Imaging, pathology, and diagnosis of solitary fibrous tumor of the pancreas: A case report and review of literature.

BACKGROUND: A solitary fibrous tumor (SFT) is often located in the pleura, while SFT of the pancreas is extremely rare. Here, we report a case of SFT of the pancreas and discuss imaging, histopathology, and immunohistochemistry for accurate diagnosis and treatment. CASE SUMMARY: A 54-year-old man presented to our hospital with pancreatic occupancy for over a month. There were no previous complaints of discomfort. His blood pressure was normal. Blood glucose, tumor markers, and enhanced computed tomography (CT) suggested a malignant tumor. Because the CT appearance of pancreatic cancer varies, we could not confirm the diagnosis; therefore, we performed endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Pathology and immunohistochemistry were consistent with SFT of the pancreas. The postoperative pathology and immunohistochemistry were consistent with the puncture results. The patient presented for a follow-up examination one month after discharge with no adverse effects. CONCLUSION: Other diseases must be excluded in patients with a pancreatic mass that cannot be diagnosed. CT and pathological histology have diagnostic value for pancreatic tumors. Endoscopic puncture biopsy under ultrasound can help diagnose pancreatic masses that cannot be diagnosed preoperatively. Surgery is an effective treatment for SFT of the pancreas; however, long-term follow-up is strongly recommended because of the possibility of malignant transformation of the tumor.

Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer.

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 µM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.

Relationship between initial red cell distribution width and ΔRDW and mortality in cardiac arrest patients.

AIMS: There has been a lack of research examining the relationship between red cell distribution width (RDW) and the prognosis of cardiac arrest (CA) patients. The prognostic value of the changes in RDW during intensive care unit (ICU) hospitalization for CA patients has not been investigated. This study aims to investigate the correlation between RDW measures at ICU admission and RDW changes during ICU hospitalization and the prognosis of CA patients and then develop a nomogram that predicts the risk of mortality of these patients. METHODS AND RESULTS: A retrospective cohort study is used to collect clinical characteristics of CA patients (>18 years) that are on their first admission to ICU with RDW data measured from the Medical Information Mart for Intensive Care IV Version 2.0 database. Patients are randomly divided into a development cohort (75%) and a validation cohort (25%). The primary outcome is 30 and 360 day all-cause mortality. ΔRDW is defined as the RDW on ICU discharge minus RDW on ICU admission. A multivariate Cox regression model is applied to test whether the RDW represents an independent risk factor that affects the all-cause mortality of these patients. Meanwhile, the dose-response relationship between the RDW and the mortality is described by restricted cubic spine (RCS). A prediction model is constructed using a nomogram, which is then assessed using receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). A total of 1278 adult CA patients are included in this study. We found that non-survivors have a higher level of RDW and ΔRDW compared with survivors, and the mortality rate is higher in the high RDW group than in the normal RDW group. The Kaplan-Meier survival curve indicates that patients in the normal RDW group had a higher cumulative survival rate at 30 and 360 days than those in the high RDW group (log-rank test, χ2  = 36.710, χ2  = 54.960, both P values <0.05). The multivariate Cox regression analysis shows that elevated RDW at ICU admission (>15.50%) is an independent predictor of 30 [hazard ratio = 1.451, 95% confidence interval (CI) = 1.181-1.782, P < 0.001] and 360 day (hazard ratio = 1.393, 95% CI = 1.160-1.671, P < 0.001) all-cause mortality among CA patients, and an increase in RDW during ICU hospitalization (ΔRDW ≥ 0.4%) can serve as an independent predictor of mortality among these patients. A non-linear relationship between the RDW measured at ICU admission and the increased risk of mortality rate of these patients is shown by the RCS. This study established and validated a nomogram based on six variables, anion gap, first-day Sequential Organ Failure Assessment score, cerebrovascular disease, malignant tumour, norepinephrine use, and RDW, to predict mortality risk in CA patients. The consistency indices of 30 and 360 day mortality of CA patients in the validation cohort are 0.721 and 0.725, respectively. The nomogram proved to be well calibrated in the validation cohort. DCA curves indicated that the nomogram provided a higher net benefit over a wide, reasonable range of threshold probabilities for predicting mortality in CA patients and could be adapted for clinical decision-making. CONCLUSIONS: Elevated RDW levels on ICU admission and rising RDW during ICU hospitalization are powerful predictors of all-cause mortality for CA patients at 30 and 360 days, and they can be used as potential clinical biomarkers to predict the bad prognosis of these patients. The newly developed nomogram, which includes RDW, demonstrates high efficacy in predicting the mortality of CA patients.

