bluuebunny/crossref_metadata_2025_split huggingface dataset:
Not every estimate counts – evaluation of cell composition estimation approaches in brain bulk tissue data
Authors: Toker Lilah , Nido Gonzalo S. , Tzoulis Charalampos 
Published: June 2023

Abstract
Background
Variation in cell composition can dramatically impact analyses in bulk tissue samples. A commonly employed approach to mitigate this issue is to adjust statistical models using estimates of cell abundance derived directly from omics data. While an arsenal of estimation methods exists, the applicability of these methods to brain tissue data and whether or not cell estimates can sufficiently account for confounding cellular composition has not been adequately assessed.

Methods
We assessed the correspondence between different estimation methods based on transcriptomic (RNA sequencing, RNA-seq) and epigenomic (DNA methylation and histone acetylation) data from brain tissue samples of 49 individuals. We further evaluated the impact of different estimation approaches on the analysis of H3K27 acetylation chromatin immunoprecipitation sequencing (ChIP-seq) data from entorhinal cortex of individuals with Alzheimer’s disease and controls.

Results
We show that even closely adjacent tissue samples from the same Brodmann area vary greatly in their cell composition. Comparison across different estimation methods indicates that while different estimation methods applied to the same data produce highly similar outcomes, there is a surprisingly low concordance between estimates based on different omics data modalities. Alarmingly, we show that cell type estimates may not always sufficiently account for confounding variation in cell composition.

Conclusions
Our work indicates that cell composition estimation or direct quantification in one tissue sample should not be used as a proxy to the cellular composition of another tissue sample from the same brain region of an individual—even if the samples are directly adjacent. The highly similar outcomes observed among vastly different estimation methods, highlight the need for brain benchmark datasets and better validation approaches. Finally, unless validated through complementary experiments, the interpretation of analyses outcomes based on data confounded by cell composition should be done with great caution, and ideally avoided all together.
Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies
Authors: Kahrizi Mohammad Saeed , Mousavi Elnaz , Khosravi Armin , Rahnama Sara , Salehi Ali , Nasrabadi Navid , Ebrahimzadeh Farnoosh , Jamali Samira 
Published: June 2023

AbstractMesenchymal stem/stromal cells (MSCs)‐based therapy brings the reassuring capability to regenerative medicine through their self‐renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
TRPA1 promotes the maturation of embryonic stem cell-derived cardiomyocytes by regulating mitochondrial biogenesis and dynamics
Authors: Ding Qianqian , Liu Xianji , Qi Yanxiang , Yao Xiaoqiang , Tsang Suk Ying 
Published: June 2023

Abstract
Background
Cardiomyocytes derived from pluripotent stem cells (PSC-CMs) have been widely accepted as a promising cell source for cardiac drug screening and heart regeneration therapies. However, unlike adult cardiomyocytes, the underdeveloped structure, the immature electrophysiological properties and metabolic phenotype of PSC-CMs limit their application. This project aimed to study the role of the transient receptor potential ankyrin 1 (TRPA1) channel in regulating the maturation of embryonic stem cell-derived cardiomyocytes (ESC-CMs).

Methods
The activity and expression of TRPA1 in ESC-CMs were modulated by pharmacological or molecular approaches. Knockdown or overexpression of genes was done by infection of cells with adenoviral vectors carrying the gene of interest as a gene delivery tool. Immunostaining followed by confocal microscopy was used to reveal cellular structure such as sarcomere. Staining of mitochondria was performed by MitoTracker staining followed by confocal microscopy. Calcium imaging was performed by fluo-4 staining followed by confocal microscopy. Electrophysiological measurement was performed by whole-cell patch clamping. Gene expression was measured at mRNA level by qPCR and at protein level by Western blot. Oxygen consumption rates were measured by a Seahorse Analyzer.

