bluuebunny/crossref_metadata_2025 huggingface dataset:
Aerosol‐Assisted Chemical Vapour Deposition of Lead Chalcogenide Thin Films from [Pb((SePiPr2)2N)(S2CNHexMe)]
Authors: Boadi Nathaniel Owusu , Saah Selina Ama , Mensah Michael Baah , Awudza Johannes A. M.
Published: November 2020

In this study, [Pb((SePiPr2)2N)(S2CNHexMe)], a novel complex, was synthesised by refluxing [Pb(S2CNHexMe)2] and [Pb((SePiPr2)2N)2] complexes for 2 hours in chloroform and precipitating with methanol. The microelemental analysis, FT‐IR, and NMR spectroscopies were performed on the complex and the melting point was determined. The crystal structure of this new compound has been determined. The structure showed a distorted square pyramidal geometry with 2 sulphur and 2 selenium atoms coordinating the central atom at the base of the pyramid and a lone pair occupying the axial position of the lead atom. The complex was used to deposit lead chalcogenide thin films by the aerosol‐assisted chemical vapour deposition (AACVD) method at 300, 350, 400, and 450°C. The thin films matched with the powder X‐ray diffraction (pXRD) pattern for cubic PbSe with a (200) preferred orientation at all the deposition temperatures. The scanning electron microscopy (SEM) and energy dispersive X‐ray spectroscopy (EDAX) indicated that cubic PbSe crystals were formed.
Deep Transfer Learning-Based Fault Diagnosis for Gearbox under Complex Working Conditions
Authors: Wan Zitong , Yang Rui , Huang Mengjie
Published: November 2020

In the large amount of available data, information insensitive to faults in historical data interferes in gear fault feature extraction. Furthermore, as most of the fault diagnosis models are learned from offline data collected under single/fixed working condition only, this may cause unsatisfactory performance for complex working conditions (including multiple and unknown working conditions) if not properly dealt with. This paper proposes a transfer learning-based fault diagnosis method of gear faults to reduce the negative effects of the abovementioned problems. In the proposed method, a cohesion evaluation method is applied to select sensitive features to the task with a transfer learning-based sparse autoencoder to transfer the knowledge learnt under single working condition to complex working conditions. The experimental results on wind turbine drivetrain diagnostics simulator show that the proposed method is effective in complex working conditions and the achieved results are better than those of traditional algorithms.
Analysis Based on the Three Objective Educational Domains for Final Summative Secondary Examinations of Science Subject (Chemistry, Physics, and Biology)
Authors: Alhashem Fatimah , Agha Nasser
Published: November 2020

The aim of this study is to determine the representation of the areas of educational objectives (cognitive, psychomotor, and emotional) measured by the science, chemistry, physics, and biology (2018-2019) examination questions in the State of Kuwait (objective, categorical) and the availability of science operations. Content analysis was used as a method to analyze the final examinations in the lens of the three educational objectives domains. The results of the study showed that the number of questions of the science subjects (chemistry, physics, and biology) for the second semester of the academic year 2018-2019 was 136 questions as 46, 48, and 42and that the average of all questions focused on questions related to lower cognitive levels. The study concluded with a set of recommendations to develop the process of final examinations for secondary schools and to rethink about the process of evaluating students with science concepts rather than limiting the subjects to sets of information from textbooks.
Wave Attenuation and Dispersion in a 6 mm Diameter Viscoelastic Split Hopkinson Pressure Bar and Its Correction Method
Authors: Zhang Haotian , Ma Linjian , Luo Zongmu , Zhang Ning
Published: November 2020

The propagation characteristics of viscoelastic waves have been investigated with a 6 mm diameter split Hopkinson pressure bar (SHPB) made of polymethyl methacrylate (PMMA). The strain signals in SHPB tests were improved by the pulse shaping technique. Based on the experimentally determined propagation coefficients, the amplitude attenuation and wave dispersion induced by viscoelastic effects at different impact velocities were quantitatively analyzed. The results indicate that the high-frequency harmonics attenuate faster in a higher phase velocity. With an increase in the impact velocity, the amplitude attenuation of the viscoelastic wave changes slightly during propagation, while the waveform dispersion gradually intensifies. A feasible method by waveform prediction was proposed to verify the validity and applicability of the propagation coefficient. The results indicate that the strain obtained from the small diameter viscoelastic SHPB can be effectively modified by utilizing the propagation coefficient. Furthermore, it is preferred to adopt the propagation coefficient obtained at low impact velocity for correction when the impact velocity varies. Moreover, the PMMA-steel bar impact test was performed to further illustrate the accuracy of the propagation coefficient and the effectiveness of the correction method.
Leptospirosis Presenting with Features of Thrombotic Microangiopathy
Authors: Ebad Chaudhry Adeel , Moollan Nabeehah , Rafi Ahmed Adeel , Dorman Anthony , Magee Colm
Published: November 2020

