A Machine Learning Model Based on Counterfactual Theory for Treatment Decision of Hepatocellular Carcinoma Patients.

Purpose: To predict the efficacy of patients treated with hepatectomy and transarterial chemoembolization (TACE) based on machine learning models using clinical and radiomics features. Patients and Methods: Patients with HCC whose first treatment was hepatectomy or TACE from June 2016 to July 2021 were collected in the retrospective cohort study. To ensure a causal effect of treatment effect and treatment modality, perfectly matched patients were obtained according to the principle of propensity score matching and used as an independent test cohort. Inverse probability of treatment weighting was used to control bias for unmatched patients, and the weighted results were used as the training cohort. Clinical characteristics were selected by univariate and multivariate analysis of cox proportional hazards regression, and radiomics features were selected using correlation analysis and random survival forest. The machine learning models (Deathhepatectomy and DeathTACE) were constructed to predict the probability of patient death after treatment (hepatectomy and TACE) by combining clinical and radiomics features, and an optimal treatment regimen was recommended. In addition, a prognostic model was constructed to predict the survival time of all patients. Results: A total of 418 patients with HCC who received either hepatectomy (n=267, mean age, 58 years ± 11 [standard deviation]; 228 men) or TACE (n=151, mean age, 59 years ± 13 [standard deviation]; 127 men) were recruited. After constructing the machine learning models Deathhepatectomy and DeathTACE, patients were divided into the hepatectomy-preferred and TACE-preferred groups. In the hepatectomy-preferred group, hepatectomy had a significantly prolonged survival time than TACE (training cohort: P < 0.001; testing cohort: P < 0.001), and vise versa for the TACE-preferred group. In addition, the prognostic model yielded high predictive capability for overall survival. Conclusion: The machine learning models could predict the outcomes difference between hepatectomy and TACE, and prognostic models could predict the overall survival for HCC patients.

Radiomics nomogram based on MRI water imaging identifying symptomatic nerves of patients with primary trigeminal neuralgia: A preliminary study.

The study proposes a combined nomogram based on radiomics features from magnetic resonance neurohydrography and clinical features to identify symptomatic nerves in patients with primary trigeminal neuralgia. We retrospectively analyzed 140 patients with clinically confirmed trigeminal neuralgia. Out of these, 24 patients constituted the external validation set, while the remaining 116 patients contributed a total of 231 nerves, comprising 118 symptomatic nerves, and 113 normal nerves. Radiomics features were extracted from the MRI water imaging (t2-mix3d-tra-spair). Radiomics feature selection was performed using L1 regularization-based regression, while clinical feature selection utilized univariate analysis and multivariate logistic regression. Subsequently, radiomics, clinical, and combined models were developed by using multivariate logistic regression, and a nomogram of the combined model was drawn. The performance of nomogram in discriminating symptomatic nerves was assessed through the area under the curve (AUC) of receiver operating characteristics, accuracy, and calibration curves. Clinical applications of the nomogram were further evaluated using decision curve analysis. Five clinical factors and 13 radiomics signatures were ultimately selected to establish predictive models. The AUCs in the training and validation cohorts were 0.77 (0.70-0.84) and 0.82 (0.72-0.92) with the radiomics model, 0.69 (0.61-0.77) and 0.66 (0.53-0.79) with the clinical model, 0.80 (0.74-0.87), and 0.85 (0.76-0.94) with the combined model, respectively. In the external validation set, the AUCs for the clinical, radiomics, and combined models were 0.70 (0.60-0.79), 0.78 (0.65-0.91), and 0.81 (0.70-0.93), respectively. The calibration curve demonstrated that the nomogram exhibited good predictive ability. Moreover, The decision curve analysis curve indicated shows that the combined model holds high clinical application value. The integrated model, combines radiomics features from magnetic resonance neurohydrography with clinical factors, proves to be effective in identify symptomatic nerves in trigeminal neuralgia. The diagnostic efficacy of the combined model was notably superior to that of the model constructed solely from conventional clinical features.

