bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma
Authors: Schaettler Maximilian O , Desai Rupen , Wang Anthony Z , Livingstone Alexandra J , Kobayashi Dale K , Coxon Andrew T , Bowman-Kirigin Jay A , Liu Connor J , Li Mao , Bender Diane E , White Michael J , Kranz David M , Johanns Tanner M , Dunn Gavin P 
Published: February 2023

BackgroundAdoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)–engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.MethodsWe employed single-cell PCR to isolate a TCR specific for the Imp3D81Nneoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response.ResultsWe isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors.ConclusionsWe generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma.
ABCA3-related interstitial lung disease beyond infancy
Authors: Li Yang , Seidl Elias , Knoflach Katrin , Gothe Florian , Forstner Maria Elisabeth , Michel Katarzyna , Pawlita Ingo , Gesenhues Florian , Sattler Franziska , Yang Xiaohua , Kroener Carolin , Reu-Hofer Simone , Ley-Zaporozhan Julia , Kammer Birgit , Krüger-Stollfuß Ingrid , Dinkel Julien , Carlens Julia , Wetzke Martin , Moreno-Galdó Antonio , Torrent-Vernetta Alba , Lange Joanna , Krenke Katarzyna , Rumman Nisreen , Mayell Sarah , Sismanlar Tugba , Aslan Ayse , Regamey Nicolas , Proesmans Marijke , Stehling Florian , Naehrlich Lutz , Ayse Kilinc , Becker Sebastian , Koerner-Rettberg Cordula , Plattner Erika , Manali Effrosyni D , Papiris Spyridon A , Campo Ilaria , Kappler Matthias , Schwerk Nicolaus , Griese Matthias 
Published: February 2023

BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, theABCA3sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.
Lessons from the implementation of a trauma center-based program to support primary care providers in managing opioids and pain after trauma hospitalization
Authors: Baldwin Laura-Mae , Katers Laura A , Sullivan Mark D , Gordon Debra B , James Adrienne , Tauben David J , Arbabi Saman 
Published: February 2023

BackgroundDecreasing exposure to prescription opioids is critical to lowering risk of opioid misuse, overdose and opioid use disorder. This study reports a secondary analysis of a randomized controlled trial implementing an opioid taper support program directed to primary care providers (PCPs) of patients discharged from a level I trauma center to their homes distant from the center, and shares lessons for trauma centers in supporting these patients.MethodsThis longitudinal descriptive mixed-methods study uses quantitative/qualitative data from trial intervention arm patients to examine implementation challenges and outcomes: adoption, acceptability, appropriateness, feasibility, fidelity. In the intervention, a physician assistant (PA) contacted patients after discharge to review their discharge instructions and pain management plan, confirm their PCP’s identity and encourage PCP follow-up. The PA reached out to the PCP to review the discharge instructions and offer ongoing opioid taper and pain management support.ResultsThe PA reached 32 of 37 patients randomized to the program. Of these 32, 81% discussed topics not targeted by the intervention (eg, social/financial). The PA identified and reached a PCP’s office for only 51% of patients. Of these, all PCP offices (100% adoption) received one to four consults (mean 1.9) per patient (fidelity). Few consults were with PCPs (22%); most were with medical assistants (56%) or nurses (22%). The PA reported that it was not routinely clear to patients or PCPs who was responsible for post-trauma care and opioid taper, and what the taper instructions were.ConclusionsThis level I trauma center successfully implemented a telephonic opioid taper support program during COVID-19 but adapted the program to allow nurses and medical assistants to receive it. This study demonstrates a critical need to improve care transition from hospitalization to home for patients discharged after trauma.Level of evidenceLevel IV.
Performance evaluation of high-dimensional quantum key distribution with single-photon detector based on avalanche photodiode
Authors: Li Dong-Dong , Tang Yan-Lin , Zhao Mei-Sheng , Tao Jun , Dai Yun-Qi , Zhou Lei , Tang Shi-Biao , Zhao Yong 
Published: February 2023

The current theoretical analysis model for high-dimensional quantum key distribution (QKD) was developed without carefully considering the dead time and after-pulse of the single-photon detectors. Here, we propose a new model that accounts for these two effects. With this model, we analyze the effects of various properties of the single-photon detector on the performance of the high-dimensional quantum key distribution and show numerically that the high-dimensional quantum key distribution can be achieved up to 180 km with InGaAs/InP-type single-photon detectors. This work can improve our understanding of the factors that determine the performance of high-dimensional quantum key distribution and will help to promote the application of single-photon detectors based on avalanche photodiodes in high-dimensional quantum key distribution.
Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance
Authors: Marqués Miriam , Corral Sonia , Sánchez-Díaz María , del Pozo Natalia , Martínez de Villarreal Jaime , Schweifer Norbert , Zagorac Ivana , Hilberg Frank , Real Francisco X. 
Published: February 2023

