bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seismic evidence for lithospheric boudinage and its implications for continental rifting
Authors: Nguyen Luan C. , Levander Alan , Niu Fenglin , Morgan Julia , Li Guoliang 
Published: May 2022

AbstractThe continental rifting that precedes the breakup of a continent and the formation of a new ocean basin is one of the key processes of plate tectonics. Although often viewed as a two-dimensional process, rifted margins exhibit significant variations along strike. We document along-strike variations developed during the ca. 200–160 Ma continental rifting that formed the margins of the Gulf of Mexico ocean basin. Rayleigh-wave ambient noise tomography reveals a zone of high and low seismic velocity resembling large scale geologic boudins in the mantle lithosphere of the northwestern Gulf of Mexico margin. These features become progressively less prominent eastward following the transition from a magma-poor to a magma-rich passive margin. We infer that mantle refertilization and thickness of the pre-rift lithosphere control deformation style and the along-strike variations in continental rifting. Our results also suggest that deformation during rifting produces long-lived features that persist long after breakup and, therefore, can be used to study rifted margins globally.
Learning from Indigenous knowledge holders on the state and future of wild Pacific salmon
Authors: Reid Andrea J. , Young Nathan , Hinch Scott G. , Cooke Steven J. 
Published: May 2022

In response to colonial research paradigms that have subjugated Indigenous Peoples, knowledges, lands, and waters, Indigenous research methodologies have emerged to center Indigenous visions and voices in research practice. Here, we employ such methodologies to improve collective understanding of the state and future of wild Pacific salmon ( Oncorhynchus spp.) and fish–people–place relationships across British Columbia’s three largest salmon-producing rivers: the Fraser, Skeena, and Nass. Through partnerships with 18 communities of “Salmon People” and semi-structured interviews with 48 knowledge holders (i.e., Elders), we learned that, on average, Elders spent more than half of a century actively engaged in salmon fishing and processing. Modern salmon catches are reported to be approximately one-sixth of what they were estimated to be five to seven decades ago, and the top five threats to salmon identified by Elders included ( i) aquaculture, ( ii) climate change, ( iii) contaminants, ( iv) industrial development, and ( v) infectious diseases. Threat priorities varied regionally, reflecting distinct lived experiences and regional variation in the prevalence and impact of different threats. Elders perceived threats to salmon equally as threats to aquatic health and human well-being, with evidence that the relationships between people and water, and salmon and people, are being profoundly transformed.
Privacy-preserving quantum protocol for finding the maximum value
Authors: Shi Run-hua , Li Yi-fei 
Published: May 2022

AbstractIn this paper, we first define a primitive protocol of secure multiparty computations to privately compute the logic operator “OR” (SMC_OR). Accordingly, we design a feasible quantum SMC_OR protocol by using single photons, which can achieve information-theoretical security in the semi-honest model. Furthermore, we adopt the proposed quantum SMC_OR protocol to solve an interesting but important privacy-preserving problem, i.e., finding the maximum value among many secrets. Finally, we simulate the related quantum protocols in Qiskit and verify the correctness and the feasibility of the proposed protocols.
Modules with finitely many small submodules
Authors: Chaturvedi Avanish Kumar , Kumar Nirbhay 
Published: May 2022

O. A. S. Karamzadeh et al. [On rings with a unique proper essential right ideal, Fund. Math. 183 (2004) 229–244] introduced a class of modules with unique proper essential submodule, such modules are called as ue-modules. A. Azarang and F. Shahrisvand [Rings with only finitely many essential right ideals, Comm. Algebra 47 (2019) 2843–2854] introduced the idea of fe-module and called a module with finitely many essential submodules as a fe-module. Here, we introduce and study the classes of modules dual to them. The class of modules with finitely many small submodules is defined as fs-modules and modules with a unique nonzero small submodule are defined as us-modules.
Initial Phase I Safety Study of Gedatolisib plus Cofetuzumab Pelidotin for Patients with Metastatic Triple-Negative Breast Cancer
Authors: Radovich Milan , Solzak Jeffrey P. , Wang Chao J. , Hancock Bradley A. , Badve Sunil , Althouse Sandra K. , Bray Steven M. , Storniolo Anna Maria V. , Ballinger Tarah J. , Schneider Bryan P. , Miller Kathy D. 
Published: May 2022

