bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of intra- and peritumoral immune cell subpopulations in head and neck squamous cell carcinomas – comprehensive analysis of the TCGA-HNSC cohort and immunohistochemical validation on 101 patients
Authors: Knebel Moritz , Körner Sandrina , Kühn Jan Philipp , Wemmert Silke , Brust Lukas , Smola Sigrun , Wagner Mathias , Bohle Rainer M. , Morris Luc G. T. , Pandey Abhinav , Schick Bernhard , Linxweiler Maximilian 
Published: June 2023

BackgroundDue to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells.MethodsThe overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4+CXCR5, Foxp3 and CD68.ResultsOverall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients’ overall survival in the TCGA-HNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p&lt;0.0001), macrophages (p=0.0042), regulatory T cells (p=0.0306), lymphocytes (p=0.0001), and cytotoxic T cells (p=0.0242) were identified as highly significant predictors of improved patient survival. Using immunohistochemical detection of these immune cells in a second independent validation cohort of 101 HNSCC patients, we confirmed the prognostic relevance of follicular T helper cells, cytotoxic T cells and lymphocytes. In multivariable analysis, HPV negativity and advanced UICC stages were identified as additional prognostic biomarkers associated with poor outcome.ConclusionOur study highlights the prognostic relevance of the immunological tumor environment in head and neck cancer and demonstrates that a more detailed analysis of immune cell composition and immune cell subtypes is necessary to accurately prognosticate. We observed the highest prognostic relevance for lymphocytes, cytotoxic T cells, and follicular T helper cells, suggesting further investigations focusing on these specific immune cell subpopulations not only as predictors of patient prognosis but also as promising targets of new immunotherapeutic strategies.
Dock2 generates characteristic spatiotemporal patterns of Rac activity to regulate neutrophil polarisation, migration and phagocytosis
Authors: Machin Polly A. , Johnsson Anna-Karin E. , Massey Ellie J. , Pantarelli Chiara , Chetwynd Stephen A. , Chu Julia Y. , Okkenhaug Hanneke , Segonds-Pichon Anne , Walker Simon , Malliri Angeliki , Fukui Yoshinori , Welch Heidi C. E. 
Published: June 2023

IntroductionRac-GTPases and their Rac-GEF activators play important roles in neutrophil-mediated host defence. These proteins control the adhesion molecules and cytoskeletal dynamics required for neutrophil recruitment to inflamed and infected organs, and the neutrophil effector responses that kill pathogens.MethodsHere, we used live cell TIRF-FRET imaging in neutrophils from Rac-FRET reporter mice with deficiencies in the Rac-GEFs Dock2, Tiam1 or Prex1/Vav1 to evaluate if these proteins activate spatiotemporally distinct pools of Rac, and to correlate patterns of Rac activity with the neutrophil responses they control.ResultsAll the GEFs were required for neutrophil adhesion, and Prex1/Vav1 were important during spreading and for the velocity of migration during chemotaxis. However, Dock2 emerged as the prominent regulator of neutrophil responses, as this GEF was required for neutrophil polarisation and random migration, for migration velocity during chemokinesis, for the likelihood to migrate and for the speed of migration and of turning during chemotaxis, as well as for rapid particle engulfment during phagocytosis. We identified characteristic spatiotemporal patterns of Rac activity generated by Dock2 which correlate with the importance of the Rac-GEF in these neutrophil responses. We also demonstrate a requirement for Dock2 in neutrophil recruitment during aseptic peritonitis.DiscussionCollectively, our data provide a first direct comparison of the pools of Rac activity generated by different types of Rac-GEFs, and identify Dock2 as a key regulator of polarisation, migration and phagocytosis in primary neutrophils.
Cannabidiol (CBD) for the treatment of subcutaneous treprostinil (Remodulin®) site pain: a case report
Authors: Brewer Jacqueline , Kimber Amy 
Published: June 2023

