bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)
Authors: Reid Tony , Oronsky Bryan , Caroen Scott , Quinn Mary , Williams Jeannie , Cabrales Pedro , Abrouk Nacer
Published: March 2023

Background

Bromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options.

Methods

This single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03.

Results

Twelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination.

Conclusions

The combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted.

Clinical trial registration

ClinicalTrials.gov identifier, NCT02518958.
Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry
Authors: Ljungman Per , Tridello Gloria , Piñana Jose Luis , Ciceri Fabio , Sengeloev Henrik , Kulagin Alexander , Mielke Stephan , Yegin Zeynep Arzu , Collin Matthew , Einardottir Sigrun , Lepretre Sophie Ducastelle , Maertens Johan , Campos Antonio , Metafuni Elisabetta , Pichler Herbert , Folber Frantisek , Solano Carlos , Nicholson Emma , Yüksel Meltem Kurt , Carlson Kristina , Aguado Beatriz , Besley Caroline , Byrne Jenny , Heras Immaculada , Dignan Fiona , Kröger Nicolaus , Robin Christine , Khan Anjum , Lenhoff Stig , Grassi Anna , Dobsinska Veronika , Miranda Nuno , Jimenez Maria-Jose , Yonal-Hindilerden Ipek , Wilson Keith , Averbuch Dina , Cesaro Simone , Xhaard Alienor , Knelange Nina , Styczynski Jan , Mikulska Malgorzata , de la Camara Rafael
Published: March 2023

Introduction

COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients.

Methods

This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic.

Results

The median age was 50.3 years (min – max; 1.0 – 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min – max; 0.0 – 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 – 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 – 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022.

Discussion

Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.
T lymphocyte characteristics and immune repertoires in the epicardial adipose tissue of heart failure patients
Authors: Zhang Xu-Zhe , Chen Xian-Li , Tang Ting-Ting , Zhang Si , Li Qin-Lin , Xia Ni , Nie Shao-Fang , Zhang Min , Zhu Zheng-Feng , Zhou Zi-Hua , Dong Nian-Guo , Cheng Xiang
Published: March 2023

Background

Epicardial adipose tissue (EAT) acts as an active immune organ and plays a critical role in the pathogenesis of heart failure (HF). However, the characteristics of immune cells in EAT of HF patients have rarely been elucidated.

Methods

To identify key immune cells in EAT, an integrated bioinformatics analysis was performed on public datasets. EAT samples with paired subcutaneous adipose tissue (SAT), heart, and peripheral blood samples from HF patients were collected in validation experiments. T cell receptor (TCR) repertoire was assessed by high-throughput sequencing. The phenotypic characteristics and key effector molecules of T lymphocytes in EAT were assessed by flow cytometry and histological staining.

Results

Compared with SAT, EAT was enriched for immune activation-related genes and T lymphocytes. Compared with EAT from the controls, activation of T lymphocytes was more pronounced in EAT from HF patients. T lymphocytes in EAT of HF patients were enriched by highly expanded clonotypes and had greater TCR clonotype sharing with cardiac tissue relative to SAT. Experiments confirmed the abundance of IFN-γ+ effector memory T lymphocytes (TEM) in EAT of HF patients. CCL5 and GZMK were confirmed to be associated with T lymphocytes in EAT of HF patients.

Conclusion

EAT of HF patients was characterized by pronounced immune activation of clonally expanded IFN-γ+ TEM and a generally higher degree of TCR clonotypes sharing with paired cardiac tissue.
Immune damage mechanisms of COVID-19 and novel strategies in prevention and control of epidemic
Authors: Sun Yuting , Luo Bin , Liu Yueping , Wu Yuzhang , Chen Yongwen
Published: March 2023

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has diverse clinical manifestations, which is the main feature of the disease, and the fundamental reason is the different immune responses in different bodies among the population. The damage mechanisms of critical illness by SARS-CoV-2 and its variants, such as hyperinflammatory response, a double-edged function of type I interferon, and hyperactivation of the complement system, are the same as other critical illnesses. Targeting specific immune damage mechanisms of COVID-19, we scored the first to put forward that the responses of T cells induced by acute virus infection result in “acute T-cell exhaustion” in elderly patients, which is not only the peripheral exhaustion with quantity reduction and dysfunction of T cells but also the central exhaustion that central immune organs lost immune homeostasis over peripheral immune organs, whereas the increased thymic output could alleviate the severity and reduce the mortality of the disease with the help of medication. We discovered that immune responses raised by SARS-CoV-2 could also attack secondary lymphoid organs, such as the spleen, lymphoid nodes, and kidneys, in addition to the lung, which we generally recognize. Integrated with the knowledge of mechanisms of immune protection, we developed a coronavirus antigen diagnostic kit and therapeutic monoclonal antibody. In the future, we will further investigate the mechanisms of immune damage and protection raised by coronavirus infection to provide more scientific strategies for developing new vaccines and immunotherapies.
Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia
Authors: Huang Yueting , Zheng Huijian , Zhu Yuwen , Hong Yan , Zha Jie , Lin Zhijuan , Li Zhifeng , Wang Caiyan , Fang Zhihong , Yu Xingxing , Liu Long , Xu Bing
Published: March 2023

Introduction

Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored.

