bluuebunny/crossref_metadata_2025 huggingface dataset:
A Naturally Occurring Soluble Form of Vascular Endothelial Growth Factor Receptor 2 Detected in Mouse and Human Plasma
Authors: Ebos John M.L. , Bocci Guido , Man Shan , Thorpe Philip E. , Hicklin Daniel J. , Zhou Danielle , Jia Xiaohong , Kerbel Robert S.
Published: May 2022

Angiogenesis and vasculogenesis are regulated in large part by several different growth factors and their associated receptor tyrosine kinases (RTKs). Foremost among these is the vascular endothelial growth factor (VEGF) family including VEGF receptor (VEGFR)-2 and -1. VEGFR ligand binding and biological activity are regulated at many levels, one of which is by a soluble, circulating form of VEGFR-1 (sVEGFR-1). This sVEGFR-1 can act as a competitive inhibitor of its ligand, serve as a possible biomarker, and play important roles in cancer and other diseases such as preeclampsia. Recombinant forms of sVEGFR-2 have been shown to have antiangiogenic activity, but a naturally occurring sVEGFR-2 has not been described previously. Here, we report such an entity. Having a molecular weight of ∼160 kDa, sVEGFR-2 can be detected in mouse and human plasma with several different monoclonal and polyclonal anti-VEGFR-2 antibodies using both ELISA and immunoprecipitation techniques. In vitro studies have determined that the sVEGFR-2 fragment can be found in the conditioned media of mouse and human endothelial cells, thus suggesting that it may be secreted, similar to sVEGFR-1, or proteolytically cleaved from the cell. Potential biological activity of this protein was inferred from experiments in which mouse sVEGFR-2 could bind to VEGF-coated plates. Similar to sVEGFR-1 and other soluble circulating RTKs, sVEGFR-2 may have regulatory consequences with respect to VEGF-mediated angiogenesis as well as potential to serve as a quantitative biomarker of angiogenesis and antiangiogenic drug activity, particularly for drugs that target VEGF or VEGFR-2.
AND-34 Activates Phosphatidylinositol 3-Kinase and Induces Anti-Estrogen Resistance in a SH2 and GDP Exchange Factor–Like Domain-Dependent Manner
Authors: Felekkis Kyriacos N. , Narsimhan Radha P. , Near Richard , Castro Ariel F. , Zheng Yi , Quilliam Lawrence A. , Lerner Adam
Published: May 2022

AND-34, a 95-kDa protein with modest homology to Ras GDP exchange factors, associates with the focal adhesion protein p130Cas. Overexpression of AND-34 confers anti-estrogen resistance in breast cancer cell lines, a property linked to its ability to activate Rac. Here, we show that both the GDP exchange factor–like domain and the SH2 domain of AND-34 are required for Rac activation and for resistance to the estrogen receptor (ER) antagonist ICI 182,780. As phosphatidylinositol 3-kinase (PI3K) signaling can regulate Rac activation, we examined the effects of AND-34 on PI3K. Overexpression of AND-34 in MCF-7 cells increased PI3K activity and augmented Akt Ser473 phosphorylation and kinase activity. Inhibition of PI3K with LY294002 or a dominant-negative p85 construct blocked AND-34-mediated Rac and Akt activation. Although R-Ras can activate PI3K, transfection with constitutively active R-Ras failed to induce Rac activation and AND-34 overexpression failed to induce R-Ras activation. Treatment of either vector-only or AND-34-transfected ZR-75-1 cells with ICI 182,780 markedly diminished ERα levels, suggesting that AND-34-induced anti-estrogen resistance is likely to occur by an ERα-independent mechanism. Treatment of a ZR-75-1 breast cancer cell line stably transfected with AND-34 plus 2 μmol/L LY294002 or 10 μmol/L NSC23766, a Rac-specific inhibitor, abrogated AND-34-induced resistance to ICI 182,780. Our studies suggest that AND-34-mediated PI3K activation induces Rac activation and anti-estrogen resistance in human breast cancer cell lines.
Inhibition of IκBα Nuclear Export as an Approach to Abrogate Nuclear Factor-κB–Dependent Cancer Cell Survival
Authors: O'Connor Shelby , Shumway Stuart , Miyamoto Shigeki
Published: May 2022

