bluuebunny/crossref_metadata_2025 huggingface dataset:
Educational Attainment and Cancer Incidence in a Large Nationwide Prospective Cohort
Authors: Hodge James M. , Patel Alpa V. , Islami Farhad , Jemal Ahmedin , Hiatt Robert A.
Published: October 2023

Background:

Educational attainment is a social determinant of health and frequently used as an indicator of socioeconomic status. Educational attainment is a predictor of cancer mortality, but associations with site-specific cancer incidence are variable. The aim of this study was to evaluate the association of educational attainment and site-specific cancer incidence adjusting for known risk factors in a large prospective cohort.

Methods:

Men and women enrolled in the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline were included in this study (n = 148,965). Between 1992 and 2017, 22,810 men and 17,556 women were diagnosed with incident cancer. Cox proportional hazards regression models were used to estimate age- and multivariable-adjusted risk and 95% confidence intervals of total and site-specific cancer incidence in persons with lower versus higher educational attainment.

Results:

Educational attainment was inversely associated with age-adjusted cancer incidence among men but not women. For specific cancer sites, the multivariable-adjusted risk of cancer in the least versus most educated individuals remained significant for colon, rectum, and lung cancer among men and lung and breast cancer among women.

Conclusions:

Educational attainment is associated with overall and site-specific cancer risk though adjusting for cancer risk factors attenuates the association for most cancer sites.

Impact:

This study provides further evidence that educational attainment is an important social determinant of cancer but that its effects are driven by associated behavioral risk factors suggesting that targeting interventions toward those with lower educational attainment is an important policy consideration.
Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk
Authors: Larsson Susanna C. , Höijer Jonas , Sun Jing , Li Xue , Burgess Stephen , Michaëlsson Karl
Published: October 2023

Background:

Observational studies have suggested that the gut hormone ghrelin is an early marker of future risk of developing gastrointestinal cancer. However, whether ghrelin is a causal risk factor remains unclear. We conducted a genome-wide association study (GWAS) of plasma ghrelin and used Mendelian randomization (MR) to investigate the possible causal association between ghrelin and gastrointestinal cancer risk.

Methods:

Genetic variants associated with plasma ghrelin were identified in a GWAS comprising 10,742 Swedish adults in the discovery (N = 6,259) and replication (N = 4,483) cohorts. The association between ghrelin and gastrointestinal cancer was examined through a two-sample MR analysis using the identified genetic variants as instruments and GWAS data from the UK Biobank, FinnGen, and a colorectal cancer consortium.

Results:

GWAS found associations between multiple genetic variants within ±200 kb of the GHRL gene and plasma ghrelin. A two-sample MR analysis revealed that genetically predicted higher plasma ghrelin levels were associated with a lower risk of gastrointestinal cancer in UK Biobank and in a meta-analysis of the UK Biobank and FinnGen studies. The combined OR per approximate doubling of genetically predicted plasma ghrelin was 0.91 (95% confidence interval, 0.85–0.99; P = 0.02). Colocalization analysis revealed limited evidence of shared causal variants for plasma ghrelin and gastrointestinal cancer at the GHRL locus (posterior probability H4 = 24.5%); however, this analysis was likely underpowered.

Conclusions:

Our study provides evidence in support of a possible causal association between higher plasma ghrelin levels and a reduced risk of gastrointestinal cancer.

Impact:

Elevated plasma ghrelin levels might reduce the risk of gastrointestinal cancer.
Table S3 from Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1–positive Triple-negative Breast Cancer
Authors: Carter Jodi M. , Polley Mei-Yin C. , Leon-Ferre Roberto A. , Sinnwell Jason , Thompson Kevin J. , Wang Xue , Ma Yaohua , Zahrieh David , Kachergus Jennifer M. , Solanki Malvika , Boughey Judy C. , Liu Minetta C. , Ingle James N. , Kalari Krishna R. , Couch Fergus J. , Thompson E. Aubrey , Goetz Matthew P.
Published: October 2023

Xcell-based immune feature estimate data
Table S2 from Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1–positive Triple-negative Breast Cancer
Authors: Carter Jodi M. , Polley Mei-Yin C. , Leon-Ferre Roberto A. , Sinnwell Jason , Thompson Kevin J. , Wang Xue , Ma Yaohua , Zahrieh David , Kachergus Jennifer M. , Solanki Malvika , Boughey Judy C. , Liu Minetta C. , Ingle James N. , Kalari Krishna R. , Couch Fergus J. , Thompson E. Aubrey , Goetz Matthew P.
Published: October 2023

Inter-Assay Agreement between PD-L1 SP142 and 22C3 Assay Scores in TNBC TMA
Data from Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199
Authors: Wang Beatrice T. , Kothambawala Tasnim , Wang Ling , Matthew Thomas J. , Calhoun Susan E. , Saini Avneesh K. , Kotturi Maya F. , Hernandez Genevive , Humke Eric W. , Peterson Marvin S. , Sinclair Angus M. , Keyt Bruce A.
Published: October 2023

Abstract
Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.
Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma
Authors: Enokido Takayoshi , Horie Masafumi , Yoshino Seiko , Suzuki Hiroshi I. , Matsuki Rei , Brunnström Hans , Micke Patrick , Nagase Takahide , Saito Akira , Miyashita Naoya
Published: October 2023

Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95–3p/miR-95–5p, miR-124–3p, and members of the miR-17∼92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124–3p and members of the miR-17∼92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124–3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124–3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.