Methods

Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry.

Results

T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1+TIGIT+). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1+TIGIT+ T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4+ T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4+ T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITI+CD8+ T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival.

Discussion

In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.
The prognostic significance of human ovarian aging-related signature in breast cancer after surgery: A multicohort study
Authors: Hua Xin , Zhu Qi-Wei , Zhang Yi-Nuan , Cao Lu , Wang Meng-Di , Gao Yun-Sheng , Chen Jia-Yi
Published: March 2023

Background

Recent studies have shown that ovarian aging is strongly associated with the risk of breast cancer, however, its prognostic impact on breast cancer is not yet fully understood. In this study, we performed a multicohort genetic analysis to explore its prognostic value and biological features in breast cancer.

Methods

The gene expression and clinicopathological data of 3366 patients from the The Cancer Genome Atlas (TCGA) cohort, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort and the GSE86166 cohort were analyzed. A total of 290 ovarian aging-related genes (OARGs) were included in the establishment of the prognostic model. Furthermore, functional mechanisms analysis, drug sensitivity, and immune cell infiltration were investigated using bioinformatic methods.

Results

An eight OARG-based signature was established and validated using independent cohorts. Two risk subgroups of patients with distinct survival outcomes were identified by the OARG-based signature. A nomogram with good predictive performance was developed by integrating the OARG risk score with clinicopathological factors. Moreover, the OARG-based signature was correlated with DNA damage repair, immune cell signaling pathways, and immunomodulatory functions. The patients in the low-risk subgroup were found to be sensitive to traditional chemotherapeutic, endocrine, and targeted agents (doxorubicin, tamoxifen, lapatinib, etc.) and some novel targeted drugs (sunitinib, pazopanib, etc.). Moreover, patients in the low-risk subgroup may be more susceptible to immune escape and therefore respond less effectively to immunotherapy.

Conclusions

In this study, we proposed a comprehensive analytical method for breast cancer assessment based on OARG expression patterns, which could precisely predict clinical outcomes and drug sensitivity of breast cancer patients.
Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome
Authors: Amberger Albert , Pertoll Johanna , Traunfellner Pia , Kapferer-Seebacher Ines , Stoiber Heribert , Klimaschewski Lars , Thielens Nicole , Gaboriaud Christine , Zschocke Johannes
Published: March 2023

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, lack of attached gingiva and thin and fragile gums leading to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. Previously we showed that pEDS pathogenic variants trigger intracellular activation of C1r and/or C1s, leading to extracellular presence of activated C1s. However, the molecular link relating activated C1r and C1s proteases to the dysregulated connective tissue homeostasis in pEDS is unknown. Using cell- and molecular-biological assays, we identified activated C1s (aC1s) as an enzyme which degrades collagen I in cell culture and in in vitro assays. Matrix collagen turnover in cell culture was assessed using labelled hybridizing peptides, which revealed fast and comprehensive collagen protein remodeling in patient fibroblasts. Furthermore, collagen I was completely degraded by aC1s when assays were performed at 40°C, indicating that even moderate elevated temperature has a tremendous impact on collagen I integrity. This high turnover is expected to interfere with the formation of a stable ECM and result in tissues with loose compaction a hallmark of the EDS phenotype. Our results indicate that pathogenesis in pEDS is not solely mediated by activation of the complement cascade but by inadequate C1s-mediated degradation of matrix proteins, confirming pEDS as a primary connective tissue disorder.
Surfactant protein A alters endosomal trafficking of influenza A virus in macrophages
Authors: Yau Eric , Yang Linlin , Chen Yan , Umstead Todd M. , Atkins Hannah , Katz Zoe E. , Yewdell Jonathan W. , Gandhi Chintan K. , Halstead E. Scott , Chroneos Zissis C.
Published: March 2023