Deregulation of the transcription factor nuclear factor-κB (NF-κB) leading to its constitutive activation is frequently observed in human cancer. Because altered NF-κB activities often promote the survival of malignant cells, its inhibition is regarded as a promising anticancer strategy. Because activation of the latent cytoplasmic NF-κB complex can be induced by a wide variety of different stimuli, its deregulation may occur by an equally large number of distinct mechanisms. This diversity raises a conundrum in conceptualizing general approaches to attenuate NF-κB activity in cancer. Here, we provide evidence that inhibition of IκBα nuclear export is a viable target to generally abrogate constitutive NF-κB activity in different cancer cell types. We show that inhibition of IκBα nuclear export has an important course of events in cancer cells harboring constitutive NF-κB activity—an initial increase in the pool of stable nuclear NF-κB/IκBα complexes that leads to a reduction of constitutive NF-κB activity and subsequent induction of apoptosis. Importantly, similar effects on multiple different cancer cell types indicate that inhibition of nuclear export of IκBα leads to broad inhibition of constitutive NF-κB activation regardless of various deregulated, upstream events involved.
Somatic Mitochondrial DNA Mutations in Neurofibromatosis Type 1-Associated Tumors
Authors: Kurtz Andreas , Lueth Maria , Kluwe Lan , Zhang Tingguo , Foster Rosemary , Mautner Victor-Felix , Hartmann Melanie , Tan Duan-Jun , Martuza Robert L. , Friedrich Reinhard E. , Driever Pablo Hernáiz , Wong Lee-Jun C.
Published: May 2022

Neurofibromatosis type 1 is an autosomal dominantly inherited disease predisposing to a multitude of tumors, most characteristically benign plexiform neurofibromas and diffuse cutaneous neurofibromas. We investigated the presence and distribution of somatic mitochondrial DNA (mtDNA) mutations in neurofibromas and in nontumor tissue of neurofibromatosis type 1 patients. MtDNA alterations in the entire mitochondrial genome were analyzed by temporal temperature gradient gel electrophoresis followed by DNA sequencing. Somatic mtDNA mutations in tumors were found in 7 of 19 individuals with cutaneous neurofibromas and in 9 of 18 patients with plexiform neurofibromas. A total of 34 somatic mtDNA mutations were found. All mutations were located in the displacement loop region of the mitochondrial genome. Several plexiform neurofibromas from individual patients had multiple homoplasmic mtDNA mutations. In cutaneous neurofibromas, the same mtDNA mutations were always present in tumors from different locations of the same individual. An increase in the proportion of the mutant mtDNA was always found in the neurofibromas when compared with nontumor tissues. The somatic mtDNA mutations were present in the Schwann cells of the analyzed multiple cutaneous neurofibromas of the same individual. The observed dominance of a single mtDNA mutation in multiple cutaneous neurofibromas of individual patients indicates a common tumor cell ancestry and suggests a replicative advantage rather than random segregation for cells carrying these mutated mitochondria.
Molecular Characterization of the Transition to Malignancy in a Genetically Engineered Mouse-Based Model of Ductal Carcinoma In situ
Authors: Namba Ruria , Maglione Jeannie E. , Young Lawrence J.T. , Borowsky Alexander D. , Cardiff Robert D. , MacLeod Carol L. , Gregg Jeffrey P.
Published: May 2022

A transplantable model of human ductal carcinoma in situ that progresses to invasive carcinoma was developed from a genetically engineered mouse (GEM). Additional lines were established using early mammary premalignant lesions from transgenic MMTV-PyV-mT mice. These lines were verified to be premalignant and transplanted repeatedly to establish stable and predictable properties. Here, we report the first in-depth molecular analysis of neoplastic progression occurring in one premalignant transplantable GEM-derived line. Oligonucleotide microarrays showed that many genes are differentially expressed between the quiescent and prelactating mammary gland and the premalignant GEM outgrowth. In contrast, a small but consistent group of genes was associated with the transformation from premalignancy to tumor. This suggests that the majority of gene expression changes occur during the premalignant transition from normal to premalignancy, whereas many fewer changes occur during the malignant transition from premalignancy to invasive carcinoma. The premalignant transition is associated with several cell cycle–related genes and the up-regulation of oncogenes is associated with various cancers (Ccnd11, Cdk4, Myb, and Ect2). The changes identified in the malignant transition included genes previously associated with human breast cancer progression. Misregulation of the insulin-like growth factor and transforming growth factor-β signaling pathways and the stromal-epithelial interaction were implicated. Our results suggest that this transplantable GEM-based model recapitulates human ductal carcinoma in situ at both histologic and molecular levels. With consistent tumor latency and molecular profiles, this model provides an experimental platform that can be used to assess functional genomics and molecular pharmacology and to test promising chemoprevention strategies.
Mad 1 Inhibits Cell Growth and Proliferation but Does Not Promote Differentiation or Overall Survival in Human U-937 Monoblasts
Authors: Hultquist Anne , Cetinkaya Cihan , Wu Siqin , Castell Alina , Erlandsson Anna , Larsson Lars-Gunnar
Published: May 2022

