Transarterial chemoembolization combined with molecular targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma beyond the up-to-seven criteria: a propensity score-matching analysis.

PURPOSE: Not all patients benefit from transarterial chemoembolization (TACE) due to the heterogeneity of the tumour burden in intermediate-stage hepatocellular carcinoma (HCC). To compare the outcomes of transarterial chemoembolization (TACE) combined with molecular-targeted agents plus immune checkpoint inhibitors (TACE-MTAs-ICIs) with those of TACE for patients with unresectable hepatocellular carcinoma (uHCC) that were beyond the up-to-seven criteria. PATIENTS AND METHODS: Between January 2019 and July 2022, 130 patients diagnosed with uHCC beyond the up-to-seven criteria were retrospectively identified, including 47 patients who received TACE-MTAs-ICIs and 83 patients who received TACE alone. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included tumour response and adverse events (AEs). RESULTS: There were 43 matched patients. The median OS and PFS times in the TACE-MTAs-ICIs group were significantly longer than those in the TACE group (OS: 27.2 vs. 15.9 months, p = 0.007; PFS: 15.4 months vs. 4.8 months, p < 0.001). The objective response rate (ORR) in the TACE-MTAs-ICIs group was higher than that in the TACE group (65.1% vs. 37.2%, p = 0.010). Reversible AEs (grade 3 or 4) occurred differently in TACE-MTAs-ICIs and TACE groups (83.7% vs. 51.2%, p = 0.001). Univariate and multivariate analyses revealed that TACE-MTAs-ICIs treatment was an independent favourable prognostic factor for both PFS and OS (p < 0.001). CONCLUSION: For uHCC patients beyond the up-to-seven criteria, TACE-MTAs-ICIs provided superior ORR and OS. Early combined TACE and systemic treatment should shift for patients who are beyond these criteria.

The ORR and median OS reached 65.1% and 27.2 months, respectively, in the treatment model of TACE-MTAs-ICIs for patients with unresectable HCC that were beyond the up-to-seven criteria.TACE-TKI-ICI yielded a synergistic effect on these patients and was an independent favourable prognostic factor for PFS and OS.

Radiosurgery versus observation for brainstem cavernous malformations: a 5-year multicentre cohort study.

The role of radiosurgery in preventing haemorrhage in brainstem cavernous malformations remains a subject of debate. This study aims to evaluate whether radiosurgery provides a protective benefit against haemorrhage in these patients. This multicentre, prospective observational study was conducted in 17 centres and enrolled eligible patients with brainstem cavernous malformations consecutively. Data collected included clinical baseline information, radiosurgery planning details, periodic follow-up evaluations, and any adverse radiation effects. The primary outcome of the study was the incidence of first prospective haemorrhage, while the secondary outcome was the development of new or worsening neurological dysfunctions. The impact of radiosurgery was assessed using multivariate Cox regression analysis. From March 2016 to August 2018, the study enrolled 377 patients: 280 in the observation group receiving standard care alone and 97 in the radiosurgery group receiving both radiosurgery and standard care. The overall cohort consisted of 173 females (45.9%) with a mean age of 40.5 years (range, 18-68 years), and there were no significant differences in baseline characteristics between the two groups. After a median follow-up period of 70 months, haemorrhage occurred in 25.0% (n = 70) of patients in the observation group and 10.3% (n = 10) of patients in the radiosurgery group. Multivariate Cox regression analysis identified radiosurgery as an independent protective factor against haemorrhage (hazard ratio 0.379, 95% confidence interval 0.195-0.738, P = 0.004). Following 1:2 propensity score matching, the incidence of prospective haemorrhage were 24.9% (45/181) in the observation group compared to 10.3% (10/97) in the radiosurgery group (hazard ratio 0.379, 95% confidence interval 0.190-0.755, P = 0.006). Adverse radiation effects were observed in 12 patients (12.4%), with none were permanent. Additionally, new or worsening neurological dysfunctions were significantly more common in the observation group (28.9%) compared to the radiosurgery group (16.5%) (P = 0.016). These results suggest that radiosurgery is associated with a low rate of haemorrhage in patients with brainstem cavernous malformations and could provide a benefit in selected patients. However, further research is required to confirm these findings.

Modification of gel properties of Meretrix meretrix (clam) with polysaccharides: physical characterization and interaction mechanism.

