bluuebunny/crossref_metadata_2025 huggingface dataset:
T-BET drives the conversion of human type 3 innate lymphoid cells into functional NK cells
Authors: Kiekens Laura , Wahlen Sigrid , Persyn Eva , De Vos Zenzi , Taghon Tom , Vandekerckhove Bart , Leclercq Georges
Published: October 2022

Type 3 innate lymphoid cells (ILC3s) are characterized by RORγt expression and they produce IL-22 upon activation. ILC3s play a role in maintenance of barrier integrity in the intestine. Under inflammatory conditions, the ILC composition of the mucosal tissues is altered due to a high degree of plasticity. It has been extensively demonstrated that both murine and human ILC3s convert into ILC1s to mediate appropriate immune responses. However, plasticity between human ILC3s and NK cells is less well documented. As T-BET and EOMES are key transcription factors in NK cell differentiation, we investigated whether ectopic T-BET or EOMES expression converts human ILC3s into NK cells. ILC3s with ectopic T-BET and EOMES expression downregulate RORγt expression, while T-BET-overexpressing ILC3s additionally upregulate EOMES expression. High E ctopic T-BET expression in ILC3s results in transdifferentiation towards CD94+ NK cells, whereas ectopic EOMES overexpression results in dedifferentiation of ILC3s into CD94-CD117-/low cells but is ineffective in NK cell generation. Dedifferentiating ILC3s from both T-BET and EOMES overexpression cultures upregulate NK cell receptors, perforin and granzyme B. Finally, IL-22 secretion is completely blocked in transdifferentiating ILC3s with both T-BET and EOMES ectopic expression, whereas only T-BET overexpression increases IFN-γ secretion and cytotoxicity. Altogether, these findings demonstrate that human ILC3s can convert into functional NK cells, wherein T-BET, and not EOMES, is the main driver.
The IgG glycome of SARS-CoV-2 infected individuals reflects disease course and severity
Authors: Siekman Sterre L. , Pongracz Tamas , Wang Wenjun , Nouta Jan , Kremsner Peter G. , da Silva-Neto Pedro Vieira , Esen Meral , Kreidenweiss Andrea , Held Jana , Trapé Átila Alexandre , Fendel Rolf , de Miranda Santos Isabel Kinney Ferreira , Wuhrer Manfred ,   ImmunoCovid Consortium
Published: October 2022

Immunoglobulin G (IgG) antibodies play an important role in the immune response against viruses such as SARS-CoV-2. As the effector functions of IgG are modulated by N-glycosylation of the Fc region, the structure and possible function of the IgG N-glycome has been under investigation in relation to divergent COVID-19 disease courses. Through LC-MS analysis we studied both total IgG1 and spike protein-specific IgG1 Fc glycosylation of 129 German and 163 Brazilian COVID-19 patients representing diverse patient populations. We found that hospitalized COVID-19 patients displayed decreased levels of total IgG1 bisection and galactosylation and lowered anti-S IgG1 fucosylation and bisection as compared to mild outpatients. Anti-S IgG1 glycosylation was dynamic over the disease course and both anti-S and total IgG1 glycosylation were correlated to inflammatory markers. Further research is needed to dissect the possible role of altered IgG glycosylation profiles in (dys)regulating the immune response in COVID-19.
Maternal nutrients and 15N Leucine tracing in Sebastes schlegelii
Authors: Du Tengfei , Xiao Yongshuang , Liu Qinghua , Guo Teng , Gao Guang , Li Jun
Published: October 2022

Sebastes schlegelii is a commercially important fishery resource that is also a representative viviparous fish species in the Northeast Asian Sea. The mode of nutritional supply of embryos fertilized and developed in vivo is not clear. To screen biomarkers for nutrient transfer between mother and embryo, we studied the composition of and changes in maternal plasma at different developmental stages. The results showed that the plasma of S. schlegelii was rich in nutrients, including 16 hydrolysed amino acids, 20 fatty acids, glucose and fructose. The contents of amino acids in the plasma reached 3.44-4.58 g/100 g, which is approximately 3-5 times that of fatty acids and 44-155 times that of sugar. Thirteen amino acids, 15 fatty acids and glucose showed an increasing trend in the early stage of embryonic development and a decreasing trend in the later stage. The contents of leucine, as an essential amino acid in early development, changed significantly in maternal blood and was therefore selected as a biomarker. The results of isotope labelling showed that 15N leucine was not detected in the eggs, gastrula embryos or organogenesis embryos, but a high abundance of 14N leucine was detected in the eggs and embryos of the control and experimental groups, indicating that leucine, an essential amino acid for aquatic animals, plays an important role in gamete and embryo development. An abundance in 15N-labelled leucine was detected in the embryonic blood and ovarian villi but not in the embryos, which indicates that the ample free naturally abundant leucine in maternal blood during the middle and late developmental stages of the eggs and embryos was not absorbed or utilized. These results showed that eggs and embryos had certain autonomy and selectivity when absorbing nutrients and gave priority to the active transport of certain complex macromolecular nutrients that could meet their needs for a variety of nutrients at the same time.
Designing a novel chimeric multi-epitope vaccine against Burkholderia pseudomallei, a causative agent of melioidosis
Authors: Alsowayeh Noorah , Albutti Aqel
Published: October 2022

