled bile or tumor cells into the wound or shedding of tumor cells due to pneumoperitoneum-induced loss of the peritoneal barrier at the trocar site. In the absence of distant metastasis, treatment should include wide port site excision with malignancy-free surgical margins. Conclusion. Abdominal wall metastasis from gallbladder carcinoma is rare, and its synchronous presentation with a malignant neoplasm of the colon is exceptional. This is the first report of a patient with abdominal wall metastasis from a gallbladder adenocarcinoma operated eleven years ago that debuted synchronously with two adenocarcinomas of the left colon and sigma.
Effects of Nonelastic Taping and Dual Task on Kinematics and Kinetics of the Ankle Joint
Authors: Wang TaoLi , Zhong RongZhou , Liu ShaSha , Hu GuoJiong , Niu WenXin , Wang YuBin
Published: March 2021

Objectives. The purpose of this experimental study was to investigate the effects of nonelastic taping and dual task on ankle kinematics and kinetics in gait analysis of healthy adults. Methods. A total of 21 healthy adults completed trials of gait analysis using a Vicon system combining ground walking with different cognitive task conditions (none, modified Stroop color/character naming, and serial-7 subtraction), with or without nonelastic taping. Ankle kinematics and kinetics including speed, ankle plantarflexion and inversion angle, ground reaction force (GRF), and stride time variability (STV) under all conditions of taping (YES or NO) and cognitive task (none, naming, and subtraction) were characterized and analyzed with repeated-measures ANOVA. Results. As regards cognitive performance, the serial-7 subtraction performance under walking conditions with and without taping was significantly poorer than simple sitting condition (

P
<
0.001

). For kinematics and kinetics, STV showed statistically significant decrease (

P
=
0.02

) when subjects underwent taping application. Vertical GRF was significantly greater under taping than barefoot (

P
=
0.001

). Ankle plantarflexion at initial contact (IC) under the dual-task walking was significantly more than under simple walking (

P
=
0.008

). Conclusions. Applications of nonelastic taping and dual task may lead to the STV, vertical GRF, ankle plantarflexion, and speed alterations because of restricted joint range of motion and changed sensorimotor neural circuit. When healthy adults performed dual-task walking, central neural resources allocation was disturbed, leading to weakened performance in both motor and cognitive tasks.
Abstract IA009: Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis
Authors: Kang Yibin
Published: March 2021

TGF-β signaling is a well established pathway driving different steps of bone metastasis progression. Wnt signaling plays a dichotomous role in bone metastasis, with recent studies showing that inhibition of Wnt signaling by DKK1 is critical for avoidance of immune clearance of dormant bone micrometastasis and activation of osteoclast activity during osteolytic outgrowth. On the other hand, engagement of bone vascular E-selectin by disseminated tumor cells (DTCs) promotes metastatic colonization in bone by activating Wnt signaling to enhance tumor initiating activity of DTCs. These findings imply a complex interplay between TGF-b and Wnt signaling in different stages of bone metastasis development that allows efficient colonization, dormancy and outgrowth of secondary tumors in bone. What mediates the dynamic transition of TGF-β and Wnt signaling states during metastasis is currently unknown. Here we present data describing a novel phase-separated organelle organized by bone metastasis promoting protein Dact1 which mediates the crosstalk of TGF-β and Wnt signaling. We found that Dact1 is induced by TGF-β signaling and forms dynamically regulated biomolecular condensates that suppress Wnt signaling. A high level of Dact1 expression is associated with an elevated risk of bone metastasis in breast cancer patients and Dact1 is necessary for bone metastasis in mouse models of breast and prostate cancers.

Citation Format: Yibin Kang. Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA009.
Abstract IA011: Conventional dendritic cells as regulators of therapeutic response in pancreas cancer
Authors: DeNardo David G.
Published: March 2021

In these studies, we utilized spontaneous models of pancreatic and lung cancer to examine how neo-antigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) resulted in exacerbation of the inflammatory and fibrotic tumor microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early- stage PDAC leads to disease restraint, while restoration of cDC function thru treatment with both CD40 agonists and FLT3L in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

Citation Format: David G. DeNardo. Conventional dendritic cells as regulators of therapeutic response in pancreas cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA011.
Abstract IA018: Linking obesity-associated inflammation with cancer metastasis
Authors: McDowell Sheri A. , Luo Robin , Spicer Jonathan D. , Dannenberg Andrew J. , Walsh Logan A. , Quail Daniela F.
Published: March 2021