Implications:

Our study revealed unique miRNA profiles of ASCL1-positive LUADs and identified ASCL1-regulated miRNAs with functional relevance.
Data from Tumor cell–intrinsic c-Myb upregulation stimulates antitumor immunity in a murine colorectal cancer model
Authors: van Gogh Merel , Glaus Garzon Jesus F. , Sahin Dilara , Knopfova Lucia , Benes Petr , Boyman Onur , Jurisica Igor , Borsig Lubor
Published: October 2023

Abstract
The transcription factor c-Myb is overexpressed in many different types of solid tumors, including colorectal cancer. However, its exact role in tumorigenesis is unclear. In this study, we show that tumor-intrinsic c-Myb expression in mouse models of colon cancer and melanoma suppresses tumor growth. While no differences in proliferation, apoptosis, and angiogenesis of tumors were evident tumors with distinct levels of c-Myb expression, we observed changes in intratumoral immune cell infiltrates. MC38 tumors with upregulated c-Myb expression showed increased numbers of CD103+ dendritic cells and eosinophils, but decreased tumor-associated macrophages (TAMs). Concomitantly, an increase in the number of activated cytotoxic CD8+ T cells upon c-Myb upregulation was observed, which correlated with a pro-inflammatory tumor microenvironment and increased numbers of M1 polarized TAMs. Mechanistically, c-Myb upregulation in immunogenic MC38 colon cancer cells resulted in enhanced expression of immunomodulatory genes, including those encoding 2-microglobulin and IFNβ, and decreased expression of the gene encoding the chemokine receptor CCR2. The increased numbers of activated cytotoxic CD8+ T cells contributed to tumor growth attenuation. In poorly immunogenic CT26, LLC, and B16-BL6 tumor cells, c-Myb upregulation did not affect the immunomodulatory gene expression. Despite this, c-Myb upregulation led to reduced B16-BL6 tumor growth but it did not affect tumor growth of CT26 and LLC tumors. Altogether, we postulate that c-Myb functions as a tumor suppressor in a tumor cell–type specific manner and modulates antitumor immunity.
Data from Glioblastoma Vascular Plasticity Limits Effector T-cell Infiltration and Is Blocked by cAMP Activation
Authors: Qin Zixi , Huang Youwei , Li Zeying , Pan Guopeng , Zheng Liangying , Xiao Xiao , Wang Fang , Chen Jiahong , Chen Xueqin , Lin Xi , Li Kai , Yan Guangmei , Zhang Haipeng , Xing Fan
Published: October 2023

Abstract
Glioblastoma (GBM) is the deadliest form of brain cancer. It is a highly angiogenic and immunosuppressive malignancy. Although immune checkpoint blockade therapies have revolutionized treatment for many types of cancer, their therapeutic efficacy in GBM has been far less than expected or even ineffective. In this study, we found that the genomic signature of glioma-derived endothelial cells (GdEC) correlates with an immunosuppressive state and poor prognosis of patients with glioma. We established an in vitro model of GdEC differentiation for drug screening and used this to determine that cyclic adenosine monophosphate (cAMP) activators could effectively block GdEC formation by inducing oxidative stress. Furthermore, cAMP activators impaired GdEC differentiation in vivo, normalized the tumor vessels, and altered the tumor immune profile, especially increasing the influx and function of CD8+ effector T cells. Dual blockade of GdECs and PD-1 induced tumor regression and established antitumor immune memory. Thus, our study reveals that endothelial transdifferentiation of GBM shapes an endothelial immune cell barrier and supports the clinical development of combining GdEC blockade and immunotherapy for GBM.

