bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL
Authors: Moser Russell , Annis James , Nikolova Olga , Whatcott Cliff , Gurley Kay , Mendez Eduardo , Moran-Jones Kim , Dorrell Craig , Sears Rosalie C. , Kuo Calvin , Han Haiyong , Biankin Andrew , Grandori Carla , Von Hoff Daniel D. , Kemp Christopher J. 
Published: July 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next-generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS-mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TRAIL, effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy, with direct translational implications for current clinical trials on metastatic pancreatic cancer patients.

Significance:
This study utilizes functional genetic and pharmacological profiling of KRAS-mutant pancreatic adenocarcinoma to identify therapeutic strategies and finds that TFIIH inhibition synergizes with TRAIL to induce apoptosis in KRAS-driven pancreatic cancer.
Gain of Chromosome 1q Perturbs a Competitive Endogenous RNA Network to Promote Melanoma Metastasis
Authors: Xu Xiaonan , Wang Kaizhen , Vera Olga , Verma Akanksha , Jasani Neel , Bok Ilah , Elemento Olivier , Du Dongliang , Yu Xiaoqing , Karreth Florian A. 
Published: July 2022

Abstract

Somatic copy-number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA), which sponge miRNAs to posttranscriptionally regulate gene expression in a protein coding–independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs.

Significance:
The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester tumor suppressor microRNAs underlies the oncogenic activity of chromosome 1q gains.
NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression
Authors: Qin Qizhi , Gomez-Salazar Mario , Tower Robert J. , Chang Leslie , Morris Carol D. , McCarthy Edward F. , Ting Kang , Zhang Xinli , James Aaron W. 
Published: July 2022

Abstract

Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression.

Significance:
NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell–ECM interactions in sarcomagenesis and disease progression.
Cancer-Related Reductions in Survival: Extent and Duration Evaluated Using a Large Cohort Study of Twins, 1943–2011
Authors: Villumsen Martin Dalgaard , Ahrenfeldt Linda Juel , Christensen Kaare , Ewertz Marianne , Hjelmborg Jacob B. 
Published: July 2022

AbstractBackground:The time during which there is an increased risk of death for cancer survivors was evaluated in a large twin study, which allows for matching on shared components such as age, genes, and socioeconomic factors in childhood.Methods:By use of data from Danish registers, time to death from initial cancer was studied prospectively in twins in two different settings. The twins were diagnosed with at least one cancer in the period 1943 to 2011. Setting I included 5,680 same-sex twin pairs aged 6 and over, while Setting II included 3,218 twin individuals from age 70 and over. The study provides comparisons within twin pairs and across birth cohorts, age at diagnoses, and time at diagnosis.Results:In 2001 to 2011, the 5-year mortality risk for a twin surviving cancer after the age of 70 was twofold that of the co-twin, regardless of sex and zygosity, and it was 1.5-fold if the twin survived the initial 9 months. After 5 to 6 years, the mortality risk corresponded to that of the co-twin. In previous decades, the excess hazard risk was considerably higher for both older and younger cohorts. There were no indications of change in relative survival across old birth cohorts.Conclusions:This large twin study suggested that for a cancer-treatment survivor diagnosed at age 70 or later, the additional mortality risk was largely absent 5 years later, by which time the survival relative to the co-twin was 60%.Impact:Elevated mortality risk after cancer is offset after 5 to 6 years.
Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy
Authors: Davar Diwakar , Zarour Hassane M. 
Published: July 2022

Abstract
Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) proteins transformed the management of advanced cancers. Many tumor-intrinsic factors modulate immunological and clinical responses to such therapies, but ample evidence also implicates the gut microbiome in responses. The gut microbiome, comprising the bacteria, archaea, fungi, and viruses that live in the human digestive tract, is an established determinant of host immunity, but its impact on response to ICI therapy in mice and humans with cancer has only recently been appreciated. Therapeutic interventions to optimize microbiota composition to improve immunotherapy outcomes show promise in mice and humans with cancer. In this review, we discuss the rationale for gut microbiome–based cancer therapies, the results from early-phase clinical trials, and possible future developments.
Facts and Hopes for Immunotherapy in Renal Cell Carcinoma
Authors: Yao Chen , Zhang Tian , Wu Tuoqi , Brugarolas James 
Published: July 2022

Abstract
Immunotherapy has made a significant impact in many tumors, including renal cell carcinoma (RCC). RCC has been known to be immunoresponsive since the cytokine era of IFNα and IL2, but only a small number of patients had durable clinical benefit. Since then, discoveries of key tumor drivers, as well as an understanding of the contribution of angiogenesis and the tumor microenvironment (TME), has led to advances in drug development, ultimately transforming patient outcomes. Combinations of anti-angiogenic agents with immune checkpoint inhibitors are now standard of care. Current challenges include patient selection for immunotherapy combinations, resistance acquisition, and optimally sequencing therapies. Further discoveries about RCC biology, the TME, and resistance mechanisms will likely pave the way for the next generation of therapies.
A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17–11)
Authors: Jung Hyun Ae , Park Keon-Uk , Cho Sanghee , Lim Jinyeong , Lee Keun-Wook , Hong Min Hee , Yun Tak , An Ho Jung , Park Woong-Yang , Pereira Sergio , Ock Chan-Young , Keam Bhumsuk 
Published: July 2022

Abstract

Purpose:
Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy.