AbstractPurpose:The PI3K pathway is dysregulated in the majority of triple-negative breast cancers (TNBC), yet single-agent inhibition of PI3K has been ineffective in TNBC. PI3K inhibition leads to an immediate compensatory upregulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a phase I clinical trial combining gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody–drug conjugate against the cell-surface PTK7 protein (Wnt pathway coreceptor) with an auristatin payload.Patients and Methods:Participants (pt) had metastatic TNBC or estrogen receptor (ER) low (ER and PgR &lt; 5%, HER2-negative) breast cancer, and had received at least one prior chemotherapy for advanced disease. The primary objective was safety. Secondary endpoints included overall response rate (ORR), clinical benefit at 18 weeks (CB18), progression-free survival (PFS), and correlative analyses.Results:A total of 18 pts were enrolled in three dose cohorts: gedatolisib 110 mg weekly + cofetuzumab pelidotin 1.4 mg/kg every 3 weeks (n = 4), 180 mg + 1.4 mg/kg (n = 3), and 180 mg + 2.8 mg/kg (n = 11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached ≥grade 3 severity. Myelosuppression was uncommon. ORR was 16.7% (3/18). An additional 3 pts had stable disease (of these 2 had stable disease for &gt;18 weeks); CB18 was 27.8%. Median PFS was 2.0 months (95% confidence interval for PFS: 1.2–6.2). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways.Conclusions:The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.
A Road Map for Designing Phase I Clinical Trials of Radiotherapy–Novel Agent Combinations
Authors: Brown Sarah R. , Hinsley Samantha , Hall Emma , Hurt Chris , Baird Richard D. , Forster Martin , Scarsbrook Andrew F. , Adams Richard A. 
Published: May 2022

Abstract
Radiotherapy has proven efficacy in a wide range of cancers. There is growing interest in evaluating radiotherapy–novel agent combinations and a drive to initiate this earlier in the clinical development of the novel agent, where the scientific rationale and preclinical evidence for a radiotherapy combination approach are high. Optimal design, delivery, and interpretation of studies are essential. In particular, the design of phase I studies to determine safety and dosing is critical to an efficient development strategy. There is significant interest in early-phase research among scientific and clinical communities over recent years, at a time when the scrutiny of the trial methodology has significantly increased. To enhance trial design, optimize safety, and promote efficient trial conduct, this position paper reviews the current phase I trial design landscape. Key design characteristics extracted from 37 methodology papers were used to define a road map and a design selection process for phase I radiotherapy–novel agent trials. Design selection is based on single- or dual-therapy dose escalation, dose-limiting toxicity categorization, maximum tolerated dose determination, subgroup evaluation, software availability, and design performance. Fifteen of the 37 designs were identified as being immediately accessible and relevant to radiotherapy–novel agent phase I trials. Applied examples of using the road map are presented. Developing these studies is intensive, highlighting the need for funding and statistical input early in the trial development to ensure appropriate design and implementation from the outset. The application of this road map will improve the design of phase I radiotherapy–novel agent combination trials, enabling a more efficient development pathway.
Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer
Authors: Sheehan Beshara , Neeb Antje , Buroni Lorenzo , Paschalis Alec , Riisnaes Ruth , Gurel Bora , Gil Veronica , Miranda Susana , Crespo Mateus , Guo Christina , Jiménez Vacas Juan , Figueiredo Ines , Ferreira Ana , Welti Jon , Yuan Wei , Carreira Suzanne , Sharp Adam , de Bono Johann 
Published: May 2022

Abstract

Purpose:
Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)–PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression.

Experimental Design:
To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer “Oncology Set”) and treated tumor cells with repeated ionizing irradiation.

Results:
The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion.

