bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the MVCT-based radiomic features as prognostic factor in patients with head and neck squamous cell carcinoma
Authors: Abe Kota , Kadoya Noriyuki , Ito Kei , Tanaka Shohei , Nakajima Yujiro , Hashimoto Shimpei , Suda Yuhi , Uno Takashi , Jingu Keiichi
Published: August 2023

Background

Megavoltage computed tomography (MVCT) images acquired during each radiotherapy session may be useful for delta radiomics. However, no studies have examined whether the MVCT-based radiomics has prognostic power. Therefore, the purpose of this study was to examine the prognostic power of the MVCT-based radiomics for head and neck squamous cell carcinoma (HNSCC) patients.

Methods

100 HNSCC patients who received definitive radiotherapy were analyzed and divided into two groups: training (n = 70) and test (n = 30) sets. MVCT images obtained using TomoTherapy for the first fraction of radiotherapy and planning kilovoltage CT (kVCT) images obtained using Aquilion LB CT scanner were analyzed. Primary gross tumor volume (GTV) was propagated from kVCT to MVCT images using rigid registration, and 107 radiomic features were extracted from the GTV in MVCT and kVCT images. Least absolute shrinkage and selection operator (LASSO) Cox regression model was used to examine the association between overall survival (OS) and rad score calculated for each patient by weighting the feature value through the coefficient when features were selected. Then, the predictive values of MVCT-based and kVCT-based rad score and patient-, treatment-, and tumor-specific factors were evaluated.

Results

C-indices of the rad score for MVCT- and kVCT-based radiomics were 0.667 and 0.685, respectively. The C-indices of 6 clinical factors were 0.538–0.622. The 3-year OS was significantly different between high- and low-risk groups according to the MVCT-based rad score (50% vs. 83%; p < 0.01).

Conclusions

Our results suggested that MVCT-based radiomics had stronger prognostic power than any single clinical factor and was a useful prognostic factor when predicting OS in HNSCC patients.
Predictive value of glycemic gap and stress glycemia ratio among critically ill patients with acute kidney injury: a retrospective analysis of the MIMIC-III database
Authors: Xia Wenkai , Li Chenyu , Kuang Meisi , Wu Yu , Xu Lingyu , Hu Hong
Published: August 2023

Background and aims

Acute hyperglycemia has been identified as a risk factor for acute kidney injury occurrence and mortality in various diseases. The aim of the current study was to investigate the relationship between stress-induced hyperglycemia and adverse outcomes in critically ill patients with AKI.

Methods

We extracted clinical data from Multiparameter Intelligent Monitoring in Intensive Care III version 1.4. Blood glucose and glycosylated hemoglobin during the first 24 h of ICU admission were used to calculate glycemic gap and stress hyperglycemia ratio (SHR). The outcomes included ICU mortality and need for renal replacement therapy. The association of the glycemic gap and SHR with outcomes were determined via logistic regression model and receiver-operating curves. The subgroup analysis of patients with and without diabetes was performed separately.

Results

Higher glycemic gap and SHR were observed in patients who had increased need of RRT, higher mortality rates and longer ICU stay. Multivariate analysis demonstrated that higher glycemic gap (OR 1.01, 95%CI 1.00-1.02, P = 0.015), as well as SHR (OR 1.32; 95%CI 1.07–1.64, P = 0.009), were independently associated with ICU mortality after adjusting for potential covariates. In subgroup analysis, the association of glycemic gap and SHR were only significant in the non-diabetic population as for the outcome of ICU mortality (OR 2.25, 95%CI 1.64–3.08, P < 0.001 and OR 1.99; 95%CI 1.46–2.72, P < 0.001, respectively).

