bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of target gene regulation by the two Epstein-Barr virus oncogene LMP1 domains essential for B-cell transformation
Authors: Mitra Bidisha , Beri Nina Rose , Guo Rui , Burton Eric M. , Murray-Nerger Laura A. , Gewurz Benjamin E. 
Published: November 2023

ABSTRACT
The Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1) mimics CD40 signaling and is expressed by multiple malignancies. Two LMP1 C-terminal cytoplasmic tail regions, termed transformation essential sites (TES) 1 and 2, are critical for EBV transformation of B lymphocytes into immortalized lymphoblastoid cell lines (LCL). However, TES1 versus TES2 B-cell target genes have remained incompletely characterized, and whether both are required for LCL survival has remained unknown. To define LCL LMP1 target genes, we profiled transcriptome-wide effects of acute LMP1 CRISPR knockout (KO) prior to cell death. To then characterize specific LCL TES1 and TES2 roles, we conditionally expressed wildtype, TES1 null, TES2 null, or double TES1/TES2 null LMP1 alleles upon endogenous LMP1 KO. Unexpectedly, TES1 but not TES2 signaling was critical for LCL survival. The LCL dependency factor cFLIP, which plays obligatory roles in blockade of LCL apoptosis, was highly downmodulated by loss of TES1 signaling. To further characterize TES1 vs TES2 roles, we conditionally expressed wildtype, TES1, and/or TES2 null LMP1 alleles in two Burkitt models. Systematic RNAseq analyses revealed gene clusters that responded more strongly to TES1 vs TES2, that respond strongly to both or that are oppositely regulated. Robust TES1 effects on cFLIP induction were again noted. TES1 and 2 effects on expression of additional LCL dependency factors, including BATF and IRF4, and on EBV super-enhancers were identified. Collectively, these studies suggest a model by which LMP1 TES1 and TES2 jointly remodel the B-cell transcriptome and highlight TES1 as a key therapeutic target.

IMPORTANCE
Epstein-Barr virus (EBV) causes multiple human cancers, including B-cell lymphomas. In cell culture, EBV converts healthy human B-cells into immortalized ones that grow continuously, which model post-transplant lymphomas. Constitutive signaling from two cytoplasmic tail domains of the EBV oncogene latent membrane protein 1 (LMP1) is required for this transformation, yet there has not been systematic analysis of their host gene targets. We identified that only signaling from the membrane proximal domain is required for survival of these EBV-immortalized cells and that its loss triggers apoptosis. We identified key LMP1 target genes, whose abundance changed significantly with loss of LMP1 signals, or that were instead upregulated in response to switching on signaling by one or both LMP1 domains in an EBV-uninfected human B-cell model. These included major anti-apoptotic factors necessary for EBV-infected B-cell survival. Bioinformatics analyses identified clusters of B-cell genes that respond differently to signaling by either or both domains.
Characterization of HcaA, a novel autotransporter protein in
Helicobacter cinaedi
, and its role in host cell adhesion
Authors: Aoki Sae , Mori Shigetarou , Matsui Hidenori , Shibayama Keigo , Kenri Tsuyoshi , Rimbara Emiko 
Published: November 2023

ABSTRACT

Helicobacter cinaedi
infects the human gut and causes invasive infections such as bacteremia and cellulitis through bacterial translocation. However, the mechanism by which
H. cinaedi
attaches to host cells and establishes infection remains unclear. This study aimed to investigate the relationship between a novel putative autotransporter protein,
H. cinaedi
autotransporter protein A (HcaA), and its role in pathogenicity. The cytotoxicity of
H. cinaedi
infection in colon epithelial cell lines (Caco-2 and HT29) was assessed using a lactate dehydrogenase assay, and it was found that cytotoxicity significantly decreased upon HcaA knockout. Adhesion assays further revealed that the HcaA-knockout strain showed significantly reduced attachment to the human epithelial colorectal adenocarcinoma (Caco-2) cell line compared to that of the wild-type strain. Moreover, the recombinant HcaA protein demonstrated strong adhesion properties to the human monocytic cell line (U937). The adhesive activity was diminished when the Arg-Gly-Asp (RGD) motif in HcaA was replaced with RAD, indicating that the RGD motif in HcaA is crucial for host cell adhesion. To determine the role of HcaA in
H. cinaedi
infection
in vivo
, C57BL/6 mice were orally infected with wild-type and HcaA-knockout
H. cinaedi
strains. Bacterial colonization was assessed 7, 14, and 28 days post-infection. At 7 days post-infection, colonization was significantly lower in mice infected with the HcaA-knockout strain compared to those infected with the wild-type strain. In conclusion, our findings suggest that HcaA, a novel putative autotransporter protein in
H. cinaedi
, plays a significant role as an adhesin in establishing colonization.