Leptospirosis is an exceptionally rare infectious disease in the Republic of Ireland. Leptospirosis can present with or mimic thrombotic microangiopathies (TTP/HUS). A 48-year-old male presented to a peripheral hospital with a short history of diarrhoea, anaemia, hyperbilirubinemia, raised lactate dehydrogenase, thrombocytopenia, and severe acute kidney injury and was transferred to our tertiary care kidney centre. A form of acute thrombotic microangiopathy (TMA) was suspected. However, no schistocytes were seen on the blood film, and the reticulocyte count was depressed. A kidney biopsy was performed before initiating any potential treatment which revealed acute interstitial nephritis (AIN). Leptospirosis was considered and subsequently serologically confirmed. The patient was managed with antimicrobials and supportive therapy. Acute kidney injury is common in leptospirosis and is often due to AIN. Initial presentation can mimic TMA; however, a differential diagnosis of leptospirosis should be considered even in nonendemic areas due to re-emergence of the disease.
SCUBE3 Is Likely a Susceptibility Gene for Systemic Lupus Erythematosus for Chinese Populations
Authors: Qi Yuan-yuan , Zhao Ya-fei , Zhai Ya-ling , Zhang Xiao-xue , Wang Xiao-yang , Liu Xina-ran , Cui Yan , Ning Xiang-hui , Zhao Zhan-Zheng
Published: November 2020

Background. Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic disposition with more than 100 susceptibility genes identified until now. However, our knowledge on SLE genetic background is still limited. The present study was aimed at evaluating the role of single nucleotide polymorphisms (SNPs) in SCUBE3, a TGF-β signaling activator, with SLE susceptibility in Chinese populations. Methods. A total of 2801 individuals (490 cases and 493 controls from GWAS cohort and 1003 cases and 815 controls from our cohort) were enrolled, and SNPs located 10 kb up- and downstream of SCUBE3 (chr6:35182190-35218609) were included in the genetic association study. Multiple layers of bioinformatics were conducted, and the levels of SCUBE3 expression were confirmed. Results. Of the 31 SNPs in SCUBE3 tested, 24 SNPs were significantly associated with SLE atp≤0.05. The top locus was rs1888822 withp=8.74∗10−6in the discovery cohort and was confirmed by the replication cohort withp=0.012. Additionally, the levels of SCUBE3 mRNA expression were significantly lower in patients with SLE comparing with healthy controls (p=4.28∗10−4). Further expression data from ArrayExpress showed that the expression of SCUBE3 was also lower in CD3+ T cells and B cells from patients with SLE. Conclusions. Our research revealed that variants in SCUBE3, which encode SCUBE3 as a TGF-β signaling activator, can be considered as a new genetic susceptibility factor for systemic lupus erythematosus. And the reduced mRNA expression of SCUBE3 was first reported in patients with SLE.
Razonamiento clínico en kinesiología mediante aprendizaje basado en casos
Authors: Contreras Briceño Felipe Andrés , Villaseca Rojas Yenny , Espinosa Ramírez Maximiliano , Villarroel Stargo Gregory , Moscoso Altamira Gonzalo , Chamorro GinÃ© Magdalena , Nicoletti Santoni Natalia , Espinoza Vallejos Macarena , García Valdés Patricio , Fernandez Mincone Tiziana , Rojas Muñoz Cynthia
Published: November 2020

Introducción: En cursos clínicos con gran número de estudiantes, las experiencias clínicas con pacientes reales son limitadas, dificultando el logro de objetivos de aprendizaje. La didáctica aprendizaje basado en casos (ABC) promueve el pensamiento crítico y trabajo coolaborativo, aspectos esenciales para desarrollar competencias profesionales. El objetivo de este estudio fue reportar si la incorporación de la metodología ABC en una asignatura clínica curricular promueve el razonamiento clínico en la formación en kinesiología. Metodología: En la asignatura curricular “evaluación cardiorrespiratoria en kinesiología”, 10 grupos de 7 estudiantes desarrollaron casos clínicos de temas disciplinares seleccionados bajo criterio de jueces por expertos del área, y lo presentaron al resto de sus compañeros. Un académico guió la reflexión del tema tratado en el ABC, fomentando la discusión entre los estudiantes. Al finalizar la asignatura se evaluó la percepción de la didáctica educativa mediante encuesta y logro de objetivos de aprendizaje con indicadores académicos.Resultados: Los estudiantes reportaron gran satisfacción con la metodología, mayor preparación para actividades de campo clínico y mejoras en sus habilidades comunicacionales. El promedio obtenido en las interrogaciones y en las actividades clínicas fue superior a versiones previas de la asignatura, aumentando el porcentaje de aprobación y satisfacción con el curso. Conclusión: La incorporación de la didáctica de ABC fomentó el razonamiento clínico, reflexión y habilidades comunicacionales mejorando el rendimiento académico y promoviendo competencias profesionales. Como producto final se elaboró un libro de descarga libre con los temas tratados en los ABC, titulado: “Identificando problemas kinesiológicos: aprendizaje basado en casos”.
Respuesta a medicamentos biológicos en pacientes con artritis reumatoide según nivel de actividad al inicio
Authors: Flores Costa Javiera , Durán  Santa Cruz Josefina
Published: November 2020