The Mad family proteins are transcriptional repressors belonging to the basic region/helix-loop-helix/leucine zipper family. They share a common obligatory dimerization partner, Max, with the oncoprotein c-Myc and antagonize the function of Myc to activate transcription. The Myc/Max/Mad network has therefore been suggested to function as a molecular switch that regulates cell growth and differentiation by controlling a common set of genes. To study the biological consequences of Mad1 expression for hematopoietic cell growth and differentiation, we used the U-937 monocytic differentiation model to generate cells with inducible Mad1 expression using the reversed tetracycline-controlled transactivator system. The elevated expression of Mad1 in these cells resulted in increased Mad1/Max heterodimer formation correlating with reduced expression of the Myc/Mad target gene ODC. Mad1-expressing U-937 cells in suspension culture proliferated slower and exhibited an increased number of cells in the G1 phase of the cell cycle. Further, growth in semisolid medium was almost completely inhibited. Mad1-expression, however, neither enforced spontaneous differentiation nor enhanced differentiation induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, retinoic acid (RA), or vitamin D3 but rather led to delayed RA-stimulated differentiation. Mad1-expressing cells were further found to be reduced in cell size in all phases of the cells cycle and particularly in response to RA-induced differentiation. Unexpectedly, whereas Fas-induced apoptosis was slightly attenuated in Mad1-expressing U-937 cells, Mad1 sensitized the cells to tumor necrosis factor–α-induced apoptosis. These results suggest that Mad1 primarily regulates cell growth and proliferation in these cells, whereas its role in cellular differentiation and survival seems to be more complex.
Topoisomerase I and II Inhibitors Control Caspase-2 Pre-Messenger RNA Splicing in Human Cells
Authors: Solier Stéphanie , Lansiaux Amélie , Logette Emmanuelle , Wu Jane , Soret Johann , Tazi Jamal , Bailly Christian , Desoche Lydie , Solary Eric , Corcos Laurent
Published: May 2022

We have recently shown that the topoisomerase II inhibitor, etoposide (VP16), could trigger caspase-2 pre-mRNA splicing in human leukemic cell lines. This leads to increased inclusion of exon 9, which is specifically inserted into the short caspase-2S isoform mRNA and absent from the long caspase-2L isoform mRNA. One of the consequences of this alternative splicing is a decrease in the total amount of the mature form of caspase-2L mRNA and protein. In this study, we analyzed the effects of several representative molecules of various classes of cytotoxic agents on caspase-2 pre-mRNA splicing in both U937 leukemic cells and in HeLa cervix carcinoma cells. Very strikingly, both topoisomerase I (camptothecin and homocamptothecin derivatives) and II (VP16, amsacrine, doxorubicin, mitoxantrone) inhibitors induced exon 9 inclusion. DNA intercalating glycosyl indolocarbazole derivatives as well as DNA alkylating agents, such as cisplatin and melphalan, antimetabolites like 5-fluorouracil, and mitotic spindle poisons like vinblastine had no effect. Therefore, both classes of DNA topoisomerases can control pre-mRNA splicing of the caspase-2 transcript. In addition, the splicing reaction brought about by camptothecin was hampered in human CEM/C2 and in murine P388-45R leukemic deficient in topoisomerase I activity. Conversely, VP16 did not trigger caspase-2 alternative splicing in human HL60/MX2 leukemic cells harboring a mutant topoisomerase II. Minigene transfection analysis revealed that topoisomerase inhibitors did not change the splicing profile when cis-acting elements in intron-9, reported to control exon 9 inclusion independently of drug treatment, were removed. Rather, our experiments suggest that exon 9 inclusion induced by topoisomerase inhibitors reflects the activity exerted by topoisomerase I or II on proteins that control splicing reactions, or their direct involvement in pre-mRNA splicing.
In vivo Recombination After Chronic Damage Exposure Falls to Below Spontaneous Levels in “Recombomice”
Authors: Kovalchuk Olga , Hendricks Carrie A. , Cassie Scott , Engelward Andrew J. , Engelward Bevin P.
Published: May 2022

All forms of cancer are initiated by heritable changes in gene expression. Although point mutations have been studied extensively, much less is known about homologous recombination events, despite its role in causing sequence rearrangements that contribute to tumorigenesis. Although transgenic mice that permit detection of point mutations have provided a fundamental tool for studying point mutations in vivo, until recently, transgenic mice designed specifically to detect homologous recombination events in somatic tissues in vivo did not exist. We therefore created fluorescent yellow direct repeat mice, enabling automated detection of recombinant cells in vivo for the first time. Here, we show that an acute dose of ionizing radiation induces recombination in fluorescent yellow direct repeat mice, providing some of the first direct evidence that ionizing radiation induces homologous recombination in cutaneous tissues in vivo. In contrast, the same total dose of radiation given under chronic exposure conditions suppresses recombination to levels that are significantly below those of unexposed animals. In addition, global methylation is suppressed and key DNA repair proteins are induced in tissues from chronically irradiated animals (specifically AP endonuclease, polymerase β, and Ku70). Thus, increased clearance of recombinogenic lesions may contribute to suppression of homologous recombination. Taken together, these studies show that fluorescent yellow direct repeat mice provide a rapid and powerful assay for studying the recombinogenic effects of both short-term and long-term exposure to DNA damage in vivo and reveal for the first time that exposure to ionizing radiation can have opposite effects on genomic stability depending on the duration of exposure.
Role of the DNA Methyltransferase Variant DNMT3b3 in DNA Methylation
Authors: Weisenberger Daniel J. , Velicescu Mihaela , Cheng Jonathan C. , Gonzales Felicidad A. , Liang Gangning , Jones Peter A.
Published: May 2022