Integrative analysis from multi-center studies identifies a weighted gene co-expression network analysis-based Tregs signature in ovarian cancer.

Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs-related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co-expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning-derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning-based prognostic model for OC patients, which could be useful in clinical practice.

SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Value of ultrasound guided biopsy combined with Xpert Mycobacterium tuberculosis/resistance to rifampin assay in the diagnosis of chest wall tuberculosis.

BACKGROUND: The thoracic wall lesions, particularly chest wall tuberculosis, and chest wall tumors and other pyogenic wall and actinomycetes infections, almost always present as a diagnostic challenge. AIM: To explore the value of ultrasound-guided biopsy combined with the Xpert Mycobacterium tuberculosis/resistance to rifampin (MTB/RIF) assay to diagnose chest wall tuberculosis. METHODS: We performed a retrospective study of patients with chest wall lesions from March 2018 to March 2021. All patients received the ultrasound-guided biopsy for pathology examination, acid-fast Bacillus staining, mycobacterial culture, and Xpert MTB/RIF analysis. The sensitivity, specificity, and area under the curve (AUC) were calculated for these diagnostic tests, either individually or combined. Rifampicin resistance results were compared between the mycobacterial culture and the Xpert MTB/RIF assay. RESULTS: In 31 patients with the chest wall lesion biopsy, 22 patients were diagnosed with chest wall tuberculosis. Of them, 3, 6, and 21 patients tested positive for mycobacterial culture, acid-fast stain, and Xpert MTB/RIF assay, respectively. The rifampicin resistance results of the 3 culture-positive patients were consistent with their Xpert MTB/RIF assay results. When considering the sensitivity, specificity, and AUC value, the Xpert MTB/RIF assay (95.5%, 88.9%, and 0.92, respectively) was a better choice than the acid-fast Bacillus stain (27.3%, 100.0%, and 0.64, respectively) and mycobacterial culture (13.6%, 100.0%, 0.57, respectively). No complications were reported during the procedure. CONCLUSION: Ultrasound guided biopsy combined with Xpert MTB/RIF has high value in the diagnosis of chest wall tuberculosis, and can also detect rifampicin resistance.

Synthesis of Imidazo[1,2-a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process.

A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Analysis of Risk Factors for Postherpetic Neuralgia in Patients With Postmalignancy Herpes Zoster.

BACKGROUND: The high risk of developing postherpetic neuralgia (PHN) is associated with severe immunosuppressive diseases. A malignancy itself, as well as surgery, radiotherapy, and other treatments, can lead to changes in the immune status of the body and predispose patients with a malignancy to PHN. OBJECTIVE: To investigate the risk factors of postherpetic neuralgia in herpes zoster (HZ) after a malignant tumor and to provide better preventive strategies for clinical practice. STUDY DESIGN: A retrospective cohort study. SETTING: The Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China. METHODS: Patients who developed HZ after being diagnosed with a malignant tumor in the Affiliated Hospital of Southwest Medical University from September 2018 through March 2022 were included in the research. A total of 70 patients were included, including 31 men and 39 women, aged 18- 82 years old (mean, SD: 59.77 ± 13.95). According to the occurrence of PHN, they were divided into a non-PHN (n = 46) and a PHN group (n = 24). General information about the patients was collected, including clinical data, treatment status, and prognosis. Univariate and multivariate analyses were conducted of influencing factors. RESULTS: A total of 19 factors, including gender, age, and white blood cell count, were included. A univariate analysis showed that there were differences in age, tumor stage, Numeric Rating Scale (NRS-11) score, and the use of antiviral drugs between the 2 groups; these differences were statistically significant, P <0.05. A multifactorial analysis revealed that the acute phase NRS-11 score (odds ratio [OR] = 4.21; 95% CI, 1.59-2.24, P = 0.004), antiviral drug use (OR = 0.28; 95% CI, 0.10-0.82, P = 0.020), and tumor stage (OR = 0.28, 95% CI, 0.08-0.98, P = 0.047) were statistically significant for the effect of PHN occurring in postmalignancy HZ. There was a statistically significant difference between the group with severe pain in the acute phase NRS-11 score and the group with mild and moderate pain, P < 0.05. There was a statistically significant difference between the group treated with 2 antivirals and the group not treated with antivirals, P < 0.05. LIMITATIONS: There are some limitations in our research. It was conducted at a single center, with a single race, and had a small sample size. A larger-scale study should be conducted to analyze the influencing factors of PHN in patients with herpes zoster after a malignant tumor. CONCLUSIONS: The NRS-11 score in the acute phase, whether the use of antiviral drugs in sufficient quantities, and tumor staging are the influencing factors of PHN after malignant tumors.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated. METHODS: Through analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. RESULTS: We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. CONCLUSIONS: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

