bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer
Authors: Cruz-Duarte Raquel , Rebelo de Almeida Cátia , Negrão Magda , Fernandes Afonso , Borralho Paula , Sobral Daniel , Gallego-Paez Lina M. , Machado Daniel , Gramaça João , Vílchez José , Xavier Ana T. , Ferreira Miguel Godinho , Miranda Ana R. , Mansinho Helder , Brito Maria J. , Pacheco Teresa R. , Abreu Catarina , Lucia-Costa Ana , Mansinho André , Fior Rita , Costa Luís , Martins Marta 
Published: January 2022

Abstract

Purpose:
Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance.

Experimental Design:
We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab.

Results:
In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab.

Conclusions:
Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.
Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer
Authors: Zizzari Ilaria Grazia , Di Filippo Alessandra , Botticelli Andrea , Strigari Lidia , Pernazza Angelina , Rullo Emma , Pignataro Maria Gemma , Ugolini Alessio , Scirocchi Fabio , Di Pietro Francesca Romana , Rossi Ernesto , Gelibter Alain , Schinzari Giovanni , D'Amati Giulia , Rughetti Aurelia , Marchetti Paolo , Nuti Marianna , Napoletano Chiara 
Published: January 2022

Abstract

Purpose:
CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment.

Experimental Design:
Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings.

Results:
The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells.

Conclusions:
We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.
Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study
Authors: Herrera Alex F. , Patel Manish R. , Burke John M. , Advani Ranjana , Cheson Bruce D. , Sharman Jeff P. , Penuel Elicia , Polson Andrew G. , Liao Chen Di , Li Chunze , Schuth Eva , Vaze Anjali , Samineni Divya , Elstrom Rebecca , Cooper James , Diefenbach Catherine 
Published: January 2022

Abstract

Purpose:
Targeting CD79B using antibody–drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast with ADCs with heterogeneous loads.

Patients and Methods:
This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following ≥1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3–4.8 mg/kg); 9 received combination therapy (3.6–4.8 mg/kg) with rituximab.

Results:
Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses ≥1.2 mg/kg. Response rate in all-treated patients (N = 60) was 47% (n = 28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n = 28) and patients with DLBCL (n = 20).

Conclusions:
DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging antitumor activity advocates continuation of investigations into novel ADC technologies.
GFI1 Cooperates with IKZF1/IKAROS to Activate Gene Expression in T-cell Acute Lymphoblastic Leukemia
Authors: Sun Wenxiang , Guo Jingtao , McClellan David , Poeschla Alexandra , Bareyan Diana , Casey Mattie J. , Cairns Bradley R. , Tantin Dean , Engel Michael E. 
Published: January 2022

Abstract

Growth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known. We show that in T–acute lymphoblastic leukemia (ALL) cells, GFI1 and IKAROS are transcriptional partners that co-occupy regulatory regions of hallmark T-cell development genes. Transcriptional profiling reveals a subset of genes directly transactivated through the GFI1—IKAROS partnership. Among these is NOTCH3, a key factor in T-ALL pathogenesis. Surprisingly, NOTCH3 expression by GFI1 and IKAROS requires the GFI1 SNAG domain but occurs independent of SNAG—LSD1 binding. GFI1 variants deficient in LSD1 binding fail to activate NOTCH3, but conversely, small molecules that disrupt the SNAG—LSD1 interaction while leaving the SNAG primary structure intact stimulate NOTCH3 expression. These results identify a noncanonical transcriptional control mechanism in T-ALL which supports GFI1-mediated transactivation in partnership with IKAROS and suggest competition between LSD1-containing repressive complexes and others favoring transactivation.

