Hereditary hemorrhagic telangiectasia involving portal venous system: A case report and review of the literature.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population. It is characterized by vasodilation, which affects specific organs, such as the skin, mucous membranes, brain, lungs, gastrointestinal tract, liver, and others. However, HHT rarely involves the portal venous system to cause serious clinical complications. CASE SUMMARY: A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT. Computed tomography angiography confirmed the presence of an arteriovenous fistula (AVFs). Considering this specific manifestation, whole exome sequencing was performed. After a comprehensive evaluation, a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia. The postoperative symptoms of the patient were quickly relieved. Unfortunately, two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs. CONCLUSION: For patients with diffuse superior mesenteric AVFs, selective mesenteric arterial embolization may lead to positive short-term outcomes.

Identification of undescribed key impurities of homoharringtonine bulk drug.

The knowledge of impurities is an important issue and the base of quality control in modern drugs. To date, the quality control of the antitumor drug homoharringtonine (HHT) is still not sufficiently solved and needs to be improved. Six main impurities, drupacine, cephalotaxine, desmethylcephalotaxinone, harringtonine, 3-O-acetyl-cephalotaxine and 2'R,3'S-isoharringtonine were traced during HHT drug production by HPLC and LC-MS analyses. Additionally, we were able to isolate and identify three undescribed key trace impurities, neohomoharringtonines A-C. Their structures were established by 1D-, and 2D NMR experiments combined with mass spectrometry. An improved quality inspection ability of HHT was constructed.

A tumour-selective cascade activatable self-detained system for drug delivery and cancer imaging.

Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders.

Microenvironment-Induced In Situ Self-Assembly of Polymer-Peptide Conjugates That Attack Solid Tumors Deeply.

In cancer treatment, the unsatisfactory solid-tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an in vivo self-assembly strategy and designed polymer-peptide conjugates (PPCs) that underwent an acid-induced hydrophobicity increase with a narrow pH-response range (from 7.4 to 6.5). In situ self-assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC50 values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH-sensitive moiety cis-aconitic anhydride (CAA), and a cell-penetrating peptide TAT were conjugated onto poly(ß-thioester) backbones to produce PT-K-CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration in vivo, CAA responds to the weak acid, leading to the self-assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep-penetration ability for enhanced cancer therapy is provided by this in vivo assembly strategy.

Glutathione-sensitive PEGylated curcumin prodrug nanomicelles: Preparation, characterization, cellular uptake and bioavailability evaluation.

The anti-tumor efficacy of curcumin can be markedly improved by nano-drug self-delivery systems with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, a type of novel, glutathione (GSH)-responsive, PEGylated prodrug nano-micelles (PPNMs) was prepared by self-assembly of curcumin-s-s-vitamin E/mPEG2k-DSPE mixture. The PPNMs (entrapment efficiency: 96.7%) was acceptably stable in water with a mean particle size of 29.84 nm. Compared with curcumin-loaded mPEG2k-DSPE nano-micelles (CUR-NMs), PPNMs showed a higher drug loading (1.68% vs 27.3%) and remarkably improved the chemical stability of curcumin in phosphate buffer saline (PBS) (pH = 7.4), 10% FBS culture medium, and rat plasma. In vitro release study showed that PPNMs could redox responsively control the release of curcumin from the prodrug. Moreover, PPNMs showed a cytotoxicity in HepG2 cells similar to that of the free curcumin; however, when the HepG2 cells were pretreated with 1 mM GSH, PPNMs displayed a markedly enhanced cytotoxicity and cellular uptake than the free curcumin. After intravenous injection, PPNMs showed an increased half-life in blood circulation (10.6-fold) and bioavailability (107-fold) compared with the free curcumin injection. Altogether, the prodrug nano-micelles represent a promising preparation for sustained and controlled delivery of curcumin with enhanced antitumor activity.

Gender, Age, and Concomitant Diseases of Colorectal Diverticulum in China: A Study of 7,964 Cases.