BackgroundPulmonary arterial hypertension occurs as a result of vascular remodeling and dysregulation of endothelial cells that narrows small pulmonary arteries and raises precapillary pressures. Pulmonary arterial hypertension is a rare and progressive disease characterized by dyspnea, chest pain, and syncope. Parenteral treprostinil is indicated for the treatment of pulmonary arterial hypertension to diminish symptoms associated with exercise. Up to 92% of patients treated with treprostinil via subcutaneous delivery experienced infusion site pain and approximately 23% discontinued treatment due to site pain. Cannabidiol salve may have analgesic and anti-inflammatory properties and could be an additional option for patients with infusion site pain.Case reportTwo patients with pulmonary arterial hypertension were treated with cannabidiol salve. Both patients reported a reduction in infusion site pain without the need for narcotics.ConclusionThese two cases suggest that cannabidiol salve may help to minimize redness and alleviate pain at the infusion site. Additional studies are required to test the effectiveness of cannabidiol in a larger group of patients with infusion site pain.
Adaptation of the binding domain of Lactobacillus acidophilus S-layer protein as a molecular tag for affinity chromatography development
Authors: Muruaga Emanuel J. , Uriza Paula J. , Eckert Gonzalo A. K. , Pepe María V. , Duarte Cecilia M. , Roset Mara S. , Briones Gabriel 
Published: June 2023

IntroductionThe S-layer proteins are a class of self-assembling proteins that form bi-dimensional lattices named S-Layer on the cell surface of bacteria and archaea. The protein SlpA, which is the major constituent of the Lactobacillus acidophilus S-layer, contains in its C-terminus region (SlpA284 − 444), a protein domain (named here as SLAPTAG) responsible for the association of SlpA to the bacterial surface. SLAPTAG was adapted for the development of a novel affinity chromatography method: the SLAPTAG-based affinity chromatography (SAC).MethodsProteins with different molecular weights or biochemical functions were fused in-frame to the SLAPTAG and efficiently purified by a Bacillus subtilis-derived affinity matrix (named Bio-Matrix or BM). Different binding and elution conditions were evaluated to establish an optimized protocol.ResultsThe binding equilibrium between SLAPTAG and BM was reached after a few minutes of incubation at 4°C, with an apparent dissociation constant (KD) of 4.3μM. A reporter protein (H6-GFP-SLAPTAG) was used to compare SAC protein purification efficiency against commercial immobilized metal affinity chromatography. No differences in protein purification performance were observed between the two methods. The stability and reusability of the BM were evaluated, and it was found that the matrix remained stable for more than a year. BM could be reused up to five times without a significant loss in performance. Additionally, the recovery of bound SLAP-tagged proteins was explored using proteolysis with a SLAP-tagged version of the HRV-3c protease (SLAPASE). This released the untagged GFP while the cut SLAPTAG and the SLAPASE were retained in the BM. As an alternative, iron nanoparticles were linked to the BM, resulting in BMmag. The BMmag was successfully adapted for a magnetic SAC, a technique with potential applications in high-throughput protein production and purification.DiscussionThe SAC protocol can be adapted as a universal tool for the purification of recombinant proteins. Furthermore, the SAC protocol utilizes simple and low-cost reagents, making it suitable for in-house protein purification systems in laboratories worldwide. This enables the production of pure recombinant proteins for research, diagnosis, and the food industry.
Machine learning prediction of motor function in chronic stroke patients: a systematic review and meta-analysis
Authors: Li Qinglin , Chi Lei , Zhao Weiying , Wu Lei , Jiao Chuanxu , Zheng Xue , Zhang Kaiyue , Li Xiaoning 
Published: June 2023