Introducción: la Ley Ricarte Soto (LRS) permite a pacientes con artritis reumatoide refractaria acceder a medicamentos biológicos. Sin embargo con esta regulación los pacientes inician éstos con actividad alta de enfermedad por un período prolongado, luego de recibir al menos 3 fármacos sintéticos. Previo a la implementación de esta ley no era necesario cumplir estos requisitos. Objetivos: comparar la respuesta a tratamiento lograda con el uso de medicamentos biológicos según niveles de actividad al inicio mediante la comparación de pacientes con biológicos antes y después de la LRS. Métodos: tomando datos del Programa de atención de pacientes con artritis reumatoide de la Red de Salud UC-Christus se compraró grupos de pacientes que accedieron a biológicos pre y post implementación de la LRS. Se analizó el cambio en DAS28 y la categorización de actividad de enfermedad según DAS28. Se realizó una regresión lineal evaluando edad, seropositividad y DAS28 pre tratamiento. Resultados: se encontró una diferencia significativa en el cambio de DAS28 a los 6 meses de tratamiento (p=0,02) y en la regresión solo con el DAS28 pre tratamiento (p=0,00). Dentro del grupo de pacientes que requirió cambio de biológico, los pacientes post ley iniciaron la terapia más activos y presentaban mayor persistencia de actividad severa a los 6 meses de tratamiento (11% vs 25%). Conclusiones: si bien el nivel de actividad al inicio no influyó en la respuesta a los 6 meses de tratamiento, si influyó en la persistencia de actividad severa en quienes requirieron cambio de biológico.
Estafiloma peripapilar, presentación clínica y diagnósticos diferenciales en anomalías congénitas de nervio óptico
Authors: Bagolini Fuentes Matías José , Salgado Cristian
Published: November 2020

Un paciente de 3 meses con sospecha de estrabismo presenta al examen una gran anisometropía con -9.50 esfera en su ojo izquierdo y al fondo de ojo destaca una papila alterada similar a la papila de Morning-Glory. Las anomalías congénitas de nervio óptico (ACNO) son un grupo de condiciones que se presentan clínicamente como baja agudeza visual, estrabismo y/o nistagmus. El diagnóstico diferencial es clínico y complejo por la sobre posición morfológica entre estas. Los principales diagnósticos diferenciales son la papila de Morning-Glory, el coloboma y la hipoplasia de nervio óptico. Se recomienda manejo multidisciplinario por sus asociaciones sistémicas.
Onicomicosis en paciente inmunocompetente por Aspergillus sección Candidi.
Authors: Carballo Graciela Mariel , Miranda Jimena Agostina , Fidalgo Daniela Mariel , Consigli Carlos , Arechavala Alicia
Published: November 2020

Introducción: los hongos miceliales no dermatofitos (HMND) pueden causar un gran número de infecciones, entre ellas, la onicomicosis. Su implicancia como agentes patógenos y su significado clínico en esta afección, se encuentran sujetos al cumplimiento de los criterios de Walshe y Mary P. English. Presentamos un caso de onicomicosis causada por un hongo hifomiceto poco frecuente, del género Aspergillus sección Candidi, en una paciente inmunocompetente y su estrategia terapéutica. Materiales y métodos: se estudió una paciente inmunocompetente, de 43 años de edad, con lesión en uña de primer dedo del pie derecho, de 10 años de evolución. Se realizó toma de muestra para examen micológico. Resultados: el examen directo reveló la presencia de hifas hialinas irregulares, ramificadas y tabicadas, compatibles con HMND. En muestras seriadas, desarrollaron colonias blanco algodonosas, cuya micromorfología fue concordante con Aspergillus sección Candidi. La identificación fue confirmada en la Unidad de Micología del Hospital de Infecciosas Francisco Javier Muñiz de la Ciudad Autónoma de Buenos Aires, Argentina. Allí también se realizaron pruebas de sensibilidad a antifúngicos, resultando sensible a itraconazol y terbinafina.  Conclusión: exponemos un caso de onicomicosis causada por Aspergillus sección Candidi, HMND no queratinolítico, de escasa frecuencia de aparición, siendo el primer caso descripto y publicado en Argentina. También se planteó una estrategia terapéutica efectiva, que condujera a la cura clínica y microbiológica, de la uña de la paciente.
Estudio de un neo-epítope para detección de anticuerpos antitransglutaminasa en enfermedad celíaca
Authors: Verbeke Sandra Mariela , Gutierrez Nancy , Catalán Miguel , Canals Andrea
Published: November 2020

