Endoscopic endonasal transsphenoidal surgery for unusual sellar lesions: eight cases and review of the literature.

Background: Preoperative imaging for some unusual lesions in the sellar region can pose challenges in establishing a definitive diagnosis, impacting treatment strategies. Methods: This study is a retrospective analysis of eight cases involving unusual sellar region lesions, all treated with endoscopic endonasal transsphenoidal surgery (EETS). We present the clinical, endocrine, and radiological characteristics, along with the outcomes of these cases. Results: Among the eight cases, the lesions were identified as follows: Solitary fibrous tumor (SFT) in one case, Lymphocytic hypophysitis (LYH) in one case, Cavernous sinus hemangiomas (CSH) in one case, Ossifying fibroma (OF) in two cases; Sphenoid sinus mucocele (SSM) in one case, Pituitary abscess (PA) in two cases. All patients underwent successful EETS, and their diagnoses were confirmed through pathological examination. Postoperatively, all patients had uneventful recoveries without occurrences of diabetes insipidus or visual impairment. Conclusion: Our study retrospectively analyzed eight unusual lesions of the sellar region. Some lesions exhibit specific imaging characteristics and clinical details that can aid in preoperative diagnosis and inform treatment strategies for these unusual sellar diseases.

Clinical efficacy of HAIC (FOLFOX) combined with lenvatinib plus PD-1 inhibitors vs. TACE combined with lenvatinib plus PD-1 inhibitors in the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombus and arterioportal fistulas.

This study aimed to evaluate the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and PD1 inhibitors vs. transarterial chemoembolization (TACE) combined with lenvatinib and PD1 inhibitors in the treatment of unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) and artery-portal shunts (APFs). HCC Patients with PVTT and APFs who received HAIC in combination with PD1 inhibitor or TACE in combination with lenvatinib and PD1 inhibitor from March 2019 to May 2023 in Zhongshan People's Hospital were included. The objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), median duration of response (mDOR), and adverse events (AEs) were assessed. A total of 95 patients were enrolled in this study, including 34 cases in the HAIC+L+P group and 61 cases in the TACE+L+P group. According to the RECIST1.1, the ORR was 52.9% and 27.9%, and the DCR was 100% and 88.5%, respectively (P values =0.03 and < 0.001, respectively). The mOS of HAIC+L+P group and TACE+L+P group were 25.00 and 19.30 months, respectively (P=0.035). The mPFS of the two groups were 21.74 and 8.74 months, respectively (P=0.0066). The mDOR of the two groups was 20.43 and 9.13 months, respectively (P=0.067). Compared with TACE in combination with lenvatinib and PD-1 inhibitors, HAIC (FOLFOX) in combination with lenvatinib and PD-1 inhibitors can improve tumor response and prolong OS, PFS, and DOR in HCC patients with PVTT and APFs.

Survival benefit of local consolidative therapy for patients with single-organ metastatic pancreatic cancer: a propensity score-matched cross-sectional study based on 17 registries.

Background: The continuous exploration of oligometastatic disease has led to the remarkable achievements of local consolidative therapy (LCT) and favorable outcomes for this disease. Thus, this study investigated the potential benefits of LCT in patients with single-organ metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: Patients with single-organ metastatic PDAC diagnosed between 2010 - 2019 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to minimize selection bias. Factors affecting survival were assessed by Cox regression analysis and Kaplan-Meier estimates. Results: A total of 12900 patients were identified from the database, including 635 patients who received chemotherapy combined with LCT with a 1:1 PSM with patients who received only chemotherapy. Patients with single-organ metastatic PDAC who received chemotherapy in combination with LCT demonstrated extended median overall survival (OS) by approximately 57%, more than those who underwent chemotherapy alone (11 vs. 7 months, p < 0.001). Furthermore, the multivariate Cox regression analysis revealed that patients that received LCT, younger age (< 65 years), smaller tumor size (< 50 mm), and lung metastasis (reference: liver) were favorable prognostic factors for patients with single-organ metastatic PDAC. Conclusion: The OS of patients with single-organ metastatic pancreatic cancer who received LCT may be prolonged compared to those who received only chemotherapy. Nevertheless, additional prospective randomized clinical trials are required to support these findings.

