bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
Authors: Wong Kwong-Kwok , Chang Yi-Mieng , Tsang Yvonne T.M. , Perlaky Laszlo , Su Jack , Adesina Adekunle , Armstrong Dawna L. , Bhattacharjee Meenakshi , Dauser Robert , Blaney Susan M. , Chintagumpala Murali , Lau Ching C.
Published: June 2022

Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs suggests that JPA without myelin basic protein–positively stained tumor cells may have a higher tendency to progress.
Protein Expression Profiling Identifies Subclasses of Breast Cancer and Predicts Prognosis
Authors: Jacquemier Jocelyne , Ginestier Christophe , Rougemont Jacques , Bardou Valérie-Jeanne , Charafe-Jauffret Emmanuelle , Geneix Jeannine , Adélaïde José , Koki Alane , Houvenaeghel Gilles , Hassoun Jacques , Maraninchi Dominique , Viens Patrice , Birnbaum Daniel , Bertucci François
Published: June 2022

Breast cancer is a heterogeneous disease whose evolution is difficult to predict by using classic histoclinical prognostic factors. Prognostic classification can benefit from molecular analyses such as large-scale expression profiling. Using immunohistochemistry on tissue microarrays, we have monitored the expression of 26 selected proteins in more than 1,600 cancer samples from 552 consecutive patients with early breast cancer. Both an unsupervised approach and a new supervised method were used to analyze these profiles. Hierarchical clustering identified relevant clusters of coexpressed proteins and clusters of tumors. We delineated protein clusters associated with the estrogen receptor and with proliferation. Tumor clusters correlated with several histoclinical features of samples, including 5-year metastasis-free survival (MFS), and with the recently proposed pathophysiologic taxonomy of disease. The supervised method identified a set of 21 proteins whose combined expression significantly correlated to MFS in a learning set of 368 patients (P < 0.0001) and in a validation set of 184 patients (P < 0.0001). Among the 552 patients, the 5-year MFS was 90% for patients classified in the “good-prognosis class” and 61% for those classified in the “poor-prognosis class” (P < 0.0001). This difference remained significant when the molecular grouping was applied according to lymph node or estrogen receptor status, as well as the type of adjuvant systemic therapy. In multivariate analysis, the 21-protein set was the strongest independent predictor of clinical outcome. These results show that protein expression profiling may be a clinically useful approach to assess breast cancer heterogeneity and prognosis in stage I, II, or III disease.
Comparative Genomic Hybridization Profiles in Human BRCA1 and BRCA2 Breast Tumors Highlight Differential Sets of Genomic Aberrations
Authors: van Beers Erik H. , van Welsem Tibor , Wessels Lodewyk F.A. , Li Yunlei , Oldenburg Rogier A. , Devilee Peter , Cornelisse Cees J. , Verhoef Senno , Hogervorst Frans B.L. , van't Veer Laura J. , Nederlof Petra M.
Published: June 2022

BRCA1 or BRCA2 germline mutations cause ∼30% of breast cancers within high-risk families. This represents 5% of total breast cancer incidence. Although BRCA1 and BRCA2 are both implicated in DNA repair and genome stability, it is unknown whether BRCA1 and BRCA2 are associated with similar or distinct diseases. In a previous study we reported that BRCA1-related breast carcinomas show a distinct genomic profile as determined by comparative genomic hybridization (CGH). We now hypothesize that, if functionally equivalent, mutations in BRCA1 and BRCA2 would result in similar genomic profiles in tumors. Here we report the chromosomal gains and losses as measured by CGH in 25 BRCA2-associated breast tumors and compared them with our existing 36 BRCA1 and 30 control profiles. We compared all chromosomal regions and determined the regions of differential gain or loss between tumor classes and controls. BRCA2 and control tumors have very similar genomic profiles. As a consequence, and in contrast to BRCA1-associated tumors, CGH profiles from BRCA2-associated tumors could not be distinguished from control tumors using the classification methodology as we have developed before. The largest number of significant differences existed between BRCA1 and controls, followed by BRCA1 compared with BRCA2, suggesting different tumor development pathways for BRCA1 and BRCA2.
Receptor for Hyaluronan-Mediated Motility Correlates with Centrosome Abnormalities in Multiple Myeloma and Maintains Mitotic Integrity
Authors: Maxwell Christopher A. , Keats Jonathan J. , Belch Andrew R. , Pilarski Linda M. , Reiman Tony
Published: June 2022