Obesity is associated with increased incidence and mortality of multiple tumor types, and competes with smoking tobacco as the leading preventable risk factor for all cancer-related deaths. In breast cancer, epidemiological studies have shown that obesity is linked to enhanced metastasis to lung and liver. However, it is not known how to improve cancer outcomes in the obese patient population as the mechanistic link between obesity and cancer progression is currently lacking. Using genetic and diet-induced obesity mouse models, it was previously shown that obesity promotes pulmonary metastasis of breast cancer by inducing lung neutrophilia via a IL5–GM-CSF signaling axis. We have now determined that neutrophils are reprogrammed by obesity within the lung to produce elevated levels of reactive oxygen species (ROS) and release neutrophil extracellular traps (NETs). This in turn weakens endothelial barrier integrity, leading to enhanced microvascular permeability and tumor cell extravasation into the lung parenchyma. This effect can be reversed by targeting ROS via pharmacological or genetic approaches, or by preventing NETosis using PAD4 inhibitors. To confirm the translational relevance of our findings, we performed imaging mass cytometry on lung metastasis samples from cancer patients, and observed a significant correlation between body mass index and NETosis, neutrophil oxidative burst, and ROS status. Given the high prevalence of obesity on an international scale, our data provide insight into mechanisms of cancer progression for a significant proportion of the adult population, including (potentially) those who are metabolically obese but normal weight.

Citation Format: Sheri A. McDowell, Robin Luo, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh, Daniela F. Quail. Linking obesity-associated inflammation with cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA018.
Abstract IA026: Activating a collaborative innate-adaptive immune response to control metastasis
Authors: Egeblad Mikala
Published: March 2021

Tumor-associated macrophages (TAMs) promote metastasis and inhibit cytotoxic T cells. Yet, macrophages can be polarized to kill cancer cells. Macrophage polarization could therefore be a strategy for controlling cancer. We have found that monophosphoryl lipid A (MPLA, a derivative of lipopolysaccharide [LPS]) with IFNγ can polarize macrophages isolated from metastatic pleural effusions of breast cancer patients to kill cancer cells in vitro. Injecting tumors with MPLA+IFNγ reduced primary tumor growth, greatly suppressed metastasis, and enhanced the response to chemotherapy in breast and ovarian cancer mouse models. Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. Mechanistically, the combined MPLA+IFNγ treatment stimulated type I interferon signaling, reprogramed TAMs (CD206+) to tumoricidal macrophages (iNOS+), and activated cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). MPLA and IFNγ are already used individually in clinical practice and together represent a previously unexplored approach to engage a systemic anti-tumor immune response.

Citation Format: Mikala Egeblad. Activating a collaborative innate-adaptive immune response to control metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA026.
Abstract LT005: Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy
Authors: Siolas Despina , Vucic Emily , Kurz Emma , Hajdu Cristina , Bar-Sagi Dafna
Published: March 2021

KRASG12D mutations in tumor cells can modify the immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), though the effects of secondary genetic alterations have been unexplored. After oncogenic KRAS, TP53 is the most frequently mutated gene in PDAC, however the immune effects of neomorphic TP53 mutations have not been defined. We sought to evaluate the non-cell-autonomous role of mutant p53 in modulating the immune microenvironment of pancreatic cancer by comparing the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) genetically engineered to express the Trp53R172H gain-of-function mutation to their p53 wildtype control. We found orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC had a distinct immune profile in comparison to KrasG12D/+;Trp53+/+ tumors, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy.

Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT005.
Abstract LT010: Pleiotrophin drives pro-metastatic immune niche within breast tumor microenvironment
Authors: Ganguly Debolina , Sorrelle Noah , Dominguez Adrian , Toombs Jason , Schmidt Marcel , Mora Fa Valdes , Ortega David Gallego , Wellstein Anton , Brekken Rolf A.
Published: March 2021

Background: Pleiotrophin (PTN), a heparin binding cytokine important during embryonic development, is expressed at elevated levels in several cancers, including breast cancer. High PTN expression in serum and tumor tissues of breast cancer patients correlates with worse outcome. Previous studies indicate PTN contributes to angiogenesis, hematopoiesis, and inflammation; however, the function of PTN in breast cancer progression and metastasis has not been elucidated.

Methods: The effect of anti-PTN therapy (mAb; 3B10) on breast tumor progression and pulmonary metastasis was evaluated in four preclinical models of breast cancer: 4T1, E0771, Met-1, MMTV-PyMT. In addition, the effect of global loss of PTN using Ptn-deficient mice was evaluated in two murine models of breast cancer. Tissues from these experiments were analyzed by RNAseq and histology for changes in angiogenesis, hematopoiesis, immune cell infiltration, and cytokine/chemokine expression.