DPA-Zinc around Polyplexes Acts Like PEG to Reduce Protein Binding While Targeting Cancer Cells.

Gene therapy holds great promise as an effective treatment for many diseases of genetic origin. Gene therapy works by employing cationic polymers, liposomes, and nanoparticles to condense DNA into polyplexes via electronic interactions. Then, a therapeutic gene is introduced into target cells, thereby restoring or changing cellular function. However, gene transfection efficiency remains low in vivo due to high protein binding, poor targeting ability, and substantial endosomal entrapment. Artificial sheaths containing PEG, anions, or zwitterions can be introduced onto the surface of gene carriers to prevent interaction with proteins; however, they reduce the cellular uptake efficacy, endosomal escape, targeting ability, thereby, lowering gene transfection. Here, it is reported that linking dipicolylamine-zinc (DPA-Zn) ions onto polyplex nanoparticles can produce a strong hydration water layer around the polyplex, mimicking the function of PEGylation to reduce protein binding while targeting cancer cells, augmenting cellular uptake and endosomal escape. The polyplexes with a strong hydration water layer on the surface can achieve a high gene transfection even in a 50% serum environment. This strategy provides a new solution for preventing protein adsorption while improving cellular uptake and endosomal escape.

Publication trends of primary angle-closure disease during 1991-2022: a bibliometric analysis.

AIM: To perform a bibliometric analysis in the field of primary angle-closure disease (PACD) research to characterize current global trends and compare contributions from different countries, institutions, journals, and authors. METHODS: All PACD-related publications from 1991 to 2022 from the Web of Science Core Collection database were extracted. Microsoft Excel and VOSviewer were used to collect publication data, analyze publication trends, and visualize relevant results. RESULTS: A total of 1721 publications with 34 591 citations were identified. China produced the most publications (554) while ranking third in citations (8220 times). The United States contributed the most citations (12 315 times) with publications (362) ranking second. The Investigative Ophthalmology Visual Science was the most productive journal concerning PACD, and Aung Tin was the author with the highest number of publications in the field. Keywords were classified into three clusters, epidemiology and pathogenesis research, optical coherence tomography (OCT) and other imaging examinations, and glaucoma surgery treatment. Genome-wide association, susceptibility loci, OCT, and combined phacoemulsification have become new hot research topics in recent years since 2015. CONCLUSION: China, the United States, and Singapore make the most outstanding contributions in the field of PACD research. OCT, combined phacoemulsification, and gene mutation-related study, are considered the potential focus for future research.

GSK-3ß inhibition alleviates arthritis pain via reducing spinal mitochondrial reactive oxygen species level and inflammation.