IMPORTANCE

Helicobacter
species are classified as gastric or enterohepatic according to their habitat. Among enterohepatic
Helicobacter
species, which inhabit the intestine, colon, and liver,
Helicobacter cinaedi
has been most frequently isolated from humans.
H. cinaedi
often causes bacteremia and cellulitis in immunocompromised hosts. Here, we focused on the
H. cinaedi
autotransporter protein A (HcaA), a novel virulence factor in
H. cinaedi
. We discovered that HcaA contributes to cell adhesion via its Arg-Gly-Asp motif. Furthermore, in animal experiments, bacterial colonization was reduced in mice infected with HcaA-knockout strains, supporting the hypothesis that HcaA contributes to
H. cinaedi
adhesion to host cells. Our study provides a novel mechanism for the establishment of
H. cinaedi
infections and provides new insights into the role of autotransporter proteins in the establishment of
Helicobacter
infection.
Development of a murine model to study the cerebral pathogenesis of
Aspergillus fumigatus
Authors: Kelty Martin T. , Beattie Sarah R. 
Published: November 2023

ABSTRACT

Fungal infections of the central nervous system are associated with high mortality and limited treatment options due to the poor permeability of the blood brain barrier to most antifungal drugs. The most common pathogenic mold is
Aspergillus fumigatus
, which typically causes invasive pulmonary disease that can disseminate to extrapulmonary organs, including the brain, resulting in cerebral aspergillosis (CA). Currently, the best treatment option for CA is antifungal therapy combined with resection of infected tissue; however, mortality rates of these infections still approach 100%. Despite these unacceptably high mortality rates, relatively little is known about the fungal determinants that allow
Aspergillus
to successfully establish infection and grow within the brain. Here, we present a murine model designed to study the fungal pathogenesis of CA using tail vein inoculation in C5-complement-deficient mice. In this model, mice develop a robust fungal burden in the brain and display hallmarks of invasive aspergillosis seen in both murine models of invasive aspergillosis and in human cases of CA. We highlight the role of one fungal transcription factor, PacC, in the hematogenous dissemination of
A. fumigatus
to extrapulmonary organs including the brain. This model will enable pathogenesis studies in a largely unexplored area of
A. fumigatus
infections with the goal of identifying novel targets and pathways for the development of more efficacious antifungal therapies to treat these infections.

IMPORTANCE

Molds are environmental fungi that can cause disease in immunocompromised individuals. The most common pathogenic mold is
Aspergillus fumigatus,
which is typically inhaled into the lungs and causes invasive pulmonary disease. In a subset of these patients, this infection can spread from the lungs to other organs including the brain, resulting in cerebral aspergillosis. How
A. fumigatus
causes brain disease is not well understood and these infections are associated with extremely high mortality rates. Thus, we developed an animal model to study the pathogenesis of cerebral aspergillosis to better understand this disease and develop better treatments for these life-threatening infections.
Multiple phosphorylation sites regulate the activity of the repressor Mig1 in
Candida albicans
Authors: Ramírez-Zavala Bernardo , Betsova Darina , Schwanfelder Sonja , Krüger Ines , Mottola Austin , Krüger Thomas , Kniemeyer Olaf , Brakhage Axel A. , Morschhäuser Joachim 
Published: November 2023

