bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential responses of pulmonary vascular cells from PAH patients and controls to TNFα and the effect of the BET inhibitor JQ1
Authors: Mumby Sharon , Perros Frederic , Grynblat Julien , Manaud Gregoire , Papi Alberto , Casolari Paolo , Caramori Gaetano , Humbert Marc , John Wort S. , Adcock Ian M. 
Published: July 2023

Abstract
Background
Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and inflammation. Bromodomain and extra-terminal (BET) proteins are required for the expression of a subset of NF-κB-induced inflammatory genes which can be inhibited by the BET mimic JQ1+. We hypothesised that JQ+ would supress TNFα-driven inflammatory responses in human pulmonary vascular cells from PAH patients.

Methods
Immunohistochemical staining of human peripheral lung tissue (N = 14 PAH and N = 12 non-PAH) was performed for the BET proteins BRD2 and 4. Human pulmonary microvascular endothelial cells (HPMEC) and pulmonary artery smooth muscle cells (HPASMC) from PAH patients (N = 4) and non-PAH controls (N = 4) were stimulated with TNFα in presence or absence of JQ1+ or its inactive isomer JQ1–. IL-6 and -8 mRNA was measured by RT-qPCR and protein levels by ELISA. Chromatin immunoprecipitation analysis was performed using EZ-ChIP™ and NF-κB p65 activation determined using a TransAm kit. MTT assay was used to measure cell viability.

Results
Nuclear staining of BRD2 and BRD4 was significantly (p < 0.0001) increased in the lung vascular endothelial and smooth muscle cells from PAH patients compared to controls with normal lung function. TNFα-driven IL-6 release from both HPMECs and HPASMCs was greater in PAH cells than control cells. Levels of CXCL8/IL-8 protein release was higher in PAH HPASMCs than in control cells with similar release observed in HPMECs. TNFα-induced recruitment of activated NF-κB p65 to the IL-6 and CXCL8/IL-8 promoters were similar in both cell types and between subject groups. JQ1+ suppressed TNFα-induced IL-6 and CXCL8/IL-8 release and mRNA expression to a comparable extent in control and PAH HPMECs and HPASMCs. JQ1 had a greater efficacy on IL-6 release in HPMEC and on CXCL8/IL-8 release in HPASMC.

Conclusion
BET inhibition decreases TNFα driven inflammation in primary pulmonary vascular cells. The anti-inflammatory actions of JQ1 suggests distinct cell-specific regulatory control of these genes. BET proteins could be a target for future therapies for PAH.
Smoking behavior change and risk of cardiovascular disease incidence and mortality in patients with type 2 diabetes mellitus
Authors: Jeong Su-Min , Yoo Jung Eun , Park Junhee , Jung Wonyoung , Lee Kyu Na , Han Kyungdo , Lee Cheol Min , Nam Ki-Woong , Lee Seung-Pyo , Shin Dong Wook 
Published: July 2023

Abstract
Background
We aimed to examine the association between smoking behavior change and risk of cardiovascular disease (CVD) incidence and mortality in patients with type 2 diabetes mellitus (T2DM).

Methods
This study used nationwide data from the Korean National Health Insurance System and included 349,137 T2DM patients who smoked. Smoking behavior changes were defined with five groups: quitters, reducers I (≥ 50% reduction), reducers II (20–50% reduction), sustainers (± 20%), and increasers (≥ 20% increase) from the number of cigarettes/day at the baseline.

Results
During a median follow-up of 5.1 years, 6,514 cases of myocardial infarction (MI) (1.9%), 7,837 cases of ischemic stroke (IS) (2.2%), and 14,932 deaths (4.3%) were identified. Quitters had a significantly decreased risk of MI (adjusted hazard ratio [aHR] 0.80, 95% CI 0.75–0.86) and IS (aHR 0.80, 95% CI 0.75–0.85) compared to sustainers, whereas reducers did not have a significant association with the risk of MI (aHR 1.03, 95% CI 0.94–1.13) and IS (aHR 1.00, 95% CI 0.92–1.08) in reducer I. Quitters also had a lower all-cause and CVD mortality than sustainers.

Conclusions
Smoking cessation was associated with decreased CVD incidence, and all-cause and CVD mortality among T2DM patients. However, smoking reduction was not associated with decreased risks for these.
ROS impairs tumor vasculature normalization through an endocytosis effect of caveolae on extracellular SPARC
Authors: Zhao Ye , Yu Jing , Huang Ai , Yang Qin , Li Guiling , Yang Yong , Chen Yeshan 
Published: August 2023

Abstract
Background
The accumulation of reactive oxygen species (ROS) in tumor microenvironment (TME) is an important player for tumorigenesis and progression. We aimed to explore the outcomes of ROS on tumor vessels and the potential regulated mechanisms.