BackgroundRecent studies have reported that machine learning (ML), with a relatively strong capacity for processing non-linear data and adaptive ability, could improve the accuracy and efficiency of prediction. The article summarizes the published studies on ML models that predict motor function 3–6 months post-stroke.MethodsA systematic literature search was conducted in PubMed, Embase, Cochorane and Web of Science as of April 3, 2023 for studies on ML prediction of motor function in stroke patients. The quality of the literature was assessed using the Prediction model Risk Of Bias Assessment Tool (PROBAST). A random-effects model was preferred for meta-analysis using R4.2.0 because of the different variables and parameters.ResultsA total of 44 studies were included in this meta-analysis, involving 72,368 patients and 136 models. Models were categorized into subgroups according to the predicted outcome Modified Rankin Scale cut-off value and whether they were constructed based on radiomics. C-statistics, sensitivity, and specificity were calculated. The random-effects model showed that the C-statistics of all models were 0.81 (95% CI: 0.79; 0.83) in the training set and 0.82 (95% CI: 0.80; 0.85) in the validation set. According to different Modified Rankin Scale cut-off values, C-statistics of ML models predicting Modified Rankin Scale&gt;2(used most widely) in stroke patients were 0.81 (95% CI: 0.78; 0.84) in the training set, and 0.84 (95% CI: 0.81; 0.87) in the validation set. C-statistics of radiomics-based ML models in the training set and validation set were 0.81 (95% CI: 0.78; 0.84) and 0.87 (95% CI: 0.83; 0.90), respectively.ConclusionML can be used as an assessment tool for predicting the motor function in patients with 3–6 months of post-stroke. Additionally, the study found that ML models with radiomics as a predictive variable were also demonstrated to have good predictive capabilities. This systematic review provides valuable guidance for the future optimization of ML prediction systems that predict poor motor outcomes in stroke patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022335260, identifier: CRD42022335260.
The effect of combining action observation in virtual reality with kinesthetic motor imagery on cortical activity
Authors: Lakshminarayanan Kishor , Shah Rakshit , Daulat Sohail R. , Moodley Viashen , Yao Yifei , Madathil Deepa 
Published: June 2023

IntroductionIn the past, various techniques have been used to improve motor imagery (MI), such as immersive virtual-reality (VR) and kinesthetic rehearsal. While electroencephalography (EEG) has been used to study the differences in brain activity between VR-based action observation and kinesthetic motor imagery (KMI), there has been no investigation into their combined effect. Prior research has demonstrated that VR-based action observation can enhance MI by providing both visual information and embodiment, which is the perception of oneself as part of the observed entity. Additionally, KMI has been found to produce similar brain activity to physically performing a task. Therefore, we hypothesized that utilizing VR to offer an immersive visual scenario for action observation while participants performed kinesthetic motor imagery would significantly improve cortical activity related to MI.MethodsIn this study, 15 participants (9 male, 6 female) performed kinesthetic motor imagery of three hand tasks (drinking, wrist flexion-extension, and grabbing) both with and without VR-based action observation.ResultsOur results indicate that combining VR-based action observation with KMI enhances brain rhythmic patterns and provides better task differentiation compared to KMI without action observation.DiscussionThese findings suggest that using VR-based action observation alongside kinesthetic motor imagery can improve motor imagery performance.
Heterogenous profiles between primary lung cancers and paired brain metastases reveal tumor evolution
Authors: Chen Yanming , Dai Xiaoxiao , Wang Ji , Tao Chuming , Wang Ye , Zhu Qing , Wang Zhongyong , Zhang Tan , Lan Qing , Zhao Jizong 
Published: June 2023

BackgroundBrain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary lung cancers and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary lung cancers and BMs, and the evolutionary process remains little known.MethodsTo deeply insight into the extent of inter-tumor heterogeneity at a single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 10 patients with matched primary lung cancers and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary lung cancers and BMs were evaluated by utilizing whole-exome sequencing (WESeq) and immunohistochemical analysis.ResultsIn addition to inheriting genomic phenotype and molecular phenotype from the primary lung cancers, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at a single-patient level. By analysis of a multi-metastases case (Case 3) of cancer cells’ subclonal composition, we found similar multiple subclonal clusters in the four spatial and temporal isolated brain metastatic focus, with the characteristics of polyclonal dissemination. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0002) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary lung cancers. Additionally, tumor microvascular density (MVD) also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.ConclusionOur study revealed the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary lung cancers and BMs, which also provided novel insight for formulating individualized treatment strategies for BMs.
Efficacy and safety of histone deacetylase inhibitors in peripheral T-cell lymphoma: a systematic review and meta-analysis on prospective clinical trials
Authors: Yang Peipei , Tao Yali , Zhao Ailin , Shen Kai , Li He , Wang Jinjin , Zhou Hui , Wang Zhongwang , Wang Mengyao , Qu Ying , Zhang Li , Zheng Yuhuan , Niu Ting 
Published: June 2023