ABSTRACT

The highly conserved heterotrimeric protein kinase SNF1 is important for metabolic adaptations in the pathogenic yeast
Candida albicans
. A key function of SNF1 is to inactivate the repressor protein Mig1 and thereby allow the expression of genes that are required for the utilization of alternative carbon sources when the preferred carbon source, glucose, is absent or becomes limiting. However, how SNF1 controls Mig1 activity in
C. albicans
has remained elusive. Using a phosphoproteomics approach, we found that Mig1 is phosphorylated at multiple serine residues. Replacement of these serine residues by nonphosphorylatable alanine residues strongly increased the repressor activity of Mig1 in cells lacking a functional SNF1 complex, indicating that additional protein kinases are involved in the regulation of Mig1. Unlike wild-type Mig1, whose levels strongly decreased when the cells were grown on sucrose or glycerol instead of glucose, the levels of a mutant Mig1 protein lacking nine phosphorylation sites remained high under these conditions. Despite the increased protein levels and the absence of multiple phosphorylation sites, cells with a functional SNF1 complex could still sufficiently inhibit the hyperactive Mig1 to enable wild-type growth on alternative carbon sources. In line with this, phosphorylated forms of the mutant Mig1 were still detected in the presence and absence of a functional SNF1, demonstrating that Mig1 contains additional, unidentified phosphorylation sites and that downstream protein kinases are involved in the control of Mig1 activity by SNF1.

IMPORTANCE

The SNF1 protein kinase signaling pathway, which is highly conserved in eukaryotic cells, is important for metabolic adaptations in the pathogenic yeast
Candida albicans
. However, so far, it has remained elusive how SNF1 controls the activity of one of its main effectors, the repressor protein Mig1 that inhibits the expression of genes required for the utilization of alternative carbon sources when glucose is available. In this study, we have identified multiple phosphorylation sites in Mig1 that contribute to its inactivation. Mutation of these sites strongly increased Mig1 repressor activity in the absence of SNF1, but SNF1 could still sufficiently inhibit the hyperactive Mig1 to enable growth on alternative carbon sources. These findings reveal features of Mig1 that are important for controlling its repressor activity. Furthermore, they demonstrate that both SNF1 and additional protein kinases regulate Mig1 in this pathogenic yeast.
Differences in risk and costs between prehospital identified low-risk men and women with chest pain
Authors: Aarts Goaris W A , Camaro Cyril , Rodwell Laura , Adang Eddy M M , van Hout Roger , Brok Gijs , Hoare Anouk , de Pooter Frank P C , de Wit Walter , Cramer Gilbert E , van Kimmenade Roland R J , Ouwendijk Eva , Rutten Martijn , Zegers Erwin , van Geuns Robert-Jan M , Gomes Marc E R , Damman Peter , van Royen Niels 
Published: November 2023

ObjectivePrehospital rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in low-risk patient with a point-of-care troponin measurement reduces healthcare costs with similar safety to standard transfer to the hospital. Risk stratification is performed identical for men and women, despite important differences in clinical presentation, risk factors and age between men and women with NSTE-ACS. Our aim was to compare safety and healthcare costs between men and women in prehospital identified low-risk patients with suspected NSTE-ACS.MethodsIn the Acute Rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART (History, ECG, Age, Risk factors and Troponin) score assessment and a single poInt of CAre troponin randomised trial, the HEAR (History, ECG, Age and Risk factors) score was assessed by ambulance paramedics in suspected NSTE-ACS patients. Low-risk patients (HEAR score ≤3) were included. In this substudy, men and women were compared. Primary endpoint was 30-day major adverse cardiac events (MACE), secondary endpoints were 30-day healthcare costs and the scores for the HEAR score components.ResultsA total of 863 patients were included, of which 495 (57.4%) were women. Follow-up was completed in all patients. In the total population, MACE occurred in 6.8% of the men and 1.6% of the women (risk ratio (RR) 4.2 (95% CI 1.9 to 9.2, p<0.001)). In patients with ruled-out ACS (97% of the total population), MACE occurred in 1.4% of the men and in 0.2% of the women (RR 7.0 (95% CI 2.0 to 14.2, p<0.001). Mean healthcare costs were €504.55 (95% CI €242.22 to €766.87, p<0.001) higher in men, mainly related to MACE.ConclusionsIn a prehospital population of low-risk suspected NSTE-ACS patients, 30-day incidence of MACE and MACE-related healthcare costs were significantly higher in men than in women.Trial registration numberNCT05466591.
Twelve-month follow-up effects of cognitive training after heart valve surgery on cognitive functions and health-related quality of life: a randomised clinical trial
Authors: Butz Marius , Gerriets Tibo , Sammer Gebhard , El-Shazly Jasmin , Tschernatsch Marlene , Braun Tobias , Meyer Rolf , Schramm Patrick , Doeppner Thorsten R , Böning Andreas , Mengden Thomas , Choi Yeong-Hoon , Schönburg Markus , Juenemann Martin 
Published: November 2023