Conclusions

The glycemic gap and SHR might serve as a potential prognostic indicator of ICU mortality in critically ill patients with AKI, especially in the non-diabetic population.
A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation
Authors: Javaid Hira , Barberis Alessandro , Chervova Olga , Nassiri Isar , Voloshin Vitaly , Sato Yusuke , Ogawa Seishi , Fairfax Benjamin , Buffa Francesca , Humphrey Timothy C.
Published: August 2023

SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition ofde-novoDNA methylation.SETD2is frequently mutated in cancer, however, the functional impact ofSETD2loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that bothSETD2mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested. In renal cancer, these DNA methylation changes are associated with altered gene expression of oncogenes, tumour suppressors, and genes involved in neoplasm invasiveness, includingTP53, FOXO1, andCDK4. This suggests a new role forSETD2loss in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Moreover, using a robust machine learning methodology, we develop and validate a 3-CpG methylation signature which is sufficient to predictSETD2mutation status with high accuracy and correlates with patient prognosis.
Concordance between transbronchial lung cryobiopsy and surgical lung biopsy for interstitial lung disease in the same patients
Authors: Baba Tomohisa , Takemura Tamiko , Okudela Koji , Hebisawa Akira , Matsushita Shoichiro , Iwasawa Tae , Yamakawa Hideaki , Nakagawa Hiroaki , Ogura Takashi
Published: July 2023

Background

The diagnostic accuracy and safety of transbronchial lung cryobiopsy (TBLC) via a flexible bronchoscope under sedation compared with that of surgical lung biopsy (SLB) in the same patients is unknown.

Methods

Retrospectively the data of fifty-two patients with interstitial lung diseases (median age: 63.5 years; 21 auto-antibody positive) who underwent TBLC followed by SLB (median time from TBLC to SLB: 57 days) was collected. The samples from TBLC and SLB were randomly labelled to mask the relationship between the two samples. Diagnosis was made independently by pathologists, radiologists, and pulmonary physicians in a stepwise manner, and a final diagnosis was made at multidisciplinary discussion (MDD). In each diagnostic step the specific diagnosis, the diagnostic confidence level, idiopathic pulmonary fibrosis (IPF) diagnostic guideline criteria, and treatment strategy were recorded.

Results

Without clinical and radiological information, the agreement between the histological diagnoses by TBLC and SLB was 42.3% (kappa [κ] = 0.23, 95% confidence interval [CI]: 0.08–0.39). However, the agreement between the TBLC-MDD and SLB-MDD diagnoses and IPF/non-IPF diagnosis using the two biopsy methods was 65.4% (κ = 0.57, 95% CI: 0.42–0.73) and 90.4% (47/52), respectively. Out of 38 (73.1%) cases diagnosed with high or definite confidence at TBLC-MDD, 29 had concordant SLB-MDD diagnoses (agreement: 76.3%, κ = 0.71, 95% CI: 0.55–0.87), and the agreement for IPF/non-IPF diagnoses was 97.4% (37/38). By adding the pathological diagnosis, the inter-observer agreement of clinical diagnosis improved from κ = 0.22 to κ = 0.42 for TBLC and from κ = 0.27 to κ = 0.38 for SLB, and the prevalence of high or definite diagnostic confidence improved from 23.0% to 73.0% and from 17.3% to 73.0%, respectively. Of all 383 TBLC performed during the same period, pneumothorax occurred in 5.0% of cases, and no severe bleeding, acute exacerbation of interstitial lung disease, or fatal event was observed.

Conclusions

TBLC via a flexible bronchoscope under deep sedation is safely performed, and the TBLC-MDD diagnosis with a high or definite confidence level is concordant with the SLB-MDD diagnosis in the same patients.
Anti-cancer effect of nano-encapsulated boswellic acids, curcumin and naringenin against HepG-2 cell line
Authors: Elnawasany Sally , Haggag Yusuf A. , Shalaby Shahinaz M. , Soliman Nema A. , EL Saadany Amira A. , Ibrahim Marwa A. A. , Badria Farid
Published: July 2023

Background

liver cancer is one of the most common cancers in the world. So far, there is no gold standard treatment for hepatocellular carcinoma. We conducted this in vitro study to assess the effect of three natural products: Boswellic acids, curcumin and naringin versus corresponding nanoparticles (NPs) on Hep G2 cells proliferation.