BACKGROUND: This study investigated the contribution of 11 polysaccharides (2%, w/w), including pectin (PC), κ-carrageenan (KC), ι-carrageenan (IC), gellan gum (GG), guar gum (GM), sodium alginate (SA), konjac gum (KG), gum arabic (GA), fucoidan (FC), locust bean gum (LBG), and curdlan (CD), to the gel and microstructural properties of Meretrix meretrix clam gel (MMG). RESULTS: The hardness, springiness and chewiness of MMG with KC, IC, GG, SA and FC addition increased by ~10%-250%, while PC, GM, KG and LBG groups decreased by ~0.6% to 69%. KC, IC, SA, GG and FC decreased the cooking loss rate (CLR) by 69.4% to 88.7% and correspondingly enhanced the water holding capacity (WHC) by 10.2% to 21.4%, which was accompanied by an increased bound water and immobilized water area and high hydrogen proton density. The addition of KC transformed the MMG microstructure from a loose network with large pores to a compact, dense network, reducing lacunarity by 57.9%. The primary intermolecular forces in MMG with the incorporation of KC, IC, GG, SA and FC were hydrophobic interactions and disulfide bonds, which increased by 32.8%-105.3% and 45.6%-114.5% than MMG alone, respectively. CONCLUSION: Collectively, KC, IC, GG, SA and FC could improve the gel properties of MMG and the strongest synergistic combination was found in the MMG/KC system. This study suggests that the incorporation of polysaccharides is a strategy with potential for modifying the gel properties of shellfish surimi products. © 2024 Society of Chemical Industry.

Exploring the Potential Mechanisms of Danshen for the Treatment of Ulcerative Colitis based on Serum Pharmacochemistry, Gene Expression Profiling, and Network Pharmacology: Regulation of Cell Apoptosis and Inflammatory Response.

BACKGROUND: As a traditional Chinese medicine, Danshen shows potential efficacy for treating ulcerative colitis (UC). However, the bioactive components and mode of action were unclear. AIM OF THIS STUDY: This paper uses a combination of network pharmacology, serum medicinal chemistry, and gene expression profiling to clarify its possible molecular mechanism of action and material basis. METHODS: Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was utilized to analyze the herbal components and metabolites from the serum of Danshen-treated mice. Gene expression profiles were applied to construct a database of Danshen action targets. Then, active ingredient-target-biological functional module networks were constructed to analyze the mechanism of action. Molecular docking has further confirmed the possibility of its components to the targets. RESULTS: As a result, 193 common targets between 1684 Danshen-related DEGs and 1492 UC targets were determined as the potential targets for Danshen in treatment with UC. Serum pharmacochemistry and target prediction showed that 22 components in serum acted on 777 targets. Intersection with common targets yielded 46 core targets, and an active ingredienttarget- biological functional module network was constructed for analysis. Network prediction and molecular docking results showed that the main action modules were inflammatory response and cell apoptosis, which mainly acted on targets SRC, RELA, HSP90AA1, CTNNB1, STAT3, and CASP3. The main components of Danshen intervention in UC were predicted to include Catechol, 3,9-Dimethoxypterocarpan, 8-Prenylnaringenin, Isoferulic acid, Salvianolic acid C, and Danshensu. CONCLUSION: The present study provides a scientific foundation for further explicating the mechanisms of Danshen against UC.

Adaptive Optimal Surrounding Control of Multiple Unmanned Surface Vessels via Actor-Critic Reinforcement Learning.

In this article, an optimal surrounding control algorithm is proposed for multiple unmanned surface vessels (USVs), in which actor-critic reinforcement learning (RL) is utilized to optimize the merging process. Specifically, the multiple-USV optimal surrounding control problem is first transformed into the Hamilton-Jacobi-Bellman (HJB) equation, which is difficult to solve due to its nonlinearity. An adaptive actor-critic RL control paradigm is then proposed to obtain the optimal surround strategy, wherein the Bellman residual error is utilized to construct the network update laws. Particularly, a virtual controller representing intermediate transitions and an actual controller operating on a dynamics model are employed as surrounding control solutions for second-order USVs; thus, optimal surrounding control of the USVs is guaranteed. In addition, the stability of the proposed controller is analyzed by means of Lyapunov theory functions. Finally, numerical simulation results demonstrate that the proposed actor-critic RL-based surrounding controller can achieve the surrounding objective while optimizing the evolution process and obtains 9.76% and 20.85% reduction in trajectory length and energy consumption compared with the existing controller.