Several alternatively spliced variants of DNA methyltransferase (DNMT) 3b have been described. Here, we identified new murine Dnmt3b mRNA isoforms and found that mouse embryonic stem (ES) cells expressed only Dnmt3b transcripts that contained exons 10 and 11, whereas the Dnmt3b transcripts in somatic cells lacked these exons, suggesting that this region is important for embryonic development. DNMT3b2 and 3b3 were the major isoforms expressed in human cell lines and the mRNA levels of these isoforms closely correlated with their protein levels. Although DNMT3b3 may be catalytically inactive, it still may be biologically important because D4Z4 and satellites 2 and 3 repeat sequences, all known DNMT3b target sequences, were methylated in cells that predominantly expressed DNMT3b3. Treatment of cells with the mechanism-based inhibitor 5-aza-2′-deoxycytidine (5-Aza-CdR) caused a complete depletion of DNMT1, 3a, 3b1, and 3b2 proteins. Human DNMT3b3 and the murine Dnmt3b3-like isoform, Dnmt3b6, were also depleted although less efficiently, suggesting that DNMT3b3 also may be capable of DNA binding. Moreover, de novo methylation of D4Z4 in T24 cancer cells after 5-Aza-CdR treatment only occurred when DNMT3b3 was expressed, reinforcing its role as a contributing factor of DNA methylation. The expression of either DNMT3b2 or 3b3, however, was not sufficient to explain the abnormal methylation of DNMT3b target sequences in human cancers, which may therefore be dependent on factors that affect DNMT3b targeting. Methylation analyses of immunodeficiency, chromosomal instabilities, and facial abnormalities cells revealed that an Alu repeat sequence was highly methylated, suggesting that Alu sequences are not DNMT3b targets.
Bcl-2 Overexpression Leads to Increases in Suppressor of Cytokine Signaling-3 Expression in B Cells and De novo Follicular Lymphoma
Authors: Vanasse Gary J. , Winn Robert K. , Rodov Sofya , Zieske Arthur W. , Li John T. , Tupper Joan C. , Tang Jingjing , Raines Elaine W. , Peters Mette A. , Yeung Ka Yee , Harlan John M.
Published: May 2022

The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Eμ-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by ≥2-fold in Eμ-Bcl-2 transgenic mice (P < 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Eμ-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.
Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer
Authors: Basu Gargi D. , Pathangey Latha B. , Tinder Teresa L. , LaGioia Michelle , Gendler Sandra J. , Mukherjee Pinku
Published: May 2022

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.
Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma
Authors: Jackson Zachary , Hong Changjin , Schauner Robert , Dropulic Boro , Caimi Paolo F. , de Lima Marcos , Giraudo Maria Florencia , Gupta Kalpana , Reese Jane S. , Hwang Tae Hyun , Wald David N.
Published: May 2022

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL.

Significance:

This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone.

This article is highlighted in the In This Issue feature, p. 1825
Myofibroblasts, B Cells, and Mast Cells in Different Types of Long-Standing Acne Scars
Authors: Chancheewa Bussabong , Asawanonda Pravit , Noppakun Nopadon , Kumtornrut Chanat
Published: May 2022

Acne scars are classified into various types based on their appearances, ranging from hypertrophic to atrophic. Abnormal wound healing processes play an important role in the pathogenesis of scars; however, the exact mechanisms involved in various scar appearances have still not been elucidated. In this study, we used immunofluorescence and immunohistochemistry techniques to detect the presence of myofibroblasts, B cells, and mast cells in each type of acne scar persisting longer than 6 months. We found the highest density of myofibroblasts in hypertrophic acne scars, while in the other atrophic scars, we could not identify any myofibroblast-rich areas in our specimens. B-cell infiltration was mild and found in only 23% (4/17) of all acne scar specimens. Interestingly, mast cells were identified in all specimens, ranging from minimal to high density, and a high number of mast cells in acne scars were associated with obesity. In conclusion, myofibroblasts are abundant only in hypertrophic acne scars, and mast cells, but not B cells, might play an important role in the pathogenesis of long-standing acne scars.
Exploring Standardized Scales and Serum Biomarkers to Evaluate Changes in Pruritus due to Eczema after Japanese Kampo Treatment: A Prospective Case Series
Authors: Yoshino Tetsuhiro , Horiba Yuko , Mimura Masaru , Watanabe Kenji
Published: May 2022