Conclusions:
The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA.
Inhibition of the p53-MDM2 Interaction: Targeting a Protein-Protein Interface
Authors: Chène Patrick 
Published: May 2022

Abstract
MDM2 inhibits p53 transcriptional activity, favors its nuclear export, and stimulates its degradation. Inhibition of the p53-MDM2 interaction with synthetic molecules should therefore lead to both the nuclear accumulation and the activation of p53 followed by the death of the tumor cells from apoptosis. Inhibitors of the p53-MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type p53 in tumors. This review describes our current knowledge on the properties of the existing p53-MDM2 antagonists. Because the discovery of modulators of protein-protein interactions is an emerging field in drug discovery, the strategy used for designing inhibitors of the p53-MDM2 interaction could serve as an example for other protein interfaces.
Apolipoprotein L6, a Novel Proapoptotic Bcl-2 Homology 3–Only Protein, Induces Mitochondria-Mediated Apoptosis in Cancer Cells
Authors: Liu Zhihe , Lu Huimei , Jiang Zeyu , Pastuszyn Andrzej , Hu Chien-an A. 
Published: May 2022

Abstract
Cancer cells frequently possess defects in the genetic and biochemical pathways of apoptosis. Members of the Bcl-2 family play pivotal roles in regulating apoptosis and possess at least one of four Bcl-2 homology (BH) domains, designated BH1 to BH4. The BH3 domain is the only one conserved in proapoptotic BH3-only proteins and plays an important role in protein-protein interactions in apoptosis by regulating homodimerization and heterodimerization of the Bcl-2 family members. To date, 10 BH3-only proapoptotic proteins have been identified and characterized in the human genome. The completion of the Human Genome Project and the availability of various public databases and sequence analysis algorithms allowed us to use the bioinformatic database-mining approach to identify one novel BH3-only protein, apolipoprotein L6 (ApoL6). The full-length cDNA of ApoL6 was identified, cloned, and functionally expressed in p53-null colorectal cancer cells (DLD-1). We found that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase-9, whereas ApoL6 BH3 domain deletion allele did not. In addition, overexpression of ApoL6 also induced activation of caspase-8. Furthermore, we showed that adenovirus harboring the full-length cDNA of ApoL6 induced marked apoptosis in a variety of cancer cell types, and ApoL6 recruited and interacted with lipid/fatty acid components during the induction of apoptosis. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein induces marked apoptosis.
Epidermal Growth Factor Modulates Tyrosine Phosphorylation of a Novel Tensin Family Member, Tensin3
Authors: Cui Yumin , Liao Yi-Chun , Lo Su Hao 
Published: May 2022

Abstract
Here, we report the identification of a new tensin family member, tensin3, and its role in epidermal growth factor (EGF) signaling pathway. Human tensin3 cDNA encodes a 1445 amino acid sequence that shares extensive homology with tensin1, tensin2, and COOH-terminal tensin-like protein. Tensin3 is expressed in various tissues and in different cell types such as endothelia, epithelia, and fibroblasts. The potential role of tensin3 in EGF-induced signaling pathway is explored. EGF induces tyrosine phosphorylation of tensin3 in MDA-MB-468 cells in a time- and dose-dependent manner, but it is independent of an intact actin cytoskeleton or phosphatidylinositol 3-kinase. Activation of EGF receptor is necessary but not sufficient for tyrosine phosphorylation of tensin3. It also requires Src family kinase activities. Furthermore, tensin3 forms a complex with focal adhesion kinase and p130Cas in MDA-MB-468 cells. Addition of EGF to the cells induces dephosphorylation of these two molecules, leads to disassociation of the tensin3-focal adhesion kinase-p130Cas complex, and enhances the interaction between tensin3 and EGF receptor. Our results demonstrate that tensin3 may function as a platform for the disassembly of EGF-related signaling complexes at focal adhesions.
Detecting Cervical Cancer by Quantitative Promoter Hypermethylation Assay on Cervical Scrapings: A Feasibility Study
Authors: Reesink-Peters Nathalie , Wisman G. Bea A. , Jéronimo Carmen , Tokumaru C. Yutaka , Cohen Yoram , Dong Seung Myung , Klip Harrie G. , Buikema Henk J. , Suurmeijer Albert J.H. , Hollema Harrie , Boezen H. Marieke , Sidransky David , van der Zee Ate G.J. 
Published: May 2022