Influenza A virus infection (IAV) often leads to acute lung injury that impairs breathing and can lead to death, with disproportionate mortality in children and the elderly. Surfactant Protein A (SP-A) is a calcium-dependent opsonin that binds a variety of pathogens to help control pulmonary infections by alveolar macrophages. Alveolar macrophages play critical roles in host resistance and susceptibility to IAV infection. The effect of SP-A on IAV infection and antiviral response of macrophages, however, is not understood. Here, we report that SP-A attenuates IAV infection in a dose-dependent manner at the level of endosomal trafficking, resulting in infection delay in a model macrophage cell line. The ability of SP-A to suppress infection was independent of its glycosylation status. Binding of SP-A to hemagglutinin did not rely on the glycosylation status or sugar binding properties of either protein. Incubation of either macrophages or IAV with SP-A slowed endocytic uptake rate of IAV. SP-A interfered with binding to cell membrane and endosomal exit of the viral genome as indicated by experiments using isolated cell membranes, an antibody recognizing a pH-sensitive conformational epitope on hemagglutinin, and microscopy. Lack of SP-A in mice enhanced IFNβ expression, viral clearance and reduced mortality from IAV infection. These findings support the idea that IAV is an opportunistic pathogen that co-opts SP-A to evade host defense by alveolar macrophages. Our study highlights novel aspects of host-pathogen interactions that may lead to better understanding of the local mechanisms that shape activation of antiviral and inflammatory responses to viral infection in the lung.
Development of sustainable high performance geopolymer concrete and mortar using agricultural biomass—A strength performance and sustainability analysis
Authors: Nagaraju T. Vamsi , Bahrami Alireza , Azab Marc , Naskar Susmita
Published: March 2023

Geopolymer concrete is a sustainable substitute for traditional Portland cement concrete. In addition, rising carbon taxes on carbon emissions and energy-intensive materials like cement and lime, impacts the cost of industrial by-products due to their pozzolanic nature. This research evaluates the compressive strength and flexural strength of geopolymer concrete, and the compressive strength of geopolymer mortar. Geopolymer mortar data were used for the strength assessment employing an analytical approach, and geopolymer concrete data were utilized for the strength and sustainability performances. Using artificial neural networks (ANNs), multi-linear regression (MPR) analysis, and swarm-assisted linear regression, compressive strength models were created based on experimental datasets of geopolymer mortar mixes with variable precursors, alkali-activator percentages, Si/Al, and Na/Al ratios. The strength and sustainability performances of geopolymer concrete blends with various precursors were assessed by considering cost-efficiency, energy efficiency, and eco-efficiency. The work’s originality comes from enhancing sustainable high-performance concrete without overestimating or underestimating precursors. Extensive experimental work was done in the current study to determine the best mix of geopolymer concrete by varying silica fume, ground granulated blast furnace slag (GGBS), and rice husk ash (RHA). A scanning electron microscopic study was conducted to understand the geopolymer matrix’s microstructure further. A comprehensive discussion section is presented to explain the potential role of RHA. The replacement of conventional concrete in all its current uses may be made possible by this sustainable high-performance concrete utilizing RHA.
In silico evaluation of the mechanical stimulation effect on the regenerative rehabilitation for the articular cartilage local defects
Authors: Popov Valentin L. , Poliakov Aleksandr M. , Pakhaliuk Vladimir I.
Published: March 2023

Osteoarthritis is one of the most severe diseases of the human musculoskeletal system, and therefore, for many years, special attention has been paid to the search for effective methods of its treatment. However, even the most modern methods only in a limited number of cases in the early or intermediate stages of osteoarthritis lead to positive treatment results. In the later stages of development, osteoarthritis is practically incurable and most often ends with disability or the need for joint replacement for a large number of people. One of the main reasons hindering the development of osteoarthritis treatment methods is the peculiarities of articular cartilage, in which there is practically no vascular network and tissue homeostasis is carried out mainly due to the diffusion of nutrients present in the synovial fluid. In modern medicine, for the treatment of osteoarthritis, tissue engineering strategies have been developed based on the implantation of scaffolds populated with chondrogenic cells into the area of the defect. In vitro studies have established that these cells are highly mechanosensitive and, under the influence of mechanical stimuli of a certain type and intensity, their ability to proliferate and chondrogenesis increases. This property can be used to improve the efficiency of regenerative rehabilitation technologies based on the synergistic combination of cellular technologies, tissue engineering strategies, and mechanical tissue stimulation. In this work, using a regenerative rehabilitation mathematical model of local articular cartilage defects, numerical experiments were performed, the results of which indicate that the micro-and macro environment of the restored tissue, which changes during mechanical stimulation, has a significant effect on the formation of the extracellular matrix, and, consequently, cartilage tissue generally. The results obtained can be used to plan strategies for mechanical stimulation, based on the analysis of the results of cell proliferation experimental assessment after each stimulation procedure in vivo.
Establishment of an unfed strain of Paramecium bursaria and analysis of associated bacterial communities controlling its proliferation
Authors: Himi Eiko , Miyoshi-Akiyama Tohru , Matsushima Yuri , Shiono Iru , Aragane Seiji , Hirano Yui , Ikeda Gaku , Kitaura Yuki , Kobayashi Kyohei , Konno Daichi , Morohashi Ayata , Noguchi Yui , Ominato Yuka , Shinbo Soma , Suzuki Naruya , Takatsuka Kurama , Tashiro Hitomi , Yamada Yoki , Yamashita Kenya , Yoshino Natsumi , Kitashima Masaharu , Kotani Susumu , Inoue Kazuhito , Hino Akiya , Hosoya Hiroshi
Published: March 2023

