bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-29a-deficiency causes thickening of the basilar membrane and age-related hearing loss by upregulating collagen IV and laminin
Authors: Ma Peng , Wang Shuli , Geng Ruishuang , Gong Yongfeng , Li Mulan , Xie Daoli , Dong Yaning , Zheng Tihua , Li Bo , Zhao Tong , Zheng Qingyin
Published: May 2023

Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study using GeneChip miRNA microarray assays showed that the expression of miR-29a changes with age, however, its role in hearing loss is still unclear. In this study, we characterized the cochlear phenotype of miR-29a knockout (miR-29a–/–) mice and found that miR-29a-deficient mice had a rapid progressive elevation of the hearing threshold from 2 to 5 months of age compared with littermate controls as measured by the auditory brainstem response. Stereocilia degeneration, hair cell loss and abnormal stria vascularis (SV) were observed in miR-29a–/– mice at 4 months of age. Transcriptome sequencing results showed elevated extracellular matrix (ECM) gene expression in miR-29a–/– mice. Both Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the key differences were closely related to ECM. Further examination with a transmission electron microscope showed thickening of the basilar membrane in the cochlea of miR-29a–/– mice. Five Col4a genes (Col4a1-a5) and two laminin genes (Lamb2 and Lamc1) were validated as miR-29a direct targets by dual luciferase assays and miR-29a inhibition assays with a miR-29a inhibitor. Consistent with the target gene validation results, the expression of these genes was significantly increased in the cochlea of miR-29a–/– mice, as shown by RT-PCR and Western blot. These findings suggest that miR-29a plays an important role in maintaining cochlear structure and function by regulating the expression of collagen and laminin and that the disturbance of its expression could be a cause of progressive hearing loss.
Influence of exercise on quantity and deformability of immune cells in multiple sclerosis
Authors: Proschmann Undine , Shalchi-Amirkhiz Puya , Andres Pauline , Haase Rocco , Inojosa Hernán , Ziemssen Tjalf , Akgün Katja
Published: May 2023

Objective

The study aimed to investigate the effect of exercise on immune cell count and cell mechanical properties in people with multiple sclerosis (pwMS) on different disease-modifying treatments (DMT) vs. healthy controls (HCs).

Methods

A cohort of 16 HCs and 45 pwMS, including patients with lymphopenia (alemtuzumab and fingolimod) as well as increased lymphocyte counts (natalizumab), was evaluated for exercise-mediated effects on immune cell counts and lymphocyte deformability. As exercise paradigms, climbing stairs at normal speed or as fast as possible and cycling were used, while blood samples were collected before, immediately, and 20 as well as 60 min post-exercise. Immune cell subtypes and lymphocyte deformability were analyzed using multicolor flow cytometry and real-time deformability cytometry.

Results

An increase in lymphocytes and selected subsets was observed following exercise in HCs and all pwMS on different DMTs. Patients with lymphopenia exhibited an increase in absolute lymphocyte counts and immune cell subsets till just below or into the reference range. An increase above the upper limit of the reference range was detected in patients on natalizumab. Exercise-induced alterations were observable even in low and more pronounced in high-intensity physical activities. Lymphocyte deformability was found to be only mildly affected by the investigated exercise regimes.

Conclusion

People with multiple sclerosis (PwMS) treated with alemtuzumab, fingolimod, and natalizumab respond to acute exercise with a comparable temporal pattern characterized by the increase of immune cell subsets as HCs. The magnitude of response is influenced by exercise intensity. Exercise-mediated effects should be considered when interpreting laboratory values in patients on immunomodulatory therapy. The impact of exercise on biophysical properties should be further elucidated.
Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome
Authors: Woods Sydney , Basco Joseph , Clemens Stefan
Published: May 2023

Restless Legs Syndrome (RLS) is a common sensorimotor and a sleep disorder that affects 2.5–10% of the European and North American populations. RLS is also often associated with periodic leg movements during sleep (PLMS). Despite ample evidence of genetic contributions, the underlying mechanisms that elicit the sensory and motor symptoms remain unidentified. Clinically, RLS has been correlated with an altered central iron metabolism, particularly in the brain. While several animal models have been developed to determine the outcome of an altered iron homeostasis on brain function, the potential role of an altered iron homeostasis on sleep and sensorimotor circuits has not yet been investigated. Here, we utilize a mouse model to assess the effects of an iron-deficient (ID) but non-anemic state on sleep time and episodes, and sensorimotor reflexes in male and female mice. We found that animals on the ID diet displayed an increased expression of the transferrin receptor in the spinal cord, confirming the results of previous studies that focused only on the impact of ID in the brain. We also demonstrate that the ID diet reduced hematocrit levels compared to controls but not into the anemic range, and that animals on the ID diet exhibited RLS-like symptoms with regard to sleep onset and spinal cord reflex excitability. Interestingly, the effects on the spinal cord were stronger in females than in males, and the ID diet-induced behaviors were rescued by the return of the animals to the control diet. Taken together, these results demonstrate that diet-induced ID changes to CNS function are both inducible and reversible, and that they mimic the sleep and sensorimotor RLS symptoms experienced in the clinic. We therefore propose replacing the commonly used phrase “brain iron deficiency” (BID) hypothesis in the RLS research field with the term “iron deficiency in the central nervous system” (ID-CNS), to include possible effects of altered iron levels on spinal cord function.
An expert patient program to improve the empowerment and quality of life of people with multiple sclerosis: protocol for a multicenter pre-post intervention study
Authors: Robles-Sanchez Miguel Angel , Amil-Bujan Paloma , Bosch-Farré Cristina , Coll-Martínez Clàudia , Arévalo Maria Jesús , Anglada Elisenda , Menéndez Rebeca , Montalban Xavier , Sastre-Garriga Jaume , Ramió-Torrentà Lluís , Bertran-Noguer Carme
Published: May 2023