Isolated bronchial hemangioma causing recurrent hemoptysis: A case report.

RATIONAL: The development of bronchial hemangioma in adults is rare, and massive hemoptysis due to diffuse vascular proliferation of bronchial hemangioma is fatal. PATIENT CONCERNS: A case of a 29-year-old woman kept massive hemoptysis even after being underwent repeated interventional embolization for recurrent massive hemoptysis. Eventually, the patient was performed the operation of right upper lung lobectomy and bronchial hemangioma with extracorporeal membrane oxygenation support and was followed up for 4 years without recurrent hemoptysis. DIAGNOSES: Bronchial hemangioma. CONCLUSION: For patients with bronchial angiomas bonded with bronchial artery-pulmonary arteriovenous fistulae, the early surgical resection is recommended if bronchial artery embolization (BAE) is considered ineffective.

Solitary fibrous tumor in the saddle area treated with neuroendoscopic surgery and proton therapy: A case report and literature review.

Solitary fibrous tumor (SFT) of the central nervous system is a rare fibroblastic tumor of mesenchymal origin. SFTs in the saddle area are much less common. In January 2022, a 43-year-old female patient was admitted with SFT 3 months following partial resection of a microscopic transsphenoidal saddle area tumor at a different hospital. Magnetic resonance imaging indicated that the unresected part of the tumor was significantly enhanced on T1 enhancement, which strongly indicated a recurrence. Subsequently, the patient underwent transnasal endoscopic saddle area tumor resection at our hospital and the tumor was successfully removed. By using postoperative pathology examination, immunohistochemical analysis of Bcl-2, cluster of differentiation 99, STAT6 and vimentin, and a fusion gene test performed by high-throughput sequencing technology, the SFT was definitively diagnosed. Following 3 months of follow-up, the patient was found to have tumor recurrence in the cavernous sinus and absence of tumor growth in the pituitary fossa. Therefore, the patient received proton therapy and tumor growth was controlled effectively.

Biomimetic and NOS-Responsive Nanomotor Deeply Delivery a Combination of MSC-EV and Mitochondrial ROS Scavenger and Promote Heart Repair and Regeneration.

Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) is shown to promote cardiac repair, however, it still falls short in initiating myocardia proliferation restart. In this regard, ROS-induced DNA damage and responses are the culprit of cellcycle arrest. Here, this work constructs a hybrid cell-derived extracellular vesicle that is composed of MSC and macrophage membranes and encompasses MitoN, a ROS scavenger, to boost the healing of the heart. The MitoN, a NAD(P)H mimic, could target the mitochondrial to eliminate the ROS resuming the arrested cell cycle. The hybrid extracellular vesicle (N@MEV) could respond to the inflammatory signals generated during myocardial injury and thus enable superior targeting and enrichment to the location of the damage. L-arginine, which could be catalyzed by NOS and ROS into NO and SO provide a driving force, is immobilized within the vesicle (NA@MEV) to further enhance the N@MEV's potential to penetrate the cardiac stroma. In combination with multiple mechanisms, NA@MEV increased heart function 1.3-fold EF% versus MSC-EV in mouse myocardial injury model. A more in-depth mechanistic study found that the NA@MEV could modulate M2 macrophage; promote angiogenesis; reduce DNA damage and response, and thereby restart cardiomyocyte proliferation. Thus, this combined therapy shows synthetic effects in heart repair and regeneration.