The ciliate Paramecium bursaria harbors several hundred symbiotic algae in its cell and is widely used as an experimental model for studying symbiosis between eukaryotic cells. Currently, various types of bacteria and eukaryotic microorganisms are used as food for culturing P. bursaria; thus, the cultivation conditions are not uniform among researchers. To unify cultivation conditions, we established cloned, unfed strains that can be cultured using only sterile medium without exogenous food. The proliferation of these unfed strains was suppressed in the presence of antibiotics, suggesting that bacteria are required for the proliferation of the unfed strains. Indeed, several kinds of bacteria, such as Burkholderiales, Rhizobiales, Rhodospirillales, and Sphingomonadales, which are able to fix atmospheric nitrogen and/or degrade chemical pollutants, were detected in the unfed strains. The genetic background of the individually cloned, unfed strains were the same, but the proliferation curves of the individual P. bursaria strains were very diverse. Therefore, we selected multiple actively and poorly proliferating individual strains and compared the bacterial composition among the individual strains using 16S rDNA sequencing. The results showed that the bacterial composition among actively proliferating P. bursaria strains was highly homologous but different to poorly proliferating strains. Using unfed strains, the cultivation conditions applied in different laboratories can be unified, and symbiosis research on P. bursaria will make great progress.
Development of a food preservative from sea buckthorn together with chitosan: Application in and characterization of fresh-cut lettuce storage
Authors: Feng Kexin , Feng Xiaolin , Tan Weijian , Zheng Qinhua , Zhong Wenting , Liao Caiyu , Liu Yuntong , Li Shangjian , Hu Wenzhong
Published: March 2023

The purpose was to create a novel composite food preservative for fresh-cut lettuce using flavonoids and chitosan from sea buckthorn leaves (SBL). Sea buckthorn leaves were extracted with ethanol as the extraction solvent and ultrasonic-assisted extraction to obtain flavonoid from sea buckthorn leaf crude (FSL), and then the FSL was secondarily purified with AB-8 resin and polyamide resin to obtain flavonoid from sea buckthorn leaf purified (FSL-1). Different concentrations of FSL-1 and chitosan were made into a composite preservative (FCCP) by magnetic stirring and other methods, containing 1% chitosan preservative (CP) alone, 0.5–2 mg/ml of FSL-1 and 1% chitosan composite preservative (FCCP-1, FCCP-2, FCCP-3, and FCCP-4), and the FSL-1 concentrations were analyzed the effect of FSL-1 concentration on the physicochemical properties of the composite preservatives, including their film-forming ability, antioxidant capacity and ability to prevent bacterial growth, was analyzed. To further investigate the effect of the combined preservatives on fresh-cut lettuce, different FCCPs were applied to the surface was stored at 4°C for 7 days. Then the changes in weight loss, hardness, browning index, total chlorophyll content, SOD and MDA were analyzed. It was used to assess the physicochemical indicators of fresh-cut lettuce throughout storage. According to the results of Fourier transform infrared spectroscopy, FSL-1 and chitosan interacted to form hydrogen bonds, and the contact angle and viscosity of FCCP increased on both horizontal glass and polystyrene plates, indicating the good film-forming properties of the composite preservation solution. With the diameter of the antibacterial zone of Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Listeria monocytogenes being (21.39 ± 0.22), (17.43 ± 0.24), (15.30 ± 0.12), and (14.43 ± 0.24) mm, respectively. It was proved that the antibacterial activity of FCCP became stronger with the increase of FSL-1 concentration and had the best antibacterial effect on S. aureus. The complex preservative showed the best scavenging effect on ferric reducing antioxidant capacity, DPPH radicals (96.64%) and 2,2’-Azinobis- (3-ethylbenzthiazoline-6-sulphonate) (ABTS) radicals (99.42%) when FSL-1 was added at 2 mg/ml. When fresh-cut lettuce was coated with FCCP for the same storage time, various indicators of lettuce such as weight loss, hardness, browning index, SOD activity and MDA content were better than the control group showing good potential in fresh-cut vegetables and fruits preservation. FCCP holds great promise for food safety quality and shelf-life extension as a new natural food preservative. The waste utilization of sea buckthorn leaves can greatly improve his utilization and economic benefits.
Improvement influenza vaccine immune responses with traditional Chinese medicine and its active ingredients
Authors: Zhao Danping , Chen Xiuhong , Wang Linyuan , Zhang Jianjun , Lv Ruilin , Tan Lingyun , Chen Yawen , Tao Ran , Li Xinyu , Chen Yan , He Wei , He Jing
Published: March 2023