Results
TRPA1 was found to positively regulate the maturation of CMs. TRPA1 knockdown caused nascent cell structure, impaired Ca2+ handling and electrophysiological properties, and reduced metabolic capacity in ESC-CMs. The immaturity of ESC-CMs induced by TRPA1 knockdown was accompanied by reduced mitochondrial biogenesis and fusion. Mechanistically, we found that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), the key transcriptional coactivator related to mitochondrial biogenesis and metabolism, was downregulated by TRPA1 knockdown. Interestingly, overexpression of PGC-1α ameliorated the halted maturation induced by TRPA1 knockdown. Notably, phosphorylated p38 MAPK was upregulated, while MAPK phosphatase-1 (MKP-1), a calcium-sensitive MAPK inhibitor, was downregulated in TRPA1 knockdown cells, suggesting that TRPA1 may regulate the maturation of ESC-CMs through MKP-1-p38 MAPK-PGC-1α pathway.

Conclusions
Taken together, our study reveals the novel function of TRPA1 in promoting the maturation of CMs. As multiple stimuli have been known to activate TRPA1, and TRPA1-specific activators are also available, this study provides a novel and straightforward strategy for improving the maturation of PSC-CMs by activating TRPA1. Since a major limitation for the successful application of PSC-CMs for research and medicine lies in their immature phenotypes, the present study takes a big step closer to the practical use of PSC-CMs.

Graphical abstract
FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB
Authors: Kim Mi-Jeong , Kim Ji Young , Shin Ji Hye , Kang Yeeun , Lee Ji Su , Son Juhee , Jeong Soo-Kyung , Kim Daesik , Kim Duk-Hwan , Chun Eunyoung , Lee Ki-Young 
Published: June 2023

Abstract
Background
Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed.

Methods
We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout (FFAR2KO) A549 and FFAR2KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation.

Results
The clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2DownTLR2UpTLR3Up lung tumor tissues (LTTs) vs. FFAR2upTLR2DownTLR3Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2KO A549 and FFAR2KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines.

Conclusion
Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.
Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity
Authors: Martinez-Diz Silvia , Morales-Álvarez Carmen Maria , Garcia-Iglesias Yarmila , Guerrero-González Juan Miguel , Romero-Cachinero Catalina , González-Cabezuelo Jose María , Fernandez-Rosado Francisco Javier , Arenas-Rodríguez Verónica , Lopez-Cintas Rocío , Alvarez-Cubero Maria Jesús , Martinez-Gonzalez Luis Javier 
Published: June 2023

Abstract
Background
The use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role of ACE2, AR, MX1, ERG, ETV5 and TMPRSS2 for trying a better classification of COVID-19 through knowledge of the disease mechanisms.

Methods
A total of 329 blood samples were genotyped in ACE2, MX1 and TMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes: ERG, ETV5, AR, MX1, ACE2, and TMPRSS2. Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria.

Results
We confirm the use of ferritin (p < 0.001), D-dimer (p < 0.010), CRP (p < 0.001) and LDH (p < 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed that MX1 and AR are significantly higher expressed in mild vs severe patients (p < 0.05). ACE2 and TMPRSS2 are involved in the same molecular process of membrane fusion (p = 4.4 × 10–3), acting as proteases (p = 0.047).

Conclusions
In addition to the key role of TMPSRSS2, we reported for the first time that higher expression levels of AR are related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates that ACE2, MX1 and TMPRSS2 are relevant markers in this disease.

Graphical abstract
The temporal dynamics of dissociation: protocol for an ecological momentary assessment and laboratory study in a transdiagnostic sample
Authors: Heekerens Johannes B. , Gross James J. , Kreibig Sylvia D. , Wingenfeld Katja , Roepke Stefan 
Published: June 2023