Methods

Boswellic acid, curcumin, naringin-loaded NPs were prepared using nanoprecipitation method. Human liver (HepG2) cell line was cultured in Dulbecco’s modified Eagle’s medium (DMEM). The cell growth inhibition and cytotoxicity were evaluated by MTT assay.

Results

Boswellic acid, curcumin, naringin were able to inhibit HepG2 cells proliferation. IC50 at 24 h, 48 h showed significant lower values in NPs versus Free herbs. IC50 values of free Boswellic acids and NPs at 24 h were (24.60 ± 1.89 and 7.78 ± 0.54, P < 0.001), at 48 h were (22.45 ± 1.13 and 5.58 ± 0.27, P < 0.001) respectively. IC50 values of free curcumin and NPs at 24 h were (5.89 ± 0.8 and 3.46 ± 0.23, P < 0.05), at 48 h were (5.57 ± 0.94 and 2.51 ± 0.11, P < 0.05), respectively. For free and naringenin NPs, IC50 values at 24 h were (14.57 ± 1.78 and 7.25 ± 0.17, P < 0.01), at 48 h were (11.37 ± 1.45 and 5.21 ± 0.18, P < 0.01) respectively.

Conclusion

Boswellic acid, curcumin, naringin and their nanoprecipitation prepared nanoparticles suppressed Hep G2 cells proliferation.
Community based peer-led TB screening intervention: an innovative approach to increase TB knowledge, presumptive case identification, and referral among sexual minority people in urban Bangladesh
Authors: Sarwar Golam , Khan Shaan Muberra , Irfan Samira Dishti , Khan Mohammad Niaz Morshed , Reza Md. Masud , Rana A K M Masud , Banu Rupali Sisir , Ahmed Shahriar , Banu Sayera , Khan Sharful Islam
Published: July 2023

Introduction

One of the contributors to tuberculosis (TB) burden among vulnerable populations, such as sexual minority people, is the delay in case finding and notification. Given their socially excluded, hard-to-reach nature, community-led approaches need to be introduced to facilitate their screening of TB symptoms and their subsequent referral to TB healthcare providers. This article aimed to explore the existing challenges surrounding TB screening and referral, and the implementation facilitators and barriers of the proposed community-based TB screening model for sexual minority people in Dhaka, Bangladesh.

Methods

This study followed the quasi-experimental design using mixed methods (i.e., qualitative and quantitative) approach. The study participants who were also a part of the community-led TB screening model included sexual minority people enrolled in HIV prevention interventions. In addition to quantitative inquiry, in-depth interviews were conducted on sexual minority people, focus group discussions were also conducted on them and HIV prevention service providers, and key-informant interviews were conducted on service providers, programmatic experts and TB researchers. Data were analyzed using content, contextual and thematic approaches.

Results

The ‘Six Steps in Quality Intervention Development’ framework was used to guide the development of the community-based TB screening model. In Step 1 (identifying the problem), findings revealed low rates of TB screening among sexual minority people enrolled in the HIV prevention intervention. In Step 2 (identifying contextual factors for change), various individual, and programmatic factors were identified, which included low knowledge, low-risk perception, prioritization of HIV services over TB, and stigma and discrimination towards these populations. In Step 3 (deciding change mechanism), community-based screening approaches were applied, thus leading to Step 4 (delivery of change mechanism) which designed a community-based approach leveraging the peer educators of the HIV intervention. Step 5 (testing intervention) identified some barriers and ways forward for refining the intervention, such as home-based screening and use of social media. Step 6 (collecting evidence of effectiveness) revealed that the main strength was its ability to engage peer educators.

