Prevalence, treatment efficacy, and risk factors of vascular complications in acute pancreatitis: A case-control study.

OBJECTIVE: We aimed to investigate the prevalence of vascular complications in acute pancreatitis (AP), to compare patient outcomes using various treatments, and to explore the related risk factors. METHODS: Consecutive AP patients admitted from January 2010 to July 2017 were retrospectively included. Demographics, vascular complications, laboratory indices, and imaging findings were collected. Univariate and multivariate analyses were used to explore potential risk factors of vascular complications. RESULTS: Of 3048 AP patients, 808 (26.5%) had vascular complications, including visceral vein thrombosis, sinistral portal hypertension, and arterial complications. And 38 (4.7%) patients received anticoagulant therapy and had a higher rate of recanalization (P < 0.001). Bleeding occurred in 95 (11.8%) patients, who received further treatment. Multivariate analysis identified male gender (odds ratio [OR] 1.650, 95% confidence interval [CI] 1.101-2.472), hyperlipidemia (OR 1.714, 95% CI 1.356-2.165), disease recurrence (OR 3.727, 95% CI 2.713-5.118), smoking (OR 1.519, 95% CI 1.011-2.283), hemoglobin level (OR 0.987, 95% CI 0.981-0.993), white blood cell (WBC) count (OR 1.094, 95% CI 1.068-1.122), non-vascular local complications (OR 3.018, 95% CI 1.992-4.573), computed tomography severity index (CTSI) (OR 1.425, 95% CI 1.273-1.596), and acute physiology and chronic health evaluation (APACHE) II score (OR 1.057, 95% CI 1.025-1.090) were related to vascular complications. CONCLUSIONS: Vascular complications in AP is prevalent and their treatment is challenging. Further investigations are warranted to determine the optimal treatment strategy. Independent risk factors included male gender, hyperlipidemia, disease recurrence, smoking, WBC count, non-vascular local complications, CTSI, and APACHE II score.

Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

The role of HMGA2 in activating the IGFBP2 expression to promote angiogenesis and LUAD metastasis via the PI3K/AKT/VEGFA signaling pathway.

This study investigates the molecular mechanism of HMGA2-mediated regulation of IGFBP2 expression in the PI3K/AKT/VEGFA signaling pathway, which is involved in angiogenesis and LUAD metastasis. Target genes with prognostic implications for LUAD patients were selected using bioinformatics, and previously published literature was referenced to predict the molecular regulatory mechanisms. A549 cells were used for in vitro validation. Cell proliferation and viability were assessed using CCK-8 and EdU assays, while cell migration ability was evaluated using Transwell and wound healing assays. Changes in angiogenesis were examined using an angiogenesis assay. The targeted binding of HMGA2 with the IGFBP2 promoter was confirmed through dual luciferase reporter gene experiments and ChIP assays. In vivo validation was performed using a xenograft mouse model, and changes in angiogenesis and tumor metastasis were observed using western blot, immunofluorescence, and H&E staining. Bioinformatics analysis revealed that HMGA2 was one of the AAGs that differed between normal individuals and LUAD patients and could serve as a critical mRNA for predicting LUAD prognosis. Results from in vitro experiments demonstrated that the expression of the HMGA2 gene was significantly upregulated in LUAD cell lines. Through mediating the expression of IGFBP2, the HMGA2 gene activated the PI3K/AKT/VEGFA signaling pathway, promoting the proliferation, migration, and angiogenesis of A549 cells. In vivo, animal experiments further confirmed that HMGA2 facilitated angiogenesis and the development and metastasis of LUAD through mediating IGFBP2 expression and activating the PI3K/AKT/VEGFA signaling pathway. HMGA2 promotes angiogenesis and healthy growth and metastasis of LUAD by activating the PI3K/AKT/VEGFA signaling pathway by mediating IGFBP2 expression.