Pain is the main symptom of osteoarthritis, which severely reduces the patients' quality of life. Stimulated neuroinflammation and elevated mitochondrial oxidative stress are associated arthritis pain. In the present study, arthritis model was established by intra-articular injection of complete Freund's adjuvant (CFA) on mice. Knee swelling, pain hypersensitivity and motor disability were observed in CFA-induced mice. In spinal cord, neuroinflammation was triggered and presented as severe infiltration of inflammatory cells and up-regulated expressions of glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-κB), PYD domains-containing protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase-1) and interleukin-1 beta (IL-1ß). Mitochondrial function was disrupted and characterized as elevated expressions of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), dihydroorotate dehydrogenase (DHODH) and cytochrome C (Cyto C), and reduced expressions of Bcl-2 and Mn-superoxide dismutase (Mn-SOD) activity. Meanwhile, as a potential target for pain management, glycogen synthase kinase-3 beta (GSK-3ß) activity was up-regulated in CFA induced mice. To explore potential therapeutic options for arthritis pain, GSK-3ß inhibitor TDZD-8 was intraperitoneally injected for three days on CFA mice. Animal behavioral tests found that TDZD-8 treatment elevated mechanical pain sensitivity, suppressed spontaneous pain and recovered motor coordination. Morphological and protein expression analysis indicated that TDZD-8 treatment decreased spinal inflammation score and inflammatory related protein levels, recovered mitochondrial related protein levels, and increased Mn-SOD activity. In summary, TDZD-8 treatment inhibits GSK-3ß activity, reduces mitochondrial mediated oxidative stress, suppresses spinal inflammasome response, and alleviates arthritis pain.

High expression of the classical swine fever virus (CSFV) envelope protein E2 by a single amino acid mutation and its embedded in the pseudorabies virus (PRV) vector for immunization.

Pseudorabies (PR) and classical swine fever (CSF) are economically important infectious diseases in pigs. Most pig farms in China are vaccinated against these two diseases. Gene-deleted pseudorabies virus (PRV) can be used to develop promising and economical multivalent live attenuated viral vector vaccines. It has been reported that recombinant PRV can express a truncated E2 protein (1-338 aa), but it has not been reported that recombinant PRV can express a full-length E2 protein. We constructed nine groups of E2 proteins with different expression forms and found that the E2 protein could be expressed in vitro only when the transmembrane region of E2 was removed and the signal peptide was added. Analysis of the transmembrane region of E2 revealed that the high hydrophobicity of the E2 transmembrane region was the main reason for its inability to express. By mutating an amino acid to reduce the hydrophobicity of the transmembrane region, it was found that the full-length mutant of E2 (E2FL-muta3 or E2FL-muta4) could be expressed. The expressed full-length mutant E2 could also localize to the cell membrane. Mice immunized with a PRV vector vaccine expressing E2FL-muta3 or E2FL-muta4 developed specific cellular immunity to the E2 protein and stimulated higher levels of E2 antibody than mice immunized with a PRV vector expressing truncated E2. After immunizing the rabbits, the lethal challenge by PRV-ZJ2013 and the febrile response elicited by CSFV were simultaneously prevented. These results suggest that rPRV-dTK/gE-E2FL-muta4 is a promising bivalent vaccine against CSFV and PRV infections.

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Maternal circulating exosomal miR-185-5p levels as a predictive biomarker in patients with recurrent pregnancy loss.

PURPOSE: The aim of this study was to explore the predictive role of microRNAs (miRNAs) from maternal serum exosomes in early recurrent pregnancy loss (RPL) and the related mechanism in early pregnancy. METHODS: Maternal serum was collected from pregnant women with RPL history or women with ongoing pregnancy (OP); serum exosomes were extracted and identified. Differentially expressed (DE) miRNAs in exosomes were screened by RNA sequencing and further validated by qRT-PCR. Next, the predictive value of exosomal miRNA and the clinical indicators for subsequent miscarriage in RPL patients were evaluated. Additionally, we verified the regulatory relationship between miR-185-5p and vascular endothelial growth factor (VEGF) in decidual natural killer (dNK) cells by overloading or inhibiting the exosomal miR-185-5p level in trophoblast cells. RESULTS: The miRNA sequencing revealed 43 DE miRNAs between OP and RPL patients. The five most significant DE miRNAs (miR-22-3p, miR-185-5p, miR-335-3p, miR-362-5p, and miR-378a-3p) were selected for identification, and miR-185-5p was increased in RPL patients. The area under curve (AUC) of the receiver operating characteristic was 0.925 when using miR-185-5p as a biomarker for subsequent miscarriage in RPL patients. In addition, miR-185-5p in exosomes secreted from HTR-8 cells reduces VEGF expression of dNK cells. CONCLUSIONS: The current study, for the first time, successfully constructed the correlation between maternal circulating exosomal miR-185-5p expression pattern and RPL, which may be involved in the pathogenesis of RPL by downregulating the VEGFA of dNK cells and perturbing angiogenesis at the maternal-fetal interface.