Elevated expression of receptor for hyaluronan-mediated motility (RHAMM) within ex vivo diagnostic multiple myeloma plasma cells predicts for aggressive disease and patient survival. Here, we investigate the relationship between RHAMM and centrosomal abnormalities within multiple myeloma patient samples. We report that myeloma patient samples contain pervasive structural and numerical centrosomal abnormalities. Structural, but not numerical, centrosomal abnormalities strongly correlate with elevated RHAMM expression. As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression. RHAMM overexpression in vitro resulted in centrosomal and mitotic defects. To elucidate a mechanism for RHAMM-mediated spindle defects, we further investigated RHAMM mitotic function. RHAMM mitotic localization mirrors that of targeting protein for Xklp2 (TPX2), and RHAMM interacts with the spindle assembly factors dynein and TPX2. Like TPX2, RHAMM expression is up-regulated during mitosis. Moreover, inhibition of function experiments reveals that RHAMM and TPX2 functions converge to maintain spindle integrity after spindle assembly. We postulate that augmentation of RHAMM expression within human cancers, including myeloma, can directly affect centrosomal structure and spindle integrity and potentially modulate apoptotic and cell cycle progression pathways.
Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis
Authors: Ma David W.L. , Finnell Richard H. , Davidson Laurie A. , Callaway Evelyn S. , Spiegelstein Ofer , Piedrahita Jorge A. , Salbaum J. Michael , Kappen Claudia , Weeks Brad R. , James Jill , Bozinov Daniel , Lupton Joanne R. , Chapkin Robert S.
Published: June 2022

Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1+/− and Folbp1−/−) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1+/−). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1+/− and Folbp1−/− mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1+/+ mice. Colonic cell proliferation was increased in RFC1+/− mice relative to RFC1+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1+/+ mice, RFC1+/− mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1+/− mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1+/+ mice. In contrast, Folbp1+/− mice developed 4-fold (P < 0.05) more lesions relative to Folbp1+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.
Antiangiogenic and Antitumor Activity of a Selective PDGFR Tyrosine Kinase Inhibitor, CP-673,451
Authors: Roberts W. Gregory , Whalen Pamela M. , Soderstrom Erik , Moraski Garrett , Lyssikatos Joseph P. , Wang Huifen-F. , Cooper Beth , Baker Deborah A. , Savage Douglas , Dalvie Deepak , Atherton James A. , Ralston Sherry , Szewc Ruby , Kath John C. , Lin Jing , Soderstrom Cathy , Tkalcevic George , Cohen Bruce D. , Pollack Vince , Barth Wayne , Hungerford Will , Ung Ethan
Published: June 2022

CP-673,451 is a potent inhibitor of platelet-derived growth factor β-receptor (PDGFR-β) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-β in cells (IC50 = 1 nmol/L) being more than 450-fold selective for PDGFR-β versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-β inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-β phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-β phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC50 of 120 ng/mL in plasma at Cmax. In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. × 5, p.o., corresponding to 5.5 ng/mL at Cmax). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. × 10 days dosing routinely inhibited tumor growth (ED50 ≤ 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-β phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
RLIP76 Transports Vinorelbine and Mediates Drug Resistance in Non–Small Cell Lung Cancer
Authors: Stuckler David , Singhal Jyotsana , Singhal Sharad S. , Yadav Sushma , Awasthi Yogesh C. , Awasthi Sanjay
Published: June 2022