Introducción: La enfermedad celíaca (EC) es una patología autoinmune, que se desarrolla a cualquier edad en personas genéticamente susceptibles, y cuyo órgano diana principal es el intestino delgado. La diversidad en las formas de presentación actualmente conocidas implica un desafío permanente para el laboratorio, que debe ofrecer nuevas técnicas, cada vez más sensibles y específicas, para detectar de manera eficiente los autoanticuerpos específicos para el diagnóstico y seguimiento de estos pacientes. Nuestro objetivo fue evaluar la sensibilidad y especificidad de un nuevo antígeno para la detección de anticuerpos anti-transglutaminasa compuesto por transglutaminasa tisular unida covalentemente a péptidos deamidados de gliadina (neo-epítope) en pacientes con sospecha de EC, con biopsia duodenal como gold standard. Como objetivo secundario nos propusimos evaluar la sensibilidad y especificidad delantígeno convencional, transglutaminasa humana recombinante, para el mismo grupo de estudio. Metodología: Se realizó un estudio prospectivo, analizando muestras de pacientes con sospecha de EC o en seguimiento de dicha patología, en las que se estudiaron los anticuerpos anti-transglutaminasa con antígeno neo- epítope, y con antígeno transglutaminasa recombinante humana. Se determinó sensibilidad, especificidad, VPP, VPN y coeficiente de concordancia Kappa. Resultados: Se procesaron 56 muestras, incluidas en un período de 5 meses. La sensibilidad (100%) y especificidad (92,3%) obtenidas con la técnica de neo-epítope, en relación a la biopsia (gold standard), fue mayor que con la técnica transglutaminasa humana recombinante (88,3% y 78,9% respectivamente). La técnica con neo-epítope proporcionó un menor número de resultados en la “zona de indeterminación”. Conclusiones: Nuestros resultadosconcuer-dan con otros autores, ya que neo-epítope detecta con mayor sensibilidad y especificidad aquellos pacientes con diferente situación de presentación y transgresores de la dieta libre de gluten, quienes pueden presentar serología negativa o débilmente positiva con transglutamiasa humana recombinante. La nueva técnica neo-epítope constituiría una mejor herramienta para la pesquisa diagnóstica y de seguimiento en pacientes con EC.
Aprendizaje interprofesional en los internados de las carreras de la salud del Hospital Josefina Martínez
Authors: Barañao Patricio , Villagran Gutierrez Ignacio , Moya Osorio José , Jeldes Díaz Paz , Calvo Sanchez Fernanda , Fuentes López Eduardo , Barja Yañez Salesa
Published: November 2020

Introducción:  las dinámicas de atención en salud requieren que los profesionales que componen el equipo de salud trabajen en forma colaborativa. Sin embargo, durante su formación, las oportunidades de aprendizaje con otras disciplinas son escasas. Se reportan los resultados del primer proyecto para promover el aprendizaje interprofesional en los internos que rotan por el Hospital Josefina Martínez.  Método: de marzo a julio 2018, se realizó un taller constituido por dos sesiones, en cada rotación de internado. Participaron internos de cinco carreras en forma conjunta (kinesiología, odontología, nutrición, fonoaudiología y terapia ocupacional). Se adaptó la encuesta de disposición al aprendizaje interprofesional, para ser aplicada antes y después de cada taller. Se calcularon las medianas, rangos intercuartílicos (Q1; Q3 y se compararon los puntajes mediante test de Wilcoxon.  Resultados: hubo una disposición positiva inicial al aprendizaje interprofesional, con mejoría significativa después de los talleres en todas las dimensiones de la encuesta: Trabajo en equipo y colaboración (<0,001), trabajo centrado en el paciente (<0,001), y sentido de identidad profesional (<0,05). La diferencia del puntaje global de la encuesta también fue significativa (<0,001).  Conclusiones: se demostró un cambio favorable y significativo en las respuestas de los internos después de los talleres, en todas las dimensiones de la encuesta. En los comentarios, destacaron la relevancia de aprender con estudiantes de otras carreras, describiendo que aumentó su conocimiento sobre éstas y reforzando el impacto que dicha integración tiene en mejorar la atención y resolución de problemas en salud.
Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs
Authors: Cresswell Gregory M. , Wang Bingbing , Kischuk Erin M. , Broman Meaghan M. , Alfar Rami A. , Vickman Renee E. , Dimitrov Dimiter S. , Kularatne Sumith A. , Sundaram Chandru P. , Singhal Sunil , Eruslanov Evgeniy B. , Crist Scott A. , Elzey Bennett D. , Ratliff Timothy L. , Low Philip S.
Published: November 2020

Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME. This FRβ+ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8+ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRβ as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors.