Preoperative Radiomics Nomogram Based on CT Image Predicts Recurrence-Free Survival After Surgical Resection of Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: To construct preoperative models based on CT radiomics, radiologic and clinical features to predict recurrence-free survival (RFS) after liver resection (LR) of BCLC 0 to B stage hepatocellular carcinoma (HCC) and to classify the prognosis. MATERIALS AND METHODS: This study retrospectively analyzed 161 HCC patients who underwent radical LR. Two methods, the least absolute shrinkage and selection operator and random survival forest analysis, were performed for radiomics signature (RS) construction. Univariate and multivariate stepwise Cox regression analyses were performed to establish a combined nomogram (RCN) of RS and clinical parameters and a clinical nomogram (CN). The performance of the models was assessed comprehensively using Harrell's concordance index (C-index), the calibration curve, and decision curve analysis. The discrimination accuracy of the models was compared using integrated discrimination improvement index (IDI). The risk stratification effect was assessed with Kaplan-Meier survival analysis and subgroup analysis. RESULTS: The RCN achieved a C-index of 0.792/0.758 in the training/validation set, which was higher than the CN, RS, and BCLC stage system. The discriminatory accuracy of the RCN was improved when compared to the CN, RS, and BCLC staging systems (IDI > 0). Decision curve analysis reflected the clinical net benefit of the RCN. The RCN allows risk stratification of patients in different clinical subgroups. CONCLUSION: The integrated model combining RS and clinical factors can more effectively predict RFS after LR of BCLC 0 to B stage HCC patients and can effectively stratify the prognostic risk.

Intra-myocardial Delivery of a Novel Thermosensitive Hydrogel Inhibits Post-infarct Heart Failure After Degradation in Rat.

Whether intra-myocardial delivery of hydrogel can prevent post-infarct heart failure (HF) in a long follow-up period, especially after it is degraded, remains unclear. In this study, Dex-PCL-HEMA/PNIPAAm (DPHP) hydrogel was delivered into peri-infarct myocardium of rat when coronary artery was ligated, while PBS was employed as control. Twelve weeks later, compared with control, left ventricle remodeling was attenuated and cardiac function was preserved; serum brain natriuretic peptide, cardiac aldosterone, and pulmonary congestion were suppressed in hydrogel group. Pro-fibrogenic mRNA increased in infarct area while decreased in remote zone, as well as hypertrophic mRNA. These data proves DPHP hydrogel suppresses ventricular remodeling and HF by promoting fibrotic healing in infarct area and inhibiting reactive fibrosis and hypertrophy in remote zone. Timely intra-myocardial hydrogel implantation is an effective strategy to inhibit post-infarct cardiac remodeling and have a long-term beneficial effect even after it has been biodegraded.

Potential circulating biomarkers of circulating chemokines CCL5, MIP-1ß and HA as for early detection of cirrhosis related to chronic HBV (hepatitis B virus) infection.

BACKGROUND: Due to no clinical symptoms in the compensated stage of cirrhosis, it is usually diagnosed when decompensated complications occur. In this study, the noninvasive circulating biomarkers for early detection to compensated stage of cirrhosis in patients with chronic HBV (hepatitis B virus) infection was explored. METHODS: According to the Guideline of Prevention and Treatment of Chronic Hepatitis B (2015 Update), 78 patients with CHB (chronic hepatitis B) were divided into mild group, moderate-to-advanced group, while 73 patients with HBV-related cirrhosis were divided into compensated group and decompensated group. Nineteen cytokines and chemokines, four serum liver fibrosis markers were measured using chemiluminescence. The expression of CCL5 in liver tissue was determined with immunohistochemistry. RESULTS: The CCL5 expression level in serum increased in CHB patients with aggravated liver injury and significantly decreased in cirrhosis patients with advanced liver fibrosis. ROC analysis revealed that the serum levels of CCL5, HA and MIP-1ß were effective in distinguishing patients with cirrhosis from patients with CHB, especially for CCL5. Increasing serum level of CCL5 in CHB patients was severely associated with disease progression. CONCLUSIONS: The serum levels of CCL5, HA and MIP-1ß maybe used to distinguish cirrhosis from CHB patients, moreover, CCL5 was the most reliable marker. The increasing serum levels of CCL5 were significantly related to disease progression in CHB patients.

Redox-sensitive micelles composed of disulfide-linked Pluronic-linoleic acid for enhanced anticancer efficiency of brusatol.

Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway.

Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy.

Mitoxantrone (MIT) is an anticancer agent with photosensitive properties that is commonly used in various cancers. Multidrug resistance (MDR) effect has been an obstacle to using MIT for cancer therapy. Photochemical internalization, on account of photodynamic therapy, has been applied to improve the therapeutic effect of cancers with MDR effect. In this study, an MIT-poly(ε-caprolactone)-pluronic F68-poly(ε-caprolactone)/poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-poly(d,l-lactide-co-glycolide) (MIT-PFP/PPP) mixed micelles system was applied to reverse the effect of MDR in MCF-7/ADR cells via photochemical reaction when exposed to near-infrared light. MIT-PFP/PPP mixed micelles showed effective interaction with near-infrared light at the wavelength of 660 nm and exerted great cytotoxicity in MCF-7/ADR cells with irradiation. Furthermore, MIT-PFP/PPP mixed micelles could improve reactive oxygen species (ROS) levels, decrease P-glycoprotein activity, and increase the cellular uptake of drugs with improved intracellular drug concentrations, which induced cell apoptosis in MCF-7/ADR cells under irradiation, despite MDR effect, as indicated by the increased level of cleaved poly ADP-ribose polymerase. These findings suggested that MIT-PFP/PPP mixed micelles may become a promising strategy to effectively reverse the MDR effect via photodynamic therapy in breast cancer.

Triphenylphosphonium-modified poly(ethylene glycol)-poly(ε-caprolactone) micelles for mitochondria- targeted gambogic acid delivery.

Mitochondria are important targets for the intracellular delivery of drugs and DNA. For mitochondria-targeted delivery, a mitochondriotropic molecule, triphenylphosphonium (TPP), was applied to the synthesis of amphiphilic TPP-poly(ethylene glycol)-poly(ε-caprolactone) (TPP-PEG-PCL) polymers. The TPP-PEG-PCL polymer was used to prepare micelles using a solvent evaporation method for the delivery of gambogic acid (GA) (GA-TPP). The micelles were obtained with a favorable particle size of 150.07±11.71nm and an encapsulation efficiency of 80.78±1.36%, and they displayed homogeneous spherical shapes. The GA-TPP micelles exerted enhanced cytotoxic and pro-apoptotic effect against A549 cells compared to free GA and GA-loaded PEG-PCL (GA-PP) micelles, due to the inhibition of the expression of apoptosis-related proteins and promotion of caspase 3/7 and caspase 9 activity. Notably, the mitochondria-targeting GA-TPP micelles selectively accumulated in the mitochondria, inducing the loss of mitochondrial membrane potential and the release of cytochrome c, thereby achieving improved mitochondria-targeting effects. In conclusion, the GA-TPP micelle system shows great promise for lung cancer treatment by inducing an apoptotic effect via the mitochondrial signaling pathway.

Fabrication of "Plug and Play" Channels with Dual Responses by Host-Guest Interactions.

The "Plug and Play" template can be individually or successively grafted by dual-responsive molecules on the α-CD modified channels by host-guest interactions and can be peeled off by UV irradiation. The artificial channels present six kinds of responses cycling among four states responding to three environment stimuli, as light, pH, and temperature.

A Tat-conjugated Peptide Nucleic Acid Tat-PNA-DR Inhibits Hepatitis B Virus Replication In Vitro and In Vivo by Targeting LTR Direct Repeats of HBV RNA.

Hepatitis B virus (HBV) infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell-penetrating peptide-conjugated peptide nucleic acid (PNA), Tat-PNA-DR, was designed to target the direct repeat (DR) sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg), HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT) and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC). Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA-DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV.

MMP-responsive theranostic nanoplatform based on mesoporous silica nanoparticles for tumor imaging and targeted drug delivery.