Abstract
Current morphology-based cervical cancer screening is associated with significant false-positive and false-negative results. Tumor suppressor gene hypermethylation is frequently present in cervical cancer. It is unknown whether a cervical scraping reflects the methylation status of the underlying epithelium, and it is therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on cervical scrapings could be used as a future screening method augmenting the current approach. Cervical scrapings and paired fresh frozen cervical tissue samples were obtained from 53 cervical cancer patients and 45 controls. All scrapings were morphologically scored and analyzed with QMSP for the genes APC, DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were calculated against DNA levels of a reference gene. Hypermethylation ratios of paired fresh frozen tissue samples and scrapings of cervical cancer patients and controls were strongly related (Spearman correlation coefficient, 0.80 for APC, 0.98 for DAPK, and 0.83 for MGMT; P &lt; 0.001). More cervical cancer patients than controls were DAPK positive (P &lt; 0.001). When cutoff levels for ratios were defined to be above the highest ratio observed in controls, QMSP in cervical scrapings identified 32 (67%) of 48 cervical cancer patients. This feasibility study demonstrates that QMSP on cervical scrapings holds promise as a new diagnostic tool for cervical cancer. The addition of more genes specifically methylated in cervical cancer will further improve the assay.
MDM2 and Its Splice Variant Messenger RNAs: Expression in Tumors and Down-Regulation Using Antisense Oligonucleotides
Authors: Bartel Frank , Harris Linda C. , Würl Peter , Taubert Helge 
Published: May 2022

Abstract
Alternative splicing has an important role in expanding protein diversity. An example of a gene with more than one transcript is the MDM2 oncogene. To date, more than 40 different splice variants have been isolated from both tumor and normal tissues. Here, we review what is known about the alteration of MDM2 mRNA expression, focusing on alternative splicing and potential functions of different MDM2 isoforms. We also discuss the progress that has been made in the development of antisense oligonucleotides targeted to MDM2 for use as a potential cancer therapy.
p63 and p73: Roles in Development and Tumor Formation
Authors: Moll Ute M. , Slade Neda 
Published: May 2022

Abstract
The tumor suppressor p53 is critically important in the cellular damage response and is the founding member of a family of proteins. All three genes regulate cell cycle and apoptosis after DNA damage. However, despite a remarkable structural and partly functional similarity among p53, p63, and p73, mouse knockout studies revealed an unexpected functional diversity among them. p63 and p73 knockouts exhibit severe developmental abnormalities but no increased cancer susceptibility, whereas this picture is reversed for p53 knockouts. Neither p63 nor p73 is the target of inactivating mutations in human cancers. Genomic organization is more complex in p63 and p73, largely the result of an alternative internal promoter generating NH2-terminally deleted dominant-negative proteins that engage in inhibitory circuits within the family. Deregulated dominant-negative p73 isoforms might play an active oncogenic role in some human cancers. Moreover, COOH-terminal extensions specific for p63 and p73 enable further unique protein-protein interactions with regulatory pathways involved in development, differentiation, proliferation, and damage response. Thus, p53 family proteins take on functions within a wide biological spectrum stretching from development (p63 and p73), DNA damage response via apoptosis and cell cycle arrest (p53, TAp63, and TAp73), chemosensitivity of tumors (p53 and TAp73), and immortalization and oncogenesis (ΔNp73).
Molecular Cloning and Characterization of the von Hippel-Lindau-Like Protein
Authors: Qi Heng , Gervais Michelle L. , Li Wei , DeCaprio James A. , Challis John R.G. , Ohh Michael 
Published: May 2022