Significance:

FRβ serves as both a means to identify and target MDSCs and TAMs within the tumor, allowing for delivery of immunomodulatory compounds to tumor myeloid cells in a variety of cancers.
Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway
Authors: Harmston Nathan , Lim Jun Yi Stanley , Arqués Oriol , Palmer Héctor G. , Petretto Enrico , Virshup David M. , Madan Babita
Published: November 2020

Aberrant Wnt signaling drives a number of cancers through regulation of diverse downstream pathways. Wnt/β-catenin signaling achieves this in part by increasing the expression of proto-oncogenes such as MYC and cyclins. However, global assessment of the Wnt-regulated transcriptome in vivo in genetically distinct cancers demonstrates that Wnt signaling suppresses the expression of as many genes as it activates. In this study, we examined the set of genes that are upregulated upon inhibition of Wnt signaling in Wnt-addicted pancreatic and colorectal cancer models. Decreasing Wnt signaling led to a marked increase in gene expression by activating ERK and JNK; these changes in gene expression could be mitigated in part by concurrent inhibition of MEK. These findings demonstrate that increased Wnt signaling in cancer represses MAPK activity, preventing RAS-mediated senescence while allowing cancer cells to proliferate. These results shift the paradigm from Wnt/β-catenin primarily as an activator of transcription to a more nuanced view where Wnt/β-catenin signaling drives both widespread gene repression and activation.

Significance:

These findings show that Wnt/β-catenin signaling causes widespread gene repression via inhibition of MAPK signaling, thus fine tuning the RAS-MAPK pathway to optimize proliferation in cancer.
TriTACs, a Novel Class of T-Cell–Engaging Protein Constructs Designed for the Treatment of Solid Tumors
Authors: Austin Richard J. , Lemon Bryan D. , Aaron Wade H. , Barath Manasi , Culp Patricia A. , DuBridge Robert B. , Evnin Luke B. , Jones Adrie , Panchal Anand , Patnaik Purbasa , Ramakrishnan Vanitha , Rocha Sony S. , Seto Pui , Sexton Kenneth , Strobel Kathryn L. , Wall Russell , Yu Stephen , Yu Timothy Z. , Law Che-Leung , Baeuerle Patrick A. , Wesche Holger
Published: November 2020

T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.
Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides
Authors: Shiah Jamie V. , Grandis Jennifer R. , Johnson Daniel E.
Published: November 2020

STAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activity in cancer, it has long been considered a highly attractive target for the development of anticancer therapies. Efforts to target STAT3, however, have proven to be especially challenging, perhaps owing to the fact that transcription factors lack targetable enzymatic activity and have historically been considered “undruggable.” Small-molecule inhibitors targeting STAT3 have been limited by insufficient selectivity and potency. More recently, therapeutic approaches that selectively target STAT3 protein for degradation have been developed, offering novel strategies that do not rely on inhibition of upstream pathways or direct competitive inhibition of the STAT3 protein. Here, we review these emerging approaches, including the development of STAT3 proteolysis targeting chimera agents, as well as preclinical and clinical studies of chemically stabilized antisense molecules, such as the clinical agent AZD9150. These therapeutic strategies may robustly reduce the cellular activity of oncogenic STAT3 and overcome the historical limitations of less selective small molecules.
Abstract IA-05: Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer
Authors: Beatty Gregory
Published: November 2020

Pancreatic ductal adenocarcinoma (PDAC) has shown remarkable resistance to immunotherapy including immune checkpoint blockade, vaccines, and other immunomodulatory agents. In cancer, immunosurveillance can be regulated at both the priming and effector phases of an immune response. Based on this reasoning, we investigated a role for the CD40 pathway in mice and humans as a strategy to prime for tumor-reactive T cells. Our studies showed that systemic CD40 activation triggers productive innate immunosurveillance that sensitizes PDAC tumors to chemotherapy but is insufficient to provoke T cell dependent anti-tumor immunity. However, CD40 activation can restore the functional capacity of peritumoral T cells. Consistent with this, PDAC development associates with progressive loss in T cell priming capacity along with a deficiency in circulating dendritic cells. This biology observed in mouse models is mirrored in humans where patients with PDAC show a decrease in circulating dendritic cells and an increase in T cell dysfunction. To overcome these defects in T cell priming and deficiencies in immune health, we studied adoptive transfer of tumor-reactive chimeric antigen receptor (CAR)-modified autologous T cells in patients. Our findings show that the persistence of adoptively transferred T cells is markedly impaired in patients with PDAC compared to hematologic malignancies. In addition, CAR-T cells show limited anti-tumor activity in PDAC. This lack of efficacy has prompted our investigation into the biology of the tumor microenvironment which displays remarkable spatial heterogeneity in immune cell infiltrates. In our studies, we have identified phenotypically distinct cellular communities marked by weak (“cold”) and strong (“hot”) infiltration of T cells. We find that these distinct regions of PDAC tumors are orchestrated by unique immunoregulatory mechanisms with therapeutic implications. Overall, our findings demonstrate that immunological barriers residing both within and outside the tumor microenvironment have the potential to impair the efficacy of immunotherapy in PDAC. In addition, our data suggest that the immunogenicity of PDAC varies spatially throughout tumors raising the likelihood that multiple, distinct mechanisms of immune evasion will need to be circumvented for immunotherapy to produce benefit for most patients.