See related Spotlight by Lee et al., p. 1300
Data from ANXA1 promotes tumor immune evasion by binding PARP1 and upregulating Stat3-induced expression of PD-L1 in multiple cancers
Authors: Xiao Ding , Zeng Ting , Zhu Wei , Yu Zheng-Zheng , Huang Wei , Yi Hong , Lu Shan-Shan , Feng Juan , Feng Xue-Ping , Wu Di , Wen Qi , Zhou Jian-Hua , Yuan Li , Zhuang Wei , Xiao Zhi-Qiang
Published: October 2023

Abstract
The deregulation of annexin A1 (ANXA1), a regulator of inflammation and immunity, leads to cancer growth and metastasis. However, whether ANXA1 is involved in cancer immunosuppression is still unclear. Here, we report that ANXA1 knockdown (i) dramatically downregulates programmed cell death-ligand 1 (PD-L1) expression in breast cancer, lung cancer, and melanoma cells; (ii) promotes T cell-mediated killing of cancer cells in vitro; and (iii) inhibits cancer immune escape in immune-competent mice via downregulating PD-L1 expression and increasing the number and killing activity of CD8+ T cells. Mechanistically, ANXA1 functioned as a sponge molecule for interaction of PARP1 and Stat3. Specifically, binding of ANXA1 to PARP1 decreased PARP1’s binding to Stat3, which reduced poly(ADP-ribosyl)ation and dephosphorylation of Stat3 and thus, increased Stat3’s transcriptional activity, leading to transcriptionally upregulated expression of PD-L1 in multiple cancer cells. In clinical samples, expression of ANXA1 and PD-L1 was significantly higher in breast cancer, non-small cell lung cancer, and skin cutaneous melanoma compared to corresponding normal tissues and positively correlated in cancer tissues. Moreover, using both ANXA1 and PD-L1 proteins for predicting efficacy of anti-PD-1 immunotherapy and patient prognosis were superior to using individual proteins. Our data suggest that ANXA1 promotes cancer immune escape via binding PARP1 and upregulating Stat3-induced expression of PD-L1, that ANXA1 is a potential new target for cancer immunotherapy, and combination of ANXA1 and PD-L1 expression is a potential marker for predicting efficacy of anti-PD-1 immunotherapy in multiple cancers.
Data from Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance
Authors: Krykbaeva Irina , Bridges Kate , Damsky William , Pizzurro Gabriela A. , Alexander Amanda F. , McGeary Meaghan K. , Park Koonam , Muthusamy Viswanathan , Eyles James , Luheshi Nadia , Turner Noel , Weiss Sarah A. , Olino Kelly , Kaech Susan M. , Kluger Harriet M. , Miller-Jensen Kathryn , Bosenberg Marcus
Published: October 2023

Abstract
Checkpoint inhibitors have revolutionized cancer treatment, but resistance remains a significant clinical challenge. Myeloid cells within the tumor microenvironment can modulate checkpoint resistance by either supporting or suppressing adaptive immune responses. Using an anti–PD-1–resistant mouse melanoma model, we show that targeting the myeloid compartment via CD40 activation and CSF1R blockade in combination with anti–PD-1 results in complete tumor regression in a majority of mice. This triple therapy combination was primarily CD40 agonist-driven in the first 24 hours after therapy and showed a similar systemic cytokine profile in human patients as was seen in mice. Functional single-cell cytokine secretion profiling of dendritic cells (DC) using a novel microwell assay identified a CCL22+CCL5+ IL12-secreting DC subset as important early-stage effectors of triple therapy. CD4+ and CD8+ T cells are both critical effectors of treatment, and systems analysis of single-cell RNA sequencing data supported a role for DC-secreted IL12 in priming T-cell activation and recruitment. Finally, we showed that treatment with a novel IL12 mRNA therapeutic alone was sufficient to overcome PD-1 resistance and cause tumor regression. Overall, we conclude that combining myeloid-based innate immune activation and enhancement of adaptive immunity is a viable strategy to overcome anti–PD-1 resistance.
Long-Term Omalizumab in Elderly Patients with Chronic Urticaria: Is It a Safe Therapy?
Authors: Narváez-Fernández Emilio José , Entrala Ana , Nin-Valencia Ana , Mir-Ihara Patricia , Losantos-García Itsaso , Domínguez-Ortega Javier , González-Fernández María Ángeles , Quirce Santiago , Hernández-Cano Natalia , Cabañas Rosario , Caballero Teresa
Published: October 2023