Introduction

Multiple sclerosis (MS) causes a progressive disability, which substantially impacts the quality of life (QoL). Health interventions that meet the needs and demands of people with MS are essential to minimize QoL impairment. Expert patient programs (EPPs) facilitate health-related empowerment through peer learning. Based on a previous focus group study, we designed an EPP for MS coordinated by nursing professionals for implementation in the different MS reference units of Catalonia (Southwestern Europe). This study aims to evaluate the effects on quality of life, disease-related knowledge, and self-management related to the health process of the participants of the Expert Patient Program Catalonia™ for people with multiple sclerosis (EPPC-MS).

Methods

Pre-post intervention multicenter clinical study involving 12 groups of 12 participants: six groups including relapsing and six groups including progressive MS patients, with 144 participants from 7 MS reference units from all over Catalonia, organized in six teams. The intervention will consist of nine telematic learning peer-led sessions (one weekly session). The expert patient (EP) leading the sessions will be an individual with MS with disease-related knowledge, who will be further trained by nurses to lead the sessions. Study variables will be measured before and immediately after the intervention and 6 and 12 months after the end of the sessions and will include: QoL, emotional impact, activation of the person, MS-related knowledge, fatigue, habits and lifestyles, health services use, and program-related experience. Baseline characteristics considered will be sociodemographic data, date of MS diagnosis and type, family history, and treatment characteristics. Variables related to disease follow-up will be new relapses and characteristics and changes in the ongoing treatment. The number of sessions attended will also be collected. Study variables will be analyzed using a pre-post comparison.

Discussion

Peer-led learning programs led by EP help empower people with chronic conditions and offer them tools to improve their autonomy and QoL. This study’s intervention will be performed remotely, offering advantages both for people with chronic conditions and the healthcare system regarding the facilitation of family and work conciliation, saving time, simplifying attendance to meetings, lowering costs, and using fewer material resources.

Trial registration

NCT04988880 on September 22, 2021.
Peripapillary hyper-reflective ovoid mass-like structures (PHOMS): clinical significance, associations, and prognostic implications in ophthalmic conditions
Authors: Li Biao , Li Haoran , Huang Qun , Zheng Yanlin
Published: May 2023

Pioneering advancements in optical coherence tomography (OCT) have facilitated the discernment of peripapillary hyper-reflective ovoid mass-like structures (PHOMS), prevalent neuro-ophthalmological findings associated with an array of ophthalmic conditions, such as optic disc drusen (ODD), papilledema, myopic/tilted optic discs, non-arteritic anterior ischemic optic neuropathy (NA-AION), and optic neuritis. Despite an expanding corpus of research, numerous inquiries persist concerning their clinical significance, correlations with ocular afflictions, and prognostic implications. This comprehensive review endeavors to impart an in-depth comprehension of PHOMS, encompassing facets like conceptualization, detection, pathogenesis, and associations with diverse ophthalmic conditions. Furthermore, we underscore several unresolved quandaries and suggest prospective avenues for future exploration.
Imaging the neural substrate of trigeminal neuralgia pain using deep learning
Authors: Liang Yun , Zhao Qing , Hu Zhenhong , Bo Ke , Meyyappan Sreenivasan , Neubert John K. , Ding Mingzhou
Published: May 2023

Trigeminal neuralgia (TN) is a severe and disabling facial pain condition and is characterized by intermittent, severe, electric shock-like pain in one (or more) trigeminal subdivisions. This pain can be triggered by an innocuous stimulus or can be spontaneous. Presently available therapies for TN include both surgical and pharmacological management; however, the lack of a known etiology for TN contributes to the unpredictable response to treatment and the variability in long-term clinical outcomes. Given this, a range of peripheral and central mechanisms underlying TN pain remain to be understood. We acquired functional magnetic resonance imaging (fMRI) data from TN patients who (1) rested comfortably in the scanner during a resting state session and (2) rated their pain levels in real time using a calibrated tracking ball-controlled scale in a pain tracking session. Following data acquisition, the data was analyzed using the conventional correlation analysis and two artificial intelligence (AI)-inspired deep learning methods: convolutional neural network (CNN) and graph convolutional neural network (GCNN). Each of the three methods yielded a set of brain regions related to the generation and perception of pain in TN. There were 6 regions that were identified by all three methods, including the superior temporal cortex, the insula, the fusiform, the precentral gyrus, the superior frontal gyrus, and the supramarginal gyrus. Additionally, 17 regions, including dorsal anterior cingulate cortex (dACC) and the thalamus, were identified by at least two of the three methods. Collectively, these 23 regions are taken to represent signature centers of TN pain and provide target areas for future studies seeking to understand the central mechanisms of TN.
Six mitophagy-related hub genes as peripheral blood biomarkers of Alzheimer’s disease and their immune cell infiltration correlation
Authors: Zhao Kun , Wu Yinyan , Zhao Dongliang , Zhang Hui , Lin Jianyang , Wang Yuanwei
Published: May 2023