Citation Format: Gregory Beatty. Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-05.
Abstract IA-11: An exception to the rule: A coding functional variant at a pancreatic cancer GWAS locus
Authors: Jermusyk Ashley , Zhong Jun , Gordon Naomi , Connelly Katelyn , Perera Sumeth , Abdolalizadeh Ehssan , Zhang Tongwu , O'Brien Aidan , Hoskins Jason , Collins Irene , Eiser Daina , Yuan Chen , Risch Harvey , Jacobs Eric J. , Li Donghui , Du Mengmeng , Stolzenberg-Solomon Rachael , Klein Alison P. , Smith Jill P. , Wolpin Brian M. , Chanock Stephen J. , Shi Jianxin , Petersen Gloria M. , Westlake Christopher , Amundadottir Laufey T.
Published: November 2020

Genome wide association studies (GWAS) in 9,013 pancreatic cancer patients and 12,452 controls of European ancestry have discovered over 20 risk loci in the human genome. Here, we fine mapped one such locus on chromosome 16q23.1 in the vicinity of two Chymotrypsinogen precursor genes, CTRB1 and CTRB2. We fine-mapped this locus to rs72802365 (P=2.51x10-17, OR=1.36, 95% CI=1.31-1.40) and identified colocalization (PP=87%) with aberrant exon 5→7 CTRB2 splicing in pancreatic tissues. Imputation of a 584 bp insertion/deletion variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (P=2.83x10-16, OR=1.36, 95% CI=1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsin B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). The intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein may lead to ER stress and pancreatic inflammation, which in turn, may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.

Citation Format: Ashley Jermusyk, Jun Zhong, Naomi Gordon, Katelyn Connelly, Sumeth Perera, Ehssan Abdolalizadeh, Tongwu Zhang, Aidan O'Brien, Jason Hoskins, Irene Collins, Daina Eiser, Chen Yuan, Harvey Risch, Eric J. Jacobs, Donghui Li, Mengmeng Du, Rachael Stolzenberg-Solomon, Alison P. Klein, Jill P. Smith, Brian M. Wolpin, Stephen J. Chanock, Jianxin Shi, Gloria M. Petersen, Christopher Westlake, Laufey T. Amundadottir. An exception to the rule: A coding functional variant at a pancreatic cancer GWAS locus [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-11.
Abstract PO-010: Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq
Authors: Guerrero Paola A. , Maitra Anirban , Monberg Maria E. , Lee Jaewon J , Bernard-Pagan Vincent , Muthuswamy Senthil
Published: November 2020

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. The overwhelming majority of patients (up to 85%) present with unresectable disease, and the 5-year survival rate stands at a dire 9%. Current chemotherapeutic regimens extend survival by only a few months, and the molecular underpinnings of treatment failure in advanced disease remain largely unknown. Recently, single-cell sequencing techniques have emerged as highly effective methods to uncover intratumoral heterogeneity across many cancer types, including PDAC. These studies, and our own unpublished data, have reiterated profound transcriptomic subclonal diversity in PDAC, which likely underlies the divergent therapeutic responses and eventual treatment failure. Using a patient-derived organoid (PDO) platform, we have characterized, on the single cell level, gene expression and regulation profiles to understand the heterogeneity and clinical utility of this model. We applied predictive RNA-seq-based algorithms (CMap) to our initial PDO profiling data to design “custom” PDO combinatorial regimens as a true precision medicine-based approach. We are in the process of validating these predictions in vitro; however, preliminary single-cell RNA (scRNA-seq) data shows treatment PDOs with CMap-predicted compounds induced dramatic transcriptomic shifts in subclones reflective of an efficacious treatment strategy. Additionally, we conducted single-nuclei ATAC sequencing (snATAC-seq) of PDOs pre- and post-treatment with CMap-predicted compounds. This data, coupled to our scRNA-seq, allowed for construction of chromatin regulatory maps, and determined alterations in chromatin accessibility and gene regulation induced by targeted combinatorial therapeutics. These findings provide meaningful insight to biological processes driven by treatment-induced chromatin accessibility, and its relationship to heterogeneous transcriptional architecture. Our data suggests that differential regulation across PDO subclones may drive responses to therapy and acquired resistance mechanisms observed in the clinic, which could be predicted and therapeutically targeted with scRNA sequencing. Thus, this work represents the importance of leveraging subclonal architecture in the preclinical space to ensure both treatment efficacy and the consideration of novel therapeutic combinations in PDAC patients.