Implications:
Combinatorial diversity and cooperation between DNA binding proteins and complexes assembled by them can direct context-dependent transcriptional outputs to control cell fate and may offer new insights for therapeutic targeting in cancer.
DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFβ/PD-L1 Targeted Cancer Immunotherapy
Authors: Carr Michael I. , Chiu Li-Ya , Guo Yige , Xu Chunxiao , Lazorchak Adam S. , Yu Huakui , Qin Guozhong , Qi Jin , Marelli Bo , Lan Yan , Sun Qing , Czauderna Frank , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T. 
Published: January 2022

AbstractRadiotherapy is the most widely used cancer treatment and improvements in its efficacy and safety are highly sought-after. Peposertib (also known as M3814), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses the repair of radiation-induced DNA double-strand breaks (DSB) and regresses human xenograft tumors in preclinical models. Irradiated cancer cells devoid of p53 activity are especially sensitive to the DNA-PK inhibitor, as they lose a key cell-cycle checkpoint circuit and enter mitosis with unrepaired DSBs, leading to catastrophic consequences. Here, we show that inhibiting the repair of DSBs induced by ionizing radiation with peposertib offers a powerful new way for improving radiotherapy by simultaneously enhancing cancer cell killing and response to a bifunctional TGFβ “trap”/anti-PD-L1 cancer immunotherapy. By promoting chromosome misalignment and missegregation in p53-deficient cancer cells with unrepaired DSBs, DNA-PK inhibitor accelerated micronuclei formation, a key generator of cytosolic DNA and activator of cGAS/STING-dependent inflammatory signaling as it elevated PD-L1 expression in irradiated cancer cells. Triple combination of radiation, peposertib, and bintrafusp alfa, a fusion protein simultaneously inhibiting the profibrotic TGFβ and immunosuppressive PD-L1 pathways was superior to dual combinations and suggested a novel approach to more efficacious radioimmunotherapy of cancer.Implications:Selective inhibition of DNA-PK in irradiated cancer cells enhances inflammatory signaling and activity of dual TGFβ/PD-L1 targeted therapy and may offer a more efficacious combination option for the treatment of locally advanced solid tumors.
Word Representation Learning in Multimodal Pre-Trained Transformers: An Intrinsic Evaluation
Authors: Pezzelle Sandro , Takmaz Ece , Fernández Raquel 
Published: January 2022

AbstractThis study carries out a systematic intrinsic evaluation of the semantic representations learned by state-of-the-art pre-trained multimodal Transformers. These representations are claimed to be task-agnostic and shown to help on many downstream language-and-vision tasks. However, the extent to which they align with human semantic intuitions remains unclear. We experiment with various models and obtain static word representations from the contextualized ones they learn. We then evaluate them against the semantic judgments provided by human speakers. In line with previous evidence, we observe a generalized advantage of multimodal representations over language- only ones on concrete word pairs, but not on abstract ones. On the one hand, this confirms the effectiveness of these models to align language and vision, which results in better semantic representations for concepts that are grounded in images. On the other hand, models are shown to follow different representation learning patterns, which sheds some light on how and when they perform multimodal integration.
Infestation by Octolasmis species (Lepadiformes, Poecilasmatidae) of the marine crab Lupocycloporus gracilimanus (Decapoda, Portunidae) from India
Authors: Dash Gyanaranjan , Sen Swatipriyanka , Josileen Jose 
Published: January 2022

Abstract
The portunid crab Lupocycloporus gracilimanus from Digha, Bay of Bengal, India was investigated for an infestation by the lepadomorph cirriped Octolasmis spp. About 93% of the epibionts examined were found attached to the surface of the carapace, abdomen and legs, and these were identified as Octolasmis warwicki (EOW). Only 7% of the epibionts were attached to the branchial lamellae, and these were identified as Octolasmis angulata (EOA). Twenty-seven O. warwicki were also found to have conspecific dwarf males (CDM) attached to the scutum: probably an adaptive strategy to maximize the total insemination. Both the epibionts and the CDM showed spatial preference for the posterior mesobranchial region of the carapace. Most of the CDM (27%) were seen as a single attachment on the epibiont. The distance between the epibiont and its nearest neighbour (DNN) was found to be strongly and negatively correlated (, ) with the number of epibionts, indicating its preference to stay in an intermediate-sized group rather than remain solitary, which probably would have facilitated the evolution of dwarf males (CDMs). A higher percentage of epibionts were observed to have attached CDMs when the DNN increased, and above the 25 mm DNN, all epibionts were having CDM attachments, which is believed to be a strategy to maximize the fertilization success of CDMs by reducing sperm competition. A strong, positive correlation (, ) was observed between the carapace width of the host crab and the numbers of the infesting epibionts, proving that the larger crabs are more susceptible to the infestation compared to the smaller ones. The sex ratio of the host crab was 1 : 5.5 (Male : Female), nevertheless, only the females were infested by the epibionts. The percentage of the prevalence, relative abundance and mean intensity of EOW infestation were recorded as 46.15%, 182.05% and 394.44%, respectively. None of the crabs had serious external or internal infestations that seemed to hinder the activities of the animal. This is the first report of the infestation of these Octolasmis species on the portunid crab Lupocycloporus gracilimanus from India.
A Mughal Treatise on Essence and Existence
Authors: Nair Shankar 
Published: January 2022