Conclusion

This study indicates that a community-based peer-led TB screening approach could enhance TB screening, presumptive TB case finding and referral among these populations. Therefore, this study recommends that this approach should be incorporated to complement the existing TB program.
Moving toward precision in prenatal evidence-based home visiting to achieve good birth outcomes: assessing the alignment of local programs with their national models
Authors: Spinosa Ciara Z. , Burrell Lori , Bower Kelly M. , O’Neill Kay , Duggan Anne K.
Published: July 2023

Background

Low birthweight and preterm birth rates are higher in the United States than in other developed countries and exhibit pronounced racial inequities. Home visiting is a strategy to promote equity in birth outcomes. Research points to precision home visiting as the path to equity. The purpose of this study is to describe local programs’ risk reduction priorities, intended behavioral pathways, and expectations of home visitors; compare these local program features with those of their national model; and assess the strength of implementation systems to support staff in meeting job expectations.

Methods

We surveyed local programs implementing one of four evidence-based home visiting models that aim to promote good birth outcomes: Family Spirit, Healthy Families America, Nurse-Family Partnership, and Parents as Teachers.

Results

Representatives from 169 local programs completed the survey. Overall, 59% endorsed all their model’s high priority risks, 16% endorsed all its required behavioral pathways, and 11% endorsed all its required techniques. Local programs went beyond their national model’s explicit intentions. Overall, 91% of local programs prioritized risks beyond those of their model, 85% endorsed behavioral pathways beyond those of their model, 95% endorsed visitors’ use of techniques not explicitly endorsed by their model but compatible with it, and 19% endorsed use of techniques judged incompatible by their model. Implementation system strength was positively associated with local program and model expectations.

Conclusions

Precision home visiting to achieve health equity requires shared learning of what works best for whom. This observational study showed the Precision Paradigm’s usefulness for cross-model research to advance precision.
The effect of Covid-19 pandemic on healthcare utilization in public vs private centers in Iran: a multiple group interrupted time-series analysis
Authors: Rezaei Zohreh , Lotfi Farhad , Bayati Mohsen , Kavosi Zahra
Published: August 2023

Background

The outbreak of Coronavirus in late 2019 and its continuation in the following years has affected all human societies, government organizations, and health systems. Access to health services is an important issue during crises. The present study aimed to investigate the effect of the Covid-19 pandemic on the consumption of health services in the public sector compared to the private sector in Iran.

Methods

The research population consisted of all insured individuals covered by Iran Health Insurance Organization in Fars province, which amounts to approximately 2,700,000 people. The required information including the utilization of laboratory, radiology, medicine, and hospitalization services was extracted on a monthly basis from February 2019 to February 2021. The Multiple Group Interrupted Time Series Analysis (MGITSA) was used for data analysis along with STATA.15 software.

Results

According to the findings of MGITSA, in the short-term, the utilization of private laboratory, radiology, medication, and hospital admissions had decreased by approximately 18,066, 8210, 135,445, and 1086 times, respectively (P < 0.05). In the long-run, the use of laboratory and radiology services had increased by about 2312 and 514 times (P < 0.05), respectively. The comparison between the public and private sectors showed that in the short-term, the use of radiology services decreased by about 12,525, while the use of medication increased by about 91,471 times (P < 0.05). In the long-run, the use of laboratory services decreased by about 1514 times (P = 0.076) and no change was observed in the other services utilization (in public relative to private centers).

Conclusions

Utilization of health services in the public versus private centers, except for medication and hospitalization, significantly decreased in the short-term. However the utilization of most services returned to the usual trend in the long-term. The reduction in access to health services could impose a significant burden of various diseases, at least in the short-term, and increase health costs in the coming years.
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

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

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

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

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

Newly 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

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

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

Background

Targeting 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.

Methods

Chitosan 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).

Results

NP-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.

Conclusion

Our 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

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

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

A 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.
Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer
Authors: Mohan Riche , Kneebone A. , Eade T. , Hsiao E. , Emmett L. , Brown Christopher , Hunter J. , Hruby G.
Published: August 2023

Background

Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach.

Methods

A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET.

Results

103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures.