Background

Alzheimer’s disease (AD), a neurodegenerative disorder with progressive symptoms, seriously endangers human health worldwide. AD diagnosis and treatment are challenging, but molecular biomarkers show diagnostic potential. This study aimed to investigate AD biomarkers in the peripheral blood.

Method

Utilizing three microarray datasets, we systematically analyzed the differences in expression and predictive value of mitophagy-related hub genes (MRHGs) in the peripheral blood mononuclear cells of patients with AD to identify potential diagnostic biomarkers. Subsequently, a protein–protein interaction network was constructed to identify hub genes, and functional enrichment analyses were performed. Using consistent clustering analysis, AD subtypes with significant differences were determined. Finally, infiltration patterns of immune cells in AD subtypes and the relationship between MRHGs and immune cells were investigated by two algorithms, CIBERSORT and single-sample gene set enrichment analysis (ssGSEA).

Results

Our study identified 53 AD- and mitophagy-related differentially expressed genes and six MRHGs, which may be potential biomarkers for diagnosing AD. Functional analysis revealed that six MRHGs significantly affected biologically relevant functions and signaling pathways such as IL-4 Signaling Pathway, RUNX3 Regulates Notch Signaling Pathway, IL-1 and Megakaryocytes in Obesity Pathway, and Overview of Leukocyteintrinsic Hippo Pathway. Furthermore, CIBERSORT and ssGSEA algorithms were used for all AD samples to analyze the abundance of infiltrating immune cells in the two disease subtypes. The results showed that these subtypes were significantly related to immune cell types such as activated mast cells, regulatory T cells, M0 macrophages, and neutrophils. Moreover, specific MRHGs were significantly correlated with immune cell levels.

Conclusion

Our findings suggest that MRHGs may contribute to the development and prognosis of AD. The six identified MRHGs could be used as valuable diagnostic biomarkers for further research on AD. This study may provide new promising diagnostic and therapeutic targets in the peripheral blood of patients with AD.
Approaching the mapping limit with closed-loop mapping strategy for deploying neural networks on neuromorphic hardware
Authors: Wang Song , Yu Qiushuang , Xie Tiantian , Ma Cheng , Pei Jing
Published: May 2023

The decentralized manycore architecture is broadly adopted by neuromorphic chips for its high computing parallelism and memory locality. However, the fragmented memories and decentralized execution make it hard to deploy neural network models onto neuromorphic hardware with high resource utilization and processing efficiency. There are usually two stages during the model deployment: one is the logical mapping that partitions parameters and computations into small slices and allocate each slice into a single core with limited resources; the other is the physical mapping that places each logical core to a physical location in the chip. In this work, we propose the mapping limit concept for the first time that points out the resource saving upper limit in logical and physical mapping. Furthermore, we propose a closed-loop mapping strategy with an asynchronous 4D model partition for logical mapping and a Hamilton loop algorithm (HLA) for physical mapping. We implement the mapping methods on our state-of-the-art neuromorphic chip, TianjicX. Extensive experiments demonstrate the superior performance of our mapping methods, which can not only outperform existing methods but also approach the mapping limit. We believe the mapping limit concept and the closed-loop mapping strategy can help build a general and efficient mapping framework for neuromorphic hardware.
A data security scheme based on EEG characteristics for body area networks
Authors: Bai Tong , Jiang Yuhao , Yang Jiazhang , Luo Jiasai , Du Ya
Published: May 2023

Body area network (BAN) is a body-centered network of wireless wearable devices. As the basic technology of telemedicine service, BAN has aroused an immense interest in academia and the industry and provides a new technical method to solve the problems that exist in the field of medicine. However, guaranteeing full proof security of BAN during practical applications has become a technical issue that hinders the further development of BAN technology. In this article, we propose a data encryption method based on electroencephalogram (EEG) characteristic values and linear feedback shift register (LFSR) to solve the problem of data security in BAN. First, the characteristics of human EEG signals were extracted based on the wavelet packet transform method and as the MD5 input data to ensure its randomness. Then, an LFSR stream key generator was adopted. The 128-bit initial key obtained through the message-digest algorithm 5 (MD5) was used to generate the stream key for BAN data encryption. Finally, the effectiveness of the proposed security scheme was verified by various experimental evaluations. The experimental results showed that the correlation coefficient of data before and after encryption was very low, and it was difficult for the attacker to obtain the statistical features of the plaintext. Therefore, the EEG-based security scheme proposed in this article presents the advantages of high randomness and low computational complexity for BAN systems.
Bibliometric and visual analysis of microglia-related neuropathic pain from 2000 to 2021
Authors: Zhang Shun-Bai , Zhao Guang-Hai , Lv Tian-Run , Gong Chao-Yang , Shi Yong-Qiang , Nan Wei , Zhang Hai-Hong
Published: May 2023

Background

Microglia has gradually gained researchers’ attention in the past few decades and has shown its promising prospect in treating neuropathic pain. Our study was performed to comprehensively evaluate microglia-related neuropathic pain via a bibliometric approach.

