bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting CD73 with AB680 (Quemliclustat), a Novel and Potent Small-Molecule CD73 Inhibitor, Restores Immune Functionality and Facilitates Antitumor Immunity
Authors: Piovesan Dana , Tan Joanne B.L. , Becker Annette , Banuelos Jesus , Narasappa Nell , DiRenzo Daniel , Zhang Kristen , Chen Ada , Ginn Elaine , Udyavar Akshata R. , Yin Fangfang , Paprcka Susan L. , Purandare Bhamini , Park Timothy W. , Kimura Nikki , Kalisiak Jaroslaw , Young Stephen W. , Powers Jay P. , Schindler Uli , Sivick Kelsey E. , Walters Matthew J. 
Published: April 2022

Abstract
T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell–mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti–PD-1, to improve cancer patient outcomes.
A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies
Authors: Zimmermann Astrid , Zenke Frank T. , Chiu Li-Ya , Dahmen Heike , Pehl Ulrich , Fuchss Thomas , Grombacher Thomas , Blume Beatrix , Vassilev Lyubomir T. , Blaukat Andree 
Published: April 2022

Abstract
Radiotherapy and chemical DNA-damaging agents are among the most widely used classes of cancer therapeutics today. Double-strand breaks (DSB) induced by many of these treatments are lethal to cancer cells if left unrepaired. Ataxia telangiectasia-mutated (ATM) kinase plays a key role in the DNA damage response by driving DSB repair and cell-cycle checkpoints to protect cancer cells. Inhibitors of ATM catalytic activity have been shown to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DSB-inducing modalities. Here, we describe the pharmacological activities of two highly potent and selective ATM inhibitors from a new chemical class, M3541 and M4076. In biochemical assays, they inhibited ATM kinase activity with a sub-nanomolar potency and showed remarkable selectivity against other protein kinases. In cancer cells, the ATM inhibitors suppressed DSB repair, clonogenic cancer cell growth, and potentiated antitumor activity of ionizing radiation in cancer cell lines. Oral administration of M3541 and M4076 to immunodeficient mice bearing human tumor xenografts with a clinically relevant radiotherapy regimen strongly enhanced the antitumor activity, leading to complete tumor regressions. The efficacy correlated with the inhibition of ATM activity and modulation of its downstream targets in the xenograft tissues. In vitro and in vivo experiments demonstrated strong combination potential with PARP and topoisomerase I inhibitors. M4076 is currently under clinical investigation.
Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts
Authors: Ellegast Jana M. , Alexe Gabriela , Hamze Amanda , Lin Shan , Uckelmann Hannah J. , Rauch Philipp J. , Pimkin Maxim , Ross Linda S. , Dharia Neekesh V. , Robichaud Amanda L. , Conway Amy Saur , Khalid Delan , Perry Jennifer A. , Wunderlich Mark , Benajiba Lina , Pikman Yana , Nabet Behnam , Gray Nathanael S. , Orkin Stuart H. , Stegmaier Kimberly 
Published: April 2022

Abstract

Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1β/TNFα signaling via NFκB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.

Significance:
This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death.
See related commentary by Puissant and Medyouf, p. 1617.
This article is highlighted in the In This Issue feature, p. 1599
The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
Authors: Nirmal Ajit J. , Maliga Zoltan , Vallius Tuulia , Quattrochi Brian , Chen Alyce A. , Jacobson Connor A. , Pelletier Roxanne J. , Yapp Clarence , Arias-Camison Raquel , Chen Yu-An , Lian Christine G. , Murphy George F. , Santagata Sandro , Sorger Peter K. 
Published: April 2022

AbstractCutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1–PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.Significance:The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell–cell contact.This article is highlighted in the In This Issue feature, p. 1397
Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations
Authors: Wang Mengzhao , Yang James Chih-Hsin , Mitchell Paul L. , Fang Jian , Camidge D. Ross , Nian Weiqi , Chiu Chao-Hua , Zhou Jianying , Zhao Yanqiu , Su Wu-Chou , Yang Tsung-Ying , Zhu Viola W. , Millward Michael , Fan Yun , Huang Wen-Tsung , Cheng Ying , Jiang Liyan , Brungs Daniel , Bazhenova Lyudmila , Lee Chee Khoon , Gao Bo , Xu Yan , Hsu Wei-Hsun , Zheng Li , Jänne Pasi A. 
Published: April 2022

Abstract

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non–small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.

