bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance
Authors: Yap Timothy A. , LoRusso Patricia M. , Wong Deborah J. , Hu-Lieskovan Siwen , Papadopoulos Kyriakos P. , Holz Josefin-Beate , Grabowska Urszula , Gradinaru Cristian , Leung Kin-Mei , Marshall Sylwia , Reader Claire S. , Russell Roslin , Sainson Richard C.A. , Seal Claire J. , Shepherd Christopher J. , Germaschewski Fiona , Gliddon Daniel , Stern Omer , Young Lesley , Brewis Neil , Kayitalire Louis , Morrow Michelle 
Published: November 2022

AbstractPurpose:This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody–targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti–PD-(L)1 therapy.Patients and Methods:Patients with solid tumors, refractory to anti–PD-(L)1–based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 μg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics.Results:Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti–PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1–targeted therapy.Conclusions:FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti–PD-(L)1 therapy.See related commentary by Karapetyan and Luke, p. 835
Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death
Authors: Jenkins Laura J. , Luk Ian Y. , Fairlie W. Douglas , Lee Erinna F. , Palmieri Michelle , Schoffer Kael L. , Tan Tao , Ng Irvin , Vukelic Natalia , Tran Sharon , Tse Janson W.T. , Nightingale Rebecca , Alam Zakia , Chionh Fiona , Iatropoulos George , Ernst Matthias , Afshar-Sterle Shoukat , Desai Jayesh , Gibbs Peter , Sieber Oliver M. , Dhillon Amardeep S. , Tebbutt Niall C. , Mariadason John M. 
Published: November 2022

Abstract
The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.
The Bispecific Tumor Antigen-Conditional 4–1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
Authors: Nelson Michelle H. , Fritzell Sara , Miller Robert , Werchau Doreen , Van Citters Danielle , Nilsson Anneli , Misher Lynda , Ljung Lill , Bader Robert , Deronic Adnan , Chunyk Allison G. , Schultz Lena , Varas Laura A. , Rose Nadia , Håkansson Maria , Gross Jane , Furebring Christina , Pavlik Peter , Sundstedt Anette , Veitonmäki Niina , Ramos Hilario J. , Säll Anna , Dahlman Anna , Bienvenue David , von Schantz Laura , McMahan Catherine J. , Askmyr Maria , Hernandez-Hoyos Gabriela , Ellmark Peter 
Published: November 2022

Abstract4–1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4–1BB on tumor-specific cytotoxic T cells makes 4–1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4–1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4–1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4–1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4–1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4–1BB–mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models
Authors: Ku Amy T. , Young Adelaide I.J. , Ibrahim Ahmed Atef , Bu Wen , Jiang Weiyu , Lin Meng , Williams Laterrica C. , McCue Bryant Lee , Miles George , Nagi Chandandeep , Behbod Fariba , Li Yi 
Published: November 2022

Abstract

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.

Prevention Relevance:
PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.
Blocking MG53
S255
Phosphorylation Protects Diabetic Heart From Ischemic Injury
Authors: Lv Fengxiang , Wang Yingfan , Shan Dan , Guo Sile , Chen Gengjia , Jin Li , Zheng Wen , Feng Han , Zeng Xiaohu , Zhang Shuo , Zhang Yan , Hu Xinli , Xiao Rui-Ping 
Published: November 2022

Background:
As an integral component of cell membrane repair machinery, MG53 (mitsugumin 53) is important for cardioprotection induced by ischemia preconditioning and postconditioning. However, it also impairs insulin signaling via its E3 ligase activity-mediated ubiquitination-dependent degradation of IR (insulin receptor) and IRS1 (insulin receptor substrate 1) and its myokine function-induced allosteric blockage of IR. Here, we sought to develop MG53 into a cardioprotection therapy by separating its detrimental metabolic effects from beneficial actions.