Background: Biologics have revolutionized the treatment of many diseases. In this regard, omalizumab (OMA), an anti-IgE monoclonal antibody, is the recommended therapeutic option for patients with chronic spontaneous urticaria (CSU) refractory to second-generation H1-antihistamines. Several studies confirm the efficacy and safety of the drug. However, the literature focusing on the elderly population is scarce, as this age group is often excluded from clinical trials. Therefore, the pharmacological treatment of CSU in elderly patients is a challenge that is increased by their comorbidities and consequent polypharmacy. Objectives: We describe the real-life safety profile of OMA in elderly patients (≥70 years) with CSU and chronic inducible urticaria (CIndU). We aimed to provide data for daily clinical practice in this vulnerable patient group. Method: A retrospective review was performed of the records of patients with CSU/CIndU from May 2003 to December 2019 in the Hospital Universitario La Paz. We describe qualitative and quantitative data according to measures of central tendency. Comparisons between qualitative and quantitative data were performed with the Mann-Whitney U test and the Fisher’s test for qualitative variables. A p value <0.05 was considered statistically significant. Results and Conclusions: Eighty-nine patients were included, divided into two groups (<70 vs. ≥70 years). The overall rate of adverse events (AEs) was 48%, mainly mild. No association between age and AE was found (p = 0.789). No serious AE such as anaphylaxis was detected. CSU predominated in both groups. CIndU was less prevalent in the elderly (p = 0.017). There was no association between age and the other variables. Although the frequency of neoplasms was slightly higher in the elderly with OMA, we found no difference compared to the incidence of neoplasms in the general population. Therefore, our data suggest that OMA may be a safe treatment in elderly people with CSU/CIndU for prolonged periods of treatment, although further studies with larger samples are needed to corroborate our observations.
Psychological Stress and Gut Microbiota Composition: A Systematic Review of Human Studies
Authors: Ma Lu , Yan Yating , Webb Richard James , Li Ying , Mehrabani Sanaz , Xin Bao , Sun Xiaomin , Wang Youfa , Mazidi Mohsen
Published: October 2023

Introduction: The associations between psychological stress and gut microbiota composition are not fully understood. This study investigated associations between psychological stress and gut microbiota composition and examined the potential modifying effects of age, sex, and ethnicity on such associations. Methods: A systematic literature search was conducted using PubMed, Web of Science, PsycINFO, and Embase databases for studies published until November 2021 which examined associations between psychological stress and gut microbiota composition. Results: During the search process, 10,790 studies were identified, and after screening, 13 met the eligibility criteria and were included. The median sample size was 70, and the median age of participants was 28.0 years. Most of the included studies did not report associations between measures of alpha- and beta diversity of the gut microbiota composition and psychological stress. A few studies reported that the Shannon index, Chao 1, Simpson index, and weighted UniFrac were negatively associated with psychological stress. Significant reductions in several taxa at the phyla-, family-, and genus-levels were observed in participants with higher psychological stress. At the phylum level, the abundance of Proteobacteria and Verrucomicrobia were negatively associated with psychological stress. At the family-level, no more than two studies reported associations of the same microbiota with psychological stress. At the genus level, the following results were found in more than two studies; psychological stress was negatively associated with the abundance of Lachnospira, Lachnospiraceae, Phascolarctobacterium, Sutterella, and Veillonella, and positively associated with the abundance of Methanobrevibacter, Rhodococcus, and Roseburia. However, it was not possible to determine the influence of age, sex, or ethnicity due to the limited studies included. Conclusion: Our findings provide evidence that psychological stress is associated with changes in the abundance of the gut microbiota. Larger sample longitudinal studies are needed to determine the causal relationship between psychological stress and the gut microbiota.
Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of
CDCP1
and Cardiac Fibrosis
Authors: Liu Duan , Wang Min , Murthy Vishakantha , McNamara Dennis M. , Nguyen Thanh Thanh L. , Philips Trudy J. , Vyas Hridyanshu , Gao Huanyao , Sahni Jyotan , Starling Randall C. , Cooper Leslie T. , Skime Michelle K. , Batzler Anthony , Jenkins Gregory D. , Barlera Simona , Pileggi Silvana , Mestroni Luisa , Merlo Marco , Sinagra Gianfranco , Pinet Florence , Krejčí Jan , Chaloupka Anna , Miller Jordan D. , de Groote Pascal , Tschumperlin Daniel J. , Weinshilboum Richard M. , Pereira Naveen L.
Published: October 2023

BACKGROUND:

Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM.

METHODS:

A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction.

RESULTS:

The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the
CDCP1
(CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435;
P
=7.12×10
−7
). The variant allele was associated with improved cardiac function and decreased
CDCP1
transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis.

CONCLUSIONS:

CDCP1
may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.
Insomnia and Early Incident Atrial Fibrillation: A 16‐Year Cohort Study of Younger Men and Women Veterans
Authors: Gaffey Allison E. , Rosman Lindsey , Lampert Rachel , Yaggi Henry K. , Haskell Sally G. , Brandt Cynthia A. , Enriquez Alan D. , Mazzella Anthony J. , Skanderson Melissa , Burg Matthew M.
Published: October 2023

Background

There is growing consideration of sleep disturbances and disorders in early cardiovascular risk, including atrial fibrillation (AF). Obstructive sleep apnea confers risk for AF but is highly comorbid with insomnia, another common sleep disorder. We sought to first determine the association of insomnia and early incident AF risk, and second, to determine if AF onset is earlier among those with insomnia.