Methods

We retrospectively reviewed publications focusing on microglia-related neuropathic pain from 2000 to 2021 in WoSCC. VOS viewer software and CiteSpace software were used for statistical analyses.

Results

A total of 2,609 articles were finally included. A steady increase in the number of relevant publications was observed in the past two decades. China is the most productive country, while the United States shares the most-cited and highest H-index country. The University of London, Kyushu University, and the University of California are the top 3 institutions with the highest number of publications. Molecular pain and Pain are the most productive and co-cited journals, respectively. Inoue K (Kyushu University) is the most-contributed researcher and Ji RR (Duke University) ranks 1st in both average citations per article and H-index. Keywords analyses revealed that pro-inflammatory cytokines shared the highest burst strength. Sex differences, neuroinflammation, and oxidative stress are the emerging keywords in recent years.

Conclusion

In the field of microglia-related neuropathic pain, China is the largest producer and the United States is the most influential country. The signaling communication between microglia and neurons has continued to be vital in this field. Sexual dimorphism, neuroinflammation, and stem-cell therapies might be emerging trends that should be closely monitored.
Optimally controlling nutrition and propulsion force in a long distance running race
Authors: Cook Cameron , Chen Guoxun , Hager William W. , Lenhart Suzanne
Published: May 2023

Introduction

Runners competing in races are looking to optimize their performance. In this paper, a runner's performance in a race, such as a marathon, is formulated as an optimal control problem where the controls are: the nutrition intake throughout the race and the propulsion force of the runner. As nutrition is an integral part of successfully running long distance races, it needs to be included in models of running strategies.

Methods

We formulate a system of ordinary differential equations to represent the velocity, fat energy, glycogen energy, and nutrition for a runner competing in a long-distance race. The energy compartments represent the energy sources available in the runner's body. We allocate the energy source from which the runner draws, based on how fast the runner is moving. The food consumed during the race is a source term for the nutrition differential equation. With our model, we are investigating strategies to manage the nutrition and propulsion force in order to minimize the running time in a fixed distance race. This requires the solution of a nontrivial singular control problem.

Results

As the goal of an optimal control model is to determine the optimal strategy, comparing our results against real data presents a challenge; however, in comparing our results to the world record for the marathon, our results differed by 0.4%, 31 seconds. Per each additional gel consumed, the runner is able to run 0.5 to 0.7 kilometers further in the same amount of time, resulting in a 7.75% increase in taking five 100 calorie gels vs no nutrition.

Discussion

Our results confirm the belief that the most effective way to run a race is to run approximately the same pace the entire race without letting one's energies hit zero, by consuming in-race nutrition. While this model does not take all factors into account, we consider it a building block for future models, considering our novel energy representation, and in-race nutrition.
Partial response to niraparib in combination with tislelizumab in a patient with metastatic undifferentiated tonsillar carcinoma: a case report and literature review
Authors: Zhang Jing , Dai Zi , Liao Pei , Guan Jieshan
Published: May 2023

Undifferentiated tonsillar carcinoma is an extremely rare head and neck cancer. The treatment options are challenging due to insensitivity to chemotherapy and easy development of drug resistance. In this study, we reported a case of advanced undifferentiated tonsillar carcinoma with multiple mediastinal lymph node metastases that failed to respond to chemotherapy. Next-generation sequencing (NGS) revealed germline BReast CAncer gene (BRCA) 1 mutation and a high tumor mutational burden. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have demonstrated efficacy in solid tumors with BRCA1/2 mutations. Immune checkpoint inhibitors (ICIs) provide a treatment option for unresectable head and neck cancer. After local control treatment by embolization, niraparib and tislelizumab were administered to this patient. A partial response (PR) was achieved, and progression-free survival (PFS) and overall survival (OS) were 12 months and 19 months, respectively. This case reveals molecular profiling as an important therapeutic strategy for rare malignancies with no standard of care. Moreover, the underlying synergistic antitumor activity of PARPi and PD-L1 blockade was reviewed.
The feasibility of a “no tube, no fasting” fast-track recovery protocol after esophagectomy for esophageal cancer patients aged 75 and over
Authors: Xing Wenqun , Liu Xianben , Miao Peng , Hao Wentao , Li Keting , Wang Hao , Zheng Yan
Published: May 2023

Objective

For elderly patients aged ≥75 with esophageal cancer, whether surgical treatment is safe and effective and whether it is feasible to use a relatively radical “no tube, no fasting” fast-track recovery protocol remain topics of debate. We conducted a retrospective analysis to shed light on these two questions.