Burkholderia pseudomallei, a gram-negative soil-dwelling bacterium, is primarily considered a causative agent of melioidosis infection in both animals and humans. Despite the severity of the disease, there is currently no licensed vaccine on the market. The development of an effective vaccine against B. pseudomallei could help prevent the spread of infection. The purpose of this study was to develop a multi-epitope-based vaccine against B. pseudomallei using advanced bacterial pan-genome analysis. A total of four proteins were prioritized for epitope prediction by using multiple subtractive proteomics filters. Following that, a multi-epitopes based chimeric vaccine construct was modeled and joined with an adjuvant to improve the potency of the designed vaccine construct. The structure of the construct was predicted and analyzed for flexibility. A population coverage analysis was performed to evaluate the broad-spectrum applicability of B. pseudomallei. The computed combined world population coverage was 99.74%. Molecular docking analysis was applied further to evaluate the binding efficacy of the designed vaccine construct with the human toll-like receptors-5 (TLR-5). Furthermore, the dynamic behavior and stability of the docked complexes were investigated using molecular dynamics simulation, and the binding free energy determined for Vaccine-TLR-5 was delta total −168.3588. The docking result revealed that the vaccine construct may elicit a suitable immunological response within the host body. Hence, we believe that the designed in-silico vaccine could be helpful for experimentalists in the formulation of a highly effective vaccine for B. pseudomallei.
Fire blight resistance, irrigation and conducive wet weather improve Erwinia amylovora winter survival in cankers
Authors: Santander Ricardo D. , Khodadadi Fatemeh , Meredith Christopher L. , Rađenović Željko , Clements Jon , Aćimović Srđan G.
Published: October 2022

Erwinia amylovora causes fire blight, a disease responsible for enormous economic losses in the pome fruit-producing areas where it is present. Despite the abundant research on fire blight, information about E. amylovora population dynamics and survival in fire blight cankers and the plant defense responses to this pathogen in the infected bark are limited. In our study, we obtained fire blight cankers in apple, pear, and Asian pear cultivars showing differing resistance to the disease by shoot inoculation with E. amylovora. We collected cankers from irrigated and non-irrigated trees every 3 months in two independent field experiments and analyzed samples by viability digital PCR. We also assessed the expression of pathogenicity-related (PR) genes in the bark of selected apple and Asian pear cultivars. A logistic regression analysis revealed the impact of environmental and host factors on E. amylovora detection rates in cankers. The chances of detecting live E. amylovora cells in cankers increased significantly in those collected from irrigated trees, in July, and/or during an experiment performed in a year with an expected average rainfall when compared to samples from non-irrigated trees, collected in January, and/or during an experiment performed under environmental conditions dominated by drought. We found a positive correlation between the pathogen detection rates in cankers and the host resistance to fire blight that might be explained by lower E. amylovora survival rates in more damaged tissues of susceptible hosts. The genes PR-1, PR-2, PR-5, and PR-8 were induced in the bark surrounding apple and Asian pear fire blight cankers. Our study, involving the analysis of more than 800 canker samples, provides new knowledge about the fire blight disease cycle and lays the foundation for improved fire blight management and eradication strategies in pome fruit orchards.
PINet 1.0: A pathway network-based evaluation of drug combinations for the management of specific diseases
Authors: Hong Yongkai , Chen Dantian , Jin Yaqing , Zu Mian , Zhang Yin
Published: October 2022

Drug combinations can increase the therapeutic effect by reducing the level of toxicity and the occurrence of drug resistance. Therefore, several drug combinations are often used in the management of complex diseases. However, due to the exponential growth in drug development, it would be impractical to evaluate all combinations through experiments. In view of this, we developed Pathway Interaction Network (PINet) biological model to estimate the optimal drug combinations for various diseases. The random walk with restart (RWR) algorithm was used to capture the “disease state” and “drug state,” while PINet was used to evaluate the optimal drug combinations and the high-order drug combination1. The model achieved a mean area under the curve of a receiver operating characteristic curve of 0.885. In addition, for some diseases, PINet predicted the optimal drug combination. For example, in the case of acute myeloid leukemia, PINet correctly predicted midostaurin and gemtuzumab as effective drug combinations, as demonstrated by the results of a Phase-I clinical trial. Moreover, PINet also correctly predicted the potential drug combinations for diseases that lacked a training dataset that could not be predicted using standard machine learning models.
Single-gene knockout-coupled omics analysis identifies C9orf85 and CXorf38 as two uncharacterized human proteins associated with ZIP8 malfunction
Authors: Tan Heng Wee , Xu Yan-Ming , Liang Zhan-Ling , Cai Na-Li , Wu Yu-Yao , Lau Andy T. Y.
Published: October 2022