Citation Format: Paola A. Guerrero, Anirban Maitra, Maria E. Monberg, Jaewon J Lee, Vincent Bernard-Pagan, Senthil Muthuswamy. Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-010.
Abstract PO-016: STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment in PDAC
Authors: Lefler Julia E. , MarElia Katie , Hildreth Blake E. , Thies Katie A. , Cuitino Maria C. , Ostrowski Michael C.
Published: November 2020

One of the defining characteristics of pancreatic ductal adenocarcinoma (PDAC) is the formation of a dense stroma comprised of cancer associated fibroblasts (CAFs) and immune cell populations. This stroma is immunosuppressive and can act as a physical barrier against common therapeutic treatments. Attempts to therapeutically target the PDAC stroma have yielded contradictory results, suggesting both tumor promoting and tumor limiting roles for CAFs. These studies emphasize the need to understand important transsignaling pathways between CAFs, tumor cells, and the immune microenvironment. IL-6 is a pleiotropic cytokine involved in several physiological functions and its increased expression is strongly associated with poor survival rates in PDAC patients. STAT3 is a major downstream target of IL-6, and its aberrant activation has been implicated in PDAC tumor progression and immune evasion. IL-6 expression and the IL-6/STAT3 signaling axis in PDAC has been characterized in epithelial tumor cells, however its stromal-specific function on PDAC has yet to be elucidated. We hypothesized that the STAT3 signaling axis in pancreatic CAFs contributes to the immunosuppressive and fibrotic phenotype seen with disease progression. Employing CreLoxP technology, the fibroblast specific protein-1 (Fsp-Cre) transgene was used to conditionally delete STAT3 in fibroblasts in the PdxFlp; KrasG12D; p53 frt/frt (KPF) PDAC mouse model developed by our lab. Deletion of STAT3 in fibroblasts significantly increased the survival in a cohort of KPF mice compared to those with intact STAT3. Loss of fibroblast STAT3 also resulted in a significant decrease in ECM deposition in the pancreas. In preliminary investigations into the immune microenvironment, we found an increase in overall T cell infiltration and decrease in regulatory T cell populations in the STAT3 deleted cohort. Further, STAT3 deletion resulted in an increase in the ratio of M1 to M2 macrophages within the PDAC stroma, suggesting CAF STAT3 signaling is important to maintaining an immune microenvironment conducive to tumor progression. Ultimately, these preliminary results suggest STAT3 signaling in PDAC CAFs contributes to an overall survival disadvantage, an immunosuppressive tumor microenvironment, and an increase in ECM deposition.

Citation Format: Julia E. Lefler, Katie MarElia, Blake E. Hildreth, Katie A. Thies, Maria C. Cuitino, Michael C. Ostrowski. STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment in PDAC [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-016.
Abstract PO-031: Repurposing of alexidine dihydrochloride as an apoptosis-initiator and cell cycle inhibitor in human pancreatic cancer
Authors: Kasikci Ezgi , Aydemir Esra , Yogurtcu Bekir Mustafa , Sahin Fikrettin , Bayrak Omer Faruk
Published: November 2020

Purpose: Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1. Methods: After IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured and changes in cell cycle were analyzed. Results: AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit cell cycle in pancreatic cancer cell lines. Conclusions: As a conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.

Citation Format: Ezgi Kasikci, Esra Aydemir, Bekir Mustafa Yogurtcu, Fikrettin Sahin, Omer Faruk Bayrak. Repurposing of alexidine dihydrochloride as an apoptosis-initiator and cell cycle inhibitor in human pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-031.
Abstract PO-035: Overcoming adaptive resistance to mutant KRAS and MEK inhibitors by co-targeting mTORC1/2 in pancreatic cancer
Authors: Brown Wells , McDonald Paul , Dedhar Shoukat
Published: November 2020

Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDAC), yet KRAS has remained a difficult target to inhibit pharmacologically. While mutant KRAS-specific inhibitors have recently been developed, there is increasing awareness that adaptive resistance to these inhibitors limits their efficacy as single agents. Here, we demonstrate, using several human and mouse models of PDAC, rapid acquisition of tumor resistance in response to genetic or pharmacologic targeting of KRAS or MEK, associated with increased phosphorylation of Akt and Rictor, in an ILK-dependent manner. While pharmacologic inhibition ofmTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS or MEK inhibitors together with mTORC1/2 inhibitors results in synergistic cytotoxicity and cell death reflected by sustained inhibition of p-ERK and p-Rictor/p-Akt, and of downstream regulators of protein synthesis and cell survival. Importantly, relative to single agents alone, this combination leads to significant inhibition of tumor growth in vivo, including durable tumor regressions and increased survival. We have identified a highly effective combinatorial treatment strategy, using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.

Citation Format: Wells Brown, Paul McDonald, Shoukat Dedhar. Overcoming adaptive resistance to mutant KRAS and MEK inhibitors by co-targeting mTORC1/2 in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-035.
Abstract PO-045: Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer
Authors: Zhang Yang , Chen Xiaoyi , Gordon-Mitchell Shanisha , Pradhan Kith , Choudhary Gaurav , Bhagat Tushar D. , Agarwal Beamon , Steidl Ulrich , Maitra Anirban , Verma Amit
Published: November 2020