Patients and Methods:
This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence–powered spatial tumor-infiltrating lymphocyte analyzer, were performed.

Results:
Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6–16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%–99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (&gt; 3 points; HR, 7.0; 95% CI, 1.3–37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2–16.2; P = 0.018).

Conclusions:
Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.
Pattern of frustration formation in the functional brain network
Authors: Saberi Majid , Khosrowabadi Reza , Khatibi Ali , Misic Bratislav , Jafari Gholamreza 
Published: July 2022

Abstract
The brain is a frustrated system that contains conflictual link arrangements named frustration. The frustration as a source of disorder prevents the system from settling into low-energy states and provides flexibility for brain network organization. In this research, we tried to identify the pattern of frustration formation in the brain at the levels of region, connection, canonical network, and hemisphere. We found that frustration formation has no uniform pattern. Some subcortical elements have an active role in frustration formation, despite low contributions from many cortical elements. Frustrating connections are mostly between-network connections, and triadic frustrations are mainly formed between three regions from three distinct canonical networks. We did not find any significant differences between brain hemispheres or any robust differences between the frustration formation patterns of various life-span stages. Our results may be interesting for those who study the organization of brain links and promising for those who want to manipulate brain networks.
#peacemaker: Cultivating Pluralist Dispositions among Bandung’s Peace Communities Online and Offline
Authors: Lengauer Dayana 
Published: July 2022

Abstract
In Indonesia, the national motto of ‘unity in diversity’ is challenged, not least by a hardening of religious identities, coupled with rising levels of religious intolerance. In addition to established proponents of religious pluralism, groups of activists strive to sow the seeds of peace among the tech-savvy generation of young urbanites. By adopting the concept of ‘technology of the community’, I analyze the online and offline practices of peace activists in Bandung in 2018 to educate young #peacemakers and create spaces of empathy and solidarity. To address the emotional deprivation as well as aspirations of young people, peace groups rely on various offline and online technologies that straddle notions of comfort and discomfort, of tolerance and engagement. In creating and maintaining spaces of affective interpersonal exchange, these groups become exponents of local arrangements that are conducive to the cultivation of pluralist dispositions beyond national ideology.
Jugaad Infrastructures: Platforming Habituated Ecologies during the Kerala Floods of 2018
Authors: Eapen Gayas 
Published: July 2022

Abstract
Infrastructure has often been approached through the built, and yet hidden, substrates that facilitate modern life. In postcolonial contexts, the rise of platformized solutions tasked with performing infrastructural functions has introduced complexity in theorizing infrastructure. However, provisional and temporary solutions that bring together networks, relationships, and habitations as jugaad (informal or workaround) infrastructure have the potential to address crises beyond neoliberal capture enabled through platformization. This paper uses theories on alternative ways of assembling infrastructures to analyze a rescue portal built during the Kerala floods in 2018. It argues that these complex forms of assembling an infrastructure, even during the moments of imminent existential crisis, face the risk of platformized capture, surveillance, and governance.
The Moral Economy of Platform Work
Authors: Raval Noopur , Lalvani Simiran 
Published: July 2022

Abstract
Gig Economy platforms have become enmeshed in the fabric of urban sociality. While they have substantially disrupted conditions of labouring, participating in the platform economy has also changed social and moral norms globally. Importantly, what constitutes normative moral and prosocial interpersonal behaviour is key to making platforms function as social environments, but these norms are also constantly challenged and rearticulated through everyday practice among different stakeholders. By drawing on long-term fieldwork across gig economy platforms in urban India, we offer a typology of dynamic social and moral norms around tipping, gratitude, politeness and more that sustain platform interactions. The paper’s aim is to re-centre the vitality and dynamism of everyday media practice, social relationships, and cultural values in shaping platforms. Relatedly, moving beyond binaries of exploitation/empowerment, we show how negotiations between agents with differential power contribute to shifts in platform culture that cannot be fully explained through notions of intentionality.
Drivers’ Evaluation of Different Automated Driving Styles: Is It Both Comfortable and Natural?
Authors: Peng Chen , Merat Natasha , Romano Richard , Hajiseyedjavadi Foroogh , Paschalidis Evangelos , Wei Chongfeng , Radhakrishnan Vishnu , Solernou Albert , Forster Deborah , Boer Erwin 
Published: July 2022