Findings: TCGA data shows high PTN expression correlates with poor survival of Stage IV breast cancer patients. Furthermore, our data indicate that: a) blocking PTN pharmacologically or genetically results in a significant reduction of lung metastasis in multiple preclinical mouse models of breast cancer, b) scRNAseq and dual FISH-IHC (fluorescence in-situ hybridization and immunohistochemistry) demonstrates that endothelial cells and select population of tumor cells express PTN in the tumor microenvironment (TME), c) inhibition of PTN results in a decrease in overall inflammation with a particular decrease in neutrophil populations at primary and secondary tumor sites, d) in a genetically engineered mouse model (GEMM) of breast cancer, MMTV-PyMT, PTN expression is enriched at the metastatic site.

Conclusion: Our data suggests that PTN is important in driving a pro-metastatic immune niche within the TME that promotes tumor cell escape from the primary tumor and survival of metastatic cancer cells in secondary sites. Additionally, our studies highlight that inhibition of PTN has potential to reduce metastatic burden in breast cancer and suggest that future studies testing the combination of PTN inhibition with standard chemotherapy or immune therapy are warranted.

Citation Format: Debolina Ganguly, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Marcel Schmidt, Fa Valdes Mora, David Gallego Ortega, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives pro-metastatic immune niche within breast tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT010.
Abstract LT016: Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance
Authors: Tello-Lafoz Maria , Srpan Katja , Hu Jing , Romin Yevgeniy , Calò Annalisa , Hsu Katharine C. , Massagué Joan , Huse Morgan , Emrah Er Ekrem
Published: March 2021

Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells’ expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B’s established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells’ stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases.

Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT016.
Abstract PO001: Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer
Authors: Boral Debasish , Kenney Shelby R. , Liu Haowen N. , Marchetti Dario
Published: March 2021

Despite widespread knowledge that bone marrow-resident breast cancer cells (BMRCs) affect tumor progression, signaling mechanisms of BMRCs implicated in maintaining long-term dormancy have not been characterized. Further, there is no model of clinical dormancy that can comprehensively emulate the entire spectrum of heterogeneous clones of Circulating Tumor Cells (CTCs) present in cancer patients. To overcome these hurdles, we developed a new experimental model of clinical dormancy employing patient-isolated de novo CTCs and their injection in xenografts with subsequent tumor monitoring and CTC characterization (ex vivo CTCs). We hypothesized that significant distinctions exist between signaling pathways of bone marrow-homing vs metastasis-competent CTCs upon transplantation in xenografts. Comparative transcriptomic analyses of ex vivo vs de novo CTCs identified increased mTOR signaling – a critical pathway frequently dysregulated in breast cancer and implicated in cell survival and dormancy – with contrasting actions by its two complementary arms (mTORC2/mTORC1). Heightened mTORC2 downstream targets augmented quiescent CTCs (Ki67-/RBL2+ cells) in paired breast cancer tissues, along with high mTORC2 activity in solitary BMRCs and tissue-resident CTCs. Further, shRNA mediated knockdown of RICTOR, an essential component of mTORC2, augmented Ki67/PCNA biomarker expression and proliferation. Collectively, these findings suggest that the balance between mTORC1 vs mTORC2 signaling regulates CTC-associated mitotic and/or dormancy characteristics. Further elucidation of mTOR-mediated CTC dormancy will provide novel strategies for therapeutic interventions in patients having early-event metastatic seeding but yet to develop clinically-detectable overt metastasis.

Citation Format: Debasish Boral, Shelby R. Kenney, Haowen N. Liu, Dario Marchetti. Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO001.
Abstract PO022: Metabolic and transcriptional adaptations under hypoxic stress promote breast cancer progression
Authors: Dai Tao , Novickis Aaron , Katsuta Eriko , Takabe Kazuaki , Abrams Scott I. , Dasgupta Subhamoy
Published: March 2021