The current influenza vaccines are unable to provide effective protection in many cases, like influenza viruses strain antigenic drift or shift, and the influenza continues to cause significant annual morbidity and mortality. Improving the immune response to influenza vaccination is an unmet need. Traditional Chinese medicine (TCM) and its active ingredients are commonly known to have immunomodulatory properties. We therefore compared influenza vaccination alone or formulated with Astragali Radix (Huangqi in Chinese), and several representative ingredients of TCM, including lentinan (polysaccharide), panax notoginseng saponins (saponin), breviscapine (flavone), andrographolide (terpenoid), and a Chinese herbal compound (kangai) for their potential to enhance immune responses to influenza vaccine in mice. We found that all these TCM-adjuvants were able to increase hemagglutination inhibition (HAI) antibody titers, splenocyte proliferation, splenic T cell differentiation, bone marrow dendritic cell maturity, and both Th1 and Th2 cytokine secretion of influenza vaccine to varying degrees, and that had the characteristics of no excessive inflammatory responses and bidirectional regulation simultaneously. Taken together, our findings show that Astragali Radix exerts a more comprehensive effect on vaccine immunity, on both innate and adaptive immunity. The effects of lentinan and andrographolide on adaptive immunity were more significant, while the effects of breviscapine on innate immunity were stronger, and the other two TCM adjuvants were weaker. As the first report of a comprehensive evaluation of TCM adjuvants in influenza vaccines, the results suggest that TCM and their active ingredients are good candidates for enhancing the immune response of influenza vaccines, and that suitable TCMs can be selected based on the adjuvant requirements of different vaccines.
The occurrence, characteristics, and adaptation of A-to-I RNA editing in bacteria: A review
Authors: Liao Weixue , Nie Wenhan , Ahmad Iftikhar , Chen Gongyou , Zhu Bo
Published: March 2023

A-to-I RNA editing is a very important post-transcriptional modification or co-transcriptional modification that creates isoforms and increases the diversity of proteins. In this process, adenosine (A) in RNA molecules is hydrolyzed and deaminated into inosine (I). It is well known that ADAR (adenosine deaminase acting on RNA)-dependent A-to-I mRNA editing is widespread in animals. Next, the discovery of A-to-I mRNA editing was mediated by TadA (tRNA-specific adenosine deaminase) in Escherichia coli which is ADAR-independent event. Previously, the editing event S128P on the flagellar structural protein FliC enhanced the bacterial tolerance to oxidative stress in Xoc. In addition, the editing events T408A on the enterobactin iron receptor protein XfeA act as switches by controlling the uptake of Fe3+ in response to the concentration of iron in the environment. Even though bacteria have fewer editing events, the great majority of those that are currently preserved have adaptive benefits. Interestingly, it was found that a TadA-independent A-to-I RNA editing event T408A occurred on xfeA, indicating that there may be other new enzymes that perform a function like TadA. Here, we review recent advances in the characteristics, functions, and adaptations of editing in bacteria.
Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation
Authors: Samad Abdus , Ajmal Amar , Mahmood Arif , Khurshid Beenish , Li Ping , Jan Syed Mansoor , Rehman Ashfaq Ur , He Pei , Abdalla Ashraf N. , Umair Muhammad , Hu Junjian , Wadood Abdul
Published: March 2023