Background: We aimed to explore standardized scales and serum biomarkers for tracking changes in the symptoms and severity of pruritus due to eczema in patients treated with Kampo formulas. Patients and Methods: This prospective, single-arm, pre-post comparison case series recruited patients with pruritus mostly due to eczema who consulted the Kampo Clinic at the Keio University Hospital from June 2019 to March 2020. The participants were prescribed a personalized Kampo formula for 12 weeks. Patient profiles and symptoms were assessed every 4 weeks using the visual analog scale (VAS), patient-oriented eczema measure (POEM) scale, 5-D itch scale (5D), Skindex-16, and eczema area and severity index (EASI). Blood biomarkers and intestinal permeability indicators were measured at the first consultation and 12 weeks later. Results: Pruritus and eczema severity improved significantly over time. The VAS, POEM, 5D, and Skindex-16 scores were well-correlated. The serum interleukin-31 levels decreased significantly after a 12-week intervention. Changes in the interleukin-31 level correlated with the diamine oxidase level at week 0, suggesting the involvement of the Th2 immune system and intestinal permeability in the mechanism of Kampo formulas. Conclusion: The evaluated scales are suitable for evaluating subjective symptoms and eczema severity after Kampo treatment; further studies are required to verify the study findings.
Risk Factors for Nab-Paclitaxel and Gemcitabine-Induced Peripheral Neuropathy in Patients with Pancreatic Cancer
Authors: Catalano Martina , Ramello Monica , Conca Raffaele , Aprile Giuseppe , Petrioli Roberto , Roviello Giandomenico
Published: May 2022

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent adverse events observed with taxane use, whose disability often required modification or treatment discontinuation. The aim of this study was to assess the value of several variables as risk factors for CIPN development. Material and Methods: Eligible patients with metastatic pancreatic cancer receiving chemotherapy with nab-paclitaxel and gemcitabine were assessed in a multicenter study. Peripheral neuropathy was categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02, and a physical/neurological examination. Univariate and multivariate regression analyses were used to identify blood-based and clinical factors associated with CIPN. Results: Data were available from 153 patients from five Italian centers. Key risk factors of CIPN in univariate regression models included age, number of chemotherapy cycles, statin assumption, and concomitant comorbidities. However, in the multivariate analysis, only for age (OR 1.0, p < 0.01, 95% CI: 1.01–1.11) and the number of cycles (OR 1.22, p < 0.01, 95% CI: 1.09–1.36), the correlation with CIPN development has been confirmed. Conclusion: Our study confirms age and the number of chemotherapy cycles as CIPN risk factors. The identification and validation of different risk factors could be advantageous to prevent or optimize management of CIPN which outstandingly affect the patient’s quality of life.
CineGrid: Futuros Cinemáticos
Authors: Silva Cicero Inacio da ,   Universidade Federal de São Paulo, Almeida Jane de ,   Pontifícia Universidade Católica de São Paulo, André Thiago de ,   Universidade de São Paulo. Escola  de Comunicações e Artes
Published: May 2022

Resultado de pesquisas apresentadas no âmbito da comunidade CineGrid, este volume 8 da Coleção CINUSP provoca o espectador a explorar alguns dos caminhos e dificuldades de realização e compartilhamento de conteúdos audiovisuais de altíssima qualidade. Além disso, o livro propõe repensar esses conteúdos - seu uso como entretenimento, ciência, saúde, arte e imaginar os futuros possíveis, tendo como referência o caos criativo dos processos computacionais e das redes. O conhecimento contemporâneo é interdisciplinar, conectado e precisa, mais do que nunca, de novas formas de visualização. As inovações relatadas neste volume abrem perspectivas de produzir-se potentes imagens ainda não vistas, de lugares, escalas e objetos longínquos. O futuro indica um cenário cada vez mais cinemático, com experiências cinematográficas mais presentes e constantes, um outro mundo de imagens nos alcança. Ou, pelo contrário, somos outros e esta imagem é construída justamente para dar conta de nossa atual complexidade.
Paulo Freire e o direito à palavra dos oprimidos e das oprimidas na contemporaneidade
Authors: Amorim Célia Regina Trindade Chagas , Costa Alda Cristina Silva da
Published: May 2022

Este artigo, de natureza teórico-crítica, consiste em uma reflexão acerca do direito à palavra, embasada na matriz freiriana de comunicação. Investimos no argumento de que o direito à palavra de oprimidos e oprimidas, base da comunicação freiriana, constitui-se como fonte propulsora das lutas anticapitalista, antirracista e anti-heteropatriarcal. Duas obras paradigmáticas do pensamento latino-americano, produzidas por Paulo Freire, Pedagogia do Oprimido (1968) e Extensão ou Comunicação? (1969), lançadas no Chile, iluminaram o nosso percurso. O período no Brasil era de ditadura civil-militar (1964-1985), quando as vozes contrárias ao regime, incluindo a de Paulo Freire, foram silenciadas pelos novos donos do poder, e a saída brasileira foi a luta coletiva pela redemocratização do país. Ler o mundo, no sentido freiriano, a partir dessas obras e de outras complementares, é a nossa metodologia e pedagogia cidadãs.
Lições da pandemia: TVs Educativas como política de comunicação e educação
Authors: Aragão Wagner de Alcântara
Published: May 2022