ObjectivesPostoperative cognitive decline (POCD) or decreased health-related quality of life (HQL) have been reported after cardiac surgery. A previous investigation showed beneficial effects of postoperative cognitive training on POCD and HQL 3 months after heart surgery. Here, we present the 12-month follow-up results.MethodsThis bicentric, 1:1 randomised and treatment-as-usual controlled trial included elderly patients scheduled for elective heart valve surgery. The training consisted of paper-and-pencil-based exercises practising multiple cognitive functions for 36 min/day 6 days/week over a period of 3 weeks. Neuropsychological tests and questionnaires assessing HQL (36-Item Short Form Health Survey (SF-36)) and cognitive failures in daily living (Cognitive Failures Questionnaire) were performed presurgery and 12 months after training.ResultsTwelve months post training, the training group (n=30) showed improvements in HQL compared with the control group (n=28), especially in role limitations due to physical health (U=−2.447, p=0.015, η2=0.109), role limitations due to emotional problems (U=−2.245, p=0.025, η2=0.092), pain (U=−1.979, p=0.049, η2=0.068), average of all SF-36 factors (U=−3.237, p<0.001, η2=0.181), health change from the past year to the present time (U=−2.091, p=0.037, η2=0.075), physical component summary (U=−2.803, p=0.005, η2=0.138), and mental component summary (U=−2.350, p=0.018, η2=0.095). Furthermore, the training group (n=19) showed an improvement compared with the control group (n=27) in visual recognition memory (U=−2.137, p=0.034, η2=0.099). POCD frequency was 22% (n=6) in the control group and 11% (n=2) in the training group (χ²(1) =1.06, p=0.440; OR=2.43, 95% CI 0.43 to 13.61).ConclusionIn conclusion, postoperative cognitive training shows enhancing effects on HQL in cardiac surgery patients after 12 months.
Superiority of left heart deformation in early anthracycline-related cardiac dysfunction detection
Authors: Giang M Nhat , Nguyen H Hai , Vo Duc Tan , Ho Huynh Quang Tri , Phan Duc Thi Hong , Chau Ngoc-Hoa 
Published: November 2023

ObjectiveThis study aimed to assess the incidence of early cancer therapy-related cardiac dysfunction (CTRCD) and the characteristics of left and right heart deformations during anthracycline chemotherapy.MethodsWe prospectively enrolled a cohort of 351 chemotherapy-naïve women with breast cancer and cardiovascular risk factors who were scheduled to receive anthracycline. The left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (LV-GLS) and right ventricular and left atrial longitudinal strains were evaluated using echocardiography at baseline, before every subsequent cycles and at 3 weeks after the final anthracycline dose. CTRCD was defined as a new LVEF reduction by ≥10 percentage points to an LVEF<50% and/or a new relative decline in GLS by >15% from the baseline value.ResultsEighteen (5.1%) patients had evidence of asymptomatic CTRCD during anthracycline treatment, and 50% developed CTRCD before completing the chemotherapy regimen. In the CTRCD group, while LV-GLS decrease significantly after the first dose of anthracycline, the reduction of right ventricular free-wall longitudinal strain and left atrial reservoir strain were observed after the second dose. Other strain indices could not be used to identify early CTRCD.ConclusionsCardiotoxicity appeared soon after the initiation of anthracycline chemotherapy. Among the left-heart and right-heart mechanics, LV-GLS remains the best deformation indicator for detecting early CTRCD.
Determinants and Characteristics of Insulin Dose Requirements in Children and Adolescents with New-Onset Type 1 Diabetes: Insights from the INSENODIAB Study
Authors: Beckers Maude , Polle Olivier , Gallo Paola , Bernard Noémie , Bugli Céline , Lysy Philippe A. 
Published: November 2023