Human transmembrane protein metal cation symporter ZIP8 (SLC39A8) is a member of the solute carrier gene family responsible for intracellular transportation of essential micronutrients, including manganese, selenium, and zinc. Previously, we established a ZIP8-knockout (KO) human cell model using the CRISPR/Cas9 system and explored how the expression of ZIP8 could possibly contribute to a wide range of human diseases. To further assess the biophysiological role of ZIP8, in the current study, we employed isobaric tags for relative and absolute quantitation (iTRAQ) and detected the changes of the proteome in ZIP8-KO cells (proteomic data are available via ProteomeXchange with identifier PXD036680). A total of 286 differentially expressed proteins (206 downregulated and 80 upregulated proteins) were detected in the ZIP8-KO cell model, and subsequent bioinformatics analyses (GO, KEGG, KOG, and PPI) were performed on these proteins. Interestingly, four “uncharacterized” proteins (proteins with unknown biological function) were identified in the differentially expressed proteins: C1orf198, C9orf85, C17orf75, and CXorf38—all of which were under-expressed in the ZIP8-KO cells. Notably, C9orf85 and CXorf38 were amongst the top-10 most downregulated proteins, and their expressions could be selectively induced by essential micronutrients. Furthermore, clinical-based bioinformatic analysis indicated that positive correlations between the gene expressions of ZIP8 and C9orf85 or CXorf38 were observed in multiple cancer types. Overall, this study reveals the proteomic landscape of cells with impaired ZIP8 and uncovers the potential relationships between essential micronutrients and uncharacterized proteins C9orf85 and CXorf38. The differentially expressed proteins identified in ZIP8-KO cells could be the potential targets for diagnosing and/or treating human ZIP8-associated diseases, including but not limited to malnutrition, viral infection, and cancers.
Pre-operative external ventricle drainage improves neurological outcomes for patients with traumatic intracerebellar hematomas
Authors: Wang Bao , Gao Li , Zhang Yu , Su Ming-ming , Shi Wei , Wang Yue , Ge Shun-nan , Zhu Gang , Guo Hao , Gao Fei , Shi Ying-Wu , Cui Wen-xing , Li Zhi-hong , Qu Yan , Wang Xue-Lian
Published: October 2022

Objectives

Traumatic intracerebellar hematoma (TICH) is a very rare entity with a high morbidity and mortality rate, and there is no consensus on its optimal surgical management. In particular, whether and when to place external ventricle drainage in TICH patients without acute hydrocephalus pre-operation is still controversial.

Methods

A single-institutional, retrospective analysis of total of 47 TICH patients with craniectomy hematoma evacuation in a tertiary medical center from January 2009 to October 2020 was performed. Primary outcomes were mortality in hospital and neurological function evaluated by GOS at discharge and 6 months after the ictus. Special attention was paid to the significance of external ventricular drainage (EVD) in TICH patients without acute hydrocephalus on admission.

Results

Analysis of the clinical characteristics of the TICH patients revealed that the odds of use of EVD were seen in patients with IVH, fourth ventricle compression, and acute hydrocephalus. Placement of EVD at the bedside can significantly improve the GCS score before craniotomy, as well as the neurological score at discharge and 6 months. Compared with the only hematoma evacuation (HE) group, there is a trend that EVD can reduce hospital mortality and decrease the occurrence of delayed hydrocephalus, although the difference is not statistically significant. In addition, EVD can reduce the average NICU stay time, but has no effect on the total length of stay. Moreover, our data showed that EVD did not increase the risk of associated bleeding and intracranial infection. Interestingly, in terms of neurological function at discharge and 6 month after the ictus, even though without acute hydrocephalus on admission, the TICH patients can still benefit from EVD insertion.

Conclusion

For TICH patients, perioperative EVD is safe and can significantly improve neurological prognosis. Especially for patients whose GCS dropped by more than 2 points before the operation, EVD can significantly improve the patient's GCS score, reduce the risk of herniation, and gain more time for surgical preparation. Even for TICH patients without acute hydrocephalus on admission CT scan, EVD placement still has positive clinical significance.
The regulatory roles of circular RNAs via autophagy in ischemic stroke
Authors: Li Xiaoqin , Li Lingfei , Si Xiaoli , Zhang Zheng , Ni Zhumei , Zhou Yongji , Liu Keqin , Xia Wenqing , Zhang Yuyao , Gu Xin , Huang Jinyu , Yin Congguo , Shao Anwen , Jiang Lin
Published: October 2022

Ischemic stroke (IS) is a severe disease with a high disability, recurrence, and mortality rates. Autophagy, a highly conserved process that degrades damaged or aging organelles and excess cellular components to maintain homeostasis, is activated during IS. It influences the blood–brain barrier integrity and regulates apoptosis. Circular RNAs (circRNAs) are novel non-coding RNAs involved in IS-induced autophagy and participate in various pathological processes following IS. In addition, they play a role in autophagy regulation. This review summarizes current evidence on the roles of autophagy and circRNA in IS and the potential mechanisms by which circRNAs regulate autophagy to influence IS injury. This review serves as a basis for the clinical application of circRNAs as novel biomarkers and therapeutic targets in the future.
Protective effect of traditional Chinese medicine on non-alcoholic fatty liver disease and liver cancer by targeting ferroptosis
Authors: Wu Qiongbo , Chen Zihao , Ding Yi , Tang Yunting , Cheng Yawei
Published: October 2022