Significance:
We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC.
This article is highlighted in the In This Issue feature, p. 1599
Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C
Authors: Weiss Andreas , Lorthiois Edwige , Barys Louise , Beyer Kim S. , Bomio-Confaglia Claudio , Burks Heather , Chen Xueying , Cui Xiaoming , de Kanter Ruben , Dharmarajan Lekshmi , Fedele Carmine , Gerspacher Marc , Guthy Daniel Alexander , Head Victoria , Jaeger Ashley , Núñez Eloísa Jiménez , Kearns Jeffrey D. , Leblanc Catherine , Maira Sauveur-Michel , Murphy Jason , Oakman Helen , Ostermann Nils , Ottl Johannes , Rigollier Pascal , Roman Danielle , Schnell Christian , Sedrani Richard , Shimizu Toshio , Stringer Rowan , Vaupel Andrea , Voshol Hans , Wessels Peter , Widmer Toni , Wilcken Rainer , Xu Kun , Zecri Frederic , Farago Anna F. , Cotesta Simona , Brachmann Saskia M. 
Published: April 2022

Abstract

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors.

Significance:
JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155.
See related video: https://vimeo.com/720726054
This article is highlighted in the In This Issue feature, p. 1397
From Sister-Wife to Brother-Neighbor: Rosenzweig Reads the Song of Songs
Authors: Cooper Andrea Dara 
Published: April 2022

Abstract
This paper investigates a sibling metaphor central to Rosenzweig’s reading of the Song of Songs in The Star of Redemption, in which the lovers yearn to be united in societal fraternity. His interpretation is marked by fraternal tropes and the subsequent effacement of gender. Rosenzweig transposes the erotic energy in the Song from a celebration of difference to a longing for sameness, a move that has exegetical, philosophical, and theological implications. Ultimately, the erotic sphere of revelation is surpassed by neighborly “brotherliness” in communal redemption.
1. The Theoretical Framework
Authors: Nebel Mathias 
Published: April 2022

Mathias Nebel develops in this chapter the theoretical foundation of a common good approach to development. Building on Foucault, Arendt, Bourdieu, Giddens, Oström, Taylor, and Riordan, he proposes to understand the common good from the perspective of the interactions structuring our communal life. The chapter takes up many of the Antique and Medieval insights of the notion but then reframes the concept from the perspective of a philosophy of action. This is actually the main shift in his approach to the concept. He argues that the common good is essentially linked to the way our social interactions are generated and thrive. A common good perspective on society is therefore neither totalitarian nor conservative. On the contrary, it is creative, capable of novelty and inclusiveness; it embraces not only plurality, justice and law, but also the purpose of the good life in politics.
In the interest of pedagogical clarity, the chapter structures its theoretical insights around a vocabulary of the common good, that will then be coherently used by all other articles in this book. He distinguishes between the many specific and limited common goods existing in a society and coins the expression nexus of common goods to explain the dynamic system of specific common goods in a given society. Both are differentiated from the universal common good, which is in itself a goal and a task, and whose content is our common humanity.
Do All Isolated Traumatic Subarachnoid Hemorrhages Need to Be Transferred to a Level 1 Trauma Center?
Authors: Forney Eric D. , Montgomery Anne , Williams Marshal , Patel Mital D. , Ashley Dennis W. 
Published: April 2022