Conclusion

PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.
Exosomes promote hFOB1.19 proliferation and differentiation via LINC00520
Authors: Wu Jin , Zhang Licheng , Liu Hui , Zhang Jinhui , Tang Peifu
Published: July 2023

Background

Osteoporosis remains a significant clinical challenge worldwide. Recent studies have shown that exosomes stimulate bone regeneration. Thus, it is worthwhile to explore whether exosomes could be a useful therapeutic strategy for osteoporosis. The purpose of this study was to investigate the effects of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) on osteoblast proliferation and differentiation.

Methods

Exosomes were isolated from hucMSCs. Bioinformatics analysis was performed to identify the differentially expressed lncRNAs in myeloma-derived mesenchymal stem cells. Plasmids encoding LINC00520 or short hairpin RNA of LINC00520 were transfected into hucMSCs and then exosomes were isolated. After human osteoblasts hFOB1.19 were exposed to the obtained exosomes, cell survival, cell cycle, apoptosis and calcium deposits of hFOB1.19 cell were detected by MTT, 7-aminoactinomycin D, Annexin V-FITC/propidium iodide and Alizarin red staining, respectively.

Results

In hFOB1.19 cells, 10 × 109/mL hucMSC-derived exosomes inhibited cell proliferation, arrested cell cycle, and promoted apoptosis, while hucMSCs or 1 × 109/mL exosomes promoted cell proliferation, accelerated cell cycle, and promoted calcium deposits and the expression of OCN, RUNX2, collagen I and ALP. In hFOB1.19 cells, exosomes from hucMSCs with LINC00520 knockdown reduced the survival and calcium deposits, arrested the cell cycle, and enhanced the apoptosis, while exosomes from hucMSCs overexpressing LINC00520 enhance the proliferation and calcium deposits and accelerated the cell cycle.

Conclusions

LINC00520 functions as a modulator of calcium deposits, and exosomes derived from hucMSCs overexpressing LINC00520 might be a novel therapeutic approach for osteoporosis.
Hsa_circ_0007292 promotes chondrocyte injury in osteoarthritis via targeting the miR-1179/HMGB1 axis
Authors: Lin Zhiping , Li Peng , Tang Yangyang , Tan Hongchang , Luo Lianxiang
Published: July 2023

Background

Circular RNAs (circRNAs) have been demonstrated to participate in the progression of osteoarthritis (OA). This study aimed to investigate the role and molecular mechanism of hsa_circ_0007292 in OA.

Methods

Hsa_circ_0007292 was identified by analyzing a circRNA microarray from the Gene Expression Omnibus (GEO) database, and its expression was detected by real-time PCR in OA cartilage tissues and interleukin (IL)-1β-induced two human chondrocytes (CHON-001 and C28/I2), the OA cell models. The effects of hsa_circ_0007292 knockdown and miR-1179 overexpression on IL-1β-induced chondrocyte injury were examined by CCK-8, BrdU, flow cytometry, ELISA, and western blot. RNA pull-down assay and dual-luciferase reporter gene assay were used to analyze the interaction between hsa_circ_0007292 and miR-1179. Rescue experiments were carried out to determine the correlations among hsa_circ_0007292, miR-1179 and high mobility group box-1 (HMGB1).

Results

Hsa_circ_0007292 expression was upregulated in OA tissues and IL-1β-induced chondrocytes. Both downregulation of hsa_circ_0007292 and miR-1179 overexpression increased the proliferation and Aggrecan expression, suppressed apoptosis, matrix catabolic enzyme MMP13 expression and inflammatory factor (TNF‐α, IL‐6, and IL‐8) levels. There was a negative correlation between hsa_circ_0007292 and miR-1179, and a positive correlation between hsa_circ_0007292 and HMGB1 in OA tissues. The mechanistic study showed that hsa_circ_0007292 prevented HMGB1 downregulation by sponging miR-1179. Upregulation of HMGB1 could reverse the influence of hsa_circ_0007292 downregulation on IL-1β-induced chondrocyte injury.

Conclusions

Downregulation of hsa_circ_0007292 relieved apoptosis, extracellular matrix degradation and inflammatory response in OA via the miR-1179/HMGB1 axis, suggesting that hsa_circ_0007292 might be a potential therapeutic target for OA treatment.