Methods
Exogenous H2O2 was adopted to simulate the ROS setting. Immunofluorescence staining and ultrasonography were used to assess the vascular endothelial coverage and perfusions in the tumors inoculated with Lewis lung cancer (LLC) and melanoma (B16F10) cells of C57BL/6 mice, respectively. ELISA and western-blot were used to detect the expression of secreted acidic and cysteine-rich protein (SPARC) and Caveale-1 in human umbilical vein endothelial cells (HUVEC) extra- and intracellularly. Intracellular translocation of SPARC was observed using electron microscopy and immunofluorescence approaches.

Result
Under the context of oxidative stress, the pericyte recruitment of neovascularization in mouse lung cancer and melanoma tissues would be aberrated, which subsequently led to the disruption of the tumor vascular architecture and perfusion dysfunction. In vitro, HUVEC extracellularly SPARC was down-regulated, whereas intracellularly it was up-regulated. By electron microscopy and immunofluorescence staining, we observed that SPARC might undergo transmembrane transport via caveale-1-mediated endocytosis. Finally, the binding of SPARC to phosphorylated-caveale-1 was also detected in B16F10 tissues.

Conclusion
In the oxidative stress environment, neovascularization within the tumor occurs structural deterioration and decreased perfusion capacity. One of the main regulatory mechanisms is the migration of extracellular SPARC from the endothelium to intracellular compartments via Caveolin-1 carriers.
Association of neighborhood physical activity facilities with incident cardiovascular disease
Authors: Huang Yulin , Zhao Huimin , Deng Qiuju , Qi Yue , Sun Jiayi , Wang Miao , Chang Jie , Hu Piaopiao , Su Yuwei , Long Ying , Liu Jing 
Published: July 2023

Abstract
Background
The availability of physical activity (PA) facilities in neighborhoods is hypothesized to influence cardiovascular disease (CVD), but evidence from individual-level long-term cohort studies is limited. We aimed to assess the association between neighborhood exposure to PA facilities and CVD incidence.

Methods
A total of 4658 participants from the Chinese Multi-provincial Cohort Study without CVD at baseline (2007–2008) were followed for the incidence of CVD, coronary heart disease (CHD), and stroke. Availability of PA facilities was defined as both the presence and the density of PA facilities within a 500-m buffer zone around the participants’ residential addresses. Time-dependent Cox regression models were performed to estimate the associations between the availability of PA facilities and risks of incident CVD, CHD, and stroke.

Results
During a median follow-up of 12.1 years, there were 518 CVD events, 188 CHD events, and 355 stroke events. Analyses with the presence indicator revealed significantly lower risks of CVD (hazard ratio [HR] 0.80, 95% confidence interval ([CI] 0.65–0.99) and stroke (HR 0.76, 95% CI 0.60–0.97) in participants with PA facilities in the 500-m buffer zone compared with participants with no nearby facilities in fully adjusted models. In analyses with the density indicator, exposure to 2 and ≥ 3 PA facilities was associated with 35% (HR 0.65, 95% CI 0.47–0.91) and 28% (HR 0.72, 95% CI 0.56–0.92) lower risks of CVD and 40% (HR 0.60, 95% CI 0.40–0.90) and 38% (HR 0.62, 95% CI 0.46–0.84) lower risks of stroke compared with those without any PA facilities in 500-m buffer, respectively. Effect modifications between presence of PA facilities and a history of hypertension for incident stroke (P = 0.049), and a history of diabetes for incident CVD (P = 0.013) and stroke (P = 0.009) were noted.

Conclusions
Residing in neighborhoods with better availability of PA facilities was associated with a lower risk of incident CVD. Urban planning intervention policies that increase the availability of PA facilities could contribute to CVD prevention.
METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
Authors: García-Vílchez Raquel , Añazco-Guenkova Ana M. , Dietmann Sabine , López Judith , Morón-Calvente Virginia , D’Ambrosi Silvia , Nombela Paz , Zamacola Kepa , Mendizabal Isabel , García-Longarte Saioa , Zabala-Letona Amaia , Astobiza Ianire , Fernández Sonia , Paniagua Alejandro , Miguel-López Borja , Marchand Virginie , Alonso-López Diego , Merkel Angelika , García-Tuñón Ignacio , Ugalde-Olano Aitziber , Loizaga-Iriarte Ana , Lacasa-Viscasillas Isabel , Unda Miguel , Azkargorta Mikel , Elortza Félix , Bárcena Laura , Gonzalez-Lopez Monika , Aransay Ana M. , Di Domenico Tomás , Sánchez-Martín Manuel A. , De Las Rivas Javier , Guil Sònia , Motorin Yuri , Helm Mark , Pandolfi Pier Paolo , Carracedo Arkaitz , Blanco Sandra 
Published: July 2023

AbstractNewly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.
Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Authors: Dalens Lorraine , Niogret Julie , Richard Corentin , Chevrier Sandy , Foucher Pascal , Coudert Bruno , Lagrange Aurélie , Favier Laure , Westeel Virginie , Kim Stefano , Adotevi Olivier , Chapusot Caroline , Martin Laurent , Arnould Laurent , Kaderbhai Courèche-Guillaume , Boidot Romain 
Published: July 2023

Abstract
Background
Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment.