Colchicine prevents perioperative myocardial injury in cardiac surgery by inhibiting the formation of neutrophil extracellular traps: evidence from rat models.

OBJECTIVES: Colchicine, an anti-inflammatory agent, has been reported to improve myocardial infarction prognosis by inhibiting neutrophil extracellular traps (NETs) release. However, its role in cardiac surgery and the mechanisms behind NETs suppression remain unclear. This study aimed to explore colchicine's cardioprotective effects against perioperative myocardial injury in cardiac surgery, focusing on NETs inhibition as a novel therapeutic strategy. METHODS: Male Sprague-Dawley rats were pre-treated with colchicine (0.1 mg/kg/day) or CI-amidine (10 mg/kg/day) for 7 days before undergoing cardiopulmonary bypass and myocardial ischaemia/reperfusion injury. The model was created by subjecting the rats to cardiopulmonary bypass and myocardial ischaemia/reperfusion injury. Under 4.0% sevoflurane anaesthesia, cardiopulmonary bypass was initiated by cannulating the tail artery and right atrium, and perfusion was maintained for 4 h. Immunofluorescence detected NETs, and haematoxylin and eosin staining assessed inflammatory cell. RESULTS: We found colchicine treatment significantly reduced perioperative myocardial injury in rats. Furthermore, we observed a notable elevation of NETs in the myocardial tissue of animal models. Moreover, suppressing peptidylarginine deiminase 4 was found to markedly diminish perioperative myocardial injury in rats. Additionally, colchicine can mitigate the release of NETs by inhibiting peptidylarginine deiminase 4. CONCLUSIONS: NETs were significantly elevated during the perioperative period of cardiac surgery. Colchicine significantly mitigated myocardial injury in cardiac surgery by inhibiting NETs formation, with peptidylarginine deiminase 4 inhibition being one of its mechanisms.

FLAIR: A Phase II, Open Label, Randomized Study of Osimertinib Plus Bevacizumab Versus Osimertinib in Recurrent or Metastatic Treatment-Naïve NSCLC Patients Harboring EGFR 21L858R Mutation.

INTRODUCTION: Osimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. MATERIALS AND METHODS: FLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. RESULTS: FLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). CONCLUSIONS: This study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

Phase behavior and synergistic gelation of scallop (Patinopecten yessoensis) male gonad hydrolysates and gellan gum driven by pH.

BACKGROUND: Previous studies have investigated complexation and coacervation of scallop Patinopecten yessoensis male gonad hydrolysates (SMGHs) and polysaccharides influenced by pH and blending ratio. It has been found that SMGHs/polysaccharide composite shows better gel properties under strongly acidic conditions. Thus, the complexation and coacervation of SMGHs and gellan gum (GG) were investigated via turbidimetric titration at different pH values (1-12) and biopolymer blending ratios (9.5:0.5-6:4). RESULTS: Both pHc and pHφ1 exhibited ratio-independent behavior with constant values at approximately pH 5.8 and pH 3.8, respectively, dividing SMGHs/GG blends into three phases named mixed polymers, soluble complexes and insoluble coacervates, respectively. Overall, SMGHs and GG exhibited synergistic gelation under neutral and acidic conditions, with the initial storage modulus (G') increasing by approximately 42.5-, 573.7- and 3421-fold and 97.7-, 550.3- and 0.5-fold, respectively, at pH 7, 5 and 3, compared with SMGHs and GG. As pH decreased from 7 to 3, the initial G' and viscosity η values of SMGHs/GG gels increased by 20.1- and 2.3-fold, respectively, exhibiting the greatest increase in gel strength. Moreover, the free water in the SMGHs/GG system significantly shifted toward lower relaxation times attributed to the immobilization of the outer hydration layers. SMGHs/GG gels in the insoluble phase exhibited denser networks and rougher surfaces, supporting the enhanced rheological properties and water retention capacity of the gel. CONCLUSION: This work provides a basic foundation for the development of pH-driven SMGHs/GG gelation by examining complexation and coacervation processes. © 2024 Society of Chemical Industry.

N-Directed, Radical Relay Enantioconvergent Sulfinylation of Distal C(sp3)-H Bonds via Cobalt Catalysis.