Methods and Results

This retrospective analysis used electronic health records from a cohort study of US veterans who were discharged from military service since October 1, 2001 (ie, post‐9/11) and received Veterans Health Administration care, 2001 to 2017. Time‐varying, multivariate Cox proportional hazard models were used to examine the independent contribution of insomnia diagnosis to AF incidence while serially adjusting for demographics, lifestyle factors, clinical comorbidities including obstructive sleep apnea and psychiatric disorders, and health care utilization. Overall, 1 063 723 post‐9/11 veterans (Mean age=28.2 years, 14% women) were followed for 10 years on average. There were 4168 cases of AF (0.42/1000 person‐years). Insomnia was associated with a 32% greater adjusted risk of AF (95% CI, 1.21–1.43), and veterans with insomnia showed AF onset up to 2 years earlier. Insomnia‐AF associations were similar after accounting for health care utilization (adjusted hazard ratio [aHR], 1.27 [95% CI, 1.17–1.39]), excluding veterans with obstructive sleep apnea (aHR, 1.38 [95% CI, 1.24–1.53]), and among those with a sleep study (aHR, 1.26 [95% CI, 1.07–1.50]).

Conclusions

In younger adults, insomnia was independently associated with incident AF. Additional studies should determine if this association differs by sex and if behavioral or pharmacological treatment for insomnia attenuates AF risk.
Shared Loanword Recognition in German–English Bilinguals: The Role of Metrical Phonology
Authors: Fritz Isabella , Lahiri Aditi , Kotzor Sandra
Published: October 2023

The role of phonology in bilingual word recognition has focused on a phonemic level especially in the recognition of cognates. In this study, we examined differences in metrical structure to test whether first language (L1) metrical structure influences the processing of second language (L2) words. For that, we used words of Romance origin (e.g., reptile, signal), which both German and English have borrowed extensively. However, the existing metrical patterns are not identical nor are the borrowed vocabularies the same. Rather, those identical words differ systematically in their foot structure. We conducted a cross-modal form fragment priming EEG experiment (auditory–visual) with German native speakers who were highly proficient in English. Both behavioral and ERP results showed an effect of the native phonology and the loan status, that is, whether the loan exists only in the speaker's L2 or is shared across languages. Priming effects (RTs) were largest for nonshared loanwords indicating some interference from German (L1). This was also evident in a reduced N400 but only if the metrical structure aligned with German patterns for Germanic words, that is, two light syllables as in pigeon. If the words exist in both languages, metrical structure also mattered shown by the modulation of different ERP components across conditions. Overall, our study indicates that metrical phonology plays a role in loanword processing. Our data show that the more similar a word is in terms of its metrical phonology across L1 and L2, the more effortful the processing of a word within a priming paradigm indicating interference from the L1 phonology.
Toward the Seizure of the Grand Mosque in Mecca: The Writings and Ideology of Juhaymān al-ʿUtaybī and the Ikhwān
Authors: Bunzel Cole M.
Published: October 2023

This article seeks to explain how the pietist movement led by Juhaymān al-ʿUtaybī culminated in the seizure of the Grand Mosque in Mecca in November 1979, a pivotal event in the history of modern Saudi Arabia that contributed to the increasingly conservative orientation of Saudi policy in subsequent decades. It assesses the distinct ideology espoused by Juhaymān and his followers by examining the series of writings issued by the group in the year and a half leading up to the mosque takeover. The article provides the first comprehensive survey of these rasāʾil, focusing on the three most salient themes therein: (1) the appeal to the Wahhābī heritage, (2) the rejection of Saudi royal family rule, and (3) apocalypticism. While all three were critical components of Juhaymān’s ideology, it was his apocalyptic convictions—spelled out here in detail for the first time—that led him and his followers to stage the takeover of the Grand Mosque. The event was therefore not a “rebellion” or “uprising” in any mundane sense. The list of political demands allegedly issued by one of the militants on the first day of the mosque takeover is shown to have been almost certainly a fabrication.
Egypt: Recent Developments in Arbitration
Authors: Abdel Wahab Mohamed S. , Khaled Noha
Published: October 2023