Methods

We retrospectively collected the data of patients who underwent McKeown minimally invasive esophagectomy (MIE) combined with early oral feeding (EOF) on postoperative day 1 between April 2015 and December 2017 at Medical Group 1, Ward 1, Department of Thoracic Surgery of our hospital. Preoperative characteristics, postoperative complications, operation time, intraoperative blood loss, duration of anastomotic leakage (day), hospital stay, and survival were evaluated.

Results

Twenty-three elderly patients with esophageal cancer underwent surgery with EOF. No significant difference was observed in intraoperative measures. The incidence of postoperative complications was 34.8% (8/23). Two patients (8.7%) were terminated early during the analysis of the feasibility of EOF. For all 23 patients, the mean hospital stay was 11.4 (5-42) days, and the median survival was 51 months.

Conclusion

Patients aged ≥75 with resectable esophageal cancer can achieve long-term survival with active surgical treatment. Moreover, the “no tube, no fasting” fast-track recovery protocol is safe and feasible for elderly patients.
CEP55 as a promising biomarker and therapeutic target on gallbladder cancer
Authors: Huang Maotuan , Zhong Fuxiu , Chen Mingyuan , Hong Lingju , Chen Weihong , Abudukeremu Xiahenazi , She Feifei , Chen Yanling
Published: May 2023

Introduction

Gallbladder cancer (GBC) is a highly malignant biliary tumor with a poor prognosis. As existing therapies for advanced metastatic GBC are rarely effective, there is an urgent need to identify more effective targets for treatment.

Methods

Hub genes of GBC were identified by bioinformatics analysis and their expression in GBC was analyzed by tissue validation. The biological role of CEP55 in GBC cell and the underlying mechanism of the anticancer effect of CEP55 knockdown were evaluated via CCK8, colony formation assay, EDU staining, flow cytometry, western blot, immunofluorescence, and an alkaline comet assay.

Results

We screened out five hub genes of GBC, namely PLK1, CEP55, FANCI, NEK2 and PTTG1. CEP55 is not only overexpressed in the GBC but also correlated with advanced TNM stage, differentiation grade and poorer survival. After CEP55 knockdown, the proliferation of GBC cells was inhibited with cell cycle arrest in G2/M phase and DNA damage. There was a marked increase in the apoptosis of GBC cells in the siCEP55 group. Besides, in vivo, CEP55 inhibition attenuated the growth and promoted apoptosis of GBC cells. Mechanically, the tumor suppressor effect of CEP55 knockdown is associated with dysregulation of the AKT and ERK signaling networks.

Discussion

These data not only demonstrate that CEP55 is identified as a potential independent predictor crucial to the diagnosis and prognosis of gallbladder cancer but also reveal the possibility for CEP55 to be used as a promising target in the treatment of GBC.
Umbilical cord blood derived cellular therapy: advances in clinical development
Authors: Wang Jiasheng , Metheny Leland
Published: May 2023

While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.
Experimental assessment of robust reference genes for qRT-PCR in lung cancer studies
Authors: Gu Wei , Wang Yubin , Xu Ran , Li Jiamin , Jin Jingjie , Zhao Jing , Chen Yang , Lu Yuanzhi , Zhang Gong
Published: May 2023

Stable internal reference genes are crucial for quantitative real-time PCR (qRT-PCR) analyses in lung cancer studies. Widely used reference genes are mostly chosen by intuition or from pan-cancer transcriptome data and lack experimental validation by qRT-PCR in the context of lung cancer. This study evaluated the stability of candidate reference genes in lung cancer cell lines under normal homeostasis, hypoxia, and serum deprivation to screen for robust reference genes for qRT-PCR in lung cancer studies. The stability of reference gene combinations was also assessed. We found that most of the stably expressed genes from pan-cancer transcriptome analyses were not sufficiently stable under some of the tested conditions. CIAO1, CNOT4, and SNW1 were found to be the most stable reference genes under various conditions. Greater stability was achieved by combining more reference genes. We further used the hypoxia biomarker hypoxia-inducible factor (HIF)-2α to demonstrate that choosing inappropriate reference genes can lead to incorrect qRT-PCR results. We also found that the stable reference genes were irrelevant to malignancy, which may explain their stability under various conditions that cancer cells often encounter. This study provides a list of validated and stable qRT-PCR reference genes and reference gene combinations for lung cancer that may standardize qRT-PCR experiments in future lung cancer studies.
Real world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma
Authors: Stoff Ronen , Asher Nethanel , Laks Shachar , Steinberg Yael , Schachter Jacob , Shapira-Frommer Ronnie , Grynberg Shirly , Ben-Betzalel Guy
Published: May 2023

Introduction

Immunotherapy has revolutionized the prognosis of patients with metastatic melanoma. To date, the most active regimen is the combination of ipilimumab + nivolumab (ipi-nivo) achieving a response rate of nearly 60% and a median survival (OS) of 6 years. However, approximately 40% of patients experience primary resistance, while around 50% experience secondary resistance, highlighting the need for an effective second-line treatment option The recently published results on the use of lenvatinib + pembrolizumab in the advanced line setting led to the adoption of this regimen at our institution. Here we present our experience with this regimen, focusing on efficacy and safety.

Methods

Electronic medical records of patients treated at a tertiary referral melanoma center, with at least one cycle of anti PD-1 + lenvatinib from 2020 to 2023 were analyzed for baseline demographic characteristics, disease related characteristics and treatment outcomes.