Vinorelbine (Navelbine), an amphiphilic semisynthetic Vinca alkaloid, has displayed superior activity and decreased resistance in the treatment of advanced non–small cell lung cancer (NSCLC) compared with other members of its class. Recently, vinorelbine and cisplatin combination chemotherapy has been shown for the first time to confer a significant survival advantage in early-stage lung cancer after surgical therapy. The biological mechanisms underlying the differential response of NSCLC to cytocidal activity of vinorelbine have yet to be elucidated. Our recent findings indicate a role of RLIP76, a non–ATP binding cassette transport protein, in catalyzing the ATP-dependent efflux of structurally and functionally unrelated chemotherapeutic agents such as doxorubicin and vinblastine in NSCLC. Present studies were conducted to assess whether RLIP76 mediates vinorelbine transport and resistance. Here we show that RLIP76 catalyzes the transport of vinorelbine in a saturable manner with respect to vinorelbine (Km 75 nmol/L) and ATP (Km = 3.4 mmol/L). Three-fold overexpression of RLIP76 in NSCLC and SCLC confers increased resistance to cytotoxicity. RLIP76 overexpression causes a sustained intracellular decrease in vinorelbine concentration because of increased efflux, and anti-RLIP76 antibodies sensitize lung cancer cells to vinorelbine by inhibiting its efflux. These studies for the first time show that RLIP76 mediates vinorelbine transport and is capable of conferring drug accumulation defect and resistance to lung cancer cells.
Abstract 6285: MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer
Authors: Kaneko Yuki , Ohzawa HIdeyuki , Kimura Yuki , Tamura Kohei , Futoh Yurie , Takahashi Kazuya , Saito Akira , Tojo Mineyuki , Miyato Hideyo , Sata Naohiro , Kitayama Joji
Published: June 2022

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and an inherently chemoresistant tumor. Dense fibrotic stroma is a major obstacle for drug delivery to the tumor cells in PDAC. Pancreatic stellate cells (PSCs) are the major stromal cells responsible for fibrotic microenvironment. MicroRNA-217 (miR-217) is known mainly as a tumor suppressor. However, the detailed roles of miR-217 on pathophysiology of PDAC remain unclarified.

Methods: Expressions levels of miR-217 were measured in surgically resected human PDAC samples. Using Lipofectamine RNAiMAX, miR-217 or negative control miR (NC) were transfected in human pancreatic cancer cells, Panc-1, MIApaca-2, BxPC-3 and murine PAN02 cells, and chemosensitivities to gemcitabine and paclitaxel were investigated by MTS assay. Human hPSC-1 (obtained from Riken cell bank, Japan) was cultured in 20%FBS+DMEM and the changes of phenotypes and expression levels of miR-217 after the stimulation with TGF-β1 was measured by fluorescein microscope and digital PCR, respectively.

Results: The expression level of miR-217 was markedly downregulated in PDAC tissues than in noncancerous pancreatic tissues (P<0.001, n=9). Overexpression of miR-217 significantly inhibited the proliferation of Panc-1, MIApaca-2 and BxPC-3 (P<0.001) and migration of Panc-1, MIApaca-2 and PAN02 (P<0.05). Lipofection of miR-217 further reduced the number of PAN02 exposed to 1-5nM gemcitabine (P<0.0001) and 0.01-0.1uM paclitaxel (P=0.0085) which resulted in the reduced the IC-50 as compared with NC. Human PSC-1 stimulated with TGF-β1 (10ng/ml) significantly reduced miR-217 expression compared to nascent cells. The stimulation with TGF-β1 upregulated the expression of cancer associated fibroblast (CAF) markers, α-smooth muscle actin (SMA) and vimentin. However, the expression levels of these markers were significantly reduced by the kipofection of miR-217.

Conclusion: MiR-217 affects both cancer and stromal cells in PDAC which may regulate chemosensitivity in PDAC. Restoring miR-217 levels in tumor cells and/or PSCs could be a future therapeutic strategy.