To sustain energy production for survival in hypoxia, tumor cells undergo metabolic rewiring predominantly by accentuating glucose uptake through hypoxia-driven enhanced expression of glycolytic enzymes. 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is one of the hypoxia response glycolytic enzyme which primarily balances the glucose flux between glycolysis and pentose phosphate pathway. However, the necessity to increase PFKFB4 expression under hypoxia is poorly understood. Here, we show that PFKFB4 dependent adaptation in hypoxia promotes a tumor-intrinsic genetic alteration acquiring invasive phenotype in breast cancer. Specifically, we found that CRISPR-Cas9 PFKFB4-knock-out (KO) breast cancer cells were defective in migration under normoxic condition (21% O2) compared to wild-type (WT) cells; while this migratory defect was found more severe under hypoxic stress (1% O2). To elucidate the mechanisms of PFKFB4-driven migration, we performed RNA-sequencing which revealed that PFKFB4 induces expression of focal adhesion pathway genes including ITGB3 (integrin β3), which are essential regulators of migration and invasion. While validating the target genes by qPCR and immunoblotting, we found that a great number of focal adhesion target genes were hypoxia-response genes including ITGB3, as their expression was significantly enhanced in hypoxia, which was completely abrogated in the absence of PFKFB4. Rescuing ITGB3-expression in PFKFB4-KO cells was sufficient to restore the migratory defects in both normoxic and hypoxic conditions, suggesting that PFKFB4 promotes migration by inducing focal adhesion genes such as ITGB3 expression. Previously we have shown that PFKFB4 directly activates steroid receptor coactivator 3 (SRC-3, also known as NCOA3) so we analyzed promoter occupancy of SRC-3 on the proximal promoter of ITGB3. Our data revealed strong occupancy of SRC-3 on the ITGB3 promoter, which also contains a canonical hypoxia response element (HRE), suggesting that PFKFB4/SRC-3 signaling axis may stimulate HIF-1A transcriptional response. By further elucidating the roles of PFKFB4/SRC-3/HIF-1A axis in hypoxia in breast tumor mouse models, we will demonstrate how metabolic and transcriptional adaptations in the TME stimulates breast cancer progression and metastasis.

Citation Format: Tao Dai, Aaron Novickis, Eriko Katsuta, Kazuaki Takabe, Scott I. Abrams, Subhamoy Dasgupta. Metabolic and transcriptional adaptations under hypoxic stress promote breast cancer progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO022.
Abstract PO043: TERT expression increases with tumor grade in a cohort of IDH mutant gliomas
Authors: Caniglia John L. , Jalasutram Anvesh , Velpula Kiran K. , Guda Maheedhara R. , Bach Sarah E. , Tsung Andrew J.
Published: March 2021

Glioblastoma multiforme is the most deadly primary brain tumor, exhibiting a median survival of just 13 months despite aggressive treatments including surgery, radiation, and chemotherapy. There are two main subtypes of glioblastoma, denoted primary and secondary glioblastoma, respectively. While the former begins as a grade IV tumor, secondary glioblastomas evolve from a lineage that may include grade II astrocytomas and grade III anaplastic astrocytomas, a class of tumors which are molecularly defined by mutations in isocitrate dehydrogenase (IDH). The molecular mechanisms underlying progression of these tumors are poorly understood. Telomerase reverse transcriptase (TERT), a gene encoding for the catalytic subunit of telomerase, is upregulated in a plethora of cancers and represents a probable mechanism by which malignant cells delay senescence and evade cell death. TERT activity is the primary mechanism by which malignant cells replenish telomeres with the other being the alternative lengthening of telomeres (ALT) system, known to become active in tumors harboring loss of function mutations in ATRX. In data obtained from The Cancer Genome Atlas, significantly lower rates of survival were observed in low grade glioma patients with tumors highly expressing TERT as compared to tumors with low/medium expression. However, studies comparing the expression of TERT across different grades of glioma have not been performed to date. Using immunohistochemical staining we show that, controlling for ATRX and IDH mutational status, TERT expression increases as a function of tumor grade in a cohort of patient-derived astrocytoma, anaplastic astrocytoma, and secondary glioblastoma samples. These findings indicate that as astrocytomas progress to more aggressive tumors, TERT expression likely increases to provide enhanced genomic stability.

Citation Format: John L. Caniglia, Anvesh Jalasutram, Kiran K. Velpula, Maheedhara R. Guda, Sarah E. Bach, Andrew J. Tsung. TERT expression increases with tumor grade in a cohort of IDH mutant gliomas [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO043.
Abstract PR006: Infiltration of TRPV1+ nerves influences the ovarian cancer immune landscape
Authors: Reavis Hunter D. , Vermeer Daniel W. , Restaino Anthony C. , Kruse Allison , Knarr Matthew , Vermeer Paola D. , Drapkin Ronny
Published: March 2021