Educar e comunicar. Dois atos que se entrelaçam, de acordo com os ensinamentos de Paulo Freire. Inspirado nessa concepção, este ensaio discorre sobre a necessidade de elaboração de políticas em comunicação e educação públicas que incorporem emissoras educativas como instrumentos de ensino. Essa necessidade é evidenciada pelas restrições impostas pela pandemia da covid-19, quando tecnologias se fizeram imprescindíveis, mas a exclusão digital mostrou o sistema de radiodifusão aberta como meio de acesso universal.
Role of Sclerostin in Cardiovascular Disease
Authors: Golledge Jonathan , Thanigaimani Shivshankar
Published: May 2022

Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin’s role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83–1.57];
P
=0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53–1.59];
P
=0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.
Abstract 183: Diuretic Use In The Emergency Department And Length Of Stay In Patients Hospitalized With Congestive Heart Failure
Authors: Qadri Naureen , Thomas Chelsey , Madrid Shaina , Rush Pam , Strauss Craig , Bradley Steven M
Published: May 2022

Background:
Among hospitalized heart failure patients with evidence of fluid overload, guidelines recommend prompt use of loop diuretics to reduce morbidity. Little is known about delays in the use of loop diuretics among patients with congestive heart failure admitted from an emergency department (ED).

Methods:
We identified 2,801 patients admitted via an ED with heart failure at 12 Allina Health hospitals between January 1, 2017 and December 31, 2020. We excluded patients on observational status, no or unknown home loop diuretic dosing, no intravenous (IV) loop diuretic within 24 hours of admission, on home thiazide-like or thiazide-type diuretic and patients who received inotropes or dialysis prior to admission or within 24 hours of admission. Initial diuretic dose was compared to home dose in furosemide equivalents using the Diuretic Strategies in Patients with Acute Decompensated Heart Failure trial logic and categorized into below home dose, equivalent to home dose, or above home dose. We describe patient characteristics and length of stay by category of diuretic use.

Results:
Among 2801 admitted for heart failure and receiving IV loop diuretics within 24 hours of admission, 1048 (37%) received no IV diuretic in the ED, the initial diuretic dose was below home dose in 346 (12%) patients, equivalent to home dose in 170 (6%) patients, and above home dose in 1237 (44%) patients. Baseline characteristics by category of initial diuretic dose are presented in the Table. Mean length of stay was longest in patients receiving no diuretic in the ED (4.99 days) and shortest in patients receiving a dose above home equivalent (4.48 days) (Table).

Conclusions:
In a cohort of patients admitted for heart failure, nearly a third of patients failed to receive an IV loop diuretic in the emergency department and this was associated with a longer length of hospital stay. These findings may represent a quality improvement opportunity in the care of patients hospitalized for heart failure.
Abstract 194: Impact Of Psoriasis On The Outcomes Of St-elevation Myocardial Infarction From The Nationwide Readmission Database
Authors: Abumoawad Abdelrhman , Hamed Amr , ABDELGHANY MAHMOUD
Published: May 2022

Background:
Psoriasis is a chronic inflammatory disease which causes atherosclerosis. There is conflicting data regarding the association between psoriasis and the development of cerebrovascular diseases with increased mortality. There is also limited data about the outcomes of the psoriatic patients presenting with ST-elevation myocardial infarction (STEMI).

Methods:
We queried the Nationwide Readmissions Database (years: 2016-2019) using ICD-10 codes for patients with a primary diagnosis of STEMI who underwent primary percutaneous coronary intervention (PCI). Patients were classified into two groups according to the presence of psoriasis. Outcomes included in-hospital mortality, index admission compilations, 90-day readmission rate, and causes of readmissions.

Results:
A total of 52,796 patients with STEMI underwent PCI including 308 with psoriasis and 52,488 with no psoriasis. Mean age and gender were similar between both groups. Psoriasis patients had more prevalence of obesity, diabetes mellitus (DM) obstructive sleep apnea (OSA) and depression. In-hospital mortality rate was not significantly different between the two groups. The length of stay and the total charges were higher in the psoriasis group (Table 1). During the index admission, the most common complications were not different. However, hemorrhagic anemia was higher in the psoriatic group. There were 6,896 (13.1%) readmission in the non-psoriasis group compared to 28 (9.1%).