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with high incidence and is closely related to metabolic syndrome. If not controlled, it may eventually become hepatocellular carcinoma (HCC). Ferroptosis, a non-apoptotic form of programmed cell death (PCD), is closely related to NAFLD and HCC, and the mechanisms of action involved are more complex. Some studies have demonstrated that many drugs inhibit ferroptosis and protect liver steatosis or carcinogenesis. The role of Traditional Chinese Medicine (TCM), especially herbs or herbal extracts, has received increasing attention. However, there are relatively few review articles on the regulation of NAFLD by TCM through ferroptosis pathway. Here, we summarize the TCM intervention mechanism and application affecting NAFLD/NAFLD-HCC via regulation of ferroptosis. This article focuses on the relationship between ferroptosis and NAFLD or NAFLD-HCC and the protective effect of TCM on both by targeting ferroptosis. It not only summarizes the mechanism of early prevention and treatment of NAFLD, but also provides reference ideas for the development of TCM for the treatment of metabolic diseases and liver diseases.
The molecular mechanisms underlying neutrophil infiltration in vessel co-opting colorectal cancer liver metastases
Authors: Rada Miran , Hassan Nour , Lazaris Anthoula , Metrakos Peter
Published: October 2022

Colorectal cancer liver metastases (CRCLMs) have two major histopathological growth patterns (HGPs): desmoplastic (DHGP) and replacement (RHGP). The DHGP tumours derive their vasculature by angiogenesis, while the RHGP tumours use vessel co-option. Various studies have associated RHGP tumours with an unfavourable prognosis, as well as high levels of resistance to anti-angiogenic agents and chemotherapy. Recently, we reported higher numbers of neutrophils in the tumour microenvironment (TME) of vessel co-opting tumours compared to their angiogenic counterparts. However, the molecular mechanisms underlying this phenotype are unclear. Herein, we suggested a positive correlation between the expression of angiopoietin-1 (Ang1) in the hepatocytes and the presence of neutrophils in vessel co-opting tumours. Importantly, upregulation of Ang1 in the hepatocytes is associated with the presence of runt-related transcription factor-1 (RUNX1) in the neighboring cancer cells in vitro and in vivo. Altogether, our data suggest the molecular mechanisms by which neutrophils are infiltrated in vessel co-opting CRCLM lesions. This finding may yield novel therapeutic strategies for CRCLM patients in future.
Transanal total mesorectal excision port-assisted perineal hernia repair: A case report
Authors: Peng Xudong , Ge Yinggang , Zhang Jianwen , Wei Zhengqiang , Zhang Hongyu
Published: October 2022

Perineal hernia after abdominoperineal resection (APR) is a troublesome problem, and severe cases require surgical treatment. However, perineal hernia repair is challenging, especially when combined with intestinal adhesions. The difficulty of the operation lies in performing adhesiolysis and mesh placement under poor visibility. While there are traditional, laparoscopic and even robotic methods of performing this procedure, no easy and minimally-invasive approach has been reported. Here, we report the case of a patient with perineal hernia, who underwent transanal total mesorectal excision (TaTME) port-assisted laparoscopic perineal hernia repair. The operation was successful, the postoperative recovery was uneventful, the patient’s symptoms improved significantly, and no recurrence was found during the 4-month follow-up. The availability and safety of TaTME port-assisted perineal hernia repair provide a promising approach for hernia repair. Compared with traditional perineal or laparoscopic abdominal approaches, this procedure is less invasive and results in a better field of vision.
Case report: Ultrasonographic findings of retroperitoneum and abdominal wall metastases of renal cell carcinoma with FH gene deletion
Authors: Zhang Xuhui , Zhang Yue , Li Yongzhong , Shen Pengfei , Liu Zhenghua , Zeng Hao , Zhang Mengni , Chen Ni , Yao Jin , Huang Rui , Cai Diming
Published: October 2022

Renal cell carcinoma with FH gene deletion is a rare subtype of renal cell carcinoma. There had been few reports about ultrasonographic imaging of metastasis of renal cell carcinoma with FH gene deletion. This case reported one of the features of metastasis of renal cell carcinoma with FH gene deletion of a male patient 7 months after undergoing radical nephrectomy. He was diagnosed with a renal malignant tumor before the operation and confirmed to be primary FH gene-deficient renal cell carcinoma after undergoing radical nephrectomy in another hospital. Reexamination 7 months after the operation indicated that multiple metastases all over the body were found; therefore, he came to our hospital for further diagnosis and therapy. The tumors have metastasized in the lungs, bones, and lymph nodes adjacent to the left reproductive vessels and external iliac vessels, retroperitoneum, and abdominal wall so far as confirmed by PET/CT or MRI. Ultrasonographic findings of masses in the retroperitoneum and abdominal wall are fully discussed, which have been confirmed by biopsy and diagnosed as renal cell carcinoma with FH gene deletion by pathology.
Chemotherapy induces feedback up-regulation of CD44v6 in colorectal cancer initiating cells through β-catenin/MDR1 signaling to sustain chemoresistance
Authors: Ghatak Shibnath , Hascall Vincent C. , Karamanos Nikos , Markwald Roger R. , Misra Suniti
Published: October 2022