Citation Format: Yuki Kaneko, HIdeyuki Ohzawa, Yuki Kimura, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Naohiro Sata, Joji Kitayama. MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6285.
Abstract ND11: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers
Authors: Purkey Hans
Published: June 2022

Mutations in KRAS are the most common oncogenic driver mutations in human cancers. The KRAS G12C mutation is one of the most prevalent KRAS mutations, present in approximately 12% of non-small cell lung cancer, 4% of colorectal cancer, and up to 4% of other cancer types. The recent discovery and development of covalent KRAS G12C inhibitors provides an opportunity to inhibit what has historically been considered to be an “undruggable” target. GDC-6036 is an orally bioavailable, highly potent and selective KRAS G12C inhibitor, with a median IC50 in the sub-nanomolar range and greater than 18,000-fold selectivity for G12C versus non-G12C cell lines. GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will highlight the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development.

Citation Format: Hans Purkey. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND11.
Abstract SY17-03: Reimagining druggability using chemoproteomic platforms
Authors: Nomura Daniel K.
Published: June 2022

The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel ligandable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Our second research area focuses on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to develop new induced proximity-based therapeutic modalities. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.

Citation Format: Daniel K. Nomura. Reimagining druggability using chemoproteomic platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY17-03.
Abstract SY23-02: Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance
Authors: Er Ekrem Emrah
Published: June 2022

Tumor evolution is coupled to profound biophysical changes in cancer cells and understanding how these changes impact metastasis can reveal novel therapeutic targets. One prominent biophysical characteristic of cancer cells is their stiffness. At the early steps of the metastatic cascade, transformed cells become physically softer and this allows them to invade into and to navigate through the surrounding extracellular matrix. Conversely, cancer cells that later intravasate into circulation need to maintain a higher degree of biophysical stiffness in order to withstand shear forces that otherwise cause mechanical rupture of cancer cells during hematogenous dissemination. However, the impact of cellular stiffness on the final stage of metastatic colonization in vital secondary organs is not well understood. We recently found that increasing stiffness of disseminated cancer cells sensitizes them to destruction by cytotoxic lymphocytes. Specifically, we found that myocardin related transcription factor (MRTFA/B) activity in cancer cells increases cancer cell stiffness, which then biophysically stimulates apoptotic cytokine production and cytolytic granule secretion in the adjoining CD8+ T- and Natural Killer (NK) cells for improved cytotoxicity. Our data highlighted the in vivo prevalence of the fundamental concepts in lymphocyte mechanobiology, which posit that increasing the stiffness of the surfaces that oppose T- and NK cells increases their cytolytic function through mechano-chemical signal transduction. We termed this mechanical mode of immune surveillance “mechanosurveillance” and showed that the expression of its molecular mediators cooperates with immune checkpoint blockade therapies in melanoma models and is associated with better patient survival in the clinic. In our current work, we utilized a series of novel biophysical approaches to measure the stiffness of metastatic foci in situ and to demonstrate that physically stiffer metastatic foci are eliminated by the immune surveillance. Furthermore, we used bioinformatics analyses of patient data and loss-of-function and gain-of-function experiments to identify therapeutically actionable proteins that increase cancer cell stiffness. Our findings revealed pharmacological manipulations that increase cancer cell stiffness and provided a road map for promoting mechanosurveillance in metastatic niches.

Citation Format: Ekrem Emrah Er. Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-02.
Abstract SY24-01: Changes in adaptive landscapes and somatic evolution as we age
Authors: DeGregori James V.
Published: June 2022

Why do we get cancer? Why is cancer highly associated with old age, and why are insults like smoking, obesity, and sunlight associated with increased risk of cancers? Of course, these contexts all cause mutations, and some of these mutations can contribute to malignant phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are microenvironmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, somatic evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We will discuss the evidence from many labs for microenvironmental change driven selection in the evolution of cancer, additional support from epidemiological and clinical studies, as well as the limitations, inconsistencies and unknowns that require the attention of cancer researchers. My own lab has been using mouse models of cancer initiation, mathematical models of clonal evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. Using Monte Carlo modeling, we have explored the impact of key somatic evolutionary parameters on multi-stage carcinogenesis, revealing that two additional major mechanisms, aging-dependent somatic selection and life history-dependent evolution of species-specific tumor suppressor mechanisms, need to be incorporated into the multi-stage model of carcinogenesis to make it capable of generalizing cancer incidence across tissues and species. Using mouse models, we have shown that aging and inflammation dependent changes in tissue microenvironments dramatically impact the fitness impact of oncogenic mutations, leading to aging and inflammation driven clonal expansions in the hematopoietic compartment. These studies have also uncovered molecular mechanisms underlying oncogene-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue microenvironments so as to change the evolutionary trajectories of oncogenically-mutated cells.