Interleukin-1 Receptor Accessory Protein (IL1RAP) is a surface molecule that mediates activation of pro-inflammatory IL-1 associated signaling pathways. It is overexpressed in myeloid leukemias and is associated with worse prognosis. We aimed to evaluate IL1RAP as a target for therapy in pancreatic adenocarcinoma (PDAC). Immunohistochemistry demonstrated overexpression of IL1RAP in PDAC specimens from K-Ras/p53/Cre (KPC) mice when compared to controls. Evaluation of human PDAC tissue microarrays containing 262 samples also revealed overexpression of IL1RAP in 81% of the samples. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and frank adenocarcinoma specimens indicated that overexpression occurs on malignant EPCAM positive cells during carcinogenesis. IL1RAP knockdown via siRNA on the A6L PDAC cell line significantly reduced cell viability, invasiveness, and ability to form colonies. IL1RAP knockdown cells showed significant arrest in the G1/G0 phase of the cell cycle on flow cytometry and showed reduced phospho-ERK proliferative signaling on Western blot. RNA sequencing of IL1RAP knockdown cells indicated downregulation of several groups of genes involved in cell cycle progression, including CDK1 and TOP2A, whose reduced expression was confirmed on Western blot. Inhibition of the downstream signaling molecule IRAK4 (interleukin-1 receptor-associated kinase 4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in significantly reduced growth in pancreatic cancer cell lines and reduced proliferative phospho-ERK signaling on Western blot. Preliminary in vivo data in NSG mice showed a reduction in tumor size with oral treatments of these two IRAK4 inhibitors. Overall, our studies indicate IL1RAP is overexpressed in PDAC, and reducing IL1RAP and inhibiting downstream IRAK4 result in lowered tumor proliferation in vitro and in vivo, potentially via cell cycle arrest and reduced proliferative signaling.

Citation Format: Yang Zhang, Xiaoyi Chen, Shanisha Gordon-Mitchell, Kith Pradhan, Gaurav Choudhary, Tushar D. Bhagat, Beamon Agarwal, Ulrich Steidl, Anirban Maitra, Amit Verma. Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-045.
Abstract PO-060: Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer
Authors: Shields Mario A. , Spaulding Christina , Khalafalla Mahmoud G. , Pham Thao D.N. , Munshi Hidayatullah G.
Published: November 2020

We previously reported that Gα13 (Gna13), a member of the G12 heterotrimeric G proteins, is upregulated in pancreatic cancer patients and contributes to invasion in cancer cells in vitro. While other reports have demonstrated a tumor promoting function of Gα13 in solid tumors, Gα13 functions as a tumor suppressor in mouse models of B cell lymphoma. In this study, we evaluated the role of Gα13 in mouse models of pancreatitis and pancreatic cancer. To examine the role of Gα13 in pancreatic cancer development and progression, we crossed mice with a floxed allele of Gna13 to mice expressing oncogenic KrasG12D (KrasG12D;Pdx1-Cre). In parallel, we measured transplanted tumors established from pancreatic cell lines, where Gna13 is silenced or deleted. Further, we determined how loss of Gα13 influences cerulein-induced pancreatitis and inflammation-driven tumor progression in mice. Tumors derived from Gα13-deficient cells grew significantly slower than control cells when transplanted in either the orthotopic or subcutaneous site. However, cancer development and overall survival were unaffected in mice with heterozygous loss of Gα13, when compared to mice with intact expression of Gα13. Interestingly, in an aggressive cancer model (KrasG12D;P53R172H;Pdx1-Cre) loss of Gα13 led to faster tumor development and decreased overall survival. Furthermore, we found that Gα13 loss leads to enhanced inflammation and more progressive acinar-ductal metaplasia in pancreatitis. Overall, our results demonstrate a context-dependent role of Gα13 in the pancreas. Similar to previous reports, we show that inhibiting Gα13 in cancer cell lines limits tumor growth in vivo. However, in a genetic mouse model, loss of Gα13 promotes pancreatitis-induced inflammation and promotes tumor development and progression.

Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao D.N. Pham, Hidayatullah G. Munshi. Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-060.
Nagashima-Type Palmoplantar Keratosis with Compound Heterozygous Mutations in SERPINB7
Authors: Songsantiphap Chankiat , Suwanwatana Jirat , Ittiwut Chupong , Asawanonda Pravit , Rerknimitr Pawinee , Shotelersuk Vorasuk
Published: November 2020

Nagashima-type palmoplantar keratosis (NPPK) is a diffuse, non-syndromic (isolated), autosomal recessive palmoplantar keratoderma (PPK) with transgredients. It is characterized by non-progressive mild to moderate transgredient PPK. The mutation in SERPINB7 is reported to underlie the condition. Though many case reports/series have demonstrated various mutations in SERPINB7, the genotype-phenotype correlation in this disorder is still lacking. We herein report two brothers with NPPK. Both patients were found to be compound heterozygous for c.796C>T and c.650_653delCTGT in the SERPINB7 gene. We then summarize the previously reported cases of different mutations in SERPINB7 along with their clinical phenotypes in an attempt to shed some light on this correlation. Further investigations and systematic data collection are still needed to clarify this issue.