AbstractBackgroundDissociation is a ubiquitous clinical phenomenon. Dissociative disorders (DD) are primarily characterized by dissociation, and dissociative states are also a criterion for borderline personality disorder (BPD) and the dissociative subtype of post-traumatic stress disorder (PTSD). Dissociative reactions (e.g., depersonalization/derealization or gaps in awareness/memory) across diagnostic categories are believed to be affect contingent and theorized to serve affect regulation functions. What is not clear, however, is how self-reported affect and physiological reactivity unfold within dissociative episodes. To address this issue, the present project aims to investigate the hypothesis (1) whether self-reported distress (as indicated by arousal, e.g., feeling tense/agitated, and/or valence, e.g., feeling discontent/unwell) and physiological reactivity increase before dissociative episodes and (2) whether self-reported distress and physiological reactivity decrease during and after dissociative episodes in a transdiagnostic sample of patients with DD, BPD, and/or PTSD.MethodsWe will use a smartphone application to assess affect and dissociation 12 times per day over the course of one week in everyday life. During this time, heart and respiratory rates will be remotely monitored. Afterwards, participants will report affect and dissociative states eight times in the laboratory before, during, and after the Trier Social Stress Test. During the laboratory task, we will continuously record heart rate, electrodermal activity, and respiratory rate, as well as measure blood pressure and take salivary samples to determine cortisol levels. Our hypotheses will be tested using multilevel structural equation models. Power analyses determined a sample size of 85.DiscussionThe project will test key predictions of a transdiagnostic model of dissociation based on the idea that dissociative reactions are affect contingent and serve affect regulation functions. This project will not include non-clinical control participants. In addition, the assessment of dissociation is limited to pathological phenomena.
Successful endovascular thrombectomy with the ClotTriever System for acute subclavian vein thrombosis in venous thoracic outlet syndrome
Authors: Discalzi Andrea , Cignini Valentina , Ciferri Fernanda , Nardelli Floriana , Rossato Denis , Calandri Marco , Fonio Paolo 
Published: June 2023

Abstract
Background
The case describes a successful endovascular thrombectomy using the ClotTriever System for an acute subclavian thrombosis in venous thoracic outlet syndrome. To the best of our knowledge, this is the first case report on use of Inari ClotTriever for acute upper extremity deep venous thrombosis due to venous thoracic outlet syndrome. The rapid technical and clinical success of our intervention may be an interesting cue for interventional radiologist colleagues.

Case presentation
Upper extremity deep vein thrombosis in the setting of venous thoracic outlet syndrome generally occurs in young adults after excessive arm activity and can sometimes be managed with anticoagulation. In this case, a 29-year-old male diagnosed with acute effort-induced thrombosis of the left subclavian vein and persistent symptoms following low-molecular-weight heparin therapy underwent mechanical thrombectomy. Successful thrombectomy was completed with > 90% thrombus burden reduction and no complication. The patient experienced immediate symptom relief and vein patency was confirmed via imaging 3 months post procedure.

Conclusions
Mechanical thrombectomy is a promising treatment technique for thrombosis associated with venous thoracic outlet syndrome.
Delayed iatrogenic diaphragmatic hernia after thoracoscopic resection of diaphragm lipoma
Authors: Oka Soichi , Osaki Toshihiro , Hashimoto Teppei , Kawamura Yuichiro 
Published: June 2023

Abstract
Background
Iatrogenic diaphragmatic hernias have been reported as a rare complication of thoracic and abdominal surgery. We herein report a case of delayed iatrogenic left diaphragmatic hernia after diaphragm pedunculated lipoma resection with minimally invasive surgery.

Case presentation
A 72-year-old Japanese man was found to have an abnormal shadow by medical checkup X-ray and was admitted to our hospital. Chest computed tomography (CT) showed a 5 × 2-cm solid tumor at the left diaphragm. He was diagnosed with a left diaphragm tumor. We performed three-port video-assisted thoracic surgery. This tumor was pedunculated at the left central tendon of the diaphragm. We therefore dissected this tumor using an electric scalpel. Although there was about 5 × 4 mm in diameter slight heat damage to the diaphragm, it was not reinforced because it was very minor injury. He was diagnosed with a left diaphragmatic hernia without any symptoms by routine CT examination which scheduled 1 year after surgery. One day after hospitalization, on the morning of the operation, he suddenly complained of left back pain with acute exacerbation of the left diaphragmatic hernia. We therefore immediately performed emergency surgery and rescued this patient. No adverse events or complications were seen, and he was discharged on postoperative day 11. Three months after this surgery, this patient is doing very well.