Chemoresistance in colorectal cancer initiating cells (CICs) involves the sustained activation of multiple drug resistance (MDR) and WNT/β-catenin signaling pathways, as well as of alternatively spliced-isoforms of CD44 containing variable exon-6 (CD44v6). In spite of its importance, mechanisms underlying the sustained activity of WNT/β-catenin signaling have remained elusive. The presence of binding elements of the β-catenin-interacting transcription factor TCF4 in the MDR1 and CD44 promoters suggests that crosstalk between WNT/β-catenin/TCF4-activation and the expression of the CD44v6 isoform mediated by FOLFOX, a first-line chemotherapeutic agent for colorectal cancer, could be a fundamental mechanism of FOLFOX resistance. Our results identify that FOLFOX treatment induced WNT3A secretion, which stimulated a positive feedback loop coupling β‐catenin signaling and CD44v6 splicing. In conjunction with FOLFOX induced WNT3A signal, specific CD44v6 variants produced by alternative splicing subsequently enhance the late wave of WNT/β-catenin activation to facilitate cell cycle progression. Moreover, we revealed that FOLFOX-mediated sustained WNT signal requires the formation of a CD44v6-LRP6-signalosome in caveolin microdomains, which leads to increased FOLFOX efflux. FOLFOX-resistance in colorectal CICs occurs in the absence of tumor-suppressor disabled-2 (DAB2), an inhibitor of WNT/β-catenin signaling. Conversely, in sensitive cells, DAB2 inhibition of WNT-signaling requires interaction with a clathrin containing CD44v6-LRP6-signalosome. Furthermore, full-length CD44v6, once internalized through the caveolin-signalosome, is translocated to the nucleus where in complex with TCF4, it binds to β-catenin/TCF4-regulated MDR1, or to CD44 promoters, which leads to FOLFOX-resistance and CD44v6 transcription through transcriptional-reprogramming. These findings provide evidence that targeting CD44v6-mediated LRP6/β-catenin-signaling and drug efflux may represent a novel approach to overcome FOLFOX resistance and inhibit tumor progression in colorectal CICs. Thus, sustained drug resistance in colorectal CICs is mediated by overexpression of CD44v6, which is both a functional biomarker and a therapeutic target in colorectal cancer.
Cisplatin-based chemotherapy for the treatment of metastatic collecting duct carcinomas: A real-world, retrospective analysis
Authors: Rizzo Mimma , Chiellino Silvia , Gernone Angela , Porta Camillo
Published: October 2022

Collecting duct carcinomas (CDCs) are a particularly rare subtype of kidney cancer, endowed by a particularly poor prognosis. Since no active treatments have been established for CDCs, due to similarities with upper tract urothelial carcinomas, the use of the cisplatin-gemcitabine doublet is usually recommended. Here we report a retrospective analysis of 36 metastatic CDCs treated, as everyday clinical practice, with either cisplatin-gemcitabine or cisplatin-gemcitabine-paclitaxel from 2005 to 2021. Thirty-three patients received gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), while 3 were treated with paclitaxel (80 mg/m2, days 1 and 8), gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), every 21 days for a maximum of 6 cycles. Eight out of 36 patients (22.2%) experienced a partial response, while 9 others (25%) had a disease stabilization. No benefit was observed in the only 3 patients treated with the triplet. Median PFS was just 6 months, while median OS was 8 months. The commonest grade ≥3 treatment-related adverse events were: neutropenia (75%, 11.1% of febrile neutropenia), anemia (50%), thrombocytopenia (38.8%), and vomiting (8.3%). Dose omissions and dose reductions were common, and few frail patients started the treatment with a 25% dose reduction. In conclusion, our real-world experience confirmed the modest activity and relevant toxicity of cisplatin-based chemotherapy for the treatment of CDCs. More translational studies and novel study designs are thus badly needed in these still orphan tumors.
Oncological outcomes of neoadjuvant chemotherapy in patients with resectable synchronous colorectal liver metastasis: A result from a propensity score matching study
Authors: Jiang Yu-Juan , Zhou Si-Cheng , Chen Jing-Hua , Liang Jian-Wei
Published: October 2022

Background

The efficacy and safety of neoadjuvant chemotherapy (NAC) in treating resectable synchronous colorectal liver metastases (CRLM) remain controversial.

Methods

Data from CRLM patients who underwent simultaneous liver resection between January 2015 and December 2019 were collected from the Surveillance, Epidemiology, and End Results (SEER) database (SEER cohort, n=305) and a single Chinese Cancer Center (NCC cohort, n=268). Using a 1:2 ratio of propensity score matching (PSM), the prognostic impact of NAC for patients who underwent NAC before surgical treatment and patients who underwent surgical treatment alone was evaluated.

Results

After PSM, there was no significant difference in overall survival (OS) between patients receiving NAC prior to CRLM resection and those undergoing surgery only, in both the NCC and SEER cohorts (each P > 0.05). Age was an independent predictor of OS only in the SEER cohort (P = 0.040), while the pN stage was an independent predictor for OS only in the NCC cohort (P = 0.002). Furthermore, Disease-free survival (DFS) was comparable between the two groups in the NCC cohort. In a subgroup analysis, the DFS and OS in the NAC- group were significantly worse than those in the NAC+ group for patients with more than two liver metastases in the NCC cohort (P < 0.05 for both).