Prinsepia utilis Royle leaf extract: Ameliorative effects on allergic inflammation and skin lesions in allergic contact dermatitis and polyphenolic profiling through UPLC-MS/MS coupled to chemometric analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic contact dermatitis (ACD) is a common allergic inflammatory disease that is concomitant with skin swelling, redness, dry itching, and relapses. Prinsepia utilis Royle, a Chinese and Indian folk medicine, is rich in polyphenols with potential anti-inflammatory and skin-protective activities. However, the underlying mechanism of P. utilis leaf (PUL) in the treatment of ACD and its functional basis remains unclear. AIM OF THE STUDY: This study is aimed to explore and reveal the active substances and mechanism of PUL against ACD. MATERIALS AND METHODS: Hyaluronidase inhibitory assay and fluorescein isothiocyanate (FITC)-induced ACD mouse model were performed to assess the antiallergic effects of PUL in vitro and in vivo. Different solvents were applied to obtain multiple PUL extracts. The extracts were further tested for total phenolic content (TPC) and total flavonoid content (TFC) by using spectrophotometric assays. Polyphenolic profiles were analyzed by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), and a simultaneous quantification method was established using UPLC-QTrap-MS/MS through multiple reaction monitoring (MRM) and applied to analyze the pharmacokinetics of the multiple major polyphenols of PUL in mice. RESULTS: The water extract of PUL with the highest TPC/TFC exhibited the strongest antihyaluronidase effect (IC50 = 231.93 µg/mL). In vivo assays indicated that the oral administration of PUL water extract dose-dependently attenuated ACD-like symptoms by decreased interleukin (IL)-4, IL-5, IL-13, IL-33, thymic stromal lymphopoietin, and IgE production, suppressed eosinophil and basophil secretion, and increasing the expression of tight junction (TJ) proteins (claudin-1 [CLDN-1] and occludin). Concomitantly, UPLC-QTOF-MS/MS analysis enabled the identification of 60 polyphenols and the pharmacokinetic parameters of seven quantified constituents of PUL were characterized. Four compounds, trans-p-coumaric acid 4-O-ß-D-glucopyranoside (11), vicenin-2 (21), isoschaftoside (31), and kaempferol 3-O-(2″,6″-di-O-α-L-rhamnopyransoyl)-ß-D-glucopyranoside (38) which displayed satisfactory pharmacokinetic features, were considered as potential effective substances in PUL. CONCLUSIONS: PUL water extract ameliorated the allergic inflammation of ACD by repairing the epithelial barrier and alleviating Th2-type allergic inflammation. The anti-allergic effect of PUL is closely related to its phenolic substances, and compounds 11, 21, 31, and 38 were the active substances of PUL. It revealed that P. utilis could be developed as a new source of antiallergic agents for ACD therapy.

Application Analysis of Multidisciplinary Diagnosis and Treatment Nursing Mode Based on Doctor-Nurse-Integration for Stroke Patients Undergoing Emergency Intervention Surgery.

Purpose: To analyze the application value of multidisciplinary diagnosis and treatment (MDT) nursing mode based on doctor-nurse-integration for stroke patients undergoing emergency intervention surgery. Methods: In this study, a historical comparative study method was adopted. 118 stroke patients and medical staff (9 doctors and 11 nurses) who met the diagnosis and inclusion criteria of emergency intervention surgery admitted from July 2021 to February 2022 were treated clinically according to the traditional medical care mode (TMC group), 87 stroke patients and medical staff (9 doctors and 11 nurses) who met the diagnosis and inclusion criteria of emergency intervention surgery admitted from February 2022 to June 2022 were treated and cared according to the MDT nursing mode based on medical integration (MDT group). Comparison of perioperative time indicators, postoperative outcome indicators, treatment compliance, secondary complications and visit satisfaction between the two groups of patients, and comparison of cooperation satisfaction between the two groups of medical staff. Results: The MDT group had shorter onset-emergency physician's reception time, arrival at CT room-completion time of CT/MR, notify intervention chamber-arrival time at catheter chamber, admission-femoral artery puncture time, admission-first vessel recanalization time, mean postural restraint time than the TMC group (P < 0.05). The postoperative mortality rate in the MDT group (5.75%) was comparable to that in the TMC group (8.47%) (P > 0.05); the postoperative disability rate in the MDT group (28.74%) was less than that in the TMC group (45.76%) (P < 0.05); the NIHSS score in the MDT group was lower than that in the TMC group, and the FMA score and BI score were both higher than those in the TMC group (P < 0.05). The MDT group had higher treatment compliance than the TMC group, fewer secondary complications than the TMC group, and higher patient visit satisfaction and medical staff cooperation satisfaction than the TMC group (P < 0.05). Conclusion: The implementation of the MDT nursing mode based on the doctor-nurse-integration for stroke patients undergoing emergency intervention surgery can improve the work efficiency of rescuing patients, improve the clinical treatment outcome of patients, and improve the satisfaction of doctors, nurses, and patients.