Conclusions
Caution should be exercised when using energy devices on the diaphragmatic surface, especially the left side, to avoid causing delayed diaphragmatic hernia. In cases of surgery involving the left-side diaphragm, it seems that careful follow-up after surgery is necessary.
Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.
Authors: Verco Shelagh , Maulhardt Holly , Marin Alyson , Verco Antony 
Published: June 2023

e15187 Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]
Prevention of chemotherapy-induced neutropenia (CIN) with plinabulin (Plin) vs placebo (Plac) in patients (pts) with non-small cell lung cancer (NSCLC) treated with docetaxel (Doc): A pooled analysis from 3 randomized trials.
Authors: Blayney Douglas W. , Hurley Jasmine , Legaspi Gabrielle , Duprez Stephen , Huang Lan , Mohanlal Ramon W. 
Published: June 2023

e21163 Background: CIN can lead to increased patient/healthcare burden, resource utilization, hospitalizations, and poorer quality of life (QoL). G-CSF has a high incidence of bone pain and mild thrombopenia and is given the day after chemo. Plin, a novel non-G-CSF small molecule, protects the bone marrow stem cell, has minimal bone pain, and protects platelet precursors. Plin is given on the same day as chemo and has NSCLC anticancer efficacy (ESMO 2021, Feinstein). The CIN effects of Doc plus Plin vs Doc with Plac were pooled from 3 NSCLC clinical trials. Methods: Data from randomized trials, phase (Ph) 3 trial 103 (NCT02504489), Ph2/3 trial 105 ( NCT03102606 ), and Ph2 trial 101 (NCT00630110) were pooled. Pts were randomized to either Doc (75mg/m2) plus Plin (20mg/m2 or its pharmacokinetic equivalent) (n = 146) or Doc plus Plac (n = 296). Doc was administered on day 1 of each 21-day cycle x 4 cycles, and Plin or Plac was administered ~30 minutes after Doc. Neutrophil counts were taken at predose and day (D) 8 of each cycle in studies 101 & 103, and on predose, D1, 2, 6, 7, 8, 9, 10, 15, and 21 in study 105. Pts given G-CSF in D1-D3 were excluded. Duration of severe neutropenia (DSN) was calculated by methods previously reported (ASH 2022, Blayney). All Grade (Gr) and Gr4 neutropenia (N) rates, Absolute N count (ANC), febrile N (FN) rate, and ANC on D8 (‘nadir’) were obtained. QoL scores were obtained in studies 103 and 105 by EORTC QLQ-C30. Patient-reported adverse events (AEs) were collected. Results: Pt demographics were comparable. Plin was statistically and clinically significantly superior to Plac for All Gr and Gr4 N frequencies, Day 8 ANC (‘nadir’), and DSN (all had p < 0.0001). Febrile Neutropenia (FN) and infection rates were numerically lower (see table). Fewer pts were treated with antibiotics among pts treated with Plin. Platelet count was unaffected with Plin; grade (gr) 3/4 thrombocytopenia was < 1% with either Plin or Plac. The total frequency of treatment-emergent AEs for Plin vs Plac were 71% vs 80%. QoL scores were similar for Plin and Plac. Conclusions: In 3 independent randomized studies (101, 103, and 105), Plin demonstrated a superior benefit for CIN and showed clinical benefit for infection rate versus Plac. Additionally, Plin has the added benefits of pt convenience (same-day dosing and no additional visits or wearable device), a favorable safety and tolerability profile, anticancer efficacy, and QoL maintenance, which represents a distinct advantage over G-CSF. Clinical trial information: NCT02504489 ; NCT03102606 ; NCT00630110 . [Table: see text]