Conclusion

NAC did not have a significant prognostic impact in patients with resectable synchronous CRLM. However, patients with more than two liver metastases could be good candidates for receiving NAC.
An OX40L mRNA vaccine inhibits the growth of hepatocellular carcinoma
Authors: Deng Zhuoya , Yang Hao , Tian Yuying , Liu Zherui , Sun Fang , Yang Penghui
Published: October 2022

mRNA cancer vaccines show therapeutic potential for malignant tumors, including hepatocellular carcinoma (HCC). We optimized and synthesized stable mRNA encoding costimulator Oxford 40 ligand (OX40L). For systemic delivery, OX40L mRNAs were loaded into lipid nanoparticles (LNPs). The expression and costimulatory effects of OX40L were investigated in vitro. OX40L was expressed on the cell surface and costimulated T cells. In vivo, intratumoral injection of LNPs encapsulating OX40L mRNAs significantly reduced tumor growth and increased the survival of mice bearing H22 tumors. Importantly, CD4+ and CD8+ T cells were significantly increased in the OX40L mRNA group in vivo. Taken together, our findings provide a promising clinical strategy for immunotherapy for HCC using mRNA vaccines.
Multiscale anisotropy analysis of second-harmonic generation collagen imaging of human pancreatic cancer
Authors: Hamilton Joshua , Breggia Anne , Fitzgerald Timothy L. , Jones Michael A. , Brooks Peter C. , Tilbury Karissa , Khalil Andre
Published: October 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a minority (< 10%) of patients surviving five years past diagnosis. This could be improved with the development of new imaging modalities for early differentiation of benign and cancerous fibrosis. This study intends to explore the application of a two-photon microscopy technique known as second harmonic generation to PDAC using the 2D Wavelet Transform Modulus Maxima (WTMM) Anisotropy method to quantify collagen organization in fibrotic pancreatic tissue. Forty slides from PDAC patients were obtained and eight images were captured per each tissue category on each slide. Brownian surface motion and white noise images were generated for calibration and testing of a new variable binning approach to the 2D WTMM Anisotropy method. The variable binning method had greater resistance to wavelet scaling effects and white noise images were found to have the lowest anisotropy factor. Cancer and fibrosis had greater anisotropy factors (Fa) at small wavelet scales than normal and normal adjacent tissue. At a larger scale of 21 μm this relationship changed with normal tissue having a higher Fa than all other tissue groups. White noise is the best representative image for isotropy and the 2D WTMM anisotropy method is sensitive to changes induced in collagen by PDAC.
Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema
Authors: Buntinx F. , Lebeau A. , Gillot L. , Baudin L. , Ndong Penda R. , Morfoisse F. , Lallemand F. , Vottero G. , Nizet C. , Nizet J. L. , Blacher S. , Noel A.
Published: October 2022

Lymphedema (LD) refers to a condition of lymphatic dysfunction associated with excessive fluid accumulation, fibroadipose tissue deposition and swelling. In industrialized countries, LD development mainly results from a local disruption of the lymphatic network by an infection or cancer-related surgery (secondary LD). In the absence of efficient therapy, animal models are needed to decipher the cellular and molecular mechanisms underlying LD and test putative drugs. In this study, we optimized and characterized a murine model of LD that combines an irradiation of the mice hind limb and a radical surgery (lymph node resection associated to lymphatic vessel ligation). We investigated the respective roles of irradiation and surgery in LD formation by comparing their impacts, alone or in combination (with different intervention sequences), on eight different features of the pathology: swelling (paw thickness), indocyanine green (ICG) clearance, lymphatic vasculature remodeling, epidermal and dermal thickening, adipocyte accumulation, inflammatory cell infiltration and collagen deposition. This study supports the importance of radiation prior to surgery to experimentally induce a rapid, severe and sustained tissue remodeling harboring the different hallmarks of LD. We provide the first experimental evidence for an excessive deposition of periostin (POSTN) and tenascin-C (TNC) in LD. Through a computerized method of digital image quantification, we established the spatial map of lymphatic expansion, as well as collagen, POSTN and TNC deposition in papillary and reticular dermis of lymphedematous skins. This mouse model is available to study the patho-physiology of LD and test potential therapeutic targets.
Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis
Authors: Zhao Jie-Feng , Zou Fei-Long , Zhu Jin-Feng , Huang Chao , Bu Fan-Qin , Zhu Zheng-Ming , Yuan Rong-Fa
Published: October 2022

Background: Nano drug delivery system (NDDS) can significantly improve the delivery and efficacy of drugs against pancreatic cancer (PC) in many ways. The purpose of this study is to explore the related research fields of NDDS for PC from the perspective of bibliometrics.

Methods: Articles and reviews on NDDS for PC published between 2003 and 2022 were obtained from the Web of Science Core Collection. CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel were comprehensively used for bibliometric and visual analysis.

Results: A total of 1329 papers on NDDS for PC were included. The number of papers showed an upward trend over the past 20 years. The United States contributed the most papers, followed by China, and India. Also, the United States had the highest number of total citations and H-index. The institution with the most papers was Chinese Acad Sci, which was also the most important in international institutional cooperation. Professors Couvreur P and Kazuoka K made great achievements in this field. JOURNAL OF CONTROLLED RELEASE published the most papers and was cited the most. The topics related to the tumor microenvironment such as “tumor microenvironment”, “tumor penetration”, “hypoxia”, “exosome”, and “autophagy”, PC treatment-related topics such as “immunotherapy”, “combination therapy”, “alternating magnetic field/magnetic hyperthermia”, and “ultrasound”, and gene therapy dominated by “siRNA” and “miRNA” were the research hotspots in the field of NDDS for PC.