AIM: To analyze the epidemiological features of colorectal diverticulum (CRD) in China. METHODS: We retrospectively analyzed CRD patients in 8 tertiary hospitals located in 5 regions of China from 2000 to 2016. The detection rates, number and distribution, demographic information, concomitant disorders, and their associations were investigated. RESULTS: Of 3,446,118 cases, 7,964 (2.3%) were CRD with a mean age of 56 years (11-92 years). The detection rate increased yearly and with increasing age. Males had a higher detection rate than females (3.0 vs. 1.47%, p < 0.01) and 1.8-times higher increase rate. The detection rate increased with age; however, females of > 60 years had a 2.8-times increasing rate than males. CRD occurred most frequently in the right-side colon, followed by rectum. Multiple diverticula were common in males and increased with age, with a 3-times higher increase rate than single lesion. Single-segment CRD occurred more frequently in males than in females (80.1 vs. 76.4%, p < 0.01). Concurred colon polyps were seen in 51.05% cases. CONCLUSION: CRD detection rates increased annually and with age, particularly in senior females in China. Multiple diverticula were common in males and increased with age. CRD was predominant in the right-side colon. Polyps are the most common comorbidity associated with CRD.

Near-Infrared Laser-Driven in Situ Self-Assembly as a General Strategy for Deep Tumor Therapy.

Nanotherapeutics have encountered some bottleneck problems in cancer therapy, such as poor penetration and inefficient accumulation in tumor site. We herein developed a novel strategy for deep tissue penetration in molecular level and near-infrared (NIR) laser guided in situ self-assembly to solve these challenges. For the proof-of-concept study, we synthesized the polymer-peptide conjugates (PPCs) composed of (i) poly(ß-thioester) as thermoresponsive backbone, (ii) functional peptides (cytotoxic peptide and cell-penetrating peptide), and (iii) the NIR molecule with photothermal property. The PPCs in the molecular level with small size (<10 nm) can penetrate deeply into the interior of the tumor at body temperature. Under the irradiation of NIR laser, the temperature rise induced by photothermal molecules led to the intratumoral self-assembly of thermoresponsive PPCs. The resultant spherical nanoparticles can accumulate in tumor and enter cells effectively, inducing cell apoptosis by destroying mitochondria membrane. Through the site-specific size control, a variety of merits of PPCs are realized including deep tumor penetration, enhanced accumulation, and cellular internalization in vivo. Taking advantage of the NIR guided in situ assembly strategy, numerous polymeric or nanoscaled therapeutics with high anticancer activity can be exploited.

Macrophage-Instructed Intracellular Staphylococcus aureus Killing by Targeting Photodynamic Dimers.

The survival of Staphylococcus aureus inside phagocytes is considered to be the sticking point of long-term chronic inflammation. Here, we fabricate peptide-chlorophyll-based photodynamic therapy (PDT) agents with "sandwich" dimeric structure to enhance the PDT effect and active targeting property to eliminate intracellular infections, which could be seen as prospective antibacterial agents for inflammation.

Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration.

Peptide nanodrugs have been developed as promising antitumor chemotherapeutics because they partially overcome the drawbacks of free peptide drugs, but insufficient tumor penetration and interference of peptide function limit their further application. In this work, we have developed multifunctional peptide conjugated dendrimers for improving tumor penetration, cancer cell-specific peptide delivery and anticancer ability. The cytotoxic peptide KLAK, cell-penetrating peptide TAT and matrix metalloproteinase 2 (MMP2)-sensitive peptide-poly(ethylene glycol) (PEG) were conjugated onto dendrimers by one-pot synthesis to gain PKT-S-PEG. The enzyme-sensitive properties and incubation stability of the dendrimers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the cell viability, internalization pathway, mitochondria-regulated apoptosis and tumor penetration ability were measured by CCK-8 assay, lysosome colocalization, JC-1 assay and multicellular spheroid (MCS) experiments, respectively, in human primary glioblastoma (U87) cells. PKT-S-PEG showed significantly enhanced intracellular delivery performance, antitumor efficacy and deep tumor penetration capacity compared to a control non-MMP2 sensitive dendrimer PKT-C-PEG. The MMP2-overexpressing tumor microenvironment caused deprotection by removal of PEG, resulting in the decrease of particle size and exposure of KLAK and TAT, which enhanced tumor penetration, the entry of bioactive peptides into cells and subsequently the effective disruption of mitochondria. We believe that the peptide-dendrimer conjugate has potential for specific and effective delivery of peptide-based therapeutics into tumors.

Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS-triggered drug release.

Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP)-synthesized star-shaped poly(ε-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by ß-cyclodextrin (ß-CD) (3Br-ß-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of ß-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA30 is the best formulation tested.

Reconfigurable Peptide Nanotherapeutics at Tumor Microenvironmental pH.

Peptide nanomaterials have recently attracted considerable interest in the biomedical field. However, their poor bioavailability and less powerful therapeutic efficacy hamper their further applications. Herein, we discovered reconfigurable and activated nanotherapeutics in the tumor microenvironment. Two peptides, that is, a pH-responsive peptide HLAH and a matrix metalloprotease-2 (MMP2)-sensitive peptide with a poly(ethylene glycol) (PEG) terminal were conjugated onto the hydrophobic poly(ß-thioester)s backbones to gain the copolymer P-S-H. The therapeutic activity of the HLAH peptide could be activated in tumors owing to its reconfiguration under microenvironmental pH. The resultant copolymers self-assembled into nanoparticles under physiological condition, with HLAH in cores protected by PEG shells. The moderate size (∼100 nm) and negative potential enabled the stable circulation of P-S-H in the bloodstream. Once arrived at the tumor site, the P-S-H nanoparticles were stimulated by overexpressed MMP2 and acidic pH, and subsequently the shedding of the PEG shell and protonation of the HLAH peptide induced the reassembly of nanoparticles, resulting in the formation of nanoparticles with activated cytotoxic peptides on the surface. In vivo experiments demonstrated that the reorganized nanoassembly contained three merits: (1) effective accumulation in the tumor site, (2) enhanced antitumor capacity, and (3) no obvious toxic effect at the treatment dose. This on-site reorganization strategy provides an avenue for developing high-performance peptide nanomaterials in cancer treatment.

Self-Assembled ROS-Sensitive Polymer-Peptide Therapeutics Incorporating Built-in Reporters for Evaluation of Treatment Efficacy.

One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(ß-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to ∼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.

Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches.

The inhibition of TNF-alpha converting enzyme (TACE) has been explored as a feasible therapy for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Recently, large numbers of novel and selective TACE inhibitors have been reported. It is desirable to develop machine learning (ML) models for identifying the inhibitors of TACE in the early drug design phase and test the prediction capabilities of these ML models. This work evaluated four ML methods, support vector machine (SVM), k-nearest neighbor (k-NN), back-propagation neural network (BPNN) and C4.5 decision tree (C4.5 DT), which were trained and tested by using a diverse set of 443 TACE inhibitors and 759 non-inhibitors. A well-established feature selection method, the recursive feature elimination (RFE) method, was used to select the most appropriate descriptors for classification from a large pool of descriptors, and two evaluation methods, 5-fold cross-validation and independent evaluation, were used to assess the performances of these developed models. In this study, all these ML models have already achieved promising prediction accuracies. By using the RFE method, the prediction accuracies are further improved. In k-NN, the model gives the best prediction for TACE inhibitors (98.32%), and the SVM bears the best prediction for non-inhibitors (99.51%). Both the k-NN and SVM model give the best overall prediction accuracy (98.45%). To the best of our knowledge, the SVM model developed in this work is the first one for the classification prediction of TACE inhibitors with a broad applicability domain. Our study suggests that ML methods, particularly SVM, are potentially useful for facilitating the discovery of TACE inhibitors and for exhibiting the molecular descriptors associated with TACE inhibitors.