bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking exhumation, paleo-relief, and rift formation to magmatic processes in the western Snake River Plain, Idaho, using apatite (U-Th)/He thermochronology
Authors: Wetzel Kelsey F. , Stanley Jessica R. 
Published: February 2022

Abstract
The western Snake River Plain (WSRP) in southwest Idaho has been characterized as an intracontinental rift basin but differs markedly in topography and style from other Cordilleran extensional structures and structurally from the down-warped lava plain of the eastern Snake River Plain. To investigate mechanisms driving extension and topographic evolution, we sampled granitoid bedrock from Cretaceous and Eocene-aged plutons from the mountainous flanks of the WSRP to detail their exhumation history with apatite (U-Th)/He (AHe) thermochronometry. AHe cooling dates from seventeen samples range from 7.9 ± 1.4 Ma to 55 ± 10 Ma. Most cooling dates from Cretaceous plutons adjacent to the WSRP are Eocene, while Eocene intrusions from within the Middle Fork Boise River canyon ~35 km NE of the WSRP yield Miocene cooling dates. The AHe dates provide evidence of exhumation of the Idaho batholith during the Eocene, supporting a high relief landscape at that time, followed by decreasing relief. The Miocene AHe dates show rapid cooling along the Middle Fork Boise River that we take to indicate focused river incision due to base level fall in the WSRP. Eocene AHe dates limit magnitudes of exhumation and extension on the flanks of the WSRP during Miocene rift formation. This suggests extension was accommodated by magmatic intrusions and intrabasin faults rather than basin-bounding faults. We favor a model where WSRP extension was related to Columbia River Flood Basalt eruption and enhanced by later eruption of the Bruneau-Jarbidge and Twin Falls volcanic fields, explaining the apparent difference with other Cordilleran extensional structures.
Prevalence and severity of abnormal lung function among US former coal miners with and without radiographic coal workers’ pneumoconiosis
Authors: Go Leonard H T , Almberg Kirsten S , Rose Cecile S , Zell-Baran Lauren M , Harris Drew A , Tomann Margaret , Friedman Lee S , Weems Dolores J , Vonhof Wendy , Mastel Krista M , Cohen Robert A 
Published: February 2022

ObjectivesExamination of lung function abnormalities among coal miners has historically focused on actively working miners. This likely underestimates the true burden of chronic respiratory disease. The objective of this study was to characterise patterns and severity of lung function impairment among a population of former coal miners.MethodsCross-sectional data from 2568 former coal miners evaluated at eight US Black Lung clinics in a 12-month period were retrospectively analysed for patterns of prebronchodilator spirometric abnormality and severity of lung function impairment. Spirometry data from a subset of former miners with chest radiographs were analysed based on the presence and severity of coal workers’ pneumoconiosis (CWP).ResultsAbnormal spirometry was identified in 56.6% of subjects. The age-standardised prevalence of airflow obstruction among miners aged ≥45 years was 18.9% overall and 12.2% among never smokers. Among 1624 subjects who underwent chest radiography, the prevalence and severity of abnormal spirometry increased with worsening radiographic category for pneumoconiosis. Of never-smoking former miners without radiographic CWP, 39.0% had abnormal spirometry; 25.1% had abnormally low forced expiratory volume in 1 s (FEV1), and 17.1% had moderate to severe FEV1impairment.ConclusionsAbnormal spirometry is common among former coal miners. While ever-smoking former miners had higher rates of airflow obstruction, never-smoking former miners also demonstrated clinically significant airflow obstruction, including those without radiographic pneumoconiosis. These findings demonstrate the importance of recognising physiological as well as imaging manifestations of coal mine dust lung diseases in former miners.
Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study
Authors: van Kooten Job P , Belderbos Robert A , von der Thüsen Jan H , Aarts Mieke J , Verhoef Cornelis , Burgers Jacobus A , Baas Paul , Aalbers Arend G J , Maat Alexander P W M , Aerts Joachim G J V , Cornelissen Robin , Madsen Eva V E 
Published: February 2022

IntroductionMalignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993.Materials and methodsPatients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed.ResultsIn total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between −9.4% and −1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993–2003) to 8.9 (2004–2011) and 9.3 months from 2012 to 2018 (p<0.001).ConclusionThe peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor.
Advancing whole-of-government approaches to tobacco control: Article 5.3 and the challenge of policy coordination in Bangladesh, Ethiopia, India and Uganda
Authors: Barry Rachel Ann , Abdullah S M , Chugh Aastha , Hirpa Selamawit , Kumar Praveen , Male Denis , Ralston Rob , Wagner-Rizvi Tracey , Collin Jeff 
Published: February 2022