The expression profiles of circular RNAs and competing endogenous RNA networks in intrahepatic cholangiocarcinoma.

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse etiologies, morphologies, and clinical outcomes, but our knowledge of its epidemiology and carcinogenesis is very limited. Materials and methods: The expression patterns of circRNAs were explored in iCCA tissues and corresponding adjacent normal ones, denoted by (iCCA) and (iCCAP), respectively, using high-throughput sequencing. Results: A total of 117 differential expressed (DE) circRNAs were identified. Based on the parental transcripts of circRNAs, these DE circRNAs were related to several important GO terms and were enriched in important pathways. Two circRNA-mediated ceRNA networks were constructed and many important metabolic pathways related to mRNAs were regulated by DE circRNAs via miRNAs. Conclusion: Our study revealed the DE circRNAs in the iCCA tissues compared with iCCAP ones, suggesting that circRNAs may play crucial roles in the pathogenesis of iCCA.

Grass Carp Reovirus triggers autophagy enhancing virus replication via the Akt/mTOR pathway.

Autophagy impacts the replication cycle of many viruses. Grass Carp Reovirus (GCRV) is an agent that seriously affects the development of the grass carp aquaculture industry. The role of autophagy in GCRV infection is not clearly understood. In this study, we identified that GCRV infection triggered autophagy in CIK cells, which was demonstrated by transmission electron microscopy, the conversion of LC3B I to LC3B II and the level of autophagy substrate p62. Furthermore, we found that GCRV infection activated Akt-mTOR signaling pathway, and the conversion of LC3B I to LC3B II was increased by inhibiting mTOR with rapamycin (Rap) but decreased by activating Akt with insulin. We then assessed the effects of autophagy on GCRV replication. We found that inducing autophagy with Rap promoted GCRV proliferation but inhibiting autophagy with 3 MA or CQ inhibited GCRV replication in CIK cells. Moreover, it was found that enhancing Akt-mTOR activity by insulin, GCRV VP7 protein and viral titers of GCRV were decreased. Collectively, these results indicated that GCRV infection induced autophagy involved in GCRV replication via the Akt-mTOR signal pathway. Thus, new insights into GCRV pathogenesis and antiviral treatment strategies are provided.

Biallelic Variants in CCDC39 Gene Lead to Primary Ciliary Dyskinesia and Kartagener Syndrome.

Background: Primary ciliary dyskinesia (PCD) is a clinical syndrome characterized by cilia with an abnormal structure or function. Its main clinical manifestations comprise chronic bronchitis, cough, recurrent respiratory infections, situs inversus, and male infertility. Single-gene variants are widely assumed to be the main cause of this rare disease, and more than 40 genes have been described to be associated with its onset. CCDC39 is essential for assembling the inner dynein arms and dynein regulatory complex and is important in cilia motility. CCDC39 variants were reported as a monogenic etiology of PCD. Methods: This study investigated two unrelated Chinese patients diagnosed as PCD. The chest computed tomography scan was performed to identify PCD phenotypes of the two probands. Considering the effect of PCD on male fertility, routine semen analysis, sperm morphology examination, and scanning electron microscopy were performed to assess the semen characteristics of male proband in family 2 (F2 II-1), who had a history of infertility. Subsequently, the peripheral blood samples of probands were collected to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Results: Whole-exome sequencing revealed a homozygous CCDC39 variant in the female proband of family 1 (F1 II-1: c.286C>T:p.Arg96Ter) and two compound heterozygous CCDC39 variants in the male proband of family 2 (F2 II-1: c.732_733del: p.Ala245PhefsTer18; c.2800_2802dup:p.Val934dup). The two probands showed the typical PCD phenotypes, including chronic bronchitis, recurrent respiratory infections, and situs inversus. The male proband also showed oligoasthenoteratospermia with multiple morphological abnormalities of the sperm flagella. Additionally, CCDC39 protein level was significantly lower in the sperm of male proband than in the sperm from normal controls. Conclusion: We identified a homozygous variant reported previously and two compound heterozygous variants of CCDC39 possibly responsible for PCD pathogenesis, expanding the variant spectrum of Chinese PCD, Kartagener syndrome, and morphological abnormalities of the sperm flagella involving CCDC39.

Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors.

Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC50 = 0.08 µM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50 = 0.25 µM). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.

Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property.

Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 µM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 µM) and good selectivity over CDK2 (IC50 = 0.054 µM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.

First-Line Tyrosine Kinase Inhibitors Combined With Local Consolidative Radiation Therapy for Elderly Patients With Oligometastatic Non-Small Cell Lung Cancer Harboring EGFR Activating Mutations.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of combined applications of local consolidative radiation therapy (LCRT) and first-line tyrosine kinase inhibitors (TKIs) for the treatment of primary tumors and oligometastatic sites in oligometastatic NSCLC harboring Epidermal Growth Factor Receptor (EGFR) activating mutations. PATIENTS AND METHODS: Elderly patients with oligometastatic NSCLC (≤5 metastases) harboring EGFR activating mutations at the time of diagnosis were identified. They were treated with first-line TKIs alone or in combination with LCRT. Progression-free survival (PFS) and overall survival (OS) were estimated through the Kaplan-Meier method. RESULTS: A total of 122 elderly patients were enrolled between February 2010 and January 2018. Among them, 41.0% (n = 50) received TKIs combined with LCRT (TKIs + LCRT group), whereas 59.0% (n = 72) received TKIs monotherapy (TKIs alone group). Patients were followed up for a median length of 34 months (ranging from 7.0 to 64 months). The median PFS in TKIs + LCRT group was 17 months (95%CI: 15.37-18.63), which was significantly longer than that of the TKIs-alone group (12 months; 95%CI: 11.05-12.95) (p <0.001). Median OS in TKIs + LCRT group was 38 months (95%CI: 35.61-40.39), while that of the TKIs-alone group was 29 months (95%CI: 26.86-31.14) (p <0.001). Multivariate analyses revealed that LCRT, one to two metastases, and good ECOG PS were independent predictors for better PFS (p <0.001, p = 0.004, and p = 0.027). Moreover, LCRT, good ECOG PS, and T1-2 stage were independent predictors for better OS (p <0.001, p = 0.007 and p = 0.007). Most of the patients suffered from grade 1 to 2 toxicities, and treatment-related deaths were not recorded. CONCLUSION: First-line TKIs combined with LCRT may improve survival outcomes for elderly patients with oligometastatic NSCLC harboring EGFR activating mutations. This approach was not associated with much toxicity, therefore, it can be used for the treatment of elderly patients with oligometastatic disease.

The Application Value of ceMDCT in the Diagnosis of Gastric Cancer Extramural Vascular Invasion and Its Influencing Factors.

OBJECTIVE: To investigate the value of enhanced multislice spiral CT (ceMDCT) in the diagnosis of extramural vascular invasion of gastric cancer and the influencing factors of extramural vascular invasion. There are different methods used in this paper. METHOD: 131 patients with primary gastric cancer treated in our hospital from January 2017 to May 2019 were selected. All patients underwent surgical resection and ceMDCT examination before operation. RESULT: There were 40 cases with extramural vascular invasion of gastric cancer by surgical pathological diagnosis. The kappa value of ceMDCT in diagnosing extramural vascular invasion of gastric cancer was 0.947, and the consistency was excellent. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were 100.00%, 96.70%, 93.02%, and 100.00%, respectively. The proportions of T3-T4, tumour diameter ≥5.0 cm, and growth pattern of proximal nodular + diffuse type in patients with gastric cancer extramural vascular invasion were 92.50%, 85.00%, and 65.00%, respectively, which were significantly higher than those in patients without extramural vascular invasion (P < 0.05). The logistic regression analysis results showed that T3-T4, tumour diameter ≥5.0 cm, proximal nodular + diffuse growth pattern were the risk factors for extrahepatic vascular invasion in gastric cancer (OR = 3.751, 2.901, and 3.367, P < 0.05). CONCLUSION: ceMDCT has good application value in diagnosing gastric cancer extramural vascular invasion. The occurrence of gastric cancer extramural vascular invasion is affected by T staging, tumour diameter, and tumour growth pattern.