Conclusion:
Patients with psoriasis had higher prevalence of cardiovascular risk factors including obesity, OSA, and DM, without a significant increase in the in-hospital mortality and the 90-day readmission rate.
Abstract 195: The Effect Of Phosphodiesterase-5 Inhibitors On Major Adverse Cardiovascular Events And Mortality In A Large Cohort Of Men With Erectile Dysfunction From A Nationwide Insurance Database: A Retrospective Study
Authors: Kloner Robert A , Stanek Eric , Crowe Christopher L , Singhal Mukul , Pepe Rebecca S , Bradsher Julia , Rosen Raymond
Published: May 2022

Background:
Phosphodiesterase type 5 inhibitor (PDE-5i) medications are effective in treating Erectile Dysfunction (ED) for tens of millions of men in the US and worldwide. The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular events (MACE) (composite outcome of cardiovascular (CV) death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, or unstable angina pectoris) and all-cause death.

Methods:
A retrospective observational cohort study was conducted in a large US commercial and Medicare insurance claims database in men with ≥1 diagnosis of ED without prior MACE hospitalization within 1 year from Jan 2006 to Oct 2020. The exposed group had ≥1 claim for PDE-5i; the unexposed group had no claims for PDE-5i and were matched 2:1 on baseline risk variables. The primary outcome was MACE and secondary outcome was all-cause death, determined by multivariate Cox proportional hazard modeling. Death data were obtained via National Death Index linkage.

Results:
In this population, MACE was reduced by 13% in men exposed (n=23,816) to PDE-5is (hazard ratio (HR) 0.87; 95% Confidence Interval (CI) 0.79-0.95) vs. non-exposure (n=48,682) over mean follow up of 29 and 37 months, respectively. This was driven by reductions in coronary revascularization (HR 0.85; 0.73-0.98), heart failure (HR 0.83; 0.72-0.97), unstable angina (HR 0.78; 0.64-0.96), and CV death (HR 0.61; 0.41-0.90). PDE-5i-exposed men had a 25% reduction in all-cause death (HR 0.75; 0.65-0.87). Men without coronary artery disease but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the greatest reductions in MACE (HR 0.45; 0.37-0.54) and all-cause death (HR 0.51; 0.37-0.71) vs. the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n=6,305), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 0.64-0.97). All comparisons are significant at p<0.05.

Conclusions:
In a large population of US men with ED, PDE-5i exposure was associated with reductions in MACE, CV death, and overall death risk compared to non-exposure. Risk reduction was positively correlated with PDE-5i exposure level.
Abstract 204: Evaluation Of Impact Of Cardio-oncology Department On Cardiovascular Outcomes And Oncology Treatment: A Single Center Cross -sectional Retrospective Chart Review
Authors: Joshi Maharshi , Danley Kelsey , Rosado Melanie , Santos Volgman Annabelle , Fidler Mary J , Okwuosa Tochukwu M
Published: May 2022

Introduction:
Cardiotoxicity secondary to cancer therapy can lead to alterations or discontinuation of therapy regimens and potentially impact patient outcomes. We examined overall cardiovascular and oncology treatment outcomes among cancer patients in an urban center with an established cardio-oncology department.

Hypothesis:
We hypothesized that in adult cancer patients receiving cardiotoxic treatments, the rates of occurrences of major adverse cardiovascular events (MACE) and the rates of emergency room (ER) visits due to cardiovascular (CV) complications would differ when managed by a cardio-oncologist compared with a general cardiologist.

Method:
We performed a retrospective chart review of 127 patients managed by a general cardiologist and 254 patients managed by a cardio-oncologist for MACE, CV-related ER visits and oncology treatment modifications. Inclusion criteria included ≥18 years of age, a diagnosis of breast cancer (36.48%, 139 of 381), lung cancer (23.1%, 88 of 381), multiple myeloma (13.65%, 52 of 381) or lymphoma (26.77%, 102 of 381); and history of treatment with a known cardiotoxic agent or chest radiation therapy. A two-tailed chi-square analysis was used to compare differences. Welch’s T test analysis was used to compare the rate of ER visits.

Result:
There was significantly higher MACE among patients managed by a general cardiologist (46.46%, 59 of 127) compared with a cardio-oncologist (22.83%, 58 of 254). The rate of ER visits due to cardiovascular complications was significantly lower among those managed by a cardio-oncologist (21.26%, 54 of 254) compared with a general cardiologist (59.84%, 76 of 127). Less patients had treatment modifications, delays and discontinuations in patients managed by a cardio-oncologist (with p<0.01 for all).

Conclusion:
We found lower occurrences of MACE and CV-related ER visits in patients on cardiotoxic cancer therapy managed by a cardio-oncologist compared with a general cardiologist.
Abstract 212: Artificial Intelligence To Predict Late Onset Cardiomyopathy Among Childhood Cancer Survivors Using Electrocardiogram, Echocardiogram, And Clinical Data
Authors: Gunturkun Fatma , Mulrooney Daniel A , Davis Robert L , Armstrong Gregory T , Jefferies John L , Karabayir Ibrahim , Yasui Yutaka , Ehrhardt Matt , Srivastava Kumar , Hudson Melissa , Akbilgic Oguz
Published: May 2022

Objectives:
Applying machine learning to predict the 10-year cardiomyopathy risk among adult survivors of childhood cancer.