Aims. New-onset type 1 diabetes mellitus (T1D) in pediatric patients represents a clinical challenge for initial total daily insulin dosing (TIDD) due to substantial heterogeneity in practice and lack of consensus on the optimal starting dose. Our INSENODIAB (INsulin SEnsitivity in New Onset type 1 DIABetes) study is aimed at (1) exploring the influence of patient-specific characteristics on insulin requirements in pediatric patients with new-onset T1D; (2) constructing a predictive model for the recommended TIDD tailored to individual patient profiles; and (3) assessing potential associations between TIDD and patient outcomes at follow-up intervals of 3 and 12 months. Methods. We conducted a comprehensive analysis of medical records for children aged 6 months to 18 years, hospitalized for new-onset T1D from 2013 to 2022. The study initially involved multivariable regression analysis on a retrospective cohort (rINSENODIAB), incorporating baseline variables. Subsequently, we validated the model robustness on a prospective cohort (pINSENODIAB) with a significance threshold of 5%. The model accuracy was assessed by Pearson’s correlation. Results. Our study encompassed 103 patients in the retrospective cohort and 80 in the prospective cohort, with median TIDD at diagnosis of 1.1 IU/kg BW/day (IQR 0.5). The predictive model for optimal TIDD was established using baseline characteristics, resulting in the following formula:

TIDD

IU
/
d

=

0.09
×
Age
2

+

0.68
×
%
Weight

Loss

+

28.60
×
Veinous

pH

−

1.03
×
Veinous

bicarbonates

+

0.81
×
Weight

−
194.63

. Validation of the model using the pINSENODIAB cohort demonstrated a significant Pearson correlation coefficient of 0.74. Notably, no significant correlation was observed between TIDD at diagnosis and partial remission markers (IDAA1C, C-peptide) at 3- and 12-months postdiagnosis time points. Conclusions. In the context of new-onset T1D in pediatric patients, we identified key influencing factors for determining optimal TIDD, including age, percentage of weight loss, weight, veinous pH, and bicarbonates. These findings have paved the way for the development of a dosing algorithm to potentially expedite glycemic control stabilization and facilitate a more individualized approach to treatment regimens.
FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation
Authors: Woods Ashley , Norsworthy Kelly J. , Wang Xin , Vallejo Jonathon , Chiu Yuen Chow Edwin , Li Ruo-Jing , Sun Jielin , Charlab Rosane , Jiang Xiling , Pazdur Richard , Theoret Marc R. , de Claro R. Angelo 
Published: November 2023

Abstract
On May 25, 2022, FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) extending the indication in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) in older adults or those with comorbidities to include the combination with azacitidine. The efficacy of ivosidenib in combination with azacitidine was evaluated in Study AG120-C-009, a phase 3, multicenter, double-blind, randomized (1:1), controlled study of ivosidenib or matched placebo in combination with azacitidine in adults with previously untreated AML with an IDH1 mutation who were 75 years or older or had comorbidities that precluded use of intensive induction chemotherapy. Efficacy was established on the basis of improved event-free survival and overall survival on the ivosidenib + azacitidine arm [HR, 0.35; 95% confidence interval (CI), 0.17–0.72; P = 0.0038, and HR, 0.44; 95% CI, 0.27–0.73; P = 0.0010], respectively. Furthermore, the rate and duration of complete remission (CR) were improved with ivosidenib versus placebo [CR 47% versus 15%, two-sided P &lt; 0.0001; median duration of CR not estimable (NE; 95% CI, 13.0–NE) months versus 11.2 (95% CI, 3.2–NE) months. The safety profile of ivosidenib in combination with azacitidine was consistent with that of ivosidenib monotherapy, with important adverse reactions including differentiation syndrome (15%) and QT interval prolongation (20%).