Cobalt-catalyzed enantioconvergent cross-coupling of C(sp3)-H bonds with in situ-generated sulfenate anions is achieved to access chiral sulfoxides, which are found in the structures of many biologically active agents. The more challenging aliphatic C-H bonds as well as sterically hindered substrates containing tertiary C-H bonds could also be tolerated well. Mechanistic studies indicate that the transformation could undergo a CoIIS(O)R-mediated single-electron transfer with N-fluorocarboxamides, followed by a 1,5-hydrogen atom transfer and then a pivotal organocobalt(IV)-controlled enantioselective cross-coupling process. This novel asymmetric radical reaction for C-S bond construction could open a new door for the synthesis of sulfur-centered chiral compounds.

Cepharanthine-mediated endoplasmic reticulum stress inhibits Notch1 via binding GRP78 for suppressing hepatocellular carcinoma metastasis.

BACKGROUND: The metastasis of hepatocellular carcinoma (HCC) leads to a poor prognosis, wherein the activation of Notch1 is an essential contributor. Cepharanthine (Cep) has been identified for its effective antiviral function and versatile intracellular targets. Our previous study has only reported the anti-cancer efficacy of Cep in lung cancer, without an in-depth exploration. Herein, the present study aims to investigate the anti-metastasis effect in HCC, the target involved, and the molecular mechanism of Cep. METHODS: Stable over-expression of Notch1-N1ICD yielded C5WN1 cells compared with C5WBF344 cells. The C5WN1 cells and C5WN1 cell-bearing mice were applied as the HCC model. The bioinformatics analysis, RNA sequencing, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), microscale thermophoresis (MST), and transient knockdown techniques were carried out to identify the underlying target. The apoptosis assay, immunofluorescent staining, qRT-PCR, Western blots, Elisa, flow cytometry, migration and scratching experiments, Transmission electron microscopy (TEM), laser scanning confocal microscopy (LSCM), micro-computed tomography (micro-CT), and histopathological experiments were conducted to assay the anti-HCC efficacy, functions, and mechanism. RESULTS: Notch1 had an increased expression in HCC and contributed to metastasis thereupon. Surprisingly, Cep (2 µg/ml in vitro, 5 mg kg-1in vivo) presented potent Notch1 signaling pathway inhibitory effect and anti-metastasis efficacy in C5WN1 cells and in situ mice models as evidenced by reduced Notch1/MMP-2/MMP-9 expression, TGF-ß release, decreased cell migration, diminished pulmonary metastases, and prolonged survival. RNA sequencing showed that the differential gene of Cep-treated HCC cells was positioned in the endoplasmic reticulum (ER). Molecular docking, CETSA, DARTS, and MST further identified that the possible target of Cep was GRP78, which was distributed in the ER. As expected, Cep (2 µg/ml) up-regulated the critical molecules of ER stress such as GRP78, induced ß-amyloid accumulation, and promoted calcium burst in HCC. In contrast, suppression of GRP78 attenuated Cep-induced ER stress. Furthermore, inhibition of ER stress abated Cep-induced Notch1 inactivation and HCC cells' migration. CONCLUSIONS: Taken together, the present study finds that Cep possesses excellent anti-metastasis of HCC, wherein the GRP78 could be directly bound and activated by Cep, leading to ER stress and Notch1 blockage. This study reveals for the first time the effect, critical target, and mechanism of the Cep-mediated anti-cancer effect, providing novel insights into the molecular target therapy by phytomedicine.

Gelation properties and swallowing characteristics of heat-induced whey protein isolate/chia seed gum composite gels as dysphagia food.

Soft gels based on protein-polysaccharide composite systems play a crucial role in the dietary management of people with dysphagia. The effect of chia seed gum (CSG) on the gelling and swallowing properties of heat-induced whey protein isolate (WPI) gels (3.125-75 mg/mL) was investigated. The results showed that adding CSG reduced the gelation concentration of WPI and weak gels could form at 12.5 mg/mL WPI concentration. In addition, the viscoelasticity and water-binding capacity of the WPI/CSG composite gels were gradually enhanced with increasing WPI concentrations. The WPI/CSG composite systems can be classified as level 2-5 dysphagia-oriented foods according to the International Dysphagia Diet Standardization Initiative (IDDSI) framework. The incorporation of CSG promoted the cross-linking of protein aggregates and the formation of compact and continuous network structures, resulting in improved gelling properties of composite systems. This study contributes to the development of novel soft gel-type dysphagia foods with better textural characteristics.