Methods:
Using immunoprecipitation-mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we investigated the role of MG53 phosphorylation at serine 255 (S255). In particular, utilizing recombinant proteins and gene knock-in approaches, we evaluated the potential therapeutic effect of MG53-S255A mutant in treating cardiac ischemia/reperfusion injury in diabetic mice.

Results:

We identified S255 phosphorylation as a prerequisite for MG53 E3 ligase activity. Furthermore, MG53
S255
phosphorylation was mediated by GSK3β (glycogen synthase kinase 3 beta) and markedly elevated in the animal models with metabolic disorders. Thus, IR-IRS1-GSK3β-MG53 formed a vicious cycle in the pathogenesis of metabolic disorders where aberrant insulin signaling led to hyper-activation of GSK3β, which in turn, phosphorylated MG53 and enhanced its E3 ligase activity, and further impaired insulin sensitivity. Importantly, S255A mutant eliminated the E3 ligase activity while retained cell protective function of MG53. Consequently, the S255A mutant, but not the wild type MG53, protected the heart against ischemia/reperfusion injury in
db/db
mice with advanced diabetes, although both elicited cardioprotection in normal mice. Moreover, in S255A knock-in mice, S255A mutant also mitigated ischemia/reperfusion-induced myocardial damage in the diabetic setting.

Conclusions:
S255 phosphorylation is a biased regulation of MG53 E3 ligase activity. The MG53-S255A mutant provides a promising approach for the treatment of acute myocardial injury, especially in patients with metabolic disorders.
Mechanism by Which Inflammation and Oxidative Stress Induce Mineralocorticoid Receptor Gene Expression in Aging Vascular Smooth Muscle Cells
Authors: Ibarrola Jaime , Lu Qing , Zennaro Maria-Christina , Jaffe Iris Z. 
Published: November 2022

Background:
Vascular MR (mineralocorticoid receptor) expression increases with age driving aging-associated vascular stiffness and hypertension. MR has two isoforms (1α and 1β) with distinct 5′-untranslated and promoter sequences (P1 and P2), but the gene regulatory mechanisms remain unknown. We investigated mechanisms driving MR gene transcriptional regulation in aging human smooth muscle cells (SMC).

Methods:

MR was quantified in aortic tissue and primary human aortic SMC (HASMC) comparing adult and aged donors and adult HASMC treated with H
2
O
2
, to induce aging. Predicted transcription factor (TF) binding sites in the MR gene were validated using chromatin immunoprecipitations and reporter assays. The impact of TF inhibitors on MR isoforms and fibrosis target gene expression was examined.

Results:

Expression of both MR mRNA isoforms increased with donor age or H
2
O
2
treatment in HASMCs. HIF1α (hypoxia-inducible factor) and the inflammatory TF NFκB (nuclear factor kappa B) both increased with age in HASMCs and are predicted to bind MR promoters. H
2
O
2
induced HIF1α and NFκB expression and DNA binding of HIF1α to the MR P1 promoter and of NFκB to both MR promoters in HASMCs. HIF1α inhibition decreased MR-1α isoform expression while NFκB inhibition decreased both MR isoforms. HIF1α, NFκB, and MR inhibition decreased the expression of a SMC-MR target gene implicated in vascular fibrosis. In human aortic tissues, expression of HIF1α and NFκB each positively correlated with donor age and MR expression (
P
<0.0001).

Conclusions:
These data implicate the inflammatory TF, NFκB, and oxidative stress-induced TF, HIF1α, in regulating SMC MR transcription in aging HASMCs, which drives aging-related vascular stiffness and cardiovascular disease.
Resolvin D2 Attenuates Cardiovascular Damage in Angiotensin II-Induced Hypertension
Authors: Díaz del Campo Lucia S. , García-Redondo Ana B. , Rodríguez Cristina , Zaragoza Carlos , Duro-Sánchez Santiago , Palmas Francesco , de Benito-Bueno Angela , Socuéllamos Paula G. , Peraza Diego A. , Rodrigues-Díez Raquel , Valenzuela Carmen , Dalli Jesmond , Salaices Mercedes , Briones Ana M. 
Published: November 2022

Background:
Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension.