Recombinant pseudorabies virus (PRV) expressing stabilized E2 of classical swine fever virus (CSFV) protects against both PRV and CSFV.

Pseudorabies (PR) and classical swine fever (CSF) are economically important infectious diseases of pigs. Most pig farms in China are immunized against these two diseases. Here, we describe a stabilized E2 protein as an immunogen inserted into the PRV genome as a bivalent live virus-vectored vaccine. The E2 protein has 48 variant sites, there are 2-5 candidate amino acids per variant site, and the relative energy contribution of each amino acid to E2 energy was calculated. Combined substitutions of amino acids at the neighbor variant site (neighbor substitution) were performed to obtain the E2 protein sequence with the lowest energy (stabilized E2). Multiple amino acid substitutions at 48 variant sites were performed, and the results were consistent with neighbor substitutions. The stabilized E2 sequence was obtained, and its energy decreased by 22 Rosetta Energy Units (REUs) compared with the original sequence. After the recombinant PRV expressing stabilized E2 of CSFV was constructed, the secretion efficiency of stabilized E2 was increased by 2.97 times, and the thermal stability was increased by 10.5 times. Immunization of mice resulted in a 2-fold increase in antibody production, and a balanced antibody level against subtype 1.1 and subtype 2.1d E2 was achieved. In rabbits immunized, the lethal challenge of PRV-ZJ and the fever response induced by CSFV could be prevented simultaneously. These findings suggest that rPRV-muta/287aaE2 is a promising bivalent vaccine against CSFV and PRV infections.

Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes.

Postoperative cognitive dysfunction (POCD) is a common surgical complication. Diabetes mellitus (DM) increases risk of developing POCD after surgery. DM patients with POCD seriously threaten the quality of patients' life, however, the intrinsic mechanism is unclear, and the effective treatment is deficiency. Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD. In this study, we constructed a mouse model of DM by intraperitoneal injection of streptozotocin, and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion. We found that mouse models of DM-POCD exhibited the most serious cognitive impairment, as well as the most hippocampal neural stem cells (H-NSCs) loss and neurogenesis decline. Subsequently, we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) might promote neurogenesis and restore cognitive function in patients with DM-POCD. iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery, and then once every 3 days for 1 month thereafter. Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs, and reversed cognitive impairment in mouse models of DM-POCD. Furthermore, miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs. We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis. As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C, while miR-486-5p can inhibit FoxO1 in NSCs. We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4, CDKN2C, and FoxO1 expression in H-NSCs. Collectively, these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD, the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.

Low iron ameliorates the salinity-induced growth cessation of seminal roots in wheat seedlings.

Wheat plants are ubiquitously simultaneously exposed to salinity and limited iron availability caused by soil saline-alkalisation. Through this study, we found that both low Fe and NaCl severely inhibited the growth of seminal roots in wheat seedlings; however, sufficient Fe caused greater growth cessation of seminal roots than low Fe under salt stress. Low Fe improved the root meristematic division activity, not altering the mature cell sizes compared with sufficient Fe under salt stress. Foliar Fe spray and split-root experiments showed that low Fe-alleviating the salinity-induced growth cessation of seminal roots was dependent on local low Fe signals in the roots. Ionomics combined with TEM/X-ray few differences in the root Na+ uptake and vacuolar Na+ sequestration between two Fe levels under salt stress. Phytohormone profiling and metabolomics revealed salinity-induced overaccumulation of ACC/ethylene and tryptophan/auxin in the roots under sufficient Fe than under low Fe. Differential gene expression, pharmacological inhibitor addition and the root growth performance of transgenic wheat plants revealed that the rootward auxin efflux and was responsible for the low Fe-mediated amelioration of the salinity-induced growth cessation of seminal roots. Our findings will provide novel insights into the modulation of crop root growth under salt stress.

Emodin suppresses oxaliplatin-induced neuropathic pain by inhibiting COX2/NF-κB mediated spinal inflammation.

Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXA is often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced the pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2 (COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen species level. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.