METTL14 drives growth and metastasis of non-small cell lung cancer by regulating pri-miR-93-5p maturation and TXNIP expression.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent and aggressive malignancy responsible for a significant number of cancer-related deaths worldwide. Unraveling the molecular mechanisms governing NSCLC growth and metastasis is crucial for the identification of novel therapeutic targets and the development of effective anti-cancer strategies. One such mechanism of interest is the involvement of METTL14, an RNA methyltransferase implicated in various cellular processes, in NSCLC progression. OBJECTIVE: The objective of this study was to investigate the role of METTL14 in NSCLC development and metastasis and to elucidate the underlying molecular mechanisms. By understanding the impact of METTL14 on NSCLC pathogenesis, the study aimed to identify potential avenues for targeted therapies in NSCLC treatment. METHODS: We used bioinformatics and high-throughput transcriptome sequencing analyses to screen regulatory mechanisms affecting NSCLC. The Kaplan-Meier method assessed the correlation between METTL14 expression and the prognosis of NSCLC patients. The effects of manipulated METTL14 on malignant phenotypes of NSCLC cells were examined by colony formation assay, flow cytometry, scratch assay, and Transwell assay. The tumorigenic capacity and metastatic potential of NSCLC cells in vivo were evaluated in nude mice. RESULTS: METTL14 was overexpressed in NSCLC tissues and cell lines. Its high expression indicated a poor prognosis for NSCLC patients. METTL14 silencing promoted apoptosis and repressed proliferation, migration, and invasion of NSCLC cells. miR-93-5p targeted and inhibited TXNIP. METTL14 increased miR-93-5p expression and matured pri-miR-93-5p through m6A alteration to inhibit TXNIP, thereby inhibiting NSCLC cell apoptosis. By controlling the miR-93-5p/TXNIP axis, METTL14 increased the tumorigenic potential and lung metastasis of NSCLC cells in nude mice. CONCLUSION: This study revealed a role for METTL14 in the contribution to NSCLC development and metastasis and identified METTL14 as a potential target for NSCLC treatment.

METTL3 promotes non-small-cell lung cancer growth and metastasis by inhibiting FDX1 through copper death-associated pri-miR-21-5p maturation.

Objective: We probed into the significance of METTL3 in the maturation process of pri-miR-21-5p. We specifically investigated its impact on the regulation of FDX1 and its involvement in the progression of non-small-cell lung cancer (NSCLC). Methods: The Cancer Genome Atlas (TCGA) identified NSCLC factors. Methylation-specific PCR (MSP), clonogenic tests and flow cytometry analyzed cells. Methylated RNA immunoprecipitation (Me-RIP) and dual-luciferase studied miR-21-5p/FDX1. Mice xenografts showed METTL3's tumorigenic effect. Results: METTL3, with high expression but low methylation in NSCLC, influenced cell behaviors. Its suppression reduced oncogenic properties. METTL3 enhanced miR-21-5p maturation, targeting FDX1 and boosting NSCLC tumorigenicity in mice. Conclusion: METTL3 may promote NSCLC development by facilitating pri-miR-21-5p maturation, upregulating miR-21-5p and targeting inhibition of FDX1.

We investigated a protein called METTL3, which is overly active in lung cancer cells, and how it affects the function of other small molecules. We discovered that as the activity of METTL3 increases, the growth and mobility of lung cancer cells also enhance, potentially accelerating the progression of lung cancer. Through a series of experiments, we observed how METTL3 interacts with other small molecules and further influences the behavior of lung cancer cells. This study helps us understand the role of METTL3 in the development of lung cancer and may offer new strategies for future treatments.

Charge-assisted bond and molecular self-assembly drive the gelation of lenvatinib mesylate.

Lenvatinib mesylate (LM) is a first-line anticancer agent for the treatment of unresectable hepatocellular carcinoma, while it formed viscoelastic hydrogel when contacting with aqueous medium, which would significantly hinder its in vitro dissolution. The aim of this study was to systematicly explore the gelation mechanism and gel properties via thermal analysis, rheology, morphology and spectroscopy studies. The formed hydrogel was found to be composed of a new polymorph of crystalline LM, and its mechanical strength depended on the cross-linking degree of the fibrillar network structure. Spectroscopy analyses revealed that the intermolecular hydrogen bonds (the bifurcated hydrogen bond between the adjacent urea groups and the NH⋯OC hydrogen bond between the primary amide groups) as well as π-π stacking interactions (between the benzene ring and the quinoline ring) were suggested to be the driving forces for the self-assembly of LM during gelation process. Additionally, no gelation phenomenon was observed when suspending the base form lenvatinib in water, while it could form gel in various acidic solutions (e.g. hydrochloric acid, phosphoric acid and methanesulfonic acid) because the regenerated N+-H group increased the solubility of lenvatinib and promoted the balance between the dissolution or aggregation of LX (X: acid radical ion) molecules in solutions. In conclusion, the charge-assisted bond N+-H in LM molecule and intermolecular non-covalent interactions drived the hydrogel formation of LM in aqueous media. This study elucidates the gelation mechanism and gel properties of LM hydrogel, which would be helpful to figure out strategy to eliminate its gelation fundamentally and pave the way for its further formulation development in future.