Results

Forty-two patients were identified. The Response rate (RR) was 28% and the disease control rate was 38%. Responses were seen across different melanoma subtypes, including 67% in acral melanoma, 20% in uveal melanoma, and 25% in mucosal melanoma. Patients with a more aggressive disease manifested by elevated lactate dehydrogenase (LDH) achieved a RR of 26%, while patients with active central nervous system (CNS) metastases had a RR of 31%, and an intra-cranial RR of 23%. Responses were seen across lines of treatment, with a 25% RR in the second and third lines, and a 36% RR in the fourth and fifth lines. The median progression free survival was 3 months, and the median survival was 11 months. The treatment was not easily tolerated with 31% of the patients experiencing grade 3-4 toxicity, which was manageable through dose interruptions and reductions. Only 7% of patients discontinued the treatment due to toxicity.

Conclusion

Lenvatinib in combination with anti-PD1 had demonstrated both relative safety and efficacy in patients with metastatic melanoma of all subtypes in the advanced line setting. We are eagerly anticipating the mature results of the LEAP-004 study hoping that this regimen will receive regulatory approval, paving the way for its widespread adoption in daily practice worldwide.
Computational approaches for drug repurposing in oncology: untapped opportunity for high value innovation
Authors: Dalwadi Shraddha M. , Hunt Andrew , Bonnen Mark D. , Ghebre Yohannes T.
Published: May 2023

Historically, the effort by academia and industry to develop new chemical entities into lifesaving drugs has limited success in meeting the demands of today’s healthcare. Repurposing drugs that are originally approved by the United States Food and Drug Administration or by regulatory authorities around the globe is an attractive strategy to rapidly develop much-needed therapeutics for oncologic indications that extend from treating cancer to managing treatment-related complications. This review discusses computational approaches to harness existing drugs for new therapeutic use in oncology.
Performance of two interferon-gamma release assays for tuberculosis infection screening in Kawasaki children before immunosuppressive therapy
Authors: Chen Hao , Zheng Huiwen , Cui Lang , Xiao Jing , Li Feina , Wang Yonghong , Guo Yajie , Chen Yuying , Yuan Yue , Shen Chen
Published: May 2023

Objective

We aimed to compare QuantiFERON-TB Gold In-Tube (QFT-GIT) and X.DOT-TB for screening latent tuberculosis infection (LTBI) in kawasaki patients, and to identify the risk factors associated with indeterminate IGRA results.

Methods

We conducted a retrospective study on children with KD, who were screened for mycobacterium tuberculosis (Mtb) infection by either ELISA-based QFT-GIT or ELISPOT-based X.DOT-TB tests, admitted in Department of Cardiology, Beijing Children's Hospital from July 2019 to April 2022.

Results

A total of 1327 cases were included. Among them, 932 cases were tested by QFT-GIT and 395 cases by X.DOT-TB. The positive rate of children was 0.1% and 0.2%, and the indeterminate rate was 68.2% and 6.1% for QFT-GIT and X.DOT-TB, respectively. Patients with hypoproteinemia had a higher risk of indeterminate X.DOT-TB result. Female, critical ill, shock or hypoproteinemia presented statistically significant associations with an increased risk of indeterminate QFT-GIT result. High-dose of IVIG inhibited the release of IFN-γ by more than 90%, which might account for the high indeterminate incidence.

Conclusion

It is recommended to perform X.DOT-TB rather than QFT-GIT to screen LTBI in patients with high level of the mitogen that can inhibit IFN-γ release. For KD children with positive IGRA results, it has a higher risk of activation TB infection when treated with immunosuppressive therapy in the future. Children with KD aged <5 years old had higher frequency of indeterminate IGRA results.
An update on the development of novel antifungal agents for eumycetoma
Authors: Chandler David J. , Bonifaz Alexandro , van de Sande Wendy W. J.
Published: May 2023

Eumycetoma, a chronic subcutaneous mycosis, responds poorly to the available antifungal treatments and patients often require extensive surgical resection or amputation of the affected limb. More effective treatments are needed for eumycetoma. This article will describe some of the approaches being used to develop and evaluate new treatments for eumycetoma, summarise the latest developments and discuss the challenges that lie ahead.
Evaluation of the potential herb-drug interaction between Bojungikki-tang and PD-L1 immunotherapy in a syngeneic mouse model
Authors: Yang Sung-Yoon , Yi Jin-Mu , Chun Jaemoo , Park Seongwon , Bui Tham Thi , Yun Hwi-Yeol , Chae Jung-Woo , Jeong Mi-Kyung
Published: May 2023