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecological malignancy, with poor survival rates attributable to both late diagnosis and resistance of tumors to standard-of-care chemotherapies. Recent therapeutic strategies aim to circumvent chemoresistance by targeting tumor-extrinsic factors that support the tumor microenvironment (TME). While TME-targeted therapies such as immunotherapy and anti-angiogenics have shown promise in other chemoresistant disease states, no substantial benefit has been observed in HGSC. We have recently observed that HGSC tumors are densely infiltrated by transient receptor potential vanilloid 1 (TRPV1+) sensory nerves that are otherwise absent in normal gynecological tissues. Tumor innervation has been shown to correlate with poor prognostic outcomes in other solid tumor types and thus warrants investigation in the context of HGSC. Our preliminary data using a syngeneic mouse model of HGSC shows that diphtheria toxin-mediated ablation of TRPV1+ nerves (Trpv1-DTA) attenuates HGSC tumor growth in vivo. Furthermore, preliminary immunohistochemical analysis of HGSC tumors from wild-type versus Trpv1-DTA mice has revealed differential infiltration of immune cell populations, indicating that tumor innervation may influence immunoreactivity within the TME. These results provide us with a basis for understanding how therapeutic targeting of tumor infiltrating nerve populations may sensitize HGSC tumors to immunotherapy.

Citation Format: Hunter D. Reavis, Daniel W. Vermeer, Anthony C. Restaino, Allison Kruse, Matthew Knarr, Paola D. Vermeer, Ronny Drapkin. Infiltration of TRPV1+ nerves influences the ovarian cancer immune landscape [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PR006.
Abstract PR-07: ORCESTRA: A platform for orchestrating and sharing high-throughput multimodal data analyses
Authors: Mammoliti Anthony , Smirnov Petr , Nakano Minoru , Safikhani Zhaleh , Nair Sisira , Mer Arvind Singh , Ho Chantal , Beri Gangesh , Haibe-Kains Benjamin
Published: March 2021

Reproducibility is essential to Open Science. If a finding cannot be reproduced by independent research groups its relevance is extremely limited, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, challenged, and built upon. However, due to recent technological advances in the biological and computational sciences, experimental protocols, data analysis and interpretation have become increasingly complex. This has made reproducing research findings more challenging, with some researchers going as far as suggesting that the biomedical sciences are experiencing a "reproducibility crisis". In order to overcome these issues we developed ORCESTRA, a cloud-based platform that provides a transparent, reproducible and flexible computational framework for processing and sharing high-throughput multimodal biomedical data. The platform enables processing of genomic and pharmacological profiles of cancer samples through the use of automated processing pipelines executed by Pachyderm, a data versioning and orchestration tool. ORCESTRA creates an integrated and fully documented data object known as a PharmacoSet (PSet) for future analyses using the Bioconductor PharmacoGx package. A PSet includes cell line and drug annotations, along with molecular and pharmacological data from the largest studies and consortia. Our platform is currently being expanded to additional data types, which includes toxicogenomics, xenographic pharmacogenomic data, radiomics, and clinical genomic data. The automated pipelines can be accessed via a web interface (www.orcestra.ca). Users can view and download existing dataset or request a new one by selecting pipeline parameters. The web application provides features to improve user experience, and to accommodate different scenarios for ORCESTRA deployment. They include a personal account to save PSets, a dashboard to check the status of a requested pipeline, email notification upon the pipeline completion, handling pipeline requests while the Pachyderm cluster is offline, and “manual push” of the pipeline requests once the cluster becomes online. Funding: This project is supported by CIHR, under the frame of ERA PerMed.

Citation Format: Anthony Mammoliti, Petr Smirnov, Minoru Nakano, Zhaleh Safikhani, Sisira Nair, Arvind Singh Mer, Chantal Ho, Gangesh Beri, Benjamin Haibe-Kains. ORCESTRA: A platform for orchestrating and sharing high-throughput multimodal data analyses [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-07.
The Case for Repealing the Second Amendment? The Historical Barriers to Constitutional Change
Authors: Konig David T.
Published: March 2021

The controversy surrounding the Second Amendment—“the right of the people to keep and bear arms”—is, to a large extent, historical in nature, redolent of other matters in this country’s legal and constitutional past. But the historical analogies that might support the Amendment’s repeal do not permit easy conclusions. The issue demands that legal historians venture beyond familiar territory to confront unavoidable problems at the intersection of theory and practice and of constitutional law and popular constitutionalism. An interdisciplinary analysis of Lichtman’s Repeal the Second Amendment illuminates the political, legal, and constitutional dimensions—as well as the perils—of undertaking the arduous amending process permitted by Article V of the U.S. Constitution.