Background The management of isolated traumatic subarachnoid hemorrhage (itSAH) in non-trauma centers usually results in transfer to a Level 1 trauma center with neurosurgical capabilities. Due to lack of trauma center resources, we sought to evaluate if patients with itSAH need transfer to a Level I trauma center. Methods A retrospective review of the trauma registry was conducted from Jan 2015-Dec 2020. Patients with itSAH on initial computed tomographic imaging and a Glasgow Coma Scale score >13 were included. Patients with any other intracranial pathology, skull fractures, multi-system trauma or age less than 15 were excluded. Results 120 patients were identified with itSAH. Mean age was 63 years, and 44% were male. Mean injury severity score was 4.7 with 48% on anticoagulation/antiplatelet therapy. Radiology Reports were reviewed and only 2 scans (1.7%) showed an increase in itSAH, 98.3% reports revealed no change, improvement, or resolution. No patients deteriorated and no patients underwent neurosurgical intervention. Once admitted, 27 (23%) were treated for acute medical conditions and 39 (33%) required subspecialty medical consultations. There was no difference in increased itSAH on repeat imaging between patients on anticoagulation/antiplatelet therapy and those without. The population taking anticoagulant/antiplatelet therapy was older, more likely to have suffered a fall, have more comorbid conditions, was more likely to be treated for a non-traumatic medical condition and have a subspecialty medical consultation. Discussion Patients with itSAH do not require transfer to a Level 1 trauma center for acute neurosurgical intervention.
A Nomogram Model for Predicting the Postoperative Recurrence of Localized Laryngeal Amyloidosis
Authors: Mao Meiling , Liang Na , Ren Ran , Zhao Yihua , Ma Donglin , Liu Honggang 
Published: April 2022

Objective: To analyze the factors related to postoperative recurrence in patients with localized laryngeal amyloidosis (LocLA) and to construct a nomogram prediction model (NPM). Methods: We collected the data for LocLA patients diagnosed from March 2000 to May 2019 and clinical characteristics data were extracted. Factors related to recurrence were analyzed using multivariate logistic regression. The NPM was constructed for predicting the recurrence risk of LocLA. The receiver operating characteristic (ROC) curve evaluated the distinguishing ability using the area under curve (AUC). The calibration curve was created to evaluate the consistency of the NPM. Results: A total of 226 confirmed LocLA cases were included. One hundred seventy-five cases (77.4%) had localized single nodule, and 51 cases had more than one lesions. Sixty-three (27.9%) cases had no multinucleated giant cell (MGC) around amyloid, and 163 (72.1%) cases had MGC around amyloid. Multivariate logistic regression analysis showed that more than one lesions (odds ratio [OR] = 3.206 and 95% confidence interval [CI]: 1.492-6.888; P value: .003), subglottic involvement (OR = 2.926 and 95% CI: 1.300-6.585; P = .010), and no multinucleated giant cell (MGC) around amyloid (OR = 2.503 and 95% CI: 1.173-5.342; P = .018) had a statistically significant effect on postoperative LocLA recurrence ( P < .05). The AUC of the ROC curve was 0.753 (95% CI: 0.667-0.832). The bias-corrected curve approached the ideal curve, with an average absolute error of 0.037. Conclusions: More than one lesions, subglottic involvement, and no MGC around amyloid are risk factors for postoperative recurrence of LocLA. The NPM constructed has good applicability.
A multi-centre prospective random control study of superimposed high-frequency jet ventilation and conventional jet ventilation for interventional bronchoscopy
Authors: Wang Ting , Pei Yinghua , Qiu Xiaojian , Wang Juan , Wang Yuling , Zhang Jie 
Published: April 2022

Introduction: Superimposed high-frequency jet ventilation (SHFJV) is a new type of jet ventilation that simultaneously uses high- and low-frequency types of jet ventilation. We compared SHFJV with the conventional high-frequency jet ventilation (CHFJV) in interventional bronchoscopy in terms of safety and effectiveness. Methods: A multi-centre prospective random single-blind clinical trial was conducted by three interventional bronchoscopy centres. Patients who underwent diagnostic or therapeutic bronchoscopy under general anaesthesia were admitted and divided into two groups: SHFJV group (trial group) and CHFJV group (control group). PaO2 and PaCO2 were recorded before anaesthesia and during and after the procedure. SpO2 and etCO2 were recorded every 10 min throughout the procedure. Patients were observed until 24 h post-bronchoscopy. Results: Sixty patients were included in the study. Twenty-nine were in the trial group, and 31 were in the control group. Both groups had no significant differences in demographic data. In the control group, the PaO2 measured in the operation was higher than that in the trial group (p = 0.023). The values of etCO2 in the control group were more dispersed than those of the trial group. When the procedure time was over 90 minutes, the etCO2 in the control group significantly increased (p = 0.01), while the etCO2 in trial group remained stable (p = 0.594). There were more patients with PaCO2 ≥ 50 mmHg during the procedure in the control group than in the trial group (p = 0.042). Conclusion: SHFJV is effective and safe in interventional bronchoscopy. It may provide more effective and stabilised ventilation than CHFJV in cases with long procedure times.
Pelvic CT in addition to MRI to differentiate between rectal and sigmoid cancer on imaging using the sigmoid take-off as a landmark
Authors: Bogveradze Nino , Maas Monique , el Khababi Najim , Schurink Niels W , Lahaye Max J , Bakers Frans CH , Tanis Pieter J , Kusters Miranda , Beets Geerard L , Beets-Tan Regina GH , Lambregts Doenja MJ 
Published: April 2022