Abstract
Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin—positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.
ADAM Metallopeptidase Domain 12 Facilitates Colorectal Cancer Progression by Inhibiting Hippo Signaling Pathway Activity
Authors: Wang XiaoPeng , Zhu Mo , Zuo Hao , Hou Guowei , Xie Rui 
Published: February 2023

Abstract

This work focused on investigating the effect of A Disintegrin And Metalloproteases 12 (ADAM12) on colorectal cancer development. ADAM12 levels within colorectal cancer samples were analyzed by using The Cancer Genome Atlas (TCGA) database. Then, altogether 55 patients with colorectal cancer were enrolled to detect ADAM12 expression. ADAM12 overexpression or knockdown was transfected into colorectal cancer cells. Thereafter, this work examined colorectal cancer cell viability through Cell Counting Kit-8 (CCK-8) and cell clone forming assays. Meanwhile, nude mice were utilized for in vivo analysis. Transwell assays were conducted for detecting migration and invasion of colorectal cancer cells. In addition, mRN and protein expression was analyzed through qRT-PCR, Western blotting (WB) together with IHC staining. As a result, ADAM12 and YAP1 expression increased among colorectal cancer cases, and it indicated the dismal prognostic outcome of patients. Furthermore, ADAM12 promoted colorectal cancer cell growth, migration, invasion along with in vivo growth. ADAM12 suppressed p-MST1/MST1, p-LATS1/LATS1 together with p-YAP1 protein levels within colorectal cancer cells. ADAM12 increased YAP1 and TAZ protein levels as well as CTGF, Cyr61, and Birc5 mRNA expression in colorectal cancer cells. YAP1 inhibitor administration counteracted ADAM12’s function in promoting colorectal cancer cell growth, migration, invasion, and increasing CTGF, Cyr61, and Birc5 expression.

Implications:
Our study indicates that ADAM12 facilitates colorectal cancer progression through suppressing Hippo pathway activity, and that ADAM12 is the candidate therapeutic target and prognostic biomarker for patients with colorectal cancer.
S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes
Authors: Lin Cindy , Garcia-Gerique Laura , Bonner Erin E. , Mastio Jerome , Rosenwasser Matthew , Cruz Zachary , Lawler Michael , Bernabei Luca , Muthumani Kar , Liu Qin , Poncz Mortimer , Vogl Thomas , Törngren Marie , Eriksson Helena , Vogl Dan T. , Gabrilovich Dmitry I. , Nefedova Yulia 
Published: February 2023

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma.Significance:We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.
Modulations of Storm-Track Activity Associated with the Baroclinic Annular Mode
Authors: Nakayama Morio , Nakamura Hisashi , Okajima Satoru , Ogawa Fumiaki 
Published: February 2023

Abstract
The baroclinic annular mode (BAM) is the leading mode of variability in extratropical eddy activity characterized by its hemispheric-scale pulsing. Based on atmospheric reanalysis data for the Southern Hemisphere, this study reveals BAM-associated systematic modulations not only in fluxes associated with subweekly transient disturbances, as found by earlier studies, but also in their spatial structure involved in the dynamics of the BAM. Specifically, in the positive phase of the BAM characterized by enhanced activity of transient disturbances, their lower-tropospheric baroclinic structure becomes more distinct, and they tend to be more elongated meridionally in both the upper and lower troposphere. These BAM-associated structural modulations of the disturbances favor the more efficient baroclinic development via enhanced poleward heat transport and their downstream development, which can contribute to hemispheric-scale enhancement of kinetic energy associated with the disturbances. In addition, a tendency of the disturbances to exhibit horizontally tilting structure becomes more evident in the positive phase of the BAM, which is favorable for enhanced transport of westerly momentum from the subtropics to the midlatitude polar-front jet, or equivalently enhanced wave-activity propagation from the midlatitude storm track into the subtropics. This modulation lags the peak of anomalous kinetic energy of the disturbances, thus acting to contribute to the decay of the BAM signature. A set of numerical simulations suggests that the BAM-associated pulsing in storm-track activity and structural modulations are manifestations of atmospheric internal dynamics, which can be significantly amplified in the presence of a midlatitude oceanic frontal zone through the formation of more organized and coherent baroclinic wave packets.
Outcomes of Pigtail Catheter Placement versus Chest Tube Placement in Adult Thoracic Trauma Patients: A Systematic Review and Meta-Analysis
Authors: Beeton George , Ngatuvai Micah , Breeding Tessa , Andrade Ryan , Zagales Ruth , Khan Areeba , Santos Radleigh , Elkbuli Adel 
Published: February 2023