The new coronavirus SARS-COV-2, which emerged in late 2019 from Wuhan city of China was regarded as causing agent of the COVID-19 pandemic. The primary protease which is also known by various synonymous i.e., main protease, 3-Chymotrypsin-like protease (3CLPRO) has a vital role in the replication of the virus, which can be used as a potential drug target. The current study aimed to identify novel phytochemical therapeutics for 3CLPRO by machine learning-based virtual screening. A total of 4,000 phytochemicals were collected from deep literature surveys and various other sources. The 2D structures of these phytochemicals were retrieved from the PubChem database, and with the use of a molecular operating environment, 2D descriptors were calculated. Machine learning-based virtual screening was performed to predict the active phytochemicals against the SARS-CoV-2 3CLPRO. Random forest achieved 98% accuracy on the train and test set among the different machine learning algorithms. Random forest model was used to screen 4,000 phytochemicals which leads to the identification of 26 inhibitors against the 3CLPRO. These hits were then docked into the active site of 3CLPRO. Based on docking scores and protein-ligand interactions, MD simulations have been performed using 100 ns for the top 5 novel inhibitors, ivermectin, and the APO state of 3CLPRO. The post-dynamic analysis i.e,. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis reveal that our newly identified phytochemicals form significant interactions in the binding pocket of 3CLPRO and form stable complexes, indicating that these phytochemicals could be used as potential antagonists for SARS-COV-2.
Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts
Authors: Qin Jun , Ma Zhihui , Chen Xiaoli , Shu Shiyu
Published: March 2023

Microglia are the principal resident immune cells in the central nervous system (CNS) and play important roles in the development of CNS disorders. In recent years, there have been significant developments in our understanding of microglia, and we now have greater insight into the temporal and spatial patterns of microglia activation in a variety of CNS disorders, as well as the interactions between microglia and neurons. A variety of signaling pathways have been implicated. However, to date, all published clinical trials have failed to demonstrate efficacy over placebo. This review summarizes the results of recent important studies and attempts to provide a mechanistic view of microglia activation, inflammation, tissue repair, and CNS disorders.
Corticospinal interface to restore voluntary control of joint torque in a paralyzed forearm following spinal cord injury in non-human primates
Authors: Obara Kei , Kaneshige Miki , Suzuki Michiaki , Yokoyama Osamu , Tazoe Toshiki , Nishimura Yukio
Published: March 2023

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected “linked neuron” in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury.
Style attention based global-local aware GAN for personalized facial caricature generation
Authors: Zhao Xiuzhi , Chen Wenting , Xie Weicheng , Shen Linlin
Published: March 2023

Introduction

Caricature is an exaggerated pictorial representation of a person, which is widely used in entertainment and political media. Recently, GAN-based methods achieved automatic caricature generation through transferring caricature style and performing shape exaggeration simultaneously. However, the caricature synthesized by these methods cannot perfectly reflect the characteristics of the subject, whose shape exaggeration are not reasonable and requires facial landmarks of caricature. In addition, the existing methods always produce the bad cases in caricature style due to the simpleness of their style transfer method.

Methods

In this paper, we propose a Style Attention based Global-local Aware GAN to apply the characteristics of a subject to generate personalized caricature. To integrate the facial characteristics of a subject, we introduce a landmark-based warp controller for personalized shape exaggeration, which employs the facial landmarks as control points to warp image according to its facial features, without requirement of the facial landmarks of caricature. To fuse the facial feature with caricature style appropriately, we introduce a style-attention module, which adopts an attention mechanism, instead of the simple Adaptive Instance Normalization (AdaIN) for style transfer. To reduce the bad cases and increase the quality of generated caricatures, we propose a multi-scale discriminator to both globally and locally discriminate the synthesized and real caricature, which improves the whole structure and realistic details of the synthesized caricature.

Results

Experimental results on two publicly available datasets, the WebCaricature and the CaVINet datasets, validate the effectiveness of our proposed method and suggest that our proposed method achieves better performance than the existing methods.

Discussion

The caricatures generated by the proposed method can not only preserve the identity of input photo but also the characteristic shape exaggeration for each person, which are highly close to the real caricatures drawn by real artists. It indicates that our method can be adopted in the real application.
A novel feature of the ancient organ: A possible involvement of the subcommissural organ in neurogenic/gliogenic potential in the adult brain
Authors: Inada Hitoshi , Corales Laarni Grace , Osumi Noriko
Published: March 2023

The subcommissural organ (SCO) is a circumventricular organ highly conserved in vertebrates from Cyclostomata such as lamprey to mammals including human. The SCO locates in the boundary between the third ventricle and the entrance of the aqueduct of Sylvius. The SCO functions as a secretory organ producing a variety of proteins such as SCO-spondin, transthyretin, and basic fibroblast growth factor (FGF) into the cerebrospinal fluid (CSF). A significant contribution of the SCO has been thought to maintain the homeostasis of CSF dynamics. However, evidence has shown a possible role of SCO on neurogenesis in the adult brain. This review highlights specific features of the SCO related to adult neurogenesis, suggested by the progress of understanding SCO functions. We begin with a brief history of the SCO discovery and continue to structural features, gene expression, and a possible role in adult neurogenesis suggested by the SCO transplant experiment.
Comprehensive identification of key compounds in different quality grades of soy sauce-aroma type baijiu by HS-SPME-GC-MS coupled with electronic nose
Authors: Wu Junhai , Chen Renyuan , Li Xiaobo , Fu Zheyang , Xian Chun , Zhao Wenwu , Zhao Cheng , Wu Xinying
Published: March 2023

In the production of soy sauce-aroma type baijiu (SSAB), the quality of base liquor significantly affects the finished liquor’s quality. Moreover, low-quality liquor may cause health problems. The different quality grades of base liquor were analyzed to investigate the relationship between the quality and the key compounds in SSAB. In this study, samples were evaluated by the sensory and further analyzed by headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) coupled with electronic nose (E-nose). First, by sensory evaluation, the sauce, floral and fruity, fermented aromas and taste indicators (softness, fullness, harmony, purity and persistence) were positively correlated with the quality grade of the base liquor. The E-nose could distinguish the different quality grades of base liquor well. Second, differential compounds were identified via untargeted metabolome based on the HS-SPME-GC-MS. 16 common differential compounds were shared in the base liquor from different fermentation rounds, including 11 esters, 1 alcohol, 2 aldehydes and 2 ketones. It was found that the higher the quality grade of the base liquor, the richer the content of aromatics, alcohols, aldehydes and ketones. The principal component analysis (PCA) biplots of the differential compounds in the different quality grades of base liquor indicated that the superior-grade base liquor has a strong fruity aroma. By correlation analysis of the differential compounds and sensors responses of E-nose, furfuryl ethyl ether, butanoic acid ethyl ester, isopentyl hexanoate, nonanoic acid ethyl ester and 3-methyl-1-butanol had a significant effect on the response intensity of E-nose sensors. In the present study, the key differential compounds between the different quality grades of base liquor were identified, and the sensory differences between the base liquor were digitized.
Effect of intensity modulated radiotherapy on lymphocytes in patients with esophageal squamous cell carcinoma and its clinical significance
Authors: Tian Xiufang , Hou Yong , Guo Jianping , Wu Haiyan , Nie Limin , Wang Hang , Zhang Yan , Lv Yajuan
Published: March 2023

Background

Radiotherapy usually leads to a decrease in the total number of lymphocytes in patients with esophageal cancer. The factors that causing lymphopenia and the clinical significance of lymphopenia are studied in this article.

Patients and methods

110 patients with esophageal squamous cell carcinoma who had undergo intensity-modulated radiation therapy were enrolled. Statistical methods were used to analyze the correlation between lymphopenia and total survival in patients with esophageal cancer during radiotherapy, and analyze the correlations between nutritional factors and lymphopenia.

Results

There were 11 patients with the lowest lymphocyte value with level 1-2 during radiotherapy, accounting for 10% of all the patients, and 110 patients with level 3-4, accounting for 90% of all the patient. In all the enrolled patients, the incidence of lymphocyte nadir G1, G2, G3 and G4 MinALC during radiotherapy accounted for 0.91%, 9.09%, 62.73% and 27.27%, respectively.KM survival analysis showed that the overall survival of patients in the group (MinALC ≤ 0.41×109/L) was significantly lower than that of the patients in the other group (MinALC>0.43×109/L). Nutritional indicators were positively correlated with the decline degree of lymphocytes. The minimal value of lymphocyte can predict the occurrence of grade 3-4 radiation pneumonitis.

Conclusion

Lymphopenia induced by radiotherapy can predict survival and radiation pneumonitis. Nutritional factors such as hemoglobin and albumin were positively correlated with total lymphocytes numbers induced by radiotherapy.
Cross-attention multi-branch CNN using DCE-MRI to classify breast cancer molecular subtypes
Authors: Sun Liang , Tian Haowen , Ge Hongwei , Tian Juan , Lin Yuxin , Liang Chang , Liu Tang , Zhao Yiping
Published: March 2023

Purpose

The aim of this study is to improve the accuracy of classifying luminal or non-luminal subtypes of breast cancer by using computer algorithms based on DCE-MRI, and to validate the diagnostic efficacy of the model by considering the patient’s age of menarche and nodule size.