Abstract
This article presents an annotated translation of The Equivalence between Giving and Receiving (al-Taswiya bayna al-ifāda wa-l-qabūl), a short Arabic treatise on essence (dhāt) and existence (wujūd) composed by the South Asian philosopher-Sufi Shaykh Muḥibb Allāh Ilāhābādī (996–1058/1587–1648). Although modern scholarship has habitually referred to Muḥibb Allāh as an ardent defender of the doctrine of waḥdat al-wujūd (“unity of existence”) associated with the figure of Ibn al-ʿArabī, such generalized formulations fail to do justice to the uniqueness of Muḥibb Allāh’s intellectual contributions. Most authors who had set out to provide a philosophical defense of Ibn al-ʿArabī’s teachings – including the well-known likes of Ṣadr al-Dīn al-Qūnawī, ʿAfīf al-Dīn al-Tilimsānī, ʿAbd al-Razzāq Kāshānī, Dāwud al-Qayṣarī, ʿAbd al-Raḥmān Jāmī, Mullā Ṣadrā, and so on – had tended to prioritize a philosophically utilizable formulation of wujūd or “existence.” Muḥibb Allāh, in notable contrast, favors a presentation of the divine Reality in terms of “pure essence/quiddity” (dhāt/māhiyya maḥḍa), at times going to considerable lengths to uphold his alternative formulation. Such a strategy of argumentation is uncommon amongst philosophical defenders of Ibn al-ʿArabī, the distinctiveness of which is further enhanced by Muḥibb Allāh’s peculiar mode of disputation, which straddles the line between metaphysics and natural philosophy/physics. The Taswiya occasioned at least sixteen commentaries and refutations; this translation benefits from consulting the earliest of these, composed by Mullā Maḥmūd al-Jawnpūrī (d. 1062/1652) and Khwāja Khwurd (d. 1073/1663), as well as three later commentaries by Ḥabīb Allāh Paṭnaʾī (d. 1140/1728). Most significantly, this translation makes extensive use of Muḥibb Allāh’s own Persian auto-commentary, the Sharḥ-i taswiya, which is a critical aid for deciphering the author’s at times opaque manner of expression and argumentation.
Implementing the Duty to Cooperate under the 1982 UNCLOS for the Conservation and Sustainable Use of Biodiversity in Areas beyond National Jurisdiction under a New BBNJ Agreement
Authors: Oral Nilufer 
Published: January 2022

Abstract
This article examines the duty to cooperate under the United Nations Convention on the Law of the Sea (UNCLOS) in relation to the obligations of States to protect and preserve the marine environment and in relation to the protection of the marine environment in areas beyond national jurisdiction. It demonstrates that the new Biodiversity Beyond National Jurisdiction (BBNJ) Agreement plays an important role in creating the necessary mechanisms for cooperation, thereby fulfilling the multiple obligations that States have under UNCLOS to cooperate regarding the protection and preservation of areas beyond national jurisdiction. Additionally, the BBNJ Agreement provides an important opportunity for States to effectively operationalize the UNCLOS provisions for marine scientific research, as well as the development and transfer of marine technology and capacity building. This article further analyses the duty to cooperate in relation to area-based management tools and environmental impact assessments, which are also key components of a broad framework of global cooperation under the BBNJ Agreement.
Protection of the Marine Environment
Authors: Young Margaret A. 
Published: January 2022