IntroductionDespite an extensive evidence base on the diverse economic, environmental and social benefits of tobacco control, difficulties in establishing coordinated national approaches remain a defining challenge for Framework Convention on Tobacco Control (FCTC) implementation. Minimising tobacco industry interference is seen as key to effective coordination, and this paper analyses implementation of Article 5.3 guidelines, exploring implications for whole-of-government approaches to tobacco control in Bangladesh, Ethiopia, India and Uganda.MethodsBased on 131 semistructured interviews with government officials and other key stakeholders, we explore barriers and facilitators for promoting: (1)horizontal coordinationacross health and other policy spheres, and (2)vertical coordinationacross national and subnational governments on Article 5.3 implementation.ResultsOur analysis identifies common barriers to coordination across diverse geographical contexts and varying approaches to implementation. They highlight broadly shared experiences of limited understanding and engagement beyond health agencies; restricted responsibility and uncertainty amid conflicting mandates; tensions with wider governance practices and norms; limited capacity and authority of coordination mechanisms; and obstacles to vertical coordination across local, state and national governments. Interview data also indicate important opportunities to advance coordination across sectors and government levels, with Article 5.3 measures capable of informing changes in practices, building support in other sectors, allowing for ‘bottom-up’ innovation and being shaped by engagement with civil society.ConclusionSupporting effective implementation of Article 5.3 is key to advancing multisectoral approaches to FCTC implementation and tobacco control’s contributions to global health and sustainable development.
Inducing Non-uniform FPGA Aging Using Configuration-based Short Circuits
Authors: Cook Hayden , Arscott Jacob , George Brent , Gaskin Tanner , Goeders Jeffrey , Hutchings Brad 
Published: February 2022

This work demonstrates a novel method of accelerating FPGA aging by configuring FPGAs to implement thousands of short circuits, resulting in high on-chip currents and temperatures. Patterns of ring oscillators are placed across the chip and are used to characterize the operating frequency of the FPGA fabric.
Over the course of several months of running the short circuits on two-thirds of the reconfigurable fabric, with daily characterization of the FPGA 6 performance, we demonstrate a decrease in FPGA frequency of 8.5%. We demonstrate that this aging is induced in a non-uniform manner. The maximum slowdown outside of the shorted regions is 2.1%, or about a fourth of the maximum slowdown that is experienced inside the shorted region. In addition, we demonstrate that the slowdown is linear after the first two weeks of the experiment and is unaffected by a recovery period.
Additional experiments involving short circuits are also performed to demonstrate the results of our initial experiments are repeatable. These experiments also use a more fine-grained characterization method that provides further insight into the non-uniformed nature of the aging caused by short circuits.
Extracellular Vesicle–Packaged CDH11 and ITGA5 Induce the Premetastatic Niche for Bone Colonization of Breast Cancer Cells
Authors: Li Xiao-Qing , Zhang Rui , Lu Hong , Yue Xiao-Min , Huang Yu-Fan 
Published: February 2022

Abstract

Although most breast cancer metastases in bone cause osteolytic lesions, the osteogenic niche has commonly been described as an initiator of early-stage bone colonization of disseminated cancer cells. Tumor cell–derived extracellular vesicles (EV) have been shown to determine the organotropism of cancer cells by transferring their cargo, such as nucleic acids and proteins, to resident cells at future metastatic sites and preparing a favorable premetastatic niche. Runt-related transcription factor 2 (RUNX2) and its regulated genes have been shown to facilitate the acquisition of osteomimetic features and to enhance the bone metastatic potential of breast cancer cells. In this study, we present in vivo and in vitro evidence to clarify the role of EVs released by breast cancer cells with high RUNX2 expression in the education of osteoblasts to form an osteogenic premetastatic niche. Furthermore, different extracellular vesicular proteins were identified that mediate events subsequent to the specific recognition of tumor-derived EVs by osteoblasts via cadherin 11 (CDH11) and the induction of the osteogenic premetastatic niche by integrin α5 (ITGA5). CDH11high/ITGA5high EVs were demonstrated to be responsible for the formation of a premetastatic niche that facilitates RUNX2 high-expressing breast cancer cell colonization in bone, revealing a potential EV-based premetastatic niche blockage strategy.