Background The sigmoid take-off (STO) is a recently established landmark to discern rectal from sigmoid cancer on imaging. STO-assessment can be challenging on magnetic resonance imaging (MRI) due to varying axial planes. Purpose To establish the benefit of using computed tomography (CT; with consistent axial planes), in addition to MRI, to anatomically classify rectal versus sigmoid cancer using the STO. Material and Methods A senior and junior radiologist retrospectively classified 40 patients with rectal/rectosigmoid cancers using the STO, first on MRI-only (sagittal and oblique-axial views) and then using a combination of MRI and axial CT. Tumors were classified as rectal/rectosigmoid/sigmoid (according to published STO definitions) and then dichotomized into rectal versus sigmoid. Diagnostic confidence was documented using a 5-point scale. Results Adding CT resulted in a change in anatomical tumor classification in 4/40 cases (10%) for the junior reader and in 6/40 cases (15%) for the senior reader. Diagnostic confidence increased significantly after adding CT for the junior reader (mean score 3.85 vs. 4.27; P < 0.001); confidence of the senior reader was not affected (4.28 vs. 4.25; P = 0.80). Inter-observer agreement was similarly good for MRI only (κ=0.77) and MRI + CT (κ=0.76). Readers reached consensus on the classification of rectal versus sigmoid cancer in 78%–85% of cases. Conclusion Availability of a consistent axial imaging plane – in the case of this study provided by CT – in addition to a standard MRI protocol with sagittal and oblique-axial imaging views can be helpful to more confidently localize tumors using the STO as a landmark, especially for more junior readers.
Ubiquitin C-terminal hydrolase L1 promotes lymph node metastasis in small cell neuroendocrine carcinomas of the cervix
Authors: Zhang Yunqiang , Ding Jingxin , Zhang Xuyin , Hua Keqin 
Published: April 2022

Objective To screen for specific differentially expressed genes in small cell neuroendocrine carcinoma of the cervix (SCNEC) and to further explore their roles and mechanisms in tumor progression. Methods Differentially expressed genes in SCNEC compared with squamous cell carcinoma (SCC) and adenocarcinoma (AC) were screened by microarray and immunohistochemical analyses. The biological functions of the identified genes were examined in a SCNEC cell line using RNA interference and over-expression plasmid-transfection technologies. Co-expression network analysis and immunoprecipitation technology were used to explore the potential mechanisms. Results Compared with SCC and AC, UCHL1 (encoding ubiquitin C-terminal hydrolase L1) was identified as a specific differentially expressed gene in SCNEC, which was positively related to lymph node metastasis (LNM). Migration and invasion of SCNEC tumor cells were induced by UCHL1 over-expression and suppressed by UCHL1 down-regulation, as shown by scratch and transwell invasion assays. Co-expression network analysis suggested that Prospero homeobox protein 1 (PROX1) might interact with UCHL1, and in vivo immunoprecipitation and western blots verified that levels of ubiquitinated PROX1 were significantly decreased following UCHL1 overexpression. Conclusion UCHL1 is a potential biomarker of LNM in SCNEC. UCHL1 might promote SCNEC cell migration and invasion by reducing PROX1 ubiquitination.