IntroductionA debate currently exists regarding the efficacy of pigtail catheters vs chest tubes in the management of thoracic trauma. This meta-analysis aims to compare the outcomes of pigtail catheters vs chest tubes in adult trauma patients with thoracic injuries.MethodsThis systematic review and meta-analysis were conducted using PRISMA guidelines and registered with PROSPERO. PubMed, Google Scholar, Embase, Ebsco, and ProQuest electronic databases were queried for studies comparing the use of pigtail catheters vs chest tubes in adult trauma patients from database inception to August 15th, 2022. The primary outcome was the failure rate of drainage tubes, defined as requiring a second tube placement or VATS, unresolved pneumothorax, hemothorax, or hemopneumothorax requiring additional intervention. Secondary outcomes were initial drainage output, ICU-LOS, and ventilator days.ResultsA total of 7 studies satisfied eligibility criteria and were assessed in the meta-analysis. The pigtail group had higher initial output volumes vs the chest tube group, with a mean difference of 114.7 mL [95% CI (70.6 mL, 158.8 mL)]. Patients in the chest tube group also had a higher risk of requiring VATS vs the pigtail group, with a relative risk of 2.77 [95% CI (1.50, 5.11)].ConclusionsIn trauma patients, pigtail catheters rather than chest tubes are associated with higher initial output volume, reduced risk of VATS, and shorter tube duration. Considering the similar rates of failure, ventilator days, and ICU length-of-stay, pigtail catheters should be considered in the management of traumatic thoracic injuries.Study TypeSystematic Review and meta-analysis.
Successful Cesarean Section in a COVID-19 Patient on Extracorporeal Membrane Oxygenation (ECMO)
Authors: Coffey Philip , Sakharuk Ilya , Yoshida Shohei , Drevets Peter , Patel Vijay 
Published: February 2023

The pandemic of COVID-19-related respiratory failure has increased utilization of ECMO in diverse patient populations. There are limited published reports of ECMO use in pregnancy, and reports of successful delivery of the fetus with survival of the mother on ECMO are exceptionally rare. We present a case of Cesarean section while on ECMO for COVID-19-related respiratory failure with survival of both mother and infant. A 37-year-old pregnant female presented with dyspnea following a positive COVID-19 test. D-Dimer and CRP were elevated and chest radiography was consistent with COVID-19 pneumonia. Her respiratory status rapidly decompensated—requiring endotracheal intubation within 6 hours of presentation, and ultimately veno-venous ECMO cannulation. Three days later, fetal heart rate decelerations prompted emergent caesarean delivery. The infant was transferred to the NICU and progressed well. The patient improved and she was decannulated on hospital day 22 (ECMO day 15) before discharge to rehab on hospital day 49. In this case, ECMO allowed survival of both mother and infant in an otherwise non-survivable respiratory failure. Consistent with existing reports, we believe ECMO is a viable strategy for refractory respiratory failure in the pregnant patient.
Community partners’ experiences with medical students’ service-learning activities
Authors: Pellerano Maria B , Fingerhut Lori , Giordano Susan , Kaul Eshan , Baptiste Brittany , Jimenez Manuel E , Jahn Eric 
Published: February 2023

Background: The perspectives of community partners about their experiences working with medical students and how service-learning experiences affect the communities they serve remains understudied. Objective: This study addressed gaps in the literature by reporting on in-depth interviews conducted with community partners who participated in a well-established medical school service-learning programme. Design: A qualitative study was undertaken using semi-structured interviews and an edited coding strategy. Setting: A convenience sample was recruited from a database of organisations working with the medical school’s service-learning organisation. Method: Between 2017 and 2020, the researchers conducted semi-structured interviews with community-based organisation partners who worked with medical students through a service-learning initiative in an urban, underserved area of New Jersey, USA. The authors coded transcripts and identified themes after extensive reading, reflection and team discussion of transcripts and coded text. Authors confirmed thematic saturation after 20 interviews with 21 participants representing 18 different agencies. Results: Three main themes were developed: (1) medical students as role models, (2) community partners’ role in shaping medical student education, and (3) reciprocity between community-based organisations and the service-learning programme. Participants found that medical students connected well with young clients and motivated them to pursue higher education or healthcare careers especially when they had a shared ethnic or cultural background. Community partners helped medical students better understand ethnically and socioeconomically diverse communities from a whole-person perspective. Participants described collaborative learning and reciprocity between the service-learning programme and community-based organisations as a ‘win-win’ situation – with clients, the organisation and medical students all benefitting. Conclusion: Findings illustrate the importance of reciprocity between medical students and community partners. Incorporating partners in the design and evaluation of service-learning programmes is essential to understanding how community and academic health centres can better collaborate to promote health equity.