Methods

DCE-MRI images of patients with non-specific invasive breast cancer admitted to the Second Affiliated Hospital of Dalian Medical University were collected. There were 160 cases in total, with 84 cases of luminal type (luminal A and luminal B and 76 cases of non-luminal type (HER 2 overexpressing and triple negative). Patients were grouped according to thresholds of nodule sizes of 20 mm and age at menarche of 14 years. A cross-attention multi-branch net CAMBNET) was proposed based on the dataset to predict the molecular subtypes of breast cancer. Diagnostic performance was assessed by accuracy, sensitivity, specificity, F1 and area under the ROC curve (AUC). And the model is visualized with Grad-CAM.

Results

Several classical deep learning models were included for diagnostic performance comparison. Using 5-fold cross-validation on the test dataset, all the results of CAMBNET are significantly higher than the compared deep learning models. The average prediction recall, accuracy, precision, and AUC for luminal and non-luminal types of the dataset were 89.11%, 88.44%, 88.52%, and 96.10%, respectively. For patients with tumor size <20 mm, the CAMBNET had AUC of 83.45% and ACC of 90.29% for detecting triple-negative breast cancer. When classifying luminal from non-luminal subtypes for patients with age at menarche years, our CAMBNET model achieved an ACC of 92.37%, precision of 92.42%, recall of 93.33%, F1of 92.33%, and AUC of 99.95%.

Conclusions

The CAMBNET can be applied in molecular subtype classification of breasts. For patients with menarche at 14 years old, our model can yield more accurate results when classifying luminal and non-luminal subtypes. For patients with tumor sizes ≤20 mm, our model can yield more accurate result in detecting triple-negative breast cancer to improve patient prognosis and survival.
The progress of radiomics in thyroid nodules
Authors: Gao XiaoFan , Ran Xuan , Ding Wei
Published: March 2023

Due to the development of Artificial Intelligence (AI), Machine Learning (ML), and the improvement of medical imaging equipment, radiomics has become a popular research in recent years. Radiomics can obtain various quantitative features from medical images, highlighting the invisible image traits and significantly enhancing the ability of medical imaging identification and prediction. The literature indicates that radiomics has a high potential in identifying and predicting thyroid nodules. So in this article, we explain the development, definition, and workflow of radiomics. And then, we summarize the applications of various imaging techniques in identifying benign and malignant thyroid nodules, predicting invasiveness and metastasis of thyroid lymph nodes, forecasting the prognosis of thyroid malignancies, and some new advances in molecular level and deep learning. The shortcomings of this technique are also summarized, and future development prospects are provided.
Treatment selection for patients with relapsed or refractory follicular lymphoma
Authors: Skarbnik Alan Z. , Patel Krish
Published: March 2023

Follicular lymphoma (FL) is the second most common lymphoma in the United States and is characterized by a variable clinical course, disease heterogeneity, and a relapse-and-remittance pattern historically accompanied by successive shortening of clinical response with every line of treatment. Factors such as progression of disease within 24 months of initial treatment are associated with poor survival outcomes. Although rituximab-based regimens are preferred for early lines of treatment, no clear standard of care exists for treatment of FL in the third-line setting or later as approved third-line treatments have not been compared in a prospective, randomized clinical trial. Rather, physicians may choose from several therapeutic classes with different safety profiles and dosing regimens, with consideration of patient and disease factors. Here we describe 2 hypothetical patients with relapsing or remitting FL, an elderly patient with comorbidities, and a younger patient whose FL progressed within 24 months. These cases are used to highlight key factors that clinicians should consider when selecting therapies for relapsed or refractory FL, such as patient frailty, age, comorbidities, as well as quality of life and patient-specific preferences for less intrusive treatment regimens or longer remission times.
Case report: Low-grade myofibroblastic sarcoma resembling lymphoma on 18F-FDG PET/CT
Authors: Zhang Huan , He Liu , Hu Bin , Zhang Xiaoming , Zheng Lichun
Published: March 2023

Low-grade myofibroblastic sarcoma is a rare malignant tumor that arises from mesenchymal tissue and affects the head (particularly the tongue and oral cavity) and neck. It is characterized by local recurrence, with metastases being uncommon. We present a 72-year-old man who initially complained of a painless and progressive mass in the right inguinal region and came for consultation, and a malignant tumor was suspected based on the clinical and pelvic MRI manifestations. The 18F-FDG PET/CT revealed that the multiple lesions were located in the mediastinum, retroperitoneum, pelvis, and inguinal lymph nodes; hence, lymphoma was considered to be a combination of the symptoms. However, the histology of the ultrasound-guided puncture indicated low-grade myofibroblastic sarcoma. The patient was next administered chemotherapy, but the lesions did not undergo remission.