Conclusion: This study systematically uncovered a holistic picture of the performance of NDDS for PC-related literature over the past 20 years. We provided scholars to understand key information in this field with the perspective of bibliometrics, which we believe may greatly facilitate future research in this field.
Platelets and platelet extracellular vesicles in drug delivery therapy: A review of the current status and future prospects
Authors: Dai Zhanqiu , Zhao Tingxiao , Song Nan , Pan Kaifeng , Yang Yang , Zhu Xunbin , Chen Pengfei , Zhang Jun , Xia Chen
Published: October 2022

Platelets are blood cells that are primarily produced by the shedding of megakaryocytes in the bone marrow. Platelets participate in a variety of physiological and pathological processesin vivo, including hemostasis, thrombosis, immune-inflammation, tumor progression, and metastasis. Platelets have been widely used for targeted drug delivery therapies for treating various inflammatory and tumor-related diseases. Compared to other drug-loaded treatments, drug-loaded platelets have better targeting, superior biocompatibility, and lower immunogenicity. Drug-loaded platelet therapies include platelet membrane coating, platelet engineering, and biomimetic platelets. Recent studies have indicated that platelet extracellular vesicles (PEVs) may have more advantages compared with traditional drug-loaded platelets. PEVs are the most abundant vesicles in the blood and exhibit many of the functional characteristics of platelets. Notably, PEVs have excellent biological efficacy, which facilitates the therapeutic benefits of targeted drug delivery. This article provides a summary of platelet and PEVs biology and discusses their relationships with diseases. In addition, we describe the preparation, drug-loaded methods, and specific advantages of platelets and PEVs targeted drug delivery therapies for treating inflammation and tumors. We summarize the hot spots analysis of scientific articles on PEVs and provide a research trend, which aims to give a unique insight into the development of PEVs research focus.
The influence of pharmaceutical care in patients with advanced non-small-cell lung cancer receiving combination cytotoxic chemotherapy and PD-1/PD-L1 inhibitors
Authors: Kou Wen , Lin Yan Yan , Su Fei , Xiang Yue , Qiao Hui , Wu Xin’An , Hou Xiao-Ming
Published: October 2022

Background: Immune checkpoint inhibitors combined chemotherapy (ICIC) are widely used for various types of lung cancer in the past decade. However, ICIC related adverse events (AEs) are more serious than immune-related adverse events (irAE) or cytotoxic chemotherapy alone.

Objective: This prospective interventional study aimed to evaluate the impact of the pharmaceutical care program in reducing adverse events and analyze pharmacy interventions in patients with NSCLC who receive ICIC therapies.

Method: NSCLC patients were enrolled in this study, the pharmaceutical care program was introduced after patients received the second cycle ICIC therapies, and were followed by the pharmacist for 6 months after hospital discharge. The percentages of adverse events between patients in and after the first two cycles were analyzed and compared.

Results: After the first two treatment cycles, the clinical pharmacist proposed 67 interventions in 30 patients. The most frequent types of intervention were drug discontinuation (40.3%, 27/67) followed by drug modification (14.9%, 10/67). There were significant decreases in AEs after the second cycle with respect to nausea (≥grade-2, 14% vs. 28.3%, p = 0.039), constipation (≥grade-2, 8.8% vs. 21.7%, p = 0.039), diarrhea (≥grade-2, 6% vs. 16.7%, p = 0.031), and myelosuppression (≥grade-2, 15.8% vs. 30.0%, p = 0.022).

Conclusion: Provision of pharmaceutical care for NSCLC patients receiving ICIC therapies can optimize drug therapy and reduce adverse events.
The genus Porana (Convolvulaceae) - A phytochemical and pharmacological review
Authors: Peng Yu , Li Ye , Yang Yuanyuan , Gao Yuanqing , Ren Hui , Hu Jing , Cui Xiaomin , Lu Wenjing , Tao Hongxun , Chen Zhiyong
Published: October 2022

There are about 20 species of Porana Burm. f. worldwide in tropical and subtropical Asia, Africa and neighboring islands, Oceania, and the Americas. In China, India, and other places, this genus enjoys a wealth of experience in folk applications. Nevertheless, the chemical composition of only five species has been reported, and 59 compounds have been isolated and identified, including steroids, coumarins, flavonoids, quinic acid derivatives, and amides. Pharmacological studies revealed that extracts from this genus and their bioactive components exhibit anti-inflammatory, analgesic, antioxidant, anti-gout, anti-cancer, and anti-diabetic effects. Although this genus is abundant, the development of its pharmacological applications remains limited. This review will systematically summarize the traditional and current uses, chemical compositions, and pharmacological activities of various Porana species. Network analysis was introduced to compare and confirm its output with current research progress to explore the potential targets and pathways of chemical components in this genus. We hope to increase understanding of this genus’s medicinal value and suggest directions for rational medicinal development.
A time fractional second-grade magnetohydrodynamic dusty fluid flow model with variable conditions: Application of Fick’s and Fourier’s laws
Authors: Khan Zahid , Ali Farhad , Haq Sami Ul , Khan Ilyas
Published: October 2022