A 39-year-old woman with transient convulsions and vision disturbances: a case report.

BACKGROUND: Posterior reversible encephalopathy syndrome is a rare neurological syndrome that refers to reversible subcortical vasogenic brain edema disorder in patients with acute neurological symptoms. CASE PRESENTATION: Whether there is a direct causal relationship between pancreatitis and posterior reversible encephalopathy syndrome needs further study. We here report a 39-year-old Chinese woman who was diagnosed with pancreatitis followed by vision disturbance. The patient was finally diagnosed with posterior reversible encephalopathy syndrome. On the basis of this rare case, we analyzed the causes of visual disturbance and proposed diagnostic ideas. CONCLUSIONS: For posterior reversible encephalopathy syndrome, early identification and treatment of the primary disease are particularly important. Imaging and clinical characteristics in posterior reversible encephalopathy syndrome are usually reversible.

Copper-Catalyzed [3 + 2] Annulation of O-Acyl Oximes with p-Hydroquinones for the Synthesis of 5-Hydroxyindoles.

A copper-catalyzed [3 + 2] annulation of O-acyl oximes with 2-electron-withdrawing group substituted p-hydroquinones for the efficient synthesis of polysubstituted 5-hydroxyindoles is developed. Further intramolecular cyclization leads to the concise and rapid construction of several kinds of 3,4- and 4,5-fused polycyclic indoles.

Engineering Isomeric AIEgens Containing Tetraphenylpyrazine for Dual Memory Storage.

Tetraphenylpyrazine (TPP) is a promising heterocycle-based aggregation-induced emission luminogen (AIEgen) which has sparked multiple applications in organic light-emitting diodes, sensors, and biotherapy. However, the utility of it in developing information storage materials is relatively rare. Moreover, TPP is mostly employed as an electronic acceptor in molecular design, while the consideration of it as an electronic donor is attractive in studies which may provide a full understanding of its property to tailor the materials. In this work, we synthesize three TPP-based molecules by decorating it with acrylonitrile and isomeric pyridine units, which show AIE behavior by property inheritance from their parent unit. Interestingly, the effective intramolecular charge transfer takes place from the TPP electronic donor to the acrylonitrile and pyridine electronic acceptor, therefore inducing a remarkable solvatochromic effect as the solvent polarity improves. Moreover, it is revealed that the isomeric effect of the nitrogen atom in the pyridines may pose an influence on the absorption, solvatochromism, and AIE behavior. In addition, the acrylonitrile and pyridine groups are reactive to light and acid-base stimuli with irreversible and reversible responses, respectively. Combined with the high light-harvesting ability of these AIEgens, they show great potential in the stimuli-responsive materials for dual information storage.

Investigation and analysis of the status of cancer health popularization in China, 2023.

BACKGROUND: Cancer presents a significant public health challenge in China, necessitating broad collaboration across society. The Chinese government has articulated a goal to increase the overall five-year survival rate for cancer by 15% by 2030. Achieving this objective requires not only advances in medical technology, but also an improvement in the dissemination of knowledge pertaining to cancer prevention and treatment. AIM: To provide a comprehensive understanding of the status of cancer prevention and level of popularization in China in 2023. METHODS: From January 2023 to May 2023, online questionnaires were distributed to 3000 participants, including medical personnel, patients with cancer, their families, and the general public. There were 2711 valid responses, covering the entire nation. RESULTS: A total of 1020 medical personnel and 1691 patients with cancer, their family members, and the general public participated in the survey. Among medical personnel, 93.2% had popularized cancer health. Commonly addressed topics included cancer prevention (85.9%) and cancer screening (77.8%). Primary challenges included time constraints (73.9%), insufficient personnel and material support (66.7%), and uncertainty as to where to begin (49.3%). Among patients with cancer, their family members, and the general public, 93.4% reported reading or watching cancer science popularization materials and 56.9% expressed a desire for deeper understanding. The most sought-after topics in cancer science popularization included cancer screening (80.2%) and cancer prevention (75.8%). The greatest challenge encountered in accessing cancer health popularization was an abundance of misinformation (67.5%). CONCLUSION: Most clinical doctors, patients, family, and the general public wish to participate in cancer education. However, improvement in the quality of content in cancer prevention and treatment education is required.