Citation Format: James V. DeGregori. Changes in adaptive landscapes and somatic evolution as we age [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-01.
Abstract SY24-04: And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease
Authors: Weeraratna Ashani T.
Published: June 2022

Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging. Our new data identify Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of soluble Wnt factors enabling efficient metastatic outgrowth. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung. Further these changes are also reflected in the response of tumor cells to therapy, linking dormancy to recurrent disease.

Citation Format: Ashani T. Weeraratna. And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-04.
Abstract SY30-01: Translational issues in lung cancer disparities: A vision for cancer equity
Authors: Hughes-Halbert Chanita
Published: June 2022

Lung cancer continues to be one of the leading causes of racial disparities in cancer morbidity and mortality among adults in the United States. Over the past 20 years, efforts to address disparities in lung cancer outcomes have focused on describing racial/ethnic differences in smoking behaviors and cessation outcomes. Other research has compared racial/ethnic groups in psychosocial and geographic risk factors for smoking and barriers to cessation; self-reported perceptions of stress and neighborhood deprivation have emerged as critical determinants of persistent tobacco use and predictors of relapse in disparity populations. Considerable investments have also been made to develop novel approaches for detecting lung cancer early and therapeutic strategies for treating this disease; lung cancer screening with LDCT now has a Grade B recommendation from the US Preventive Services Task Force and screening guidelines have been revised recently to be better aligned with the smoking behaviors and disease risk profiles among smokers from disparity populations. The demonstrated ability of LDCT to reduce lung cancer mortality is a significant clinical and public health advancement because it is the only evidence-based approach for detecting lung cancer at an early stage when treatment is most likely to be curative. However, several studies have demonstrated that patients from disparity populations have reduced uptake of cancer control strategies such as LDCT because of unmet social needs and risk factors; thus, revising lung cancer screening guidelines to be more inclusive may be necessary but not sufficient for improving access among disparity populations. The purpose of this presentation is to describe the goals and objectives for translational studies that are now being conducted to enhance equity in lung cancer outcomes among disparity populations and to identify priorities for future research in lung cancer equity.

Citation Format: Chanita Hughes-Halbert. Translational issues in lung cancer disparities: A vision for cancer equity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY30-01.
Abstract SY43-02: Adapting clinical radiation therapy to immune checkpoint blockade
Authors: Formenti Silvia C.
Published: June 2022

Focal radiation therapy has demonstrated to elicit inflammatory and immune responses that contribute to cancer immunosurveillance, but may also have unwanted systemic effects. The application of ionizing radiation to cancer, which is the basis for the field of radiation oncology, has evolved to define and exploit the therapeutic window between radiation cytocidal effects in tumors versus those in normal tissue. The original standardization of specific dose-fractionation regimens reflected the results of decades of empirical experience to find the best balance between local control of the irradiated cancer and the mitigation of risk for acute and late sequelae in the exposed normal tissues. More than a century of research in radiation biology has elucidated how radiation damage recruits a classical inflammation response, activates pathways to repair tissues through scavenging of cellular debris and canonical wound repair mechanisms that aim at recovering tissue integrity. Intrinsic to this process is a robust dampening of immunogenic signals, common to those associated with wound repair, to prevent triggering of auto-immune rejections of inflamed tissues. At the same time, radiation has proimmunogenic effects, that recruit both the innate arm of the immune system (acute induction of IFN pathways) and the adaptive arm, through radiation-induced neoepitopes and enhanced cross presentation. Strategies to uncouple these opposite effects are the focus of research efforts in multiple radiation biology laboratories, worldwide. The emergence of modern cancer immunotherapy offers the opportunity to further dissect such strategies. Recent evidence suggest a new role for focal radiotherapy, to partnering and synergize with immune checkpoint blockade (ICB). Evidence is emerging both preclinically and in the clinical setting that optimal integration of radiotherapy with the available immune modifiers might require changes in standard radiation oncology practices. Variables like the type of treatment fields, the inclusion of draining nodal stations, the degree of exposure of circulating immune cells, the type of dose-fractionation and the timing of radiotherapy during ICB all can affect the success of immunoradiotherapy combinations. Hence, defining the parameters for adapting classic radiation therapy to best integrate with ICB remains a fundamental area of investigation, as it is integral to a successful partnership with immunotherapy.