Methods:
Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion.

Results:
Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype.

Conclusions:
There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.
Studying Edema Formation After Release of the Infraspinatus Tendon as an Experimental Model of Rotator Cuff Tears in Sheep: A Preliminary Imaging and Morphological Analysis
Authors: Lädermann Alexandre , Gehrke Rieke , Klein Karina , Karol Agnieszka , Darwiche Salim , Schwarzenberg Peter , Steffen Thomas , Wieser Karl , Kronen Peter , von Rechenberg Brigitte 
Published: November 2022

Background: The cause, extent, and role of muscle edema for muscle degeneration are unknown and not considered in the current literature. In vivo experiments were designed to prove muscle edema formation in the early period in a sheep model of acute rotator cuff tears. Hypothesis: Muscle edema occurs after tendon release with or without additional stretching trauma and may be associated with muscle retraction and subsequent muscle degeneration. Study Design: Controlled laboratory study. Methods: A sheep model with acute release of the infraspinatus tendon was used. An osteotomy of the greater tuberosity, including the insertion of the infraspinatus tendon, was performed in 14 sheep. To demonstrate presence of edema, magnetic resonance imaging scans were performed at 0, 2, and 4 weeks using T1-weighted, T2-weighted, proton density–weighted, and Dixon sequences. Excisional biopsy specimens were taken at 0, 3, and 4 weeks (histological results will be reported in a later publication). Two injury models were created: a nontrauma group that consisted of muscle release alone and a trauma group that included additional standardized traction to the musculotendinous unit. Evaluation of T1- and T2-weighted images included calculation of pennation angle, muscle fiber length, signal intensity (edema), and muscle volume. Muscle wet weight and volume were measured at sacrifice. Results: Edema formation was shown in all sheep and slightly more pronounced in the trauma group, where muscle intensity increased significantly between time point 0 (200 Grey Value (GV)) and weeks 2, 3, and 4 (300 GV). Edema formation started early after tendon release with a plateau between 3 and 4 weeks. Deterioration of muscle fiber bundles began also after tendon release with a peak at 4 weeks. Muscle volume decreased steadily over time. Conclusion: Muscle edema appeared early after rotator cuff tendon release, was more pronounced in the trauma group, and reached a plateau after 3 to 4 weeks. Muscle fatty content decreased within the short period of 4 weeks owing to a dilution effect. Muscle edema seems to be an essential factor in cuff tears and subsequent muscle retraction and degeneration. Clinical Relevance: This study demonstrates a new type of muscle edema of retraction and describes the characteristics of edema associated with a retracted rotator cuff tear.
Effect of Fatty Infiltration of the Infraspinatus Muscle on Outcomes and Graft Failure After Arthroscopic Superior Capsule Reconstruction for Irreparable Posterosuperior Rotator Cuff Tears
Authors: Lee Jun-Bum , Kholinne Erica , Yeom Ji Woong , Ben Hui , AlAhmadi Basim Masoud , Koh Kyung-Hwan , Jeon In-Ho 
Published: November 2022