In this paper, we report on an intelligent mesoporous silica-based multifunctional theranostic nanoplatform (designated as MMTNP) for tumor imaging as well as controlled drug release. This theranostic nanoplatform consists of MCM-41 typical mesoporous silica nanoparticles (MSNs) as a hydrophobic drug carrier, matrix metalloprotease-2 (MMP-2) activated fluorescence imaging peptides on the surface of MSNs served as diagnostic probes as well as enzyme-responsive nanovalves blocking the pores, and cRGD peptides further functionalized on the surface of MSNs for tumor targeting. In the absence of MMP-2 conditions, the proximity between the fluorescent dye 5(6)-carboxytetramethylrhodamine hydrochloride (TAMRA) and the quencher 4,4-dimethylamino-azobenzene-4'-carboxylic acid (Dabcyl) on the surface of MSNs resulted in no fluorescence. When the drug loaded nanoplatform arrived at tumor tissue with overexpressed MMP-2, the fluorescence of TAMRA became recovered efficiently due to the hydrolysis of the MMP-2 sensitive peptide substrate, realizing tumor imaging and triggering drug release. In addition, the further introduced cRGD peptide significantly enhanced the targeting efficiency through receptor-mediated endocytosis in tumor cells.

[Effect of Tiam 1 on cell proliferation and migration in head and neck squamous cell carcinoma cells].

OBJECTIVE: To investigate the effect of T lymphoma invasion and metastasis 1 (Tiam 1) overexpression in head and neck squamous cell carcinoma (HNSCC) cells. METHOD: Endogenous expression of Tiam 1 in 8 head and neck squamous cell carcinoma cell (HNSCC) lines was investigated by real-time RT-PCR. A lentivirus vector containing Tiaml was transfected into UM-SCC-47 cells, a head and neck squamous cell carcinoma cell line with little endogenous Tiaml expression. Stable clone, obtained by G418 screening, were assayed by RT-PCR and Western blot to validate the gene expression efficiency. The biological behaviors of the transduced cells were determined by cell counting, MTT and in-vitro migration assay. RESULT: Tiam 1 gene was highly expressed in M2 cell line and it's low level expression was found in UM-SCC-47. Cell counting and MTT assay showed that over-expression of Tiaml significantly promoted cell proliferation (P < 0.05). The cell monolayers overexpressed Tiaml that resulted in a significant increasment of cell migration in infected head and neck squamous cell carcinoma cell lines (P < 0.05). CONCLUSION: Tiam 1 gene plays an important role in the growth and migration in head and neck squamous cell carcinoma cell lines. It may be a useful marker for metastasis of head and neck squamous cell carcinoma.

A novel promoter mutation (HBB: c.-75G>T) was identified as a cause of ß(+)-thalassemia.

We report a novel ß-globin gene promoter mutation in a Chinese family identified using fluorescence resolution melting curve analysis and gene sequencing. The proband, who showed the phenotype of ß-thalassemia intermedia (ß-TI), was found to be a compound heterozygote for the novel mutation -25 (G>T) (HBB: c.-75G>T) and a codon 17 (HBB: c.52A>T) mutation. Moreover, conservation analysis using phyloP and phastCons indicated that the mutated base in the proband was conserved. This novel point mutation on the ß-globin gene is in close proximity to the conserved ATAA sequence located at position -25 relative to the mRNA Cap site. We performed a further comparative analysis of the clinical phenotypes and hematological parameters in this pedigree and found that the father was a carrier of the novel point mutation and showed low levels of hemoglobin (Hb), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH). Thus, the available evidence suggests that this novel mutation, -25, results in ß(+)-thalassemia (ß(+)-thal).

Dual-pH Sensitive Charge-Reversal Polypeptide Micelles for Tumor-Triggered Targeting Uptake and Nuclear Drug Delivery.

A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form ß-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive ß-carboxylic amides.

A redox-responsive drug delivery system based on RGD containing peptide-capped mesoporous silica nanoparticles.

In this paper, an intracellular glutathione (GSH) responsive mesoporous silica nanoparticle (MSN-S-S-RGD) was developed as a drug nanocarrier by immobilizing the gatekeeper (RGD containing peptide) onto MSNs using disulfide bonds. The antitumor drug, DOX was loaded onto the porous structure of the MSNs and the DOX@MSN-S-S-RGD system has been proved to be an effective nanocarrier. It was determined that most of the drug could be entrapped with only a slight leakage. After being accumulated in tumor cells via the receptor-mediated endocytosis, the surface peptide layer of DOX@MSN-S-S-RGD was removed to trigger the release of the entrapped drug to kill the tumor cell due to the cleavage of the disulfide bonds by intracellular GSH.