Objective This study investigated users’ subjective evaluation of three highly automated driving styles, in terms of comfort and naturalness, when negotiating a UK road in a high-fidelity, motion-based, driving simulator. Background Comfort and naturalness play an important role in contributing to users’ acceptance and trust of automated vehicles (AVs), although not much is understood about the types of driving style which are considered comfortable or natural. Method A driving simulator study, simulating roads with different road geometries and speed limits, was conducted. Twenty-four participants experienced three highly automated driving styles, two of which were recordings from human drivers, and the other was based on a machine learning (ML) algorithm, termed Defensive, Aggressive, and Turner, respectively. Participants evaluated comfort or naturalness of each driving style, for each road segment, and completed a Sensation Seeking questionnaire, which assessed their risk-taking propensity. Results Participants regarded both human-like driving styles as more comfortable and natural, compared with the less human-like, ML-based, driving controller. Particularly, between the two human-like controllers, the Defensive style was considered more comfortable, especially for the more challenging road environments. Differences in preference for controller by driver trait were also observed, with the Aggressive driving style evaluated as more natural by the high sensation seekers. Conclusion Participants were able to distinguish between human- and machine-like AV controllers. A range of psychological concepts must be considered for the subjective evaluation of controllers. Application Insights into how different driver groups evaluate automated vehicle controllers are important in designing more acceptable systems.
Educational level and the use of mental health services, psychotropic medication and psychotherapy among adults with a history of physician diagnosed mental disorders
Authors: Halme Marie , Rautava Päivi , Sillanmäki Lauri , Sumanen Markku , Suominen Sakari , Vahtera Jussi , Virtanen Pekka , Salo Paula 
Published: July 2022

Background: The prevalence of mental disorders is increased among people of low socioeconomic status or educational level, but it remains unclear whether their access to treatment matches their increased need. Aims: Our objective was to examine whether educational level as an indicator of socioeconomic status is associated with use of mental health services, psychotropic medication and psychotherapy in Finland. Method: Cross-sectional data from a follow-up survey of a longitudinal, population-based cohort study were used to form a sample of 3,053 men and women aged 24 to 68 with a current or previous physician diagnosed mental disorder. The prevalence of mental disorders, mental health service use and educational level were assessed with self-report questionnaire. Educational level was determined by the highest educational attainment and grouped into three levels: high, intermediate and low. The associations between educational level and mental health service -related outcomes were assessed with binary logistic regression. Covariates in the fully adjusted model were age, gender and number of somatic diseases. Results: Compared to high educational level, low educational level was associated with higher odds of using antidepressants (OR 1.35, 95% CI [1.09, 1.66]), hypnotics (OR 1.33, 95% CI [1.07, 1.66]) and sedatives (OR 2.17, 95% CI [1.69, 2.78]), and lower odds of using mental health services (OR 0.80, 95% CI [0.65, 0.98]). No associations were found between educational level and use of psychotherapy. Conclusions: The results do not suggest a general socioeconomic status related mismatch. A pharmacological emphasis was observed in the treatment of low educational background participants, whereas overall mental health service use was emphasized among high educational background participants.
Design and testing of the safety of the SARUS-CPR hood for novice resuscitators
Authors: Wasik P. , McLeod G. A. , Mountain R. , Watts S. , Briggs H. , Maini N. , Belford I. , McGuire B. , Brown W. , Clark R. , Eley I , Richardson E. , Stonebridge P. 
Published: July 2022

Background and aims Bystanders should be protected against aerosols, droplets, saliva, blood and vomitus during resuscitation after cardiac arrest The SARUS (safer - airway - resuscitation) CPR airway hood™ is a clear plastic cover and integrated mask that envelopes the head and torso. Our objectives were to test leakage using saline aerosol generation tests, then assess the performance of the hood during mock cardio-pulmonary resuscitation on a manikin. Methods A checklist was validated by comparing the performance of 10 novices against 10 experts during mock resuscitation. Thereafter, 15 novices were tested with and without the hood, in a randomised cross-over study, one week apart. Results Laboratory analysis showed a > 99% reduction of saline particles detected 5 cm, 75 cm and 165 cm above volunteers wearing the hood. On manikins, experts scored better compared to novices, 8.5 (0.7) vs 7.6 (1.2), difference (95%CI) 0.9 (0.4–1.3), P = 0.0004. Novice performance was equivalent using the hood and standard equipment, 7.3 (1.4) vs 7.3 (1.1) respectively, difference (90%CI) 0.0 (−0.3 - 0.3), P = 0.90. Conclusion Aerosol transmission reduced in the breathing zone. Simulated resuscitation by novices was equivalent with and without the hood.