Atezolizumab (a PD-L1 inhibitor) has shown remarkable efficacy and tolerability in various cancer types. Despite its efficacy and safety, atezolizumab monotherapy has limitations, such as acquired resistance and adverse events. Bojungikki-tang (BJIKT) is an herbal decoction widely prescribed in Asian countries and used to treat cancer-related symptoms including fatigue, appetite loss, gastrointestinal disorders, and other side effects from cancer therapy. Due to its immunomodulatory effects, Bojungikki-tang has been investigated as a combined treatment with anticancer agents. We evaluated the potential drug-drug interaction (DDI) between Bojungikki-tang and the anti-PD-L1 antibody based on the Food and Drug Administration (FDA) guidelines. In the study, we conducted an in vivo drug-drug interaction study using a syngeneic mouse model of CMT-167 in C57BL/6. We then determined the antibody concentrations to evaluate the pharmacokinetic (PK) drug-drug interaction and measured variable biomarkers related to therapeutic efficacy and immune response. The pharmacodynamic (PD) drug-drug interaction study investigated changes in response between anti-PD-L1 antibody monotherapy and combination therapy. Using the pharmacokinetic and pharmacodynamic data, we conducted a statistical analysis to assess drug-drug interaction potential. In the presence of Bojungikki-tang, the pharmacokinetic characteristics of the anti-PD-L1 antibody were not changed. This study suggested that combination treatment with Bojungikki-tang and atezolizumab is a safe treatment option for non-small cell lung cancer. Clinical studies are warranted to confirm this finding.
The mechanism of trans-δ-viniferin inhibiting the proliferation of lung cancer cells A549 by targeting the mitochondria
Authors: Yin Ruochun , Zhang Yiling , Su Liping , Chen Dongdong , Lou Shidi , Luo Xuecai , Wang Lin , Tang Rupei , Zhang Liang , Tian Xiaohe
Published: May 2023

Trans-δ-viniferin (TVN), as a natural extract, is a resveratrol dimer with attractive biological activities, particularly its anti-tumor character. However, the mechanism of TVN interfering with cancerous proliferation has not been fully understood. Herein in this study, we found that TVN could trigger cancerous mitochondrial membrane potential (ΔΨm) reduction, with intracellular reactive oxidative species (ROS) level increasing, leading to apoptosis, which makes TVN a promising candidate for lung cancer cells A549 treatment. Therefore, this study provides TVN as an option to meet the demand for higher antitumor availability with lower biotoxicity and other clinical applications.
Photo-thermoelastic wave propagation with changing thermal conductivity on excited pulsed laser nanoscale microelongated semiconductor material
Authors: Farhan Ashraf M. , El-Sapa Shreen , El-Bary Alaa A. , Chteoui Riadh , Lotfy Khaled
Published: May 2023

Indroduction: The novel model of a non-local elastic semiconductor material that is microelongated is created. The process of photothermal transfer is responsible for the stimulation of the material. Photo-thermoelastic theories are used when the thermal conductivity is changed for the non-local medium. Under the influence of laser pulses, the effective framework describes the nanoscale microelongation instance as well as the interference between the photo-thermoelastic propagation waves in the non-local medium. It is possible to think of thermal conductivity as a linear function of temperature when electronic and thermoelastic deformation mechanisms are described. Two-dimensional deformation (2D) is used to extract the main fields, which obtained in non-dimension.

Methods: Harmonic wave analysis, which is described by the normal mode, has been used to convert the basic equations into non-homogeneous higher-order ordinary differential equations. Applying a small subset of the possible non-local semiconductor surface conditions leads to exhaustive solutions.

Result and Discussion: The outcomes of numerical simulations for silicon (Si) are graphically shown. There are comparisons made and explanations given for the investigated physical factors like their thermal conductivity, laser pulses and microelongation parameters.
Oral CBD-rich hemp extract modulates sterile inflammation in female and male rats
Authors: Hopkins Shelby , Kelley Tel , Roller Rachel , Thompson Robert S. , Colagiovanni Dorothy B. , Chupka Kris , Fleshner Monika
Published: May 2023

Introduction: Cannabidiol (CBD) extract from the cannabis plant has biomedical and nutraceutical potential. Unlike tetrahydrocannabinol (THC), CBD products produce few psychoactive effects and pose little risk for abuse. There is emerging preclinical and clinical evidence that CBD is stress modulatory and may have anti-inflammatory properties. People across the United States legally ingest CBD-rich hemp extracts to manage mental and physical health problems, including stress and inflammation. Preclinical studies have revealed potential mechanisms for these effects; however, the impact of this prior work is diminished because many studies: 1) tested synthetic CBD rather than CBD-rich hemp extracts containing terpenes and/or other cannabinoids thought to enhance therapeutic benefits; 2) administered CBD via injection into the peritoneal cavity or the brain instead of oral ingestion; and 3) failed to examine potential sex differences. To address these gaps in the literature, the following study tested the hypothesis that the voluntary oral ingestion of CBD-rich hemp extract will attenuate the impact of stressor exposure on plasma and tissue inflammatory and stress proteins in females and males.

Methods: Adult male and female Sprague Dawley rats (10–15/group) were randomly assigned to be given cereal coated with either vehicle (coconut oil) or CBD-rich hemp extract (L-M0717, CBDrx/Functional Remedies, 20.0 mg/kg). After 7 days, rats were exposed to a well-established acute model of stress (100, 1.5 mA, 5-s, intermittent tail shocks, 90 min total duration) or remained in home cages as non-stressed controls.