Dose escalation of 3D radiotherapy is effective for esophageal squamous cell carcinoma: a multicenter retrospective analysis (3JECROG R-03).

BACKGROUND: To evaluate the impact of radiation dose escalation on overall survival (OS) in patients with non-metastatic esophageal squamous cell carcinoma (ESCC) treated with radical radiotherapy. METHODS: The clinical data of ESCC patients treated with three-dimensional (3D) radiotherapy alone or chemoradiotherapy were collected from multiple institutes and retrospectively analyzed. Patients who received radiation dose ≥40 Gy were included. Radiation dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between radiation dose and OS to be identified. Patients were stratified into five groups according to EQD2. The Kaplan-Meier method was used to assess the OS in different dose groups. Univariate and multivariate analyses were performed to evaluate the factors associated with OS. RESULTS: A total of 2,469 patients were included from 10 institutes across China. The median follow-up time was 58.3 months [95% confidence interval (CI): 56.4-60.2 months]. The median OS and PFS time were 24.3 months (95% CI: 22.5-26.2 months) and 18.0 months (95% CI: 16.4-19.6 months), respectively. The risk of death decreased sharply with a dose up to 60 to 62 Gy, before increasing slightly after the dose was elevated beyond 62 Gy. Multivariate analysis indicated that the chance of death was significantly decreased in patients who received radiotherapy doses of 60-62 Gy [P=0.028, hazard ratio (HR) 0.85, 95% CI: 0.73-0.98)], compared with those who received radiotherapy doses of 40-60 Gy. CONCLUSIONS: Our results reveal radiation dose is a significant prognostic factor of survival for ESCC patients. Higher radiation dose contributes to much more favorable survival outcomes for ESCC patients receiving radical radiotherapy by modern techniques, and 60 Gy or above might be the most optimal radiation dose.

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride.

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3+ group of CYS after coamorphization. A fluorescence quenching test with a Stern-Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.

[Inhibition of transformation from puerarin monohydrate to puerarin dihydrate by polyvinylpyrrolidones during dissolution].

Puerarin (PUE), an isoflavone with anti-inflammation, anti-oxidation and neuroprotection effects, has been widely applied to the treatment of cardiovascular diseases in clinics in China. In the current study, we reported that the active pharmaceutical ingredient (API) of marketed products was the PUE monohydrate (PUEMH). During its supersaturated dissolution, the PUE concentration quickly reached a plateau, followed by a gradually concentration decrease to another lower plateau. In order to explore the internal mechanism of above phenomenon, the solid residues after saturated dissolution test were characterized by powder X-ray diffraction (PXRD), thermal gravity analysis (TGA) and Karl Fisher titration (KFT). PXRD suggested that a novel PUE crystal different from PUEMH formed during its dissolution, the following TGA and KFT confirmed the generation of PUE dihydrate (PUEDH) with much lower solubility. Moreover, polyvinylpyrrolidones (PVPK12, PVPK30 and PVPK90) were added in the dissolution medium to investigate their potential inhibition effects on such crystal transformation during dissolution process. We observed that polymers could inhibit the transformation from PUEMH to PUEDH and result in much higher PUE concentration level than that in pure water.

Improvement of the Pharmacological Properties of Maize RIP by Cysteine-Specific PEGylation.