Citation Format: Silvia C. Formenti. Adapting clinical radiation therapy to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY43-02.
Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition
Authors: Alvarez-Breckenridge Christopher , Markson Samuel C. , Stocking Jackson H. , Nayyar Naema , Lastrapes Matt , Strickland Matthew R. , Kim Albert E. , de Sauvage Magali , Dahal Ashish , Larson Juliana M. , Mora Joana L. , Navia Andrew W. , Klein Robert H. , Kuter Benjamin M. , Gill Corey M. , Bertalan Mia , Shaw Brian , Kaplan Alexander , Subramanian Megha , Jain Aarushi , Kumar Swaminathan , Danish Husain , White Michael , Shahid Osmaan , Pauken Kristen E. , Miller Brian C. , Frederick Dennie T. , Hebert Christine , Shaw McKenzie , Martinez-Lage Maria , Frosch Matthew , Wang Nancy , Gerstner Elizabeth , Nahed Brian V. , Curry William T. , Carter Bob , Cahill Daniel P. , Boland Genevieve Marie , Izar Benjamin , Davies Michael A. , Sharpe Arlene H. , Suvà Mario L. , Sullivan Ryan J. , Brastianos Priscilla K. , Carter Scott L.
Published: June 2022

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
Identification of Drug–Cancer Associations: A Nationwide Screening Study
Authors: Kristensen Kasper Bruun , Friis Søren , Lund Lars Christian , Hallas Jesper , Cardwell Chris R. , Andreassen Bettina K. , Habel Laurel A. , Pottegård Anton
Published: June 2022

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case–control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug–cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug–cancer pairs where an association with high use and a cumulative dose–response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies.

Significance:

This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.
Breast Adjuvant Radiotherapy Amid the COVID-19 Crisis in a Hub Cancer Center, Lombardy, Italy
Authors: Leonardi Maria Cristina , Montagna Emilia , Galimberti Viviana Enrica , Zaffaroni Mattia , Rojas Damaris Patricia , Dicuonzo Samantha , Zerella Maria Alessia , Morra Anna , Sangalli Claudia , Gandini Sara , Colleoni Marco , Veronesi Paolo , Gerardi Marianna Alessandra , Alterio Daniela , Lazzari Roberta , Sarra Fiore Massimo , Bufi Giammaria , Cattani Federica , Mastrilli Fabrizio , Orecchia Roberto , Jereczek-Fossa Barbara Alicja
Published: June 2022

Introduction: During the COVID-19 pandemic, Lombardy (Northern Italy) Regional Health Council created hubs for cancer care, meant to be SARS-CoV-2-free pathways for cancer patients. The workflow of breast cancer (BC) radiotherapy (RT) in one of the hubs is presented here. Methods: Candidates to adjuvant RT during the pandemic peak of March-April 2020 were compared to those treated in the same period of 2019, and patient volume, deferral rate, and type of RT were analyzed. Statistics were calculated with χ2 or Fisher exact tests for categorical variables, and the Wilcoxon rank test for continuous variables. Results: In March-April 2020 the BC patient volume increased by 28% compared to the same period in 2019 (scheduled patients: 175 vs. 137) and amid travel restrictions it was kept high (treated patients: 136 vs. 133), mainly due to an influx from across Lombardy. RT schemes basically did not change, being already centered on hypofractionation. The increase of median time (67 vs. 74.5 days in 2019 and 2020, respectively) to the commencement of RT for low-risk patients was clinically negligible yet statistically significant (p = 0.03), and in line with the pertinent recommendations. No significant difference was found in the time interval between treatments and RT for high-risk patients. Concomitant chemoradiotherapy was avoided throughout the pandemic peak. Twenty-one women (13.6%) delayed either computed tomography simulation or RT commencement mainly because of COVID-19-related concerns and mobility restrictions. Conclusion: The workload for BC was high during the pandemic peak. Hubs allowed the continuation of oncologic treatments, while mitigating the strain on frontline COVID-19 hospitals.
Experiences of Renal Replacement Therapy Delivery in Swedish Intensive Care Units during the COVID-19 Pandemic
Authors: Hertzberg Daniel , Renberg Mårten , Nyman Jesper , Bell Max , Rimes Stigare Claire
Published: June 2022