This Article tackles two main streamlines. Firstly, the legislative updates pertaining to international arbitration within the jurisdiction. These consist in the following: (i) the establishment of a committee to work on a proposal for the amendment of the Egyptian Arbitration Law, within a limited scope of amendments; and (ii) the amendments to Prime Ministerial Decree No. 1062 of 2019 expanding the scope of review of the High Committee for Arbitration and International Disputes, by virtue of Prime Ministerial Decrees No. 2592 of 2020 and No. 3218 of 2022. Secondly, the case law updates where Egyptian courts have addressed various issues proving that the Egyptian judiciary is an arbitration-friendly seat and in alignment with international arbitration trends. Among the cited case law updates, the Egyptian Court of Cassation has expressly cited the IBA Guidelines on Conflicts of Interest in International Arbitration (2014), for the first time ever, when addressing the duty of disclosure of an arbitrator. The Court of Cassation has also set the conditions that require to be fulfilled if an arbitrator abstains from signing the arbitral award and has set definitions for deliberations and dissenting opinions. The Cairo Court of Appeal has considered the arbitrators’ illness of COVID-19 as a force majeure event that interrupts the arbitration proceedings by the force of law and held that WhatsApp instant messaging constitutes a valid means of communication in arbitral proceedings as long as the fundamental principles of arbitration are observed.
Bulbophyllum deergongense (Dendrobiinae; Malaxideae; Epidendroideae; Orchidaceae), a new species from Tibet, China
Authors: MIAO JIANG-LIN , ZHANG HUA-YUAN , ZHU WEN-TAO , LIU ZHEN , JI HONG-YU , LIU ZHONG-JIAN , ZHAI JUN-WEN
Published: October 2023

A new species of Orchidaceae, Bulbophyllum deergongense, is described from Motuo (Tibet, China) based on morphological traits and molecular phylogenetic analysis. This new species is similar to B. reptans but differs in its elongate cylindrical pseudobulbs with prominent ridges, yellowish-green flower without markings, and oblong-ovoid petal with a round apical purple-brown spot. Molecular phylogenetic analyses based on two plastid makers (matK and psbA-trnH) and two nuclear DNA (ITS and Xdh) support B. deergongense as a new species of B. section Reptantia, in which it is sister to B. reptans.
Development of yarns from recycled carbon fiber based on friction spinning technology with specific properties for thermoset composites
Authors: Abdkader Anwar , Bachor Samuel , Hasan Mir Mohammad Badrul , Cherif Chokri
Published: October 2023

Because of a growing demand and usage of carbon fiber, effective methods to re-use waste and recycled carbon fiber recoverable either from process scraps or from end-of-life components are attracting increased attention. The development of different hybrid yarn structures consisting of recycled carbon fiber and thermoplastic fibers (recycled carbon fiber content approx. 50% by weight) for thermoplastic composites have been reported earlier. Yarns with high recycled carbon fiber content (>90% by weight) required for thermoset composites are still not realizable due to high shortening in recycled carbon fiber length (≥70%) during different processing steps of spinning. The reason lies in low shear strength, smooth fiber surface and high brittleness of recycled carbon fiber. Second, a lack of crimp in recycled carbon fiber leads to drafting errors during the drawing and spinning process. In this paper, the spinning limit regarding the core to sheath ratio of noble yarns with a recycled carbon fiber content greater than 90% by weight based on friction spinning technology for thermoset composites is reported. Slivers of recycled carbon fiber solely required for the development of yarns are produced on carding and drawing machines optimized for the gentle processing of recycled carbon fiber. Furthermore, different spinning parameters such as spinning drum speed and suction air pressure are investigated and their effect on tensile properties of yarn is analyzed. The results show that yarns with high recycled carbon fiber content (>90% by weight) can be produced with reproducible quality on the DREF-3000 friction spinning machine.
Articulated vehicle rollover detection and active control based on center of gravity position metric
Authors: Yang Kuo , Liu Xinhui , Cao Bingwei , Chen Wei , Tan Peng , Cheng Xin
Published: October 2023

In this study, the adaptive adjustment technology, based on an Attitude and Heading Reference System, is applied to loaders, aiming to improve the rollover protection performance of articulated engineering vehicles. A dynamic rollover stability index for loaders is developed, coupling the roll angular velocity and the slope and height of the center of gravity. A nonlinear predictive model of the material weight is built, in order to attain the height of the center of gravity. An adaptive attitude adjustment system is proposed, totally based on electro-hydraulic proportional control technology, to adjust the attitude of the working system, so as to achieve a higher threshold value of the vehicle’s anti-tip performance. Finally, the rollover stability index and control methods, as proposed in this article, are validated using experiments. The boundary values that trigger the system’s operation are reduced to ensure safety, while the validation results prove that the proposed method is effective.
Ethical issues experienced by nurses during COVID-19 pandemic: Systematic review
Authors: Oh Younjae , Gastmans Chris
Published: October 2023

Background

Frontline nurses who care for patients with COVID-19 work in stressful environments, and many inevitably struggle with unanticipated ethical issues. Little is known about the unique, ethically sensitive issues that nurses faced when caring for patients with COVID-19.

Aim

To better understand how frontline nurses who care for patients with COVID-19 experience ethical issues towards others and themselves.