To improve the pharmacological properties of maize ribosome-inactivating protein (maize RIP) for targeting HIV-infected cells, the previously engineered TAT-fused active form of maize RIP (MOD) was further engineered for cysteine-directed PEGylation. In this work, two potential antigenic sites, namely Lys-78 and Lys-264, were identified. They were mutated to cysteine residue and conjugated with PEG5k or PEG20k. The resultant PEG derivatives of MOD variants were examined for ribosome-inactivating activity, circulating half-life and immunogenicity. Our results showed that MOD-PEG conjugates had two- to five-fold lower biological activity compared to the wild-type. Mutation of the two sites respectively did not decrease the anti-MOD IgG and IgE level in mice, but the conjugation of PEG did dramatically reduce the antigenicity. Furthermore, pharmacokinetics studies demonstrated that attachment of PEG20k prolonged the plasma half-life by five-fold for MOD-K78C and 17-fold for MOD-K264C, respectively. The site-specific mutation together with PEGylation therefore generated MOD derivatives with improved pharmacological properties.

Improved brain uptake of peptide-based CNS drugs via alternative routes of administrations of its nanocarrier delivery systems: a promising strategy for CNS targeting delivery of peptides.

INTRODUCTION: Recently, developing peptide-based drugs to treat CNS diseases has gained increasing attention in both academics and pharmaceutical industry. However, targeting delivery of peptides to brain is one of the most challenging problems faced in the treatment of CNS diseases. AREAS COVERED: After explaining the brain barriers limiting the delivery of peptides, the current review focuses on summarizing the most promising approaches for the enhancement of peptide and brain uptake, including delivery via alternative routes of administrations or using nanocarriers or intranasal administration of nanocarriers loaded with peptide. In addition, the biopharmaceutic, pharmacokinetic and pharmacodynamic details of several successful peptide-based CNS drugs are highlighted. EXPERT OPINION: Although using nanocarriers or delivery via alternative routes could improve to a certain extent the brain uptake of peptides, the magnitude of changes remains moderate. Alternatively, intranasal administration of nanocarriers loaded with peptide has been demonstrated to be an effective approach for CNS-targeted delivery of peptides.

Pharmacokinetic comparison between the long-term anesthetized, short-term anesthetized and conscious rat models in nasal drug delivery.

PURPOSE: To investigate the pharmacokinetic differences between the common nasal delivery models. METHODS: In three different rat models [long-term anesthetized (with nasal surgery), short-term anesthetized (without nasal surgery) and conscious models], tacrine and loxapine were administered via nasal, intravenous and oral routes, and the plasma pharmacokinetics were compared among different models. RESULTS: Systemic exposures of both drugs and their metabolites were consistently higher in long-term anesthetized model after all routes of administration in comparison to that of conscious model. Nasal bioavailabilities in long-term anesthetized model (tacrine 83%, loxapine 97%) were much higher than that in conscious model (tacrine 10%, loxapine 46%). Further studies on tacrine and its metabolites demonstrated no significant difference in t1/2 between short-term anesthetized and conscious models after all routes of administration; however, long-term anesthetized model showed significantly longer t1/2. Regarding the pharmacokinetic parameters (Cmax, Tmax, AUC, bioavailability) of tacrine and its metabolites, short-term anesthetized model resembled closer to conscious model than long-term anesthetized model. CONCLUSIONS: Plasma clearances of tacrine, loxapine, and their metabolites were much slower in the long-term anesthetized model of nasal delivery probably due to suppressed hepatic and renal clearances, while the short-term anesthetized model imposed less impact on tacrine pharmacokinetics and metabolism.

Pharmacokinetics and disposition of various drug loaded liposomes.

Due to great efforts in past 45 years, several liposomal products including two liposomal vaccine products have been commercialized and many more potential products are now under clinical trial stage. Although liposome has significantly reduced the toxicity of the drugs with improved or maintained the efficacy, its further development has been limited by its instabilities during preparation and storage, incompatibility with certain drugs, relative high cost of production and quality control as well as unspecified drug release time and sites in vivo. In vivo behaviors of liposomal drugs highly depend on their physiochemical properties including lipid composition, particle size, surface charge, surface modifications and the administrated dose as well as the route of administration. Based on the literature reports from the past two decades, the current review provided an updated summary of the key factors in liposomal preparations for clinical usage and its impact on the alternation of pharmacokinetic and disposition behaviors of drugs encapsulated in the liposome formulations. Clinical applications of liposomal preparation in anti-tumor agents, anti-infective agents as well as the macromolecules have been highlighted.