Background: The COVID-19 pandemic led to a rapidly increased demand for intensive care unit (ICU) and renal replacement therapy (RRT) worldwide. RRT delivery was threatened by a lack of specially trained staff and equipment. We investigated how the first wave of COVID-19 affected RRT delivery in Swedish ICUs. Methods: An Internet-based questionnaire was sent to ICU lead physicians which included quantitative and qualitative questions regarding RRT demand, equipment availability, and use of continuous renal replacement therapy (CRRT), intermittent haemodialysis (IHD), and peritoneal dialysis (PD) during spring 2020. Results: Twenty-five ICUs responded and these treated 64% of COVID-19 ICU patients in Sweden. ICU capacity increased by 292% (IQR 171–347%). Median peak capacity was reached during the 18th week of the year. RRT use increased overall by 133% and in Stockholm by 188%. 36% of units sequestered CRRT machines. IHD was used in 68% and PD in 12% of ICUs. RRT fluid and filter shortages were experienced by 45% and 33% of wards, respectively; consequently, prescription alterations were made by 24% of ICUs. Calcium solution shortages were reported in 12% of units that led to citrate protocol changes. Staffing shortages resulted in RRT sometimes being delivered by non-RRT-trained staff, safety incidents relating to this occurred, although no patient harm was reported. Conclusion: During the first wave of the COVID-19 pandemic, RRT demand increased extensively causing staff and equipment shortages, altered CRRT protocols, and increased use of IHD and PD. The impact on patient outcomes should be assessed to effectively plan for further surge capacity RRT demand.
Massive Colostomy Prolapse with an Intrastomal Ileal Hernia: A Case Report
Authors: Zuiki Toru , Ohki Jun , Miyahara Go , Lefor Alan Kawarai
Published: June 2022

A 79-year-old man underwent sigmoid colostomy about 50 years previously and sought surgical reconstruction of the colostomy. He presented with 30 cm of prolapsed stoma accompanying an intrastomal hernia which contained ileum. The prolapsed stoma which led to the intrastomal hernia was made from the distal sigmoid colon, and the everted colon wall constituted the hernia sac. A computed tomography scan was useful to demonstrate the contents of the intrastomal hernia. Reconstruction with relocation of the colostomy was considered appropriate for the presented patient. The thickened and stretched distal sigmoid colon was resected with the stoma. A new end colostomy using the descending colon was seated in the left upper quadrant. The lateral pararectus muscles which formed the 8-cm hernia orifice were closed using tension-reducing incisions. The postoperative course was uneventful.
Timing and Identification of the Cause and Treatment of a Cardiac Arrest: A Potential Survival Benefit
Authors: Dewolf Philippe , Wauters Lina , Clarebout Geraldine , Elen Jan
Published: June 2022