Methods

Systematic review of qualitative evidence carried out according to the Preferred Reporting Items for Systematic reviews and Meta-analyses on ethical literature (PRISMA-Ethics). The electronic databases PubMed, Embase, Cinahl, Web of Science, Philosopher's Index, and Scopus were queried to identify candidate articles. Articles appearing from March 1, 2020 to December 31, 2022 were considered if they met the following inclusion criteria: (1) Published qualitative and mixed method studies and (2) ethical issues experienced by nurses caring for patients with COVID-19. We appraised the quality of included studies, and data analysis was guided by QUAGOL principles.

Findings

Twenty-six studies meeting our inclusion criteria for how nurses experience ethical issues were characterised by two key themes: (1) the moral character of nurses as a willingness to respond to the vulnerability of human beings and (2) ethical issues nurses acted as barriers sometimes, impeding them from responding to requests of vulnerable human beings for dignified care.

Conclusion

Our review provides a deeper understanding of nurses’ experiences of ethically sensitive issues, while also highlighting the critical need for adjustments to be made at organisational and societal levels. Ethical issues that emerged in situations where organisational and situational constraints impeded nurses' ethical responses to patients’ appeals suggests that early practical support should be made available to resolve ethical issues recognised by nurses. Such support contributes to protecting and promoting not only the dignity of patients with COVID-19 but also of fellow humans in need during crisis.
Spontaneous expulsive choroidal hemorrhage in an elderly female with microbial keratitis
Authors: Dhoot Sanjeev Kumar
Published: October 2023

Purpose

To report spontaneous choroidal hemorrhage with the expulsion of intraocular contents in an elderly female as a complication of microbial keratitis.

Methods

Retrospective case report along with imaging.

Results

A 60-year-old female on treatment for microbial keratitis, presented with protrusion of intraocular contents and no perception of light in the right eye. Ophthalmic ultrasound demonstrated choroidal hemorrhage with coexistent retinal detachment and vitreous hemorrhage. She underwent uneventful evisceration for her condition.

Conclusion

Microbial keratitis needs aggressive medical treatment to prevent associated stromal infiltration and corneal weakening. In cases of microbial keratitis, if spontaneous choroidal hemorrhage occurs, due to thinning of the cornea and compromised integrity of the eyeball, it can lead to the complete expulsion of intraocular contents with unsalvageable loss of vision.
Real-World Survival and Treatment Regimens Across First- to Third-Line Treatment for Advanced Triple-Negative Breast Cancer
Authors: Celik Alan , Berg Tobias , Jensen Maj-Britt , Jakobsen Erik , Nielsen Hanne Melgaard , Kümler Iben , Glavicic Vesna , Jensen Jeanette Dupont , Knoop Ann
Published: October 2023

Background:

Metastatic triple-negative breast cancer (mTNBC) is an aggressive subtype of breast cancer with poor survival. Currently, the literature lacks comprehensive real-world evidence on locally recurrent and mTNBC patients. To validate the optimal treatment for patients with mTNBC, real-world evidence in combination with data from clinical trials must be evaluated as complementary.

Objectives:

The objective of the study is to examine outcomes and treatment patterns of patients with advanced triple-negative breast cancer (TNBC) utilizing real-world data of patients from all oncology sites across Denmark.

Design:

This is a retrospective, non-interventional, multi-site, population-based observational study conducted across all oncology departments in Denmark.

Methods:

We included all women diagnosed with metastatic or locally recurrent TNBC from January 1, 2017, to December 31, 2019, using the national Danish Breast Cancer Group database. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the first to third treatment line.

Results:

The study included 243 women diagnosed with metastatic or recurrent TNBC. The median OS (mOS) was 11.6 months after the first line of treatment, 6.5 months after the second line, and 6.5 months after the third line. De novo mTNBC was associated with shorter OS (mOS: 8.3 vs 14.2 months), and those with a relapse within 18 months of primary diagnosis had shorter OS than those with a relapse after 18 months (mOS: 10.0 vs 18.2). In the first line, taxane was the preferred choice of treatment for patients with de novo mTNBC, whereas capecitabine was preferred for patients with recurrent TNBC.

Conclusions:

This real-world, nationwide study demonstrated poor OS among patients with metastatic or recurrent TNBC, with a mOS of 11.6 months (95% CI, 9.9-17.3). Patients who presented with de novo mTNBC or who had a relapse of their breast cancer within 18 months of primary diagnosis had shorter OS.

Registration

The study was registered and approved by the Danish Capital Regions research overview (P-2021-605).
Real-world treatment outcomes and safety of natalizumab in Finnish multiple sclerosis patients
Authors: Verkkoniemi-Ahola Auli , Hartikainen Päivi , Hassi Katja , Kuusisto Hanna , Lahdenperä Sanni , Mehtälä Juha , Viitala Matias , Ylisaukko-oja Tero , Soilu-Hänninen Merja
Published: October 2023

Objectives

The primary objective was to evaluate long-term treatment persistence and safety of natalizumab in Finnish multiple sclerosis patients. The secondary objectives were to assess patient characteristics, use of natalizumab-related safety protocol, and treatment persistence in patients with different anti-John Cunningham virus antibody statuses (John Cunningham virus status).