Methods:
The St. Jude Lifetime Cohort Study (SJLIFE) is an ongoing study of adult survivors of childhood cancer with in-person clinical evaluations. ECG and ECHO data were obtained on participants who did not have cardiomyopathy (defined as left ventricular ejection fraction < 50% or absolute drop from baseline ≥ 10%) at initial SJLIFE evaluation and who had at least two evaluations with ECHO screening. Predictors including ECG-AI based risk (cardiomyopathy risk from our previously develop AI model using ECG-alone), ECHO parameters, age, race, sex, BMI, primary cancer diagnosis, heart rate, respiratory rate, systolic and diastolic blood pressures, smoking, diabetes, hypertriglyceridemia, hypertension, or hypercholesterolemia. Light gradient boosting machines (LGBM) were applied to predict risk for cardiomyopathy using training (60%) and validation (20%) data. The hold-out (20%) data was used to evaluate predictive performance as sensitivity, specificity, precision, negative predictive value (NPV) and AUC. Shapley Additive exPlanations method (SHAP) was used to uncover predictors’ importance.

Findings:
The study population included 1,046 survivors with mean age±std of 32.2±8.0. The median time between baseline and follow-up evaluations was 5.2 years (0.5-9.5). In the hold out set, a model using ECHO parameters-only yielded an AUC of 0.68 (CI: 0.55-0.81), ECG-AI based risk alone yielded a hold-out test AUC of 0.87 (CI: 0.79-0.95), and an AUC of 0.89 (CI: 0.82-0.96) was obtained on LGBM model when ECG, ECHO, and clinical risk factors were used together. The final model classified cardiomyopathy with 80% sensitivity, 82% specificity, precision of 32%, and NPV of 98%. SHAP results showed that ECG-AI based risk, LV Global Longitudinal Peak Strain, LV Diastolic Volume, LV systolic volume, and cumulative anthracycline dose (>200 mg/m
2
) were associated with an increased risk, and LVOT Peak gradient was associated with decreased risk.

Conclusion:
Artificial intelligence-based analyses with ECG and ECHO images may aid in cardiomyopathy risk prediction for at-risk survivors of childhood cancer.
Abstract 215: Increasing Risk Of Hospitalizations For Young-onset Stroke With Improving Survival Odds - A Nationwide Analysis Of Two Cohorts A Decade Apart In The United States
Authors: Desai Rupak , Singh Sandeep , Gowda Supreeth N , Cartagena-Santana Juliana , Valdez Confesora , Spasova Violeta , Galan Mirian , Buhl Leon Maria Cristina , Rupareliya Chintan , Alukal Thomas , Jain Akhil
Published: May 2022

Background:
The scarcity of large-scale trends data on young-onset stroke prompted us to explore the difference in stroke hospitalization and inpatient outcomes among young adults from two nationwide cohorts 10 years apart.

Methods:
The National Inpatient Sample (2007 & 2017) was utilized to identify stroke admissions among young adults(18-44 years). We compared demographics, comorbidities, inpatient outcomes and gender/racial disparities in frequency of stroke admissions and mortality between the two cohorts 10-years apart.

Results:
There was an increase in stroke admissions of young adults in 2017 (0.7%, n=58965/8,568,874, aOR: 1.48, 95%CI:1.46-1.5, p<0.001) compared to 2007 (0.4%, n=41379/10,330,126)
[Table 1]
. The 2017 cohort often included female (49.0% vs 48.4%), non-elective admissions (94.0% vs 90.9%), Medicaid beneficiary (35% vs 23.4%) and urban teaching hospitalizations (81% vs 61.6%)(p<0.05) vs. the 2007 cohort. Cardiovascular comorbidities like hypertension, hyperlipidemia, obesity, peripheral vascular disorders, congestive heart failure and atrial fibrillation/flutter were significantly more prevalent in the 2017 cohort vs. 2007. Reassuringly, with advanced medical and interventional therapeutics in the last decade, the odds of in-hospital mortality decreased in 2017 (aOR 0.84, 95%CI: 0.79-0.89) vs. 2007. Females, Caucasians and Hispanics witnessed a higher relative increase in stroke hospitalizations in 2017. In addition, compared to 2007, a significant decline in mortality was noticed among both sexes but Hispanics and Asians did not show an improvement in survival odds in2017 vs 2007.

Conclusion:
Comparison of two young stroke cohorts a decade apart shows an alarming rise in stroke hospitalizations (nearly 50% higher) with cardiovascular disease risk factors, particularly in the female gender, with declining in-hospital mortality. Persistent racial disparities warrant an inclusive approach in preventive care.