Non-Newtonian fluids along with magnetohydrodynamic flow have numerous applications in the purification of mineral oil, MHD pumps and motors, polymer fabrication, and aerodynamic heating. Thermal engineering and welding mechanics include the application of heat injectors or sinks to the abovementioned flows for heating and cooling processes. The present study deliberated comprehensively the generalized hydromagnetic dusty flow of the viscoelastic second-grade fluid between vertical plates with variable conditions. The fluid motion is induced by the oscillations of the left plate. Heat and mass transport, along with particle temperature, are considered. Partial differential equations are used to model the given flow regime. Unlike the previous published studies, the momentum equation is fractionalized from their constitutive equations before dimensionalization. The dimensionless energy and concentration equations have been fractionalized using Fick’s and Fourier’s laws. The fractionalized dimensionless system of equations is then solved by using the Laplace and finite Fourier-Sine transforms. To find the final solution, the Laplace inverse is found by the numerical approach of Zakian via PYTHON software. It is worth noting that the fluid’s velocity accelerate with increasing t, K1, Gr, and Gm and the parameters Pe, R, and t enhance the heat transfer rate. Furthermore, the parametric impact on the engineering interest quantities has been detailed in the Tables.
Complex network measures reveal optimal targets for deep brain stimulation and identify clusters of collective brain dynamics
Authors: Spiliotis Konstantinos , Butenko Konstantin , van Rienen Ursula , Starke Jens , Köhling Rüdiger
Published: October 2022

An important question in computational neuroscience is how to improve the efficacy of deep brain stimulation by extracting information from the underlying connectivity structure. Recent studies also highlight the relation of structural and functional connectivity in disorders such as Parkinson’s disease. Exploiting the structural properties of the network, we identify nodes of strong influence, which are potential targets for Deep Brain Stimulation (DBS). Simulating the volume of the tissue activated, we confirm that the proposed targets are reported as optimal targets (sweet spots) to be beneficial for the improvement of motor symptoms. Furthermore, based on a modularity algorithm, network communities are detected as set of nodes with high-interconnectivity. This allows to localise the neural activity, directly from the underlying structural topology. For this purpose, we build a large scale computational model that consists of the following elements of the basal ganglia network: subthalamic nucleus (STN), globus pallidus (external and internal parts) (GPe-GPi), extended with the striatum, thalamus and motor cortex (MC) areas, integrating connectivity from multimodal imaging data. We analyse the network dynamics under Healthy, Parkinsonian and DBS conditions with the aim to improve DBS treatment. The dynamics of the communities define a new functional partition (or segregation) of the brain, characterising Healthy, Parkinsonian and DBS treatment conditions.
Mechanisms of Na+ uptake from freshwater habitats in animals
Authors: Lee Carol Eunmi , Charmantier Guy , Lorin-Nebel Catherine
Published: October 2022

Life in fresh water is osmotically and energetically challenging for living organisms, requiring increases in ion uptake from dilute environments. However, mechanisms of ion uptake from freshwater environments are still poorly understood and controversial, especially in arthropods, for which several hypothetical models have been proposed based on incomplete data. One compelling model involves the proton pump V-type H+ATPase (VHA), which energizes the apical membrane, enabling the uptake of Na+(and other cations)viaan unknown Na+transporter (referred to as the “Wieczorek Exchanger” in insects). What evidence exists for this model of ion uptake and what is this mystery exchanger or channel that cooperates with VHA? We present results from studies that explore this question in crustaceans, insects, and teleost fish. We argue that the Na+/H+antiporter (NHA) is a likely candidate for the Wieczorek Exchanger in many crustaceans and insects; although, there is no evidence that this is the case for fish. NHA was discovered relatively recently in animals and its functions have not been well characterized. Teleost fish exhibit redundancy of Na+uptake pathways at the gill level, performed by different ion transporter paralogs in diverse cell types, apparently enabling tolerance of low environmental salinity and various pH levels. We argue that much more research is needed on overall mechanisms of ion uptake from freshwater habitats, especially on NHA and other potential Wieczorek Exchangers. Such insights gained would contribute greatly to our general understanding of ionic regulation in diverse species across habitats.
Chronic ankle instability modifies proximal lower extremity biomechanics during sports maneuvers that may increase the risk of ACL injury: A systematic review
Authors: Xu Yue , Song Bin , Ming Anghan , Zhang Congda , Ni Guoxin
Published: October 2022

The biomechanical changes in the lower extremity caused by chronic ankle instability (CAI) are not restricted to the ankle joint, but also affect the proximal joints, increasing the risk of joint injury. This study aimed to systematically review the research on CAI and lower extremity angle and movements during side-cutting, stop jumping, and landing tasks, to provide a systematic and basic theoretical basis for preventing lower extremity injury. Literature published from exception to April 2022 were searched in the PubMed, Web of Science, and SPORTDiscus databases using the keywords of “chronic ankle instability,” “side-cut,” “stop jump,” and “landing.” Only studies that compared participants with chronic ankle instability with healthy participants and assessed lower extremity kinetics or kinematics during side-cutting, stop jumping, or landing were included. The risk of bias assessment was conducted using a modified version of the Newcastle-Ottawa checklist. After title, abstract, and full text screening, 32 studies were included and the average score of the quality evaluation was 7 points (range 6–8). Among them five studies were related to the side-cut task, three studies were the stop-jump task, and twenty-four studies were related to landing. Although the results of many studies are inconsistent, participants with CAI exhibit altered lower extremity proximal joint movement strategies during side cut, stop jump, and landings, however, such alterations may increase the risk of anterior cruciate ligament injury.