Materials & Methods

All adult multiple sclerosis patients in the Finnish multiple sclerosis register who started natalizumab between 1/2006 and 12/2018 were included in this study and followed retrospectively until treatment discontinuation or end of follow-up (12/2019).

Results

In total, 850 patients were included. Median duration of natalizumab treatment was 7.8 years in John Cunningham virus negative ( n = 229) and 2.1 years in John Cunningham virus positive patients ( n = 115; p < 0.001). The most common cause for treatment discontinuation was John Cunningham virus positivity. After natalizumab discontinuation, patients who had a washout duration of less than 6 weeks had fewer relapses during the first 6 months ( p = 0.012) and 12 months ( p = 0.005) compared with patients who had a washout duration of over 6 weeks. During the median follow-up of 3.6 years, 76% of patients remained stable or improved on their Expanded Disability Status Scale.

Conclusions

Treatment persistence was very high among John Cunningham virus negative patients. The study supports long-term effectiveness of natalizumab and a washout duration of less than 6 weeks after discontinuation.
Informal Employment Under the Skin: Informality and Health Inequalities Among Chilean Workers
Authors: Ruiz Marisol E. , Bolibar Mireia , Sánchez-Mira Núria
Published: October 2023

Informal employment has been identified as an important social determinant of health. This article addresses the processes through which informal employment affects workers’ health in Chile. The study's methodological approach was based on qualitative interviews with 34 formal and informal workers. The findings show how workers perceive informal employment as negatively affecting their mental and physical health through different dimensions of their living and working conditions. Incorporating a gender perspective proves to be integral to the analysis of these processes. The article concludes by discussing how neoliberalism underlies such vulnerability processes and negatively impacts on the population's health.
Clonal evolution dissection reveals that a high MSI2 level promotes chemoresistance in T-cell acute lymphoblastic leukemia
Authors: Zhang Jingliao , Duan Yongjuan , Wu Peng , Chang Yanxia , Wang Yue , Hu Tianyuan , Liu Chao , Chen Xiaoyan , Zong Suyu , Chen Xiaoli , Wu Yangping , Jin Linlin , Lan Yang , Liu Xiaoming , Cheng Xuelian , Ding Feng , Li Tianyu , Chen Xiaojuan , Guo Ye , Chen Yumei , Yang Wenyu , Zhang Li , Zou Yao , Cheng Tao , Zhu Xiaofan , Zhang Yingchi
Published: October 2023

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5′ single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis–relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, “clonal shift” and “clonal drift” were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.
E-cadherin/β-catenin expression is conserved in human and rat erythropoiesis and marks stress erythropoiesis
Authors: Krimpenfort Rosa A. , van der Meulen Santhe A. , Verhagen Han , Driessen Michel , Filonova Galina , Hoogenboezem Mark , van den Akker Emile , von Lindern Marieke , Nethe Micha
Published: October 2023

E-cadherin is a crucial regulator of epithelial cell-to-cell adhesion and an established tumor suppressor. Aside epithelia, E-cadherin expression marks the erythroid cell lineage during human but not mouse hematopoiesis. However, the role of E-cadherin in human erythropoiesis remains unknown. Because rat erythropoiesis was postulated to reflect human erythropoiesis more closely than mouse erythropoiesis, we investigated E-cadherin expression in rat erythroid progenitors. E-cadherin expression is conserved within the erythroid lineage between rat and human. In response to anemia, erythroblasts in rat bone marrow (BM) upregulate E-cadherin as well as its binding partner β-catenin. CRISPR/Cas9–mediated knock out of E-cadherin revealed that E-cadherin expression is required to stabilize β-catenin in human and rat erythroblasts. Suppression of β-catenin degradation by glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021 also enhances β-catenin stability in human erythroblasts but hampers erythroblast differentiation and survival. In contrast, direct activation of β-catenin signaling, using an inducible, stable β-catenin variant, does not perturb maturation or survival of human erythroblasts but rather enhances their differentiation. Although human erythroblasts do not respond to Wnt ligands and direct GSK3β inhibition even reduces their survival, we postulate that β-catenin stability and signaling is mostly controlled by E-cadherin in human and rat erythroblasts. In response to anemia, E-cadherin–driven upregulation and subsequent activation of β-catenin signaling may stimulate erythroblast differentiation to support stress erythropoiesis in the BM. Overall, we uncover E-cadherin/β-catenin expression to mark stress erythropoiesis in rat BM. This may provide further understanding of the underlying molecular regulation of stress erythropoiesis in the BM, which is currently poorly understood.