BackgroundThe overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients. Therefore, this work aims to systematically evaluate the treatment outcome and safety profile of HDAC inhibitor-based treatment for untreated and relapsed/refractory (R/R) PTCL patients.MethodsThe prospective clinical trials of HDAC inhibitors for the treatment of PTCL were searched on the Web of Science, PubMed, Embase, ClinicalTrials.gov, and Cochrane Library database. The pooled overall response rate, complete response (CR) rate, and partial response rate were measured. The risk of adverse events was evaluated. Moreover, the subgroup analysis was utilized to assess the efficacy among different HDAC inhibitors and efficacy in different PTCL subtypes.ResultsFor untreated PTCL, 502 patients in seven studies were involved, and the pooled CR rate was 44% (95% CI, 39-48%). For R/R PTCL patients, there were 16 studies included, and the CR rate was 14% (95% CI, 11-16%). The HDAC inhibitor-based combination therapy exhibited better efficacy when compared with HDAC inhibitor monotherapy for R/R PTCL patients (P = 0.02). In addition, the pooled CR rate was 17% (95% CI, 13-22%), 10% (95% CI, 5-15%), and 10% (95% CI, 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. In the R/R angioimmunoblastic T-cell lymphoma subgroup, the pooled ORR was 44% (95% CI, 35-53%), higher than other subtypes. A total of 18 studies were involved in the safety assessment of treatment-related adverse events. Thrombocytopenia and nausea were the most common hematological and non-hematological adverse events, respectively.ConclusionThis meta-analysis demonstrated that HDAC inhibitors were effective treatment options for untreated and R/R PTCL patients. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes.
PD-1+ IFN-γ+ subset of CD8+ T cell in circulation predicts response to anti–PD-1 therapy in NSCLC
Authors: Chen Wenxiu , Hua Yiting , Shan Conghui , Wei Jia , Zhou Yutong , Pan Shiyang 
Published: June 2023

BackgroundTreatment with programmed cell death protein-1 (PD-1) antibodies has minimal response rates in patients with non–small cell lung cancer (NSCLC), and, actually, they are treated with chemotherapy combined with anti–PD-1 therapy clinically. Reliable markers based on circulating immune cell subsets to predict curative effect are still scarce.MethodsWe included 30 patients with NSCLC treated with nivolumab or atezolizumab plus platinum drugs between 2021 and 2022. Whole blood was collected at baseline (before treatment with nivolumab or atezolizumab). The percentage of circulating PD-1+ Interferon-γ (IFN-γ+) subset of CD8+ T cell was determined by flow cytometry. The proportion of PD-1+ IFN-γ+ was calculated after gating on CD8+ T cells. Neutrophil/lymphocyte ratio (NLR), relative eosinophil count (%), and Lactate dehydrogenase (LDH) concentration at baseline of included patients were extracted from electronic medical records.ResultsThe percentage of circulating PD-1+ IFN-γ+ subset of CD8+ T cell at baseline in responders was significantly higher than those in non-responders (P &lt; 0.05). Relative eosinophil count (%) and LDH concentration in responders showed no significance between non-responders and responders. NLR in responders was significantly lower than those in non-responders (P &lt; 0.05). Receiver operation characteristic (ROC) analysis found that the areas under the ROC curve for PD-1+ IFN-γ+ subset of CD8+ T cell and NLR were 0.7781 (95% CI, 0.5937–0.9526) and 0.7315 (95% CI, 0.5169–0.9461). Moreover, high percentage of PD-1+ IFN-γ+ subset in CD8+ T cells was relevant to long progression-free survival in patients with NSCLC treated with chemotherapy combined with anti–PD-1 therapy.ConclusionThe percentage of circulating PD-1+ IFN-γ+ subset of CD8+ T cell could be a potential marker at baseline to predict early response or progression in patients with NSCLC receiving chemotherapy combined with anti–PD-1 therapy.
Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes
Authors: Yu Katharine , Basu Amrita , Yau Christina , Wolf Denise M. , Goodarzi Hani , Bandyopadhyay Sourav , Korkola James E. , Hirst Gillian L. , Asare Smita , DeMichele Angela , Hylton Nola , Yee Douglas , Esserman Laura , van ‘t Veer Laura , Sirota Marina 
Published: June 2023

IntroductionDrug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.MethodsIn this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival.ResultsWe found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.ConclusionWe applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.