Abstract
von Hippel-Lindau (VHL) tumor suppressor protein—inactivated in VHL disease and sporadic kidney cancer—is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the α subunit of the hypoxia-inducible factor (HIF) transcription factor for subsequent destruction by the 26S proteasome. Here, we report the identification and characterization of the first VHL homologue, VHL-like protein (VLP), located on chromosome 1q21.2. A 676-bp partial cDNA encoding a 139-amino acid protein that is 78% similar to VHL was isolated by reverse transcription-PCR from human brain cerebellum and several cancer cell lines. The expression of VLP transcript is most abundant in the placenta. Like VHL, VLP contains a β domain capable of binding HIFα. However, unlike VHL, it does not contain a recognizable α domain, which is required for nucleating the multiprotein E3 ubiquitin ligase complex. The increased expression of VLP in the presence of VHL attenuated the ubiquitination of HIFα and led to the accumulation of downstream HIF target genes. These results taken together indicate that VLP functions as a dominant-negative VHL to serve as a protector of HIFα.
TAFII70 Isoform-Specific Growth Suppression Correlates With Its Ability to Complex With the GADD45a Protein
Authors: Wang Wei , Nahta Rita , Huper Gudrun , Marks Jeffrey R. 
Published: May 2022

Abstract
TAFII70, a member of the basal transcription complex implicated in p53-mediated transcription, is synthesized as several alternately spliced variants. The predominant forms found in normal and neoplastic breast epithelial cells are shown to be 72 kDa (TAFII70) and 78 kDa (TAFII80). Most cancers express higher levels of the TAFII80 isoform, whereas normal breast epithelia express higher levels of the TAFII70 isoform. Expression of TAFII70, but not TAFII80, causes dramatic growth suppression of normal and transformed breast epithelial cell lines in a p53-independent manner. Growth suppression correlates with mitotic inhibition resulting from an increased number of cells in G2. Both isoforms induce expression of the G2 arrest associated gene, GADD45a, but a novel protein-protein interaction was observed between TAFII70 (not TAFII80) and GADD45a, suggesting that this interaction is important for the observed growth arrest phenotype induced by the TAFII70 isoform. GADD45a null cells are not subject to TAFII70 inhibition, further supporting the relevance of this interaction.
Thiamine Transporter Gene Expression and Exogenous Thiamine Modulate the Expression of Genes Involved in Drug and Prostaglandin Metabolism in Breast Cancer Cells
Authors: Liu Shuqian , Stromberg Arnold , Tai Hsin-Hsiung , Moscow Jeffrey A. 
Published: May 2022

Abstract
In previous studies, we have shown that RNA levels of the thiamine transporter THTR2 were down-regulated in breast cancer tumors in comparison with normal tissues and that THTR2-mediated increases in thiamine uptake activity contributed to increased apoptosis after exposure to ionizing radiation. To further understand the biological effects of the alteration of THTR2 expression, we conducted a DNA microarray study of gene expression in THTR2-transfected breast cancer cells and found that, in addition to increased expression of THTR2 attributable to the transgene, three other genes were up-regulated &gt;2.5-fold in the transfected cells: cytochrome P450 isoform CYP4B1, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and transcription factor CRIP1. In addition, two genes were confirmed to be down-regulated in THTR2-transfected cells: trefoil factor 1 (TFF1) and Rho-GDP dissociation inhibitor (RGDI). Up-regulation of 15-PGDH and CYP4B1 expression was observed in other breast cancer cell lines transfected with THTR2, and down-regulation was observed after suppression of THTR2 with siRNA vectors. To determine the role of exogenous thiamine in the expression of these genes, we analyzed THTR2-transfected breast cancer cells grown in thiamine-depleted medium by quantitative reverse transcription-PCR and showed that three of these five genes showed evidence of regulation by exogenous thiamine in a manner concordant with the effects of THTR2 overexpression. One of the genes up-regulated by THTR2 transfection was down-regulated by thiamine depletion (CYP4B1), and two genes with decreased expression in THTR2-transfected breast cancer cells were up-regulated by thiamine depletion (TFF1 and RGDI). In summary, these studies show unexpected relationships between thiamine metabolism and genes that may be involved in the oncogenesis of breast and lung cancer.