Background: Superior capsule reconstruction (SCR) was developed as an alternative treatment for irreparable rotator cuff tears to restore superior stability of the glenohumeral joint. Although fatty infiltration (FI) of the rotator cuff muscles, especially the infraspinatus, has been implicated as a predictor of outcomes and graft integrity after rotator cuff repair, it has not been fully investigated in cases of SCR. Purpose: To evaluate the effect of FI of the infraspinatus muscle on clinical and radiological outcomes after SCR. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 55 consecutive patients with irreparable posterosuperior rotator cuff tears who underwent SCR between January 2013 and August 2020 were included retrospectively. Preoperative and postoperative clinical and radiological findings (median follow-up of >2 years), including magnetic resonance imaging results, were thoroughly reviewed. The patients were divided into 2 groups: group 1 with mild FI of the infraspinatus (Goutallier grades 0-2) and group 2 with severe FI of the infraspinatus (Goutallier grades 3-4). The American Shoulder and Elbow Surgeons score, Constant score, visual analog scale score for pain, and range of motion were evaluated. Acromiohumeral distance and rotator cuff tear arthropathy using the Hamada classification were assessed on plain radiography. Postoperative graft integrity was evaluated by magnetic resonance imaging. Graft failure was defined as complete discontinuity. Univariate and multivariable logistic regression analyses were performed to evaluate clinical and radiological findings that might be associated with successful SCR. Results: Clinical and radiological outcomes significantly improved after SCR. Graft failure was noted in 15 (27.3%) patients and was more frequent in group 2 than in group 1 (50.0% vs 14.3%, respectively; P = .004). Univariate analysis indicated a significant association between severe FI in the infraspinatus (group 2) and graft failure after SCR (odds ratio, 6.00 [95% CI, 1.65-21.80]; P = .006). Multivariable analysis indicated that FI of the infraspinatus was the only factor associated with graft failure (odds ratio, 6.37 [95% CI, 1.63-24.90]; P = .008). Conclusion: Severe FI of the infraspinatus muscle was a factor indicating a poor prognosis for graft integrity after SCR. Preoperative evaluation of FI in the rotator cuff muscles can help predict postoperative outcomes and may help guide therapeutic options.
Quantifying consultations to medical specialties during psychiatric inpatient admissions in a Queensland tertiary hospital
Authors: Holland Carissa , Hudson-Jessop Pamela 
Published: November 2022

Objectives To identify and characterise medical consultations to psychiatric inpatients. Method Retrospective cross-sectional descriptive study of 451 psychiatric inpatients’ electronic medical records between 1 January and 30 June 2021 with descriptive statistics. Results Thirty one percent ( n = 131) of inpatients required medical consultation, with 382 total consultations including ward call. Half (57.9%) were telephone advice. Main consulting specialties were general medicine (25%), anaesthetics (12%), neurology (9.9%), cardiology (6.5%) and endocrinology (6.2%). Almost all (99.0%) consultations resulted in documented management plans. Conclusions This is the first Australian descriptive study quantifying and characterising psychiatric inpatient consultation requests. Physical and psychiatric healthcare integration requires ongoing efforts, including improved referral pathways.
An Adlerian-Based Narrative Inquiry of Temporal Awareness, Resilience, and Patient-Centeredness Among Emergency Physicians—The Gyroscope Model
Authors: Gabay Gillie , Ben-Asher Smadar 
Published: November 2022

Introduction Although extensive research examined time perceptions among patients in the emergency department (ED), studies on temporal awareness among emergency physicians is scant. Salutogenics is the theoretical anchor. Methods The sample comprised ten emergency resident physicians from an Israeli public tertiary hospital. Narrative interviews were conducted. To determine the theme of the study, Adlerian narrative analysis was performed. To identify categories, semantic and content analyses were performed. Results Adlerian narrative analysis highlighted temporal awareness as a strong theme across interviews. Semantic and content analyses identified categories within temporal awareness. Analyses revealed a movement among three subcategories: A clinical task in which physicians rapidly shift along seven distinct times, temporal awareness shaping their work experience, and temporal awareness as inhibiting or enabling relationships with patients. Data-analyses identified two groups of physicians, one group driven by the need to control the time to avoid errors, experiencing anxiety and poor wellbeing, and the other, shifting from clinical tasks to patient-centeredness while removing the time factor from their considerations and experiencing resilience through manageability and meaningfulness. We introduce the “gyroscope model” for physicians to illustrate these findings and propose recommendations for practice. Discussion Understanding the complexity of the temporal continuum and the influence of shifting from the clinical task to relationships with patients may contribute to resilience of resident physician in the ED and to their self-efficacy, enriching their professional skills and capacity to cope and grow while facing the complexity of the ED