Proanthocyanidin A1 promotes the production of platelets to ameliorate chemotherapy-induced thrombocytopenia through activating JAK2/STAT3 pathway.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a severe adverse drug reaction, and the main reason for CIT is the destruction of megakaryocytes (MKs, precursor cells of platelet) in bone marrow by chemotherapy. Peanut skin, the seed coat of Arachis hypogaea L., is a traditional Chinese medicine commonly used to treat thrombocytopenia. However, its active compounds and the mechanisms remain unclear. PURPOSE: This study aims to clarify the active compounds of peanut skin to exhibit thrombogenic effects against CIT and their underlying mechanisms in vitro and in vivo. STUDY DESIGN: The bioassay-guided isolation based on the proliferation of MKs was used to explore the possible platelet-enhancing ingredients in peanut skin. HSCCC technique coupled with preparative HPLC was used to separate the active compounds. Dami cells and carboplatin-treated mice model were used to evaluate the thrombogenic effects of PS-1. Network pharmacology, molecular docking, dynamics simulation studies, kinase activity, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), isothermal dose-response fingerprint (ITDRFCETSA) and western blot analysis were performed to investigate the mechanisms of PS-1. RESULTS: Proanthocyanidin A1 (PS-1) and its stereoisomers (PS-2-4) were demonstrated to promote the proliferation of MKs (Dami cells), especially PS-1 (EC50 = 8.58 µM). Further studies demonstrated that PS-1 could induce the differentiation of Dami cells in dose/time-dependent manner. Biological target analysis showed that PS-1 directly bound to JAK2 (KD = 2.06 µM) to exert potent activating effect (EC50 = 0.66 µM). Oral administration of PS-1 (25 or 50 mg/kg) significantly improved CIT, but this effect was confirmed to be inhibited by JAK2 inhibitor AG490, indicating that PS-1 exerted its efficacy through JAK2 in vivo. CONCLUSION: Proanthocyanins (PS-1-4) derived from peanut skin were first clarified as platelet-enhancing ingredients to improve CIT. The underlying mechanism of PS-1 was proved to promote the proliferation and differentiation of MKs via JAK2/STAT3 pathway both in vitro and in vivo.

Bombyx mori Akirin hijacks a viral peptide vSP27 encoded by BmCPV circRNA and activates the ROS-NF-κB pathway against viral infection.

Bombyx mori cypovirus (BmCPV), a member of the family Reoviridae, is a model of Cypovirus, has a 10 segmented double-stranded RNA genome. However, so far, only one viral small peptide vSP27 with negative regulation on viral infection was identified; the mechanisms underlying host-BmCPV interaction are still unknown. Here, we identified that vSP27 was translated from a BmCPV derived circular RNA (circRNA-vSP27). Subsequently, results showed that vSP27 induced generation of ROS activated the NF-κB signaling pathway, induced the expression of antimicrobial peptides, and suppressed BmCPV infection. On the other hand, we identified a nuclear protein Akirin that could hijack vSP27, positively regulate the NF-κB pathway, and lead to inhibiting the viral infection. Altogether, our data suggested that BmCPV derived circRNA-vSP27 with small peptide translation activity may be employed by the host immunity in defense against the BmCPV infection.

Evaluation of amentoflavone metabolites on PARP-1 inhibition and the potentiation on anti-proliferative effects of carboplatin in A549 cells.

The present study aims to determine the major metabolites of amentoflavone (AMF) and further evaluate their inhibitory effects on PARP-1. First, different fractions (Frs. 1-9), which were collected according to retention time of AMF metabolites based on UHPLC-QTOF-MS/MS qualitative analysis, were evaluated on their inhibitory effects against PARP-1. Then, two mono-sulfate metabolites in the fractions with potent PARP-1 inhibitory effect were targetedly semi-synthesized. Moreover, three mono-sulfate conjugates (compound 8, 9 and 10), including one disulfate conjugate (compound 10), were isolated and their structures were fully elucidated by UHPLC-QTOF-MS/MS and NMR. Finally, the binding mode of compound 8 (amentoflavone-4‴-O-sulfate) toward PARP-1 and its potentiation on carboplatin (CBP) in A549 cells were investigated. This study was the first report on bioactivity evaluation of AMF metabolites in rat bile on PARP-1 and the potentiation of compound 8 on carboplatin (CBP) in A549 cells in vitro. This paper also provided scientific basis for the AMF metabolites on PARP-1 inhibition and chemosensitization.

Efficacy and Safety of Local Radiotherapy to All Oligometastatic Sites in Elderly Patients with Metachronous Oligometastatic Cancers After Initial Treatment for the Primary Tumor.

BACKGROUND AND PURPOSE: This study aimed to investigate the efficacy and safety of maintenance therapy combined with local radiotherapy at all oligometastatic sites (LRTOS) in elderly patients with metachronous oligometastatic cancers (MOC). PATIENTS AND METHODS: A total of 242 elderly patients with MOC (≤5 metastases) and primary tumor well controlled after definitive treatment was retrospectively analyzed between August 2014 and February 2020 at Beijing Geriatric Hospital and Air Force General Hospital. Patients were divided into maintenance therapy group (maintenance therapy alone) and local radiotherapy group (maintenance therapy combined with LRTOS). RESULTS: There were 86 patients in the local radiotherapy group and 156 patients in the maintenance therapy group. The median length of follow-up was 36 months (range, 8.0-62 months). Median overall survival (mOS) was 25 months (95% CI: 21.1-28.9) in the local radiotherapy group and 16 months (95% CI: 14.5-17.6) in the maintenance therapy group (p < 0.001). Multivariate analyses demonstrated that LRTOS (hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35-0.67, p < 0.001), good Eastern Cooperative Oncology Group Performance Status (ECOG PS, HR = 0.69, 95% CI: 0.49-0.97, p = 0.032), longer duration between diagnosis of primary tumor and occurrence of progression (HR = 0.87, 95% CI: 0.78-0.97, p = 0.015), and subsequent systemic treatment (HR = 0.52, 95% CI: 0.38-0.72, p < 0.001) were independent predictors of good OS. In patients who did not receive subsequent systemic treatment, their mOS was 21 months (95% CI: 12.8-29.2) for those treated with LRTOS and 14 months (95% CI: 11.4-16.6) for those who did not receive local radiotherapy (p = 0.001). Further multivariate analysis showed that LRTOS was the only independent factor for predicting good OS (HR = 0.47, 95% CI: 0.26-0.83, p = 0.010). Patients with metachronous oligometastatic lung cancer, colorectal cancer, prostate cancer, and breast cancer had higher survival benefits following LRTOS. Most patients suffered from grade 1-2 toxicities, but no treatment-related death was recorded. CONCLUSION: This retrospective study shows that elderly patients with MOC treated with LRTOS may have better survival outcomes.

Discovery of Eucalyptin C, derived from the fruits of Eucalyptus globulus Labill., as a novel selective PI3Kγ inhibitor for immunosuppressive treatment.

The fruits of Eucalyptus globulus Labill. are known to have a plenty of medicinal properties, such as anti-tumor, anti-inflammatory, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-γ (PI3Kγ) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was first discovered to be a novel selective PI3Kγ inhibitor with an IC50 value of 0.9 µmol·L-1 and selectivity over 40-fold towards the other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3Kγ. Furthermore, EuC suppressed the downstream of PI3Kγ to induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the role of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.