Discovery of Acaricidal, Insecticidal, and Fungicidal Candidates Inspired by Natural Ethyl Cinnamate Compounds Isolated from Polygonum orientale L.

As a continuation of our research on the pesticide development of Polygonum orientale L., the chemical constituents of the seeds of P. orientale were systematically investigated. Eleven natural compounds (PO-1 to PO-11) were isolated from the EtOAc extract of P. orientale. Notably, compound PO-9 and its dimeric compound PO-10 were first isolated from P. orientale and possessed excellent acaricidal activity against Tetranychus cinnabarinus. With PO-9 and PO-10 as the lead compounds, two series of cinnamate derivatives were further synthesized, and their acaricidal, insecticidal, and fungicidal activities were evaluated systematically. The insecticidal activity results showed that dimeric derivative NKY-70 displayed the highest acaricidal activity against T. cinnabarinus and insecticidal activities against Brevicoryne brassicae and Myzus persicae. Furthermore, most of these compounds showed excellent in vitro antifungal activity against plant fungi. Compound NKY-66 displayed the highest and broad spectrum of antifungal activity against 23 fungi, and the respective EC50 values were 0.09, 0.08, 0.12, 0.18, 0.12, and 0.09 mg/mL against Valsa mali, Fusarium oxysporum f. sp. cucumerinum, Fusarium graminearum, Magnaporthe oryzae, Colletotrichum capsici, and Phytophthora infestans, which were more potent than those of chlorothalonil and procymidone. Moreover, the in vivo fungicidal evaluation also demonstrated that compound NKY-66 could effectively control plant fungal diseases in the greenhouse and in the field, such as damping off, powdery mildew, and cucumber downy mildew. Therefore, these findings implied that the cinnamate derivative NKY-66 displayed superior in vitro and in vivo fungicidal activities and could be a potential candidate against plant fungal diseases.

[Efficacy and Safety of Ixazomib Combined with Thalidomide and Dexamethasone in Treatment of Multiple Myeloma].

OBJECTIVE: To investigate the efficacy and safety of ixazomib combined with thalidomide and dexamethasone in the treatment of multiple myeloma (MM). METHODS: The clinical data of 60 MM patients admitted to our center from January 2019 to June 2022 were analyzed retrospectively, including 43 newly diagnosed patients and 17 patients with recurrence and progression. All patients were treated with ixazomib combined with thalidomide and dexamethasone, and completed 2 to 7 treatment cycles. RESULTS: The overall response rate (ORR) of all patients was 98.3%. Among them, 53 patients completed 4 treatment cycles, and the ORR was 86.8%. Seventeen patients completed the whole treatment cycle, with curative effect reaching 88.2% achieving very good partial response and above, and 52.9% achieving complete response and above. Albumin and ß2-microglobulin of all patients had been improved rapidly after treatment. The deadline was August 31, 2022. The median follow-up time was 14(3-24) months, and overall survival (OS) rate was 86.67%. The OS rate of patients with recurrence and progression was significantly lower than that of newly diagnosed patients (P < 0.05). The most common adverse reaction of hematology was lymphopenia (53.3%), followed by anemia (33.3%). The most common non-hematological adverse reaction was fatigue (68.33%), followed by peripheral neuropathy (31.67%). CONCLUSION: Ixazomib combined with thalidomide and dexamethasone is effective in the treatment of MM, with good short-term efficacy, survival and safety. However, its long-term efficacy needs further observation.

The mechanism of quercetin in treating intracerebral hemorrhage was investigated by network pharmacology and molecular docking.

