bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune profiling of uveal melanoma identifies a potential signature associated with response to immunotherapy
Authors: Qin Yong , Bollin Kathryn , de Macedo Mariana Petaccia , Carapeto Fernando , Kim Kevin B , Roszik Jason , Wani Khalida M , Reuben Alexandre , Reddy Sujan T , Williams Michelle D , Tetzlaff Michael T , Wang Wei-Lien , Gombos Dan S , Esmaeli Bita , Lazar Alexander J , Hwu Patrick , Patel Sapna P 
Published: November 2020

BackgroundTo date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies.MethodsRelevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM. Immune gene expression profiling was conducted by NanoString analysis on pre-treatment and post-treatment tumors from patients (n=6) receiving immune checkpoint blockade or 4-1BB and OX40 dual costimulation. The immune signature of UM tumors responding to immunotherapy was further characterized by Ingenuity Pathways Analysis and validated in The Cancer Genome Atlas data set.ResultsBoth primary and metastatic UM tumors showed detectable infiltrating lymphocytes. Compared with primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3+, CD8+, FoxP3+ T cells, and CD68+ macrophages. Notably, levels of PD-1+ infiltrates and PD-L1+ tumor cells were low to absent in primary and metastatic UM tumors. No metastatic organ-specific differences were seen in immune infiltrates. Our NanoString analysis revealed significant differences in a set of immune markers between responders and non-responders. A group of genes relevant to the interferon-γ signature was differentially up-expressed in the pre-treatment tumors of responders. Among these genes, suppressor of cytokine signaling 1 was identified as a marker potentially contributing to the response to immunotherapy. A panel of genes that encoded pro-inflammatory cytokines and molecules were expressed significantly higher in pre-treatment tumors of non-responders compared with responders.ConclusionOur study provides critical insight into immune profiles of UM primary and metastatic tumors, which suggests a baseline tumor immune signature predictive of response and resistance to immunotherapy in UM.
Body mass index (BMI) and outcome of metastatic melanoma patients receiving targeted therapy and immunotherapy: a multicenter international retrospective study
Authors: Rutkowski Piotr , Indini Alice , De Luca Matilde , Merelli Barbara , Mariuk-Jarema Anna , Teterycz Pawel , Rogala Pawel , Lugowska Iwona , Cybulska-Stopa Bożena , Labianca Alice , Di Guardo Lorenza , Del Vecchio Michele , Pigozzo Jacopo , Randon Giovanni , Corti Francesca , Tondini Carlo Alberto , Rulli Eliana , Mandala Mario 
Published: November 2020

BackgroundObesity is a risk factor for malignancy; however, its prognostic role in patients with metastatic melanoma is controversial. We aim to investigate the prognostic role of body mass index (BMI) in patients with metastatic melanoma receiving mitogen-activated pathway kinase inhibitors (MAPKi), immune checkpoint inhibitors (ICIs) alone or their sequence.MethodsData on patients with metastatic melanoma receiving ≥1 line of systemic treatment were retrieved from prospectively collected databases. Progression-free survival (PFS) and overall survival (OS) were analyzed by means of multivariable stratified Cox regression models; disease control rate (DCR) was analyzed by multivariable stratified logistic regression models. Subgroup analyzes according to the type of treatments received, and inBRAF-mutated patients were pre-planned. All multivariable models included BMI, age, gender, American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment sequencing strategy as covariates.ResultsBetween November 2010 and November 2018, 688 patients from three Italian and two Polish centers were enrolled. 379 (57%) patients had M1c/d disease, 273 (41%) were female and the mean BMI was 27.1 (SD=4.9). Considering first-line treatment, 446 patients (66.8%) received ICIs and 222 MAPKi. No impact of BMI on OS was detected either considering the first line of ICIs, or ICIs sequencing (HR=1.02, 95% CI: 0.99 to 1.05, p=0.202, and HR=1.02, 95% CI: 0.99 to 1.04, p=0.237, respectively). A late effect of BMI on OS was found in patients treated with MAPKi: for five units increment, a 51% of risk reduction at 18 months and a 76% of risk reduction at 30 months were observed. No significant effect of BMI on PFS and DCR was found in any of the subgroup analyzes.ConclusionIn patients with metastatic melanoma receiving ICIs, there is no impact of BMI on DCR, PFS and OS. The late prognostic effect of BMI in patients treated with MAPKi should be considered hypothesis generating and needs to be further investigated.
Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy
Authors: Gao Hannan , Wu Yue , Shi Jiyun , Zhang Xin , Liu Tianyu , Hu Biao , Jia Bing , Wan Yakun , Liu Zhaofei , Wang Fan 
Published: November 2020

ObjectivesStrategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled nanobody-based imaging probe 99mTc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of 99mTc-MY1523 SPECT/CT imaging.MethodsThe binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with 99mTc by a site-specific transpeptidation of Sortase-A, and the biodistribution and single photon emission CT (SPECT)/CT were performed in mice bearing different tumors. We used interferon-γ (IFN-γ) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of 99mTc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by 99mTc-MY1523 SPECT/CT were carried out in MC-38, A20, and 4T1 tumor-bearing mouse models, followed by the testing of tumor infiltration T cells.ResultsMY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. 99mTc-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-γ intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by 99mTc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by 99mTc-MY1523 SPECT/CT imaging significantly enhanced the therapeutic efficacy in all animal models, while the tumor growth was effectively suppressed, and the survival time of mice was evidently prolonged. A correlation between dynamically upregulated PD-L1 expression and improved PD-L1 blockade therapy effectiveness was revealed, and the markedly increased infiltration of effector T cells into tumors was verified after the imaging-guided therapy.ConclusionOur results demonstrated that 99mTc-MY1523 SPECT/CT allowed a real-time, quantitative and dynamic mapping of PD-L1 expression in vivo, and the imaging-guided PD-L1 blockade immunotherapy significantly enhanced the therapeutic efficacy. This strategy merits translation into clinical practice for the better management of combination therapies with radiotherapy or chemotherapy.
Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial
Authors: Martin-Broto Javier , Hindi Nadia , Grignani Giovanni , Martinez-Trufero Javier , Redondo Andres , Valverde Claudia , Stacchiotti Silvia , Lopez-Pousa Antonio , D'Ambrosio Lorenzo , Gutierrez Antonio , Perez-Vega Herminia , Encinas-Tobajas Victor , de Alava Enrique , Collini Paola , Peña-Chilet Maria , Dopazo Joaquin , Carrasco-Garcia Irene , Lopez-Alvarez Maria , Moura David S , Lopez-Martin Jose A 
Published: November 2020

BackgroundSarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).MethodsThis single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level −1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).ResultsFrom May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).ConclusionsSunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months.Trial registration numberNCT03277924.
The Paley ilioischial limb modification of the Dega osteotomy
Authors: Bor Noam , Dujovny Eytan , Rozen Nimrod , Rubin Guy 
Published: November 2020

BackgroundWe aim to describe a modified Dega osteotomy technique in detail, emphasizing its eventual advantages in comparison to the original Dega osteotomy and ‘San Diego’ modification. We also present our related literature review on various osteotomy techniques.MethodsWe reviewed the radiological indices of 27 dysplastic hips in 25 children with cerebral palsy and developmental dislocation of the hips (9 boys, 16 girls; mean age, 5 years) who underwent a modified Dega osteotomy according to Paley.ResultsComparing the radiological indices results between our patients and those reported by the various authors in the literature, the data are almost identical.ConclusionsThe modified Dega osteotomy is the only technique wherein all two limbs of the triradiate cartilage are true, which becomes a single hinge where the osteotomy turns. Despite the similar results in the radiological indices between our patients and those in the literature, we still consider that the entire triradiate cartilage is a better hinge point for the iliac osteotomy. The difference between the osteotomy adopted in our institution and the modality described by most authors in the literature is that the latter mostly ignore or miss the ischial limb of the triradiate cartilage.
Comparative protective effects of N-acetylcysteine and melatonin against obesity-induced testicular dysfunction in rats
Authors: Khalil Sama S. , Aziz Joseph Amin , Ismail Khadiga Ahmed , El-Malkey Nanees F. 
Published: November 2020

N-acetylcysteine (NAC) and melatonin were reported to exert protective effects on testicular tissues. Thus, this study aimed to determine which of these is more efficient against obesity-induced testicular dysfunction in albino rats. A total of 32 adult male rats (195 ± 10 g) were divided into four groups: control, obese rats fed a high-fat diet (HFD), HFD+NAC (150 mg/kg per day, i.p.) and HFD+melatonin (10 mg/kg per day, i.p.), for 5 weeks. Testes and epididymis were weighed. Lipid profile, pituitary-testicular hormones, tumor necrosis factor α (TNFα), epididymal sperm parameters, testicular oxidant–antioxidant system, testicular and the epididymal histopathology and immunohistochemical localization for androgen receptors (AR) and Bax reaction were analyzed. Administration of NAC or melatonin significantly improved the lipid parameters, gonadal hormones, TNFα level, sperm count and abnormal morphology, oxidant–antioxidant system and the absolute testicular and epididymal mass with an enhancement of testicular architecture, AR expression and apoptosis as compared with that in the obese group. Additionally, as compared with the NAC group, the melatonin group had significantly reduced body mass index, total cholesterol, triglyceride, and TNFα and increased testosterone, sperm count, motility, superoxide dismutase activity, mitigated histomorphometrical changes, Bax expression, and increased testicular AR expression. Therefore, melatonin was more efficient than NAC in affording fortification against HFD-induced testicular dysfunction.
A note on the linear stability of black holes in quadratic gravity
Authors: Dioguardi Christian , Rinaldi Massimiliano 
Published: November 2020

AbstractBlack holes in f(R)-gravity are known to be unstable, especially the rotating ones. In particular, an instability develops that looks like the classical black hole bomb mechanism: the linearized modified Einstein equations are characterized by an effective mass that acts like a massive scalar perturbation on the Kerr solution in general relativity, which is known to yield instabilities. In this note, we consider a special class of f(R) gravity that has the property of being scale-invariant. As a prototype, we consider the simplest case $$f(R)=R^2$$

f

(
R
)

=

R
2

and show that, in opposition to the general case, static and stationary black holes are stable, at least at the linear level. Finally, the result is generalized to a wider class of f(R) theories.
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.
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

AbstractAlthough 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

Abstract

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

Abstract
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.