Results: Stressor exposure induced a robust stress response, i.e., increased plasma corticosterone and blood glucose, and decreased spleen weight (a surrogate measure of sympathetic nervous system activation). Overall, stress-induced increases in inflammatory and stress proteins were lower in females than males, and oral CBD-rich hemp extract constrained these responses in adipose tissue (AT) and mesenteric lymph nodes (MLN). Consistent with previous reports, females had higher levels of stress-evoked corticosterone compared to males, which may have contributed to the constrained inflammatory response measured in females.

Discussion: Results from this study suggest that features of the acute stress response are impacted by oral ingestion of CBD-rich hemp extract in female and male rats, and the pattern of changes may be sex and tissue dependent.
The relationship of muscle oxygen saturation analyzer with other monitoring and quantification tools in a maximal incremental treadmill test
Authors: Osmani Florent , Lago-Fuentes Carlos , Alemany-Iturriaga Josep , Barcala-Furelos Martín
Published: May 2023

Introduction: The study aims to explore whether NIRS derived data can be used to identify the second ventilatory threshold (VT2) during a maximal incremental treadmill test in non-professional runners and to determine if there is a correlation between SmO2 and other valid and reliable exercise performance assessment measures or parameters for maximal incremental test, such as lactate concentration (LT), RPE, HR, and running power (W).

Methods: 24 participants were recruited for the study (5 women and 19 men). The devices used consisted of the following: i) a muscle oxygen saturation analyzer placed on the vastus lateralis of the right leg, ii) the Stryd power meter for running, iii) the Polar H7 heart rate band; and iv) the lactate analyzer. In addition, a subjective perceived exertion scale (RPE 1-10) was used. All of the previously mentioned devices were used in a maximal incremental treadmill test, which began at a speed of 8 km/h with a 1% slope and a speed increase of 1.2 km/h every 3 min. This was followed by a 30-s break to collect the lactate data between each 3-min stage. Spearman correlation was carried out and the level of significance was set at p < 0.05.

Results: The VT2 was observed at 87,41 ± 6,47% of the maximal aerobic speed (MAS) of each participant. No relationship between lactate data and SmO2 values (p = 0.076; r = −0.156) at the VT2 were found. No significant correlations were found between the SmO2 variables and the other variables (p > 0.05), but a high level of significance and strong correlations were found between all the following variables: power data (W), heart rate (HR), lactate concentration (LT) and RPE (p < 0.05; r > 0.5).

Discussion: SmO2 data alone were not enough to determine the VT2, and there were no significant correlations between SmO2 and the other studied variables during the maximal incremental treadmill test. Only 8 subjects had a breakpoint at the VT2 determined by lactate data.

Conclusion: The NIRS tool, Humon Hex, does not seem to be useful in determining VT2 and it does not correlate with the other variables in a maximal incremental treadmill test.
Rosemary and neem methanolic extract: antioxidant, cytotoxic, and larvicidal activities supported by chemical composition and molecular docking simulations
Authors: Alhaithloul Haifa A. S. , Alqahtani Mesfer M. , Abdein Mohamed A. , Ahmed Mohamed A. I. , Hesham Abd El-Latif , Aljameeli Mohammad M. E. , Al Mozini Reem N. , Gharsan Fatehia N. , Hussien Suzan M. , El-Amier Yasser A.
Published: May 2023

This study aimed to employ GC–MS to assess the chemical composition of MeOH leaf extracts of R. officinalis and A. indica and evaluate their insecticidal, antioxidant, and antibacterial activities. Twelve components, representing 98.61% and 100% of the total volatile compounds, were deduced from the extracted R. officinalis and A. indica, respectively, using this method. In R. officinalis extract, limonene is typically positioned as the main component (23.03%), while the main chemicals identified in A. indica extract were methyl (E)-octadec-13-enoate (23.20%) and (2R)-1,3,8-trimethyl-4-propyl-5-ethyl-2-(1-hydroxyethyl)-7-methoxycardonylethyl-6-methylenecarbonyl-porphyrin (23.03%). Both extracts of R. officinalis and A. indica exhibited different toxicity against the stored grain pest T. castaneum, with LC50 values of 1.470 and 2.588 mg/ml, respectively. Additionally, after 4 and 5 h of treatment at a concentration of 0.2 mg/ml, the A. indica extract showed the highest levels of repellent action (81.4% and 93.4%), and the R. officinalis extract showed a good repellent rate (64.9% and 80.7%) against T. castenum larvae. With an IC50 value of 35.83 and 28.68 mg/L and a radical scavenging activity percentage of 67.76% and 72.35%, the leaf extract was found to be the most potent plant extract when tested for DPPH antioxidant activity. Overall results showed that MeOH extracts of R. officinalis and A. indica were more effective against S. aureus than E. coli. To determine how the investigated chemicals attach to the active sites of E. coli DNA gyrase A and S. aureus undecaprenyl diphosphate synthase, docking studies were carried out. The consensus score analysis showed that limonene exhibits the best binding energy with both enzymes in docking analysis and more stability in molecular dynamics simulations. The RMSD was obtained at 20.6 and 4.199 (Kcal/mole). The two compounds were successfully used in molecular dynamics simulation research to generate stable complexes with DNA gyrase A.