Abstract
The general obligation to protect and preserve the marine environment is contained in the United Nations Convention on the Law of the Sea (UNCLOS). Increasingly, marine issues are addressed in regional or multilateral trade agreements, including the covered agreements of the World Trade Organization (WTO). This article examines selected legal developments, such as provisions in regional trade agreements on marine capture fisheries, marine litter and waste management infrastructure. Rules on the use of trade measures to eliminate harmful fishing practices, and the prohibition of certain subsidies, are also explored. The article calls for attention to the impact of these developments on dispute settlement between states under UNCLOS, support for marine protected areas, and the capacity for regime interaction between relevant bodies. These issues have relevance for the conservation of marine living resources as well as other issues relating to the protection of the marine environment, including marine plastics and climate change.
Marine Scientific Research in Japan’s Practice
Authors: Huh Sookyeon 
Published: January 2022

Abstract
This article examines Japan’s state practices on marine scientific research (MSR). The survey of state practices requires the discernment of generalisability and particularity in each state practice. There are two points to note while considering the generalisabilities and particularities in Japan’s practices: first, Japan oversees MSR activities in its waters according to a non-legal instrument or a guideline, unlike neighbouring countries that use domestic legislation in MSR upon ratifying the United Nations Convention on the Law of the Sea; second, Japan faces quite a few MSR incidents in its undelimited exclusive economic zone. Thus, this article covers an outline of Japan’s guideline, its response to illegal or unregulated MSR activities in its waters, its relationships with neighbouring countries, and the failure of its attempt to legislate the MSR Law in 2007.
Navigating Digital Borderscapes: A Case Study from Rohingya Refugee Settlements in Bangladesh
Authors: Hussain Faheem , Lee Yenn 
Published: January 2022

Abstract
Based on a case study of the lived experiences of Rohingya refugees in Bangladesh between 2017 and 2019, this article focuses on displaced people’s digital needs and innovative efforts to navigate the challenges in their situation. The article first discusses the major barriers faced by Rohingya refugees in using various digital devices and platforms and how these obstacles adversely affect them in obtaining necessary information and humanitarian services. Our findings from the field highlight the uniquely important role that mobile repair shops in the camps play in providing online-offline hybrid solutions to circumvent restrictions imposed on the refugee community by the host government. The findings also show that different types of community leaders have emerged and that Rohingya women use digital means to push back against double discrimination. The article concludes with policy considerations related to the geopolitically transcendent issues of displacement, democracy, and digital rights.
An Evaluation of the Factors Affecting Failure of the Procedure in Reoperated Thyroidectomies: A Retrospective Analysis
Authors: Çomçalı Bülent , Özdemir Buket A. , Ataş Hakan , Özdemir Egemen , Tikici Deniz , Saylam Barış 
Published: January 2022

Background The aim of this study was to determine the factors affecting procedure failure in revision thyroidectomy surgery. Methods A total of 148 patients applied with revision surgery were separated into 2 groups according to the surgical success status. Comparisons were made of the 2 groups of patients where residual tissue was totally excised (Group 1, n:132) and patients where residual tissue could not be completely excised (Group 2, n:16). The patients were examined in respect of factors affecting the success of the procedure. Results The patients comprised 133 (89.9%) females and 15 (10.1%) males with a mean age of 49.68±12.02 years. Surgical failure was observed in 7 patients as the lesion could not be determined despite the use of intraoperative USG, and in 9 patients because of weak signal or signal loss. The determination of residual tissue ≤25mm on preoperative USG examination was seen to have a significant negative effect on surgical success (r=-0.329, p0.001). The patient having undergone ≥3 previous operations was determined to have a negative effect on surgical success (r=-0.229, p=0.005), and nerve damage on the opposite side to the lesion in a previous surgical procedure was determined to be the most important factor with a negative effect on surgical success (r=-0.571, p<0.001). In multinomial logistic regression analysis of the factors affecting success, the preoperative presence of nerve damage in the contralateral lobe to the lesion (OR: 33.11, 95% CI: 4.22-192.28, p<0.001) and lesion size ≤25 mm (OR: 10.10, 95% CI: 3.54-75.01, p=0.001) were determined to contribute significantly to surgical failure. Conclusion The results of this study clearly showed that as residual tissue size ≤25mm and contralateral nerve damage in the preoperative ultrasonographic evaluation are associated with surgical failure, alternative treatment methods such as radioactive iodine ablation may be preferred in these patients.