Significance:
This study provides mechanistic insights into the generation of an osteogenic premetastatic niche by breast cancer–derived EVs and identifies potential EV-derived diagnostic biomarkers and targets for breast cancer bone metastasis.
A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma
Authors: Gill Jennifer G. , Leef Samantha N. , Ramesh Vijayashree , Martin-Sandoval Misty S. , Rao Aparna D. , West Lindsey , Muh Sarah , Gu Wen , Zhao Zhiyu , Hosler Gregory A. , Vandergriff Travis W. , Durham Alison B. , Mathews Thomas P. , Aurora Arin B. 
Published: February 2022

AbstractDespite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism.Significance:This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.
Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis
Authors: Casciello Francesco , Kelly Gregory M. , Ramarao-Milne Priya , Kamal Nabilah , Stewart Teneale A. , Mukhopadhyay Pamela , Kazakoff Stephen H. , Miranda Mariska , Kim Dorim , Davis Felicity M. , Hayward Nicholas K. , Vertino Paula M. , Waddell Nicola , Gannon Frank , Lee Jason S. 
Published: February 2022

Abstract

G9a and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, yet the precise roles that these enzymes play cooperatively in cancer is unclear. We demonstrate here that frequent concurrent upregulation of both G9a and EZH2 occurs in several human tumors. These methyltransferases cooperatively repressed molecular pathways responsible for tumor cell death. In genetically distinct tumor subtypes, concomitant inhibition of G9a and EZH2 potently induced tumor cell death, highlighting the existence of tumor cell survival dependency at the epigenetic level. G9a and EZH2 synergistically repressed expression of genes involved in the induction of endoplasmic reticulum (ER) stress and the production of reactive oxygen species. IL24 was essential for the induction of tumor cell death and was identified as a common target of G9a and EZH2. Loss of function of G9a and EZH2 activated the IL24-ER stress axis and increased apoptosis in cancer cells while not affecting normal cells. These results indicate that G9a and EZH2 promotes the evasion of ER stress–mediated apoptosis by repressing IL24 transcription, therefore suggesting that their inhibition may represent a potential therapeutic strategy for solid cancers.

Significance:
These findings demonstrate a novel role for G9a and EZH2 histone methyltransferases in suppressing apoptosis, which can be targeted with small molecule inhibitors as a potential approach to improve solid cancer treatment.
A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer
Authors: Son Jieun , Jang Jaebong , Beyett Tyler S. , Eum Yoonji , Haikala Heidi M. , Verano Alyssa , Lin Mika , Hatcher John M. , Kwiatkowski Nicholas P. , Eser Pinar Ö. , Poitras Michael J. , Wang Stephen , Xu Man , Gokhale Prafulla C. , Cameron Michael D. , Eck Michael J. , Gray Nathanael S. , Jänne Pasi A. 
Published: February 2022

Abstract

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non–small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08–178–01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08–178–01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08–178–01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08–178–01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08–178–01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.

Significance:
This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.
CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade
Authors: Tong Jingshan , Tan Xiao , Song Xiangping , Gao Man , Risnik Denise , Hao Suisui , Ermine Kaylee , Wang Peng , Li Hua , Huang Yi , Yu Jian , Zhang Lin 
Published: February 2022

Abstract

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti–PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.

Significance:
This work demonstrates how inhibition of CDK4/6 sensitizes cancer cells to chemotherapy and immune checkpoint blockade and may provide a new molecular marker for improving CDK4/6-targeted cancer therapies.
See related commentary by Frank, p. 1170
The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases
Authors: Anastasia Alessia , Dellavedova Giulia , Ramos-Montoya Antonio , James Neil , Chiorino Giovanna , Russo Massimo , Baakza Hana , Wilson Joanne , Ghilardi Carmen , Cadogan Elaine B. , Giavazzi Raffaella , Bani Maria Rosa 
Published: February 2022

Abstract
Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity.
We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread. AZD7648 was administered orally in combination with PLD (dosed intravenously) or with olaparib (orally). To prove the inhibition of DNA-PK in the tumors, we measured pDNA-PKcs, pRPA32, and γH2AX, biomarkers of DNA-PK activity.
AZD7648 enhanced the therapeutic efficacy of PLD in all the OC-PDXs tested, regardless of their BRCA status or sensitivity to cisplatin or PLD. The treatment caused disease stabilization, which persisted despite therapy discontinuation for tumors growing subcutaneously, and significantly impaired the abdominal metastatic dissemination, prolonging the lifespan of mice implanted orthotopically.
AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a preexisting olaparib activity to benefit from the addition of AZD7648.
This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit patients with ovarian cancer and should be explored in clinical trials.
DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models
Authors: Yamato Michiko , Hasegawa Jun , Maejima Takanori , Hattori Chiharu , Kumagai Kazuyoshi , Watanabe Akiko , Nishiya Yumi , Shibutani Tomoko , Aida Tetsuo , Hayakawa Ichiro , Nakada Takashi , Abe Yuki , Agatsuma Toshinori 
Published: February 2022

Abstract
B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species.
The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed.
DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys.
DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting.