bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain-reactive autoantibodies in neuropsychiatric systemic lupus erythematosus
Authors: Cocco Cristina , Manca Elias , Corda Giulia , Angioni Maria Maddalena , Noli Barbara , Congia Mattia , Loy Francesco , Isola Michela , Chessa Elisabetta , Floris Alberto , Lorefice Lorena , Saba Luca , Mathieu Alessandro , Ferri Gian Luca , Cauli Alberto , Piga Matteo
Published: June 2023

Introduction

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.

Methods

To identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s).

Results

We enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients’ sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients’ sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies.

Conclusion

In conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.
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

Background

Due 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.

Methods

The 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.

Results

Overall 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<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.

Conclusion

Our 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

Introduction

Rac-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.

Methods

Here, 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.

Results

All 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.

Discussion

Collectively, 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

Background

Pulmonary 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 report

Two patients with pulmonary arterial hypertension were treated with cannabidiol salve. Both patients reported a reduction in infusion site pain without the need for narcotics.

Conclusion

These 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

Introduction

The 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).

Methods

Proteins 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.

Results

The 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.

Discussion

The 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

Background

Recent 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.

Methods

A 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.

Results

A 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>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.

Conclusion

ML 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 registration

https://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

Introduction

In 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.

Methods

In 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.

Results

Our 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.

Discussion

These 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

Background

Brain 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.

Methods

To 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.

Results

In 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.

Conclusion

Our 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

Background

The 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.

Methods

The 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.

Results

For 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.

Conclusion

This 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.
Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment
Authors: Li Jingyi , Song Yuxia , Cai Huihong , Zhou Bo , Ma Jun
Published: June 2023

Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological esophageal cancer characterized by advanced diagnosis, metastasis, resistance to treatment, and frequent recurrence. In recent years, numerous human disorders such as ESCC, have been linked to abnormal expression of circular RNAs (circRNAs), suggesting that they are fundamental to the intricate system of gene regulation that governs ESCC formation. The tumor microenvironment (TME), referring to the area surrounding the tumor cells, is composed of multiple components, including stromal cells, immune cells, the vascular system, extracellular matrix (ECM), and numerous signaling molecules. In this review, we briefly described the biological purposes and mechanisms of aberrant circRNA expression in the TME of ESCC, including the immune microenvironment, angiogenesis, epithelial-to-mesenchymal transition, hypoxia, metabolism, and radiotherapy resistance. As in-depth research into the processes of circRNAs in the TME of ESCC continues, circRNAs are promising therapeutic targets or delivery systems for cancer therapy and diagnostic and prognostic indicators for ESCC.
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

Background

Treatment 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.

Methods

We 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.

Results

The 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 < 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 < 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.

Conclusion

The 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

Introduction

Drug 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.

Methods

In 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.

Results

We 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.

Conclusion

We 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.
Radiation for hematologic malignancies: from cell killing to immune cell priming
Authors: Dabaja Bouthaina , Spiotto Michael
Published: June 2023

Over the past half-century, the role of radiotherapy has been revolutionized, in part, by a shift from intent to directly kill cancer cells to the goal of priming anti-tumor immune responses that attack both irradiated and non-irradiated tumors. Stimulation of anti-tumor immunity depends on the interplay between radiation, the tumor microenvironment, and the host immune system, which is a burgeoning concept in cancer immunology. While the interplay of radiotherapy and the immune system has been primarily studied in solid tumors, we are beginning to understand this interplay in hematological malignancies. The intent of this review is to lead readers through some of the important recent advances in immunotherapy and adoptive cell therapy, highlighting the best available evidence in support of incorporating radiation therapy and immunotherapy into the treatment of hematological malignancies. Evidence is presented regarding how radiation therapy ‘converses’ with the immune system to stimulate and enhance anti-tumor immune responses. This pro-immunogenic role of radiotherapy can be combined with monoclonal antibodies, cytokines and/or other immunostimulatory agents to enhance the regression of hematological malignancies. Furthermore, we will discuss how radiotherapy facilitates the effectiveness of cellular immunotherapies by acting as a “bridge” that facilitated CAR T cell engraftment and activity. These initial studies suggest radiotherapy may help catalyze a shift from using chemotherapy-intensive treatment to treatment that is “chemo-free” by combining with immunotherapy to target both the radiated and non-irradiated disease sites. This “journey” has opened the door for novel uses of radiotherapy in hematological malignancies due to its ability to prime anti-tumor immune responses which can augment immunotherapy and adoptive cell-based therapy.
Muslim perspectives on palliative care in perinatal and neonatal patients: a mini-review
Authors: Shoaib Abdullah B. , Vawter-Lee Marissa , Venkatesan Charu , Soliman Ayman F.
Published: June 2023

Muslims comprise nearly a quarter of the worldwide population, with significant populations in the United States, Canada, and Europe. As clinicians, it is important to be familiar with Islamic religious and cultural perspectives on medical treatment, life-prolonging measures and comfort and palliative care, but historically, this has been a gap in the literature. Recently, there have been multiple papers discussing Islamic bioethics, particularly in regards to end of life care in adults; however, there has been a lack of literature discussing the Islamic perspective on issues related to neonatal and perinatal end of life care. This paper uses clinical scenarios to review key relevant principles of Islamic law, discussing the primary and secondary sources used in formulating fatawa, including the Quran, hadith, qiyas, and ‘urf, and the importance of preservation of life and upholding of human dignity (karamah). Neonatal and perinatal scenarios are used to specifically explore the Islamic perspective on withholding and withdrawal of life-sustaining measures and determining what constitutes an acceptable quality of life. In some Islamic cultures the expertise of the patient's physician is given significant weight in making these judgments, and as such, families may appreciate frank assessment of the situation by the clinical team. Because of the various factors involved in issuing religious ruling, or fatwa, there is a wide spectrum of opinions on these rulings, and physicians should be aware of these differences, seek counsel and guidance from local Islamic leaders, and support families in their decision-making process.
Aqueous extract of Amydrium sinense (Engl.) H. Li alleviates hepatic fibrosis by suppressing hepatic stellate cell activation through inhibiting Stat3 signaling
Authors: Li Jingyan , Wu Bingmin , Zeng Lishan , Lin Ying , Chen Qiuhe , Wang Haixia , An Lin , Zhang Jiajun , Chen Siyan , Huang Junying , Zhan Ruoting , Zhang Guifang
Published: June 2023

Background: The present study aimed to investigate the protective effect of the water extract of Amydrium sinense (Engl.) H. Li (ASWE) against hepatic fibrosis (HF) and clarify the underlying mechanism.

Methods: The chemical components of ASWE were analysed by a Q-Orbitrap high-resolution mass spectrometer. In our study, an in vivo hepatic fibrosis mouse model was established via an intraperitoneal injection of olive oil containing 20% CCl4. In vitro experiments were conducted using a hepatic stellate cell line (HSC-T6) and RAW 264.7 cell line. A CCK-8 assay was performed to assess the cell viability of HSC-T6 and RAW264.7 cells treated with ASWE. Immunofluorescence staining was used to examine the intracellular localization of signal transducer and activator of transcription 3 (Stat3). Stat3 was overexpressed to analyse the role of Stat3 in the effect of ASWE on HF.

Results: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that candidate targets of ASWE, associated with protective effects against hepatic fibrosis, were related to inflammation response. ASWE ameliorated CCl4-induced liver pathological damage and reduced the liver index and alanine transaminase (ALT) and aspartate transaminase (AST) levels. ASWE also decreased the serum levels of collagen Ⅰ (Col Ⅰ) and hydroxyproline (Hyp) in CCl4-treated mice. In addition, the expression of fibrosis markers, including α-SMA protein and Acta2, Col1a1, and Col3a1 mRNA, was downregulated by ASWE treatment in vivo. The expression of these fibrosis markers was also decreased by treatment with ASWE in HSC-T6 cells. Moreover, ASWE decreased the expression of inflammatory markers, including the Tnf-α, Il6 and Il1β, in RAW264.7 cells. ASWE decreased the phosphorylation of Stat3 and total Stat3 expression and reduced the mRNA expression of the Stat3 gene in vivo and in vitro. ASWE also inhibited the nuclear shuttling of Stat3. Overexpression of Stat3 weakened the therapeutic effect of ASWE and accelerated the progression of HF.

Conclusion: The results show that ASWE protects against CCl4-induced liver injury by suppressing fibrosis, inflammation, HSC activation and the Stat3 signaling pathway, which might lead to a new approach for preventing HF.
Prevalence and risk factors of upper gastrointestinal symptoms in community pharmacies in Spain: a cross-sectional study
Authors: Puig-Moltó María , Lumbreras Blanca , López-Pintor Elsa
Published: June 2023

Background: Frequently, the community pharmacies are the only points of consultation for upper-gastrointestinal symptomology. However, the heterogeneity of symptoms often limits the correct management of the patient. The study aim is to describe the epidemiological and clinical characteristics of patients with upper-gastrointestinal symptoms who ask for advice in community pharmacies.

Methods: A cross-sectional study was performed in 134 Spanish pharmacies (June-October 2022) and we included 1,360 patients. We collected sociodemographic, clinical variables and current medication data. The pharmacist evaluated the gastrointestinal symptoms through the application of the GERD Impact Scale (GIS questionnaire). Patients were classified into three groups according to their symptoms: epigastric, retrosternal and overlapping symptoms.

Results: Median age was 49 years (interquartile range 36–62 years) and 59.3% were women. Most patients reported overlapping symptoms (738%, 54.3%), 433 (31.8%) retrosternal and 189 (13.9%) epigastric symptoms. Patients with overlapping symptoms were more likely to associated consumption of foods and/or drinks and symptoms and showed lower scores on the GIS scale (median 26, IQR 20-30) than those with epigastric (median 32, IQR 29-33) and retrosternal (median 32, IQR 28-34) symptoms (p < 0.001). Patients in treatment with a combination of alginates and antiacids were more likely to think that it better alleviated their symptoms in all the patients included (p = 0.012).

Conclusion: More than half of the patients showed overlapping symptoms and were more likely to associate their symptoms with dietary habits and having poorer scores in the GIS scale. Clinical awareness of such overlapping condition would help optimize the management of patients with upper gastrointestinal symptoms in practice.
Classifying migraine using PET compressive big data analytics of brain’s μ-opioid and D2/D3 dopamine neurotransmission
Authors: Marino Simeone , Jassar Hassan , Kim Dajung J. , Lim Manyoel , Nascimento Thiago D. , Dinov Ivo D. , Koeppe Robert A. , DaSilva Alexandre F.
Published: June 2023

Introduction: Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood in vivo. This study examined migraine patients with a novel machine learning (ML) method based on their central μ-opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface.

Methods: We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective μ-opioid receptor (μOR) radiotracer [11C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [11C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BPND), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels.

Results: CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for μOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BPND levels.

Discussion: CBDA of endogenous μ-opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur’s brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.
Mechanism of liver regeneration: 20-year bibliometric analyses
Authors: Qi Jingshu , Dai Yunkai , Sun Xin , Liu Chenghai
Published: June 2023

Objectives: The study aims to explore the most influential countries, institutions, journals, authors, “research hotspots,” and trends in the study of the mechanism of liver regeneration (MoLR) in the last 20 years using bibliometric analyses.

Methods: The literature associated with the MoLR was retrieved from the Web of Science Core Collection on 11 October 2022. CiteSpace 6.1.R6 (64-bit) and VOSviewer 1.6.18 were used for bibliometric analyses.

Results: A total of 18,956 authors from 2,900 institutions in 71 countries/regions published 3,563 studies in different academic journals on the MoLR. The United States was the most influential country. The University of Pittsburgh was the institution from which most articles on the MoLR were published. Cunshuan Xu published the most articles on the MoLR, and George K. Michalopoulos was the most frequently co-cited author. Hepatology was the journal in which most articles on the MoLR were published and the most frequently co-cited journal in this field. The research hotspots for the MoLR were origin and subsets of hepatocytes during LR; new factors and pathways in LR regulation; cell therapy for LR; interactions between liver cells in LR; mechanism of the proliferation of residual hepatocytes and trans-differentiation between cells; and prognosis of LR. The emerging topic was the mechanism of regeneration of a severely injured liver.

Conclusion: Our bibliometric analyses provide (i) a comprehensive overview of the MoLR; (ii) important clues and ideas for scholars in this field.
Application of natural polysaccharides and their novel dosage forms in gynecological cancers: therapeutic implications from the diversity potential of natural compounds
Authors: Li Yi , Zhang Chuanlong , Feng Lu , Shen Qian , Liu Fudong , Jiang Xiaochen , Pang Bo
Published: June 2023

Cancer is one of the most lethal diseases. Globally, the number of cancers is nearly 10 million per year. Gynecological cancers (for instance, ovarian, cervical, and endometrial), relying on hidden diseases, misdiagnoses, and high recurrence rates, have seriously affected women’s health. Traditional chemotherapy, hormone therapy, targeted therapy, and immunotherapy effectively improve the prognosis of gynecological cancer patients. However, with the emergence of adverse reactions and drug resistance, leading to the occurrence of complications and poor compliance of patients, we have to focus on the new treatment direction of gynecological cancers. Because of the potential effects of natural drugs in regulating immune function, protecting against oxidative damage, and improving the energy metabolism of the body, natural compounds represented by polysaccharides have also attracted extensive attention in recent years. More and more studies have shown that polysaccharides are effective in the treatment of various tumors and in reducing the burden of metastasis. In this review, we focus on the positive role of natural polysaccharides in the treatment of gynecologic cancer, the molecular mechanisms, and the available evidence, and discuss the potential use of new dosage forms derived from polysaccharides in gynecologic cancer. This study covers the most comprehensive discussion on applying natural polysaccharides and their novel preparations in gynecological cancers. By providing complete and valuable sources of information, we hope to promote more effective treatment solutions for clinical diagnosis and treatment of gynecological cancers.
Exploring the pathogenesis of colorectal carcinoma complicated with hepatocellular carcinoma via microarray data analysis
Authors: Gao Tianqi , Li Mengping , Wu Dailin , Xiao Ni , Huang Dan , Deng Li , Yang Lunwei , Tian Chunhong , Cao Yang , Zhang Jun , Gu Jihong , Yu Yang
Published: June 2023

Background: Despite the increasing number of research endeavors dedicated to investigating the relationship between colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC), the underlying pathogenic mechanism remains largely elusive. The aim of this study is to shed light on the molecular mechanism involved in the development of this comorbidity.

Methods: The gene expression profiles of CRC (GSE90627) and HCC (GSE45267) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely, functional annotation, protein‐protein interaction (PPI) network and module construction, and hub gene identification, survival analysis and co-expression analysis.

Results: A total of 150 common downregulated differentially expressed genes and 148 upregulated differentially expressed genes were selected for subsequent analyses. The significance of chemokines and cytokines in the pathogenesis of these two ailments is underscored by functional analysis. Seven gene modules that were closely connected were identified. Moreover, the lipopolysaccharide-mediated signaling pathway is intricately linked to the development of both diseases. Finally, 10 important hub genes were identified using cytoHubba, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM, and MAD2L1.

Conclusion: Our study reveals the common pathogenesis of colorectal carcinoma and hepatocellular carcinoma. These common pathways and hub genes may provide new ideas for further mechanism research.
Efferocytosis signatures as prognostic markers for revealing immune landscape and predicting immunotherapy response in hepatocellular carcinoma
Authors: Xu Ke , Liu Yu , Luo Huiyan , Wang Tengfei
Published: June 2023

Background: Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. Efferocytosis, a process in which one cell engulfs another cell, including macrophages, dendritic cells, NK cells, etc., plays a complex role in tumorigenesis, sometimes promoting and sometimes inhibiting tumor development. However, the role of efferocytosis-related genes (ERGs) in HCC progression has been poorly studied, and their regulatory effects in HCC immunotherapy and drug targeting have not been reported.

Methods: We downloaded efferocytosis-related genes from the Genecards database and screened for ERGs that showed significant expression changes between HCC and normal tissues and were associated with HCC prognosis. Machine learning algorithms were used to study prognostic gene features. CIBERSORT and pRRophetic R packages were used to evaluate the immune environment of HCC subtypes and predict treatment response. CCK-8 experiments conducted on HCC cells were used to assess the reliability of drug sensitivity prediction.

Results: We constructed a prognostic prediction model composed of six genes, and the ROC curve showed good predictive accuracy of the risk model. In addition, two ERG-related subgroups in HCC showed significant differences in tumor immune landscape, immune response, and prognostic stratification. The CCK-8 experiment conducted on HCC cells confirmed the reliability of drug sensitivity prediction.

Conclusion: Our study emphasizes the importance of efferocytosis in HCC progression. The risk model based on efferocytosis-related genes developed in our study provides a novel precision medicine approach for HCC patients, allowing clinicians to customize treatment plans based on unique patient characteristics. The results of our investigation carry noteworthy implications for the development of individualized treatment approaches involving immunotherapy and chemotherapy, thereby potentially facilitating the realization of personalized and more efficacious therapeutic interventions for HCC.
Machine learning and bioinformatics framework integration reveal potential characteristic genes related to immune cell infiltration in preeclampsia
Authors: Bai Lilian , Guo Yanyan , Gong Junxing , Li Yuchen , Huang Hefeng , Meng Yicong , Liu Xinmei
Published: June 2023

Introduction: Preeclampsia is a disease that affects both the mother and child, with serious consequences. Screening the characteristic genes of preeclampsia and studying the placental immune microenvironment are expected to explore specific methods for the treatment of preeclampsia and gain an in-depth understanding of the pathological mechanism of preeclampsia.

Methods: We screened for differential genes in preeclampsia by using limma package. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, disease ontology enrichment, and gene set enrichment analyses were performed. Analysis and identification of preeclampsia biomarkers were performed by using the least absolute shrinkage and selection operator regression model, support vector machine recursive feature elimination, and random forest algorithm. The CIBERSORT algorithm was used to analyze immune cell infiltration. The characteristic genes were verified by RT-qPCR.

Results: We identified 73 differential genes, which mainly involved in reproductive structure and system development, hormone transport, etc. KEGG analysis revealed emphasis on cytokine–cytokine receptor interactions and interleukin-17 signaling pathways. Differentially expressed genes were dominantly concentrated in endocrine system diseases and reproductive system diseases. Our findings suggest that LEP, SASH1, RAB6C, and FLT1 can be used as placental markers for preeclampsia and they are associated with various immune cells.

Conclusion: The differentially expressed genes in preeclampsia are related to inflammatory response and other pathways. Characteristic genes, LEP, SASH1, RAB6C, and FLT1 can be used as diagnostic and therapeutic targets for preeclampsia, and they are associated with immune cell infiltration. Our findings contribute to the pathophysiological mechanism exploration of preeclampsia. In the future, the sample size needs to be expanded for data analysis and validation, and the immune cells need to be further validated.