Methods
We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment).

Results
Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors.

Conclusion
Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes.

Trial registration
NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).
Uniportal video-assisted anatomical segmentectomy: an analysis of the learning curve
Authors: Han Yu , Zhang Zhenrong , Feng Hongxiang , Wen Huanshun , Su Kunsong , Xiao Fei , Liang Chaoyang , Liu Deruo 
Published: July 2023

Abstract
Background
This study aimed to demonstrate the learning curve of anatomical segmentectomy performed by uniportal video-assisted thoracoscopic surgery (U-VATS).

Method
We conducted a retrospective study of U-VATS segmentectomies performed by the same surgeon between September 2019 and August 2022. The learning curve was demonstrated using risk-adjusted cumulative sum (RA-CUSUM) analysis in terms of perioperative complications, which reflected surgical quality and technique proficiency. The surgical outcomes were also compared between different phases.

Result
The complication-based learning curve of U-VATS segmentectomy could be divided into two phases based on RA-CUSUM analysis: phase I, the initial learning phase (cases 1–50) and phase II, the proficiency phase (cases 51–141). Significantly higher complication rates (24.0 vs. 8.8%, p=0.013), longer surgical times (119.8±31.9 vs. 106.2±23.8 min, p=0.005), and more blood loss (20 [IQR, 20–30] vs. 20 [IQR, 10–20] ml, p=0.003) were observed in phase I than in phase II.

Conclusion
The learning curve of U-VATS segmentectomy consists of two phases, and at least 50 cases were required to gain technique proficiency and achieve high-quality surgical outcomes.
Targeted Silencing of NRF2 by rituximab-conjugated nanoparticles increases the sensitivity of chronic lymphoblastic leukemia cells to Cyclophosphamide
Authors: Khodakarami Atefeh , Kashani Mahsa Afsari , Nazer Atefeh , Kheshti Armin Mahmoudsalehi , Rashidi Bentolhoda , Karpisheh Vahid , Masjedi Ali , Abolhasani Shiva , Izadi Sepideh , Bagherifar Rafieh , Hejazian Seyyed Sina , Mohammadi Hamed , Movassaghpour AliAkbar , Feizi Abbas Ali Hosseinpour , Hojjat-Farsangi Mohammad , Jadidi-Niaragh Farhad 
Published: August 2023

AbstractBackgroundTargeting influential factors in resistance to chemotherapy is one way to increase the effectiveness of chemotherapeutics. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway overexpresses in chronic lymphocytic leukemia (CLL) cells and appears to have a significant part in their survival and chemotherapy resistance. Here we produced novel nanoparticles (NPs) specific for CD20-expressing CLL cells with simultaneous anti-Nrf2 and cytotoxic properties.MethodsChitosan lactate (CL) was used to produce the primary NPs which were then respectively loaded with rituximab (RTX), anti-Nrf2 Small interfering RNA (siRNAs) and Cyclophosphamide (CP) to prepare the final version of the NPs (NP-Nrf2_siRNA-CP). All interventions were done on both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMNCs).ResultsNP-Nrf2_siRNA-CP had satisfying physicochemical properties, showed controlled anti-Nrf2 siRNA/CP release, and were efficiently transfected into CLL primary cells (both PBMCs and BMNCs). NP-Nrf2_siRNA-CP were significantly capable of cell apoptosis induction and proliferation prevention marked by respectively decreased and increased anti-apoptotic and pro-apoptotic factors. Furthermore, use of anti-Nrf2 siRNA was corresponding to elevated sensitivity of CLL cells to CP.ConclusionOur findings imply that the combination therapy of malignant CLL cells with RTX, CP and anti-Nrf2 siRNA is a novel and efficient therapeutic strategy that was capable of destroying malignant cells. Furthermore, the use of NPs as a multiple drug delivery method showed fulfilling properties; however, the need for further future studies is undeniable.
SUMOylation of AnxA6 facilitates EGFR-PKCα complex formation to suppress epithelial cancer growth
Authors: Sheng Zenghua , Cao Xu , Deng Ya-nan , Zhao Xinyu , Liang Shufang 
Published: August 2023

Abstract
Background
The Annexin A6 (AnxA6) protein is known to inhibit the epidermal growth factor receptor (EGFR)-extracellular signal regulated kinase (ERK)1/2 signaling upon EGF stimulation. While the biochemical mechanism of AnxA6 inactivating phosphorylation of EGFR and ERK1/2 is not completely explored in cancer cells.