Objective: The aim of this study was to evaluate how mobile medical teams (MMTs) search for the etiology of a cardiac arrest (CA) and to investigate the association between the discovery of etiology and patient outcome. Subjects and Methods: Resuscitations of all adult patients who experienced an in- or out-of-hospital CA between 2016 and 2018 were video recorded. All video recordings were reviewed. The time to start of “cause analysis” and time to treatment by the MMT were analyzed. Also, investigations performed during etiologic evaluation were examined: heteroanamnesis, medical history-taking, clinical examinations, technical investigations, and the use of the 4Hs and 4Ts method. Results: Of the 139 CA events included in this study, the MMTs performed etiologic evaluation in only 75% of the resuscitations, and in 20% of the evaluations, they did not use the recommended 4Hs and 4Ts method. Medical history-taking and heteroanamnesis were performed in the large majority, but often without clear cause. A presumptive etiology was found in 46.8% of out-of-hospital CAs and 65.2% of in-hospital CAs. A significant association was found between return of spontaneous circulation and the discovery of presumable etiology for out-of-hospital CAs (p < 0.001). The median time to treatment was 492 s (recommended: 130–250 s) for nonshockable rhythms and 422 s (recommended: 270–390 s) for shockable rhythms, up to twice the time advised according to the guidelines. Conclusion: The current approach for etiologic evaluation is not ideal. Further research is needed to establish a more structured and simplified approach.
A Psicologia Brasileira e as Políticas LGBT no Conselho Federal de Psicologia
Authors: Aragusuku Henrique Araujo , Lee Henrique de Oliveira
Published: June 2022

A psicologia – ao longo do século XX, no Brasil e no mundo – deixou de ser apenas um saber/fazer legitimador da heteronormatividade e da cisgeneridade, para se constituir enquanto uma possibilidade de resistência e transformação da tradição sexual. Nos últimos quinze anos, tivemos transformações significativas na sociedade brasileira com o avanço dos movimentos LGBT. Essas transformações se deram em toda a vida sociocultural e política, nos mais diversos âmbitos: nas políticas e ações governamentais, nas agendas parlamentares, no mercado, na mídia, nas práticas profissionais, nas produções acadêmico-científicas, nos movimentos sociais, nos partidos políticos. A psicologia brasileira e sua autarquia profissional, o Conselho Federal de Psicologia, não estiveram ausentes de todo esse processo, passando também por intensos debates e mudanças políticas. O objetivo desse artigo é apresentar uma reflexão sobre esse processo, dando ênfase às transformações da psicologia no trato com as questões LGBT e, de forma mais específica, às políticas e ações do Conselho Federal de Psicologia (CFP). As reflexões, presentes nesse artigo, trazem elementos para pensarmos na atual conjuntura nacional, junto à historicidade das políticas que se articulam dentro da principal entidade de psicologia do país.
A Importância de Políticas Públicas no Contexto das Mudanças Climáticas Globais: o caso do setor de transporte rodoviário de passageiros no Brasil
Authors: Galbieri Rodrigo , Simões André Felipe , Mouette Dominique , Dos Santos Edmilson Moutinho
Published: June 2022

O crescimento projetado da frota brasileira de veículos é elevado, e, consequentemente, o consumo de combustíveis e das emissões de CO2 tende a se intensificar, agravando a contribuição do referido setor no aquecimento global. Esse Estudo objetiva analisar a importância de políticas públicas e os instrumentos de comando e controle de países selecionados comparando-os com a realidade brasileira, a fim de auxiliar na proposição de políticas públicas no que tange a mitigação do consumo de combustíveis e das emissões de gases de efeito estufa do setor de transportes rodoviário de passageiros no Brasil.
Responsividade Democrática no Brasil de Lula e na Argentina dos KIRCHNER
Authors: Oliveira Dias Olivia Fernanda Rocha de , Costa Gleidilson
Published: June 2022

A obra apresenta um estudo de caso dos sistemas políticos do Brasil e da Argentina, no período de 2003 a 2009, realizando um exame da responsividade democrática de maneira prática, efetivando uma análise comparativa entre as agendas dos diferentes públicos dos dois países.
Apontamentos para a Continuação do Debate Discutindo “Observações ao Texto A Guerra Civil Na França: Marx antiestatista? de Felipe Corrêa”
Authors: Corrêa Felipe
Published: June 2022

Este artigo responde “Observações ao Texto ‘A Guerra Civil na França: Marx antiestatista?’ de Felipe Corrêa” e traz novas contribuições ao debate relativas ao contexto da produção de A Guerra Civil na França e da práxis de Karl Marx depois da Comuna de Paris.