Completely laparoscopic ALPPS using round-the-liver ligation to replace parenchymal transection for a patient with multiple right liver cancers complicated with liver cirrhosis.

The "ALPPS" (associating liver partition with portal vein ligation for staged hepatectomy) procedure enables the rapid growth of the future liver remnant and extended surgical indication to patients with an "insufficient" future liver remnant. In May 2014, a 64-year-old male patient was admitted. The computed tomography (CT) scan showed multiple right liver lesions, which were diagnosed to be hepatocellular carcinoma by liver biopsy. The future liver remnant volume after right hemihepatectomy was calculated to be 35.6% based on the CT reconstruction. Completely laparoscopic ALPPS using round-the-liver ligation, which replaced liver splitting, was performed on him. The two-stage operation was performed successfully. The future liver remnant volume increased 37.9% according to the CT scan on Day 10 after the first-stage operation. The second-stage operation was performed on Day 14 after the first-stage operation. The patient recovered uneventfully. No bile leakage occurred. Thus the round-the-liver ligation can be safely executed in laparoscopy. Completely laparoscopic ALPPS using round-the-liver ligation is feasible and could result in a rapid hypertrophy of the liver remnant in patients with liver cancer complicated with cirrhosis.

Stepwise-acid-active multifunctional mesoporous silica nanoparticles for tumor-specific nucleus-targeted drug delivery.

In this paper, a novel stepwise-acid-active multifunctional mesoporous silica nanoparticle (MSN-(SA)TAT&(DMA)K11) was developed as a drug carrier. The MSN-(SA)TAT&(DMA)K11 is able to reverse its surface charge from negative to positive in the mildly acidic tumor extracellular environment. Then, the fast endo/lysosomal escape and subsequent nucleus targeting as well as intranuclear drug release can be realized after cellular internalization. Because of the difference in acidity between the tumor extracellular environment and that of endo/lysosomes, this multifunctional MSN-(SA)TAT&(DMA)K11 exhibits a stepwise-acid-active drug delivery with a tumor-specific nucleus-targeted property.

A coumarin derivative as a fluorogenic glycoproteomic probe for biological imaging.

Fluorescence imaging in living cells is typically carried out using a functionalized fluorescent dye. But it often causes strong background noise under many conditions where washing is not applicable. Here, we report on a coumarin based fluorogenic probe, which can be used as a bioorthogonal-labeling tool for glycoproteins. The results indicated that the probe was able to image glycoproteins in living cells and it may also be suitable for intracellular imaging.

Self-Assembly of Hybridized Peptide Nucleic Acid Amphiphiles.

In this report, a series of peptide nucleic acid amphiphiles (PNAAs) with hybridization properties were designed and synthesized. Driven by hydrophobic interaction, the hybridized PNAAs can form uniform micelles, the base stacking interaction from PNA segments further stabilized the micelles. The effects of hydrophobic alkyl chain length, structure of hydrophilic peptides, concentration, and pH on the self-assembly behavior of partly complementing PNAA duplexes were explored.

One-pot construction of functional mesoporous silica nanoparticles for the tumor-acidity-activated synergistic chemotherapy of glioblastoma.

Mesoporous silica nanoparticles (MSNs) have proved to be an effective carrier for controlled drug release and can be functionalized easily for use as stimuli-responsive vehicles. Here, a novel intelligent drug-delivery system (DDS), camptothecin (CPT)-loaded and doxorubicin (DOX)-conjugated MSN (CPT@MSN-hyd-DOX), is reported via a facile one-pot preparation for use in synergistic chemotherapy of glioblastoma. DOX was conjugated to MSNs via acid-labile hydrazone bonds, and CPT was loaded in the pores of the MSNs. At pH 6.5 (analogous to the pH in tumor tissues), a fast DOX release was observed that was attributed to the hydrolysis of the hydrazone bonds. In addition, a further burst release of DOX was found at pH 5.0 (analogous to the pH in lyso/endosomes of tumor cells), leading to a strong synergistic effect. In all, CPT and DOX could be delivered simultaneously into tumor cells, and this intelligent DDS has great potential for tumor-trigged drug release for use in the synergistic chemotherapy of tumors.