BACKGROUND: The aim of this study was to explore the molecular mechanism of quercetin in the treatment of intracerebral hemorrhage. METHODS: Quercetin target genes and intracerebral hemorrhage target genes were collected from 5 databases. After standardized conversion of the obtained target genes through uniprot database, cross genes of the 2 were obtained using Venny 2.1 online tool. Further, protein interaction relationships were obtained in the String database, and then core target genes were screened and visualized by Cytoscape software, and cross genes were enriched by GO and KEGG pathways. Finally, the active drug ingredients and target proteins were verified and visualized by computer. RESULTS: In this study, 197 quercetin targets were identified as potential targets for the treatment of intracerebral hemorrhage, and 7 core target genes (TP53, STAT3, AKT1, SRC, JUN, TNF, and IL6) were screened. The GO and KEGG analyses further shed light on the molecular mechanisms underlying quercetin's treatment of intracerebral hemorrhage, involving multiple biological processes and signaling pathways (such as cancer pathways, lipids, and atherosclerosis). The stable binding of quercetin to these 7 key targets was confirmed by molecular docking simulation. CONCLUSION: Quercetin may treat intracerebral hemorrhage through multi-target-multi-pathway mechanisms, including regulating apoptosis, inhibiting inflammatory response, inhibiting iron death, and regulating angiogenesis, which can help alleviate nerve damage caused by intracerebral hemorrhage.

Highly enhanced chiroptical effect from self-inclusion helical nanocrystals of tetraphenylethylene bimacrocycles.

The helical structure is often the key factor for forming and enhancing chiroptical properties, such as circular dichroism (CD) and circular polarized luminescence (CPL) effects. However, no matter whether helical molecules or helical aggregates, they usually display modest chiroptical signals, which limits their practical applications. Herein, chiral tetraphenylethylene (TPE) bimacrocycles prepared in almost quantitative yield show strong and repeatable CD signals up to more than 7000 mdeg, which is very rare for general organic compounds, besides emitting very strong CPL light with an absolute g lum value up to 6.2 × 10-2. It is found that the superhelices formed by self-inclusion between the cavity and outward cyclohexyl ring of TPE bimacrocycles in crystal state are the key factor for highly enhanced chiroptical effect, and the self-inclusion superhelices in assemblies are confirmed by High Resolution Transmission Electron Microscopy (HR-TEM), Powder X-ray Diffraction (XRD) and Fourier Transform Infrared Spectrometry (FT-IR) data. Furthermore, the chiral TPE bimacrocycle shows great potential in chiral recognition and chiral analysis not only for chiral acids but also for chiral amines, chiral amino acids, and neutral chiral alcohol. Using self-inclusion helical nanocrystals of chiral macrocycles, this work provides a new strategy for chiroptical materials with excellent chiroptical properties.

ER stress modulates Kv1.5 channels via PERK branch in HL-1 atrial myocytes: Relevance to atrial arrhythmogenesis and the effect of tetramethylpyrazine.

Endoplasmic reticulum (ER) stress is implicated in cardiac arrhythmia whereas the associated mechanisms remain inadequately understood. Kv1.5 channels are essential for atrial repolarization. Whether ER stress affects Kv1.5 channels is unknown. This study aimed to elucidate the response of Kv1.5 channels to ER stress by clarifying the unfolded protein response (UPR) branch responsible for the channel modulation. In addition, the effect of tetramethylpyrazine (TMP) on Kv1.5 channels was studied. Patch clamp and western-blot results revealed that exposure of HL-1 atrial myocytes to ER stress inducer tunicamycin upregulates Kv1.5 expression, increases Kv1.5 channel current (I Kur ) (14.91 ± 1.11 vs. 6.11 ± 1.31 pA/pF, P < 0.001), and shortened action potential duration (APD) (APD90: 82.79 ± 5.25 vs.121.11 ± 6.72 ms, P < 0.01), which could be reverted by ER stress inhibitors. Blockade of the PERK branch while not IRE1 and ATF6 branches of UPR downregulated Kv1.5 expression, accompanied by a decreased I Kur (9.03 ± 0.99 pA/pF) and a prolonged APD90 (113.69 ± 4.41 ms) (P < 0.01). PERK-mediated increases of Kv1.5 expression and I Kur were also observed in HL-1 cells incubated with thapsigargin. TMP suppressed the enhancement of I Kur (10.52 ± 0.97 vs. 17.52 ± 2.25 pA/pF, P < 0.05), prevented the shortening of APD (APD90: 110.16 ± 5.36 vs. 84.84 ± 4.58 ms, P < 0.05), and inhibited the upregulation of Kv1.5 triggered by ER stress. Our study suggests that ER stress induces upregulation and activation of Kv1.5 channels in atrial myocytes through the PERK branch of UPR. TMP prevents Kv1.5 upregulation/activation and the resultant APD shortening by inhibiting ER stress. These results may shed light on the mechanisms of atrial arrhythmogenesis and the antiarrhythmic effect of the traditional Chinese herb TMP.