Methods
Cells were transiently co-transfected with pFlag-AnxA6, pHA-UBC9 and pHis-SUMO1 plasmids to enrich the SUMOylated AnxA6 by immunoprecipitation, and the modification level of AnxA6 by SUMO1 was detected by Western blot against SUMO1 antibody. The SUMOylation level of AnxA6 was compared in response to chemical SUMOylation inhibitor treatment. AnxA6 SUMOylation sites were further identified by LC–MS/MS and amino acid site mutation validation. AnxA6 gene was silenced through AnxA6 targeting shRNA-containing pLKO.1 lentiviral transfection in HeLa cells, while AnxA6 gene was over-expressed within the Lenti-Vector carrying AnxA6 or mutant AnxA6K299R plasmid in A431 cells using lentiviral infections. Moreover, the mutant plasmid pGFP-EGFRT790M/L858R was constructed to test AnxA6 regulation on EGFR mutation-induced signal transduction. Moreover, cell proliferation, migration, and gefitinib chemotherapy sensitivity were evaluated in HeLa and A431 cells under AnxA6 konckdown or AnxA6 overexpression by CCK8, colony form and wound healing assays. And tumorigenicity in vivo was measured in epithelial cancer cells-xenografted nude mouse model.

Results
AnxA6 was obviously modified by SUMO1 conjugation within Lys (K) residues, and the K299 was one key SUMOylation site of AnxA6 in epithelial cancer cells. Compared to the wild type AnxA6, AnxA6 knockdown and its SUMO site mutant AnxA6K299R showed less suppression of dephosphorylation of EGFR-ERK1/2 under EGF stimulation. The SUMOylated AnxA6 was prone to bind EGFR in response to EGF inducement, which facilitated EGFR-PKCα complex formation to decrease the EGF-induced phosphorylation of EGFR-ERK1/2 and cyclin D1 expression. Similarly, AnxA6 SUMOylation inhibited dephosphorylation of the mutant EGFR, thereby impeding EGFR mutation-involved signal transduction. Moreover, AnxA6 knockdown or the K299 mutant AnxA6K299R conferred AnxA6 inability to suppress tumor progression, resulting in drug resistance to gefitinib in epithelial cancer cells. And in epithelial cancer cells-xenografted nude mouse model, both the weight and size of tumors derived from AnxA6 knockdown or AnxA6K299R mutation-expressing cells were much greater than that of AnxA6-expressing cells.

Conclusions
Besides EGFR gene mutation, protein SUMOylation modification of EGFR-binding protein AnxA6 also functions pivotal roles in mediating epithelial cancer cell growth and gefitinib drug effect.
Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques
Authors: Nieuwland Juliana M. , Nutma Erik , Philippens Ingrid H. C. H. M. , Böszörményi Kinga P. , Remarque Edmond J. , Bakker Jaco , Meijer Lisette , Woerdman Noor , Fagrouch Zahra C. , Verstrepen Babs E. , Langermans Jan A. M. , Verschoor Ernst J. , Windhorst Albert D. , Bontrop Ronald E. , de Vries Helga E. , Stammes Marieke A. , Middeldorp Jinte 
Published: July 2023

Abstract
Background
Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role.

Methods
To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET–CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection.

Results
TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels.

Conclusions
This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms.
Pathogenesis diagnosis of a pediatric patient suffering from multi-organ abscesses
Authors: Wu Mingkun , Xiao Haijuan , Xiao Yan , Chen Tianming , Wang Xinming , Xiao Xia , Wang Ying , Wang Jianwei , Ren Lili , Liu Gang 
Published: July 2023

AbstractA pediatric patient suffered from renal and hepatic abscesses (through hepatorenal space) and recovered by antibiotics and other therapies. By clinical analysis, the multi-organ abscesses might be caused by bloodstream-disseminated infection. In order to identify the pathogen, we collected kidney biopsy tissue, swabs, and plasma samples, and used metagenomics next-generation sequencing (mNGS) and some traditional methods. The results revealed that polymicrobial especially anaerobic bacteremia (Bacteroides fragilis, et al.) contributed to the abscess formation. What is more, systematic human adenovirus C (HAdV-C) infection was shown, and the virus was isolated. The titer of HAdV-2 neutralizing antibodies was 1/4 in the plasma after symptoms onset. Although the exact mechanism of HAdV-2 infection in multiple abscess formation has not been clarified, the case of multi-organ abscesses in the context of polymicrobial especially anaerobic bacteremia and HAdV infection in healthy children is infrequent.