Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

Corrigendum: Editorial: Recent innovations to inhibit scar formation for better skin regeneration.

[This corrects the article DOI: 10.3389/fsurg.2023.1325832.].

PD-1 blockade and radiotherapy combination for advanced Epstein-Barr virus-associated intrahepatic cholangiocarcinoma: a case report and literature review.

Advanced intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor of biliary epithelial cells, known for its extremely unfavorable prognosis. In the absence of intervention, patients typically survive for less than 5 months. Current guidelines from the Chinese Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) recommend chemotherapy-based systemic therapy as the standard treatment for advanced ICC. However, the first-line regimen, consisting of gemcitabine in combination with cisplatin, generally results in a median survival of approximately one year, which is considered suboptimal. Significant progress has been made in radiotherapy techniques, molecular diagnostics, and tumor immune microenvironments. The integration of immune and radiation therapies has revolutionized treatment strategies for cholangiocarcinoma. Moreover, combined therapeutic regimens have shown promising results in improving survival rates among patients with advanced ICC. In this study, we present a case report of a 70-year-old male patient diagnosed with stage IV ICC, featuring metastases to the retroperitoneal, left adrenal, and left supraclavicular lymph nodes. The patient exhibited a high tumor mutational load, significant microsatellite instability, and hyper-expression of PD-L1 (90%), along with positive Epstein-Barr virus-encoded RNA (EBER). Pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, was administered in conjunction with radiotherapy. As a result, considerable shrinkage and inactivation of the primary foci were observed, accompanied by the disappearance of metastases. Ultimately, the patient achieved complete remission and maintained progression-free survival for 41 months following the initial treatment. To the best of our knowledge, this represents the longest case of complete remission using a combination of immunotherapy and radiotherapy as a first-line regimen for the high tumor mutational load, microsatellite instability, and PD-L1 expression (90%) subtype of Epstein-Barr virus-associated ICC (EBVaICC). These findings suggest that the combination of PD-1 inhibitors with radiotherapy may serve as a promising therapeutic strategy for treating this particular cancer subtype.

Comprehensive Analysis of Potential Biomarkers of Acute Lymphoblastic Leukemia in Children by Using a Competing Endogenous RNA Network.

Acute lymphoblastic leukemia (ALL) is the most serious hematological carcinoma in adolescents. The significance of long noncoding RNAs (lncRNAs) and their regulative role in the proliferation and differentiation of myeloid cells in cancer has been recently reported. Nevertheless, key RNAs and the regulatory mechanism of competitive endogenous RNA (ceRNA) network affected by pediatric ALL are not fully illustrated. In this study, phase 2 and 3 pediatric ALL RNA profiles were extracted from the TARGET database and used to identify lncRNAs, microRNAs, and messenger RNAs in high-risk ALL and reconstruct the sponge ceRNA regulatory network. Results indicated that 44 lncRNAs, 25 miRNAs, and 115 mRNA were up/downregulated. Functional analysis with differentially expressed RNAs (DERNAs) showed enriched significant signaling pathways, including PI3K-Akt and p53 signaling cascades and other pathways associated with the tumor. Seventeen differential hub RNAs, including LINC00909, BZRAP1-AS1, C17orf76-AS1, HCG11, MIAT, SNHG5, SNHG15, and TP73-AS1, were identified. The Cox model of correlation indicated that 14 of these RNAs were associated with the progression of pediatric ALL. These findings would help clarify the regulatory role of several lncRNAs as well as provide insights into the leukemogenesis of pediatric ALL to further explore novel prognostic markers/therapeutic targets for ALL.

Optimal time-points for detecting expression levels of BAALC, EVI1, and WT1 genes in patients with acute myeloid leukemia: a meta-analysis.

OBJECTIVES: This meta-analysis examined the prognostic role of brain and acute leukemia, cytoplasmic (BAALC), Ecotropic virus integration site-1 (EVI1) and Wilms' tumor 1 (WT1) genes at different time-points during conventional chemotherapy. METHODS: A systematic search of publications indexed in the electronic databases from January 1988 to October 2020 was performed. Over 7525 cases of AML from 25 studies were involved. RESULTS: At diagnosis, overexpression of either BAALC or EVI1 had a negative impact on complete remission achievement (Summary Odds ratios [SORs] for BAALC = 0.32; SORs for EVI1 = 0.49) and survival outcome. The summary hazard ratios of overall survival (OS) and disease-free survival (DFS) were 1.97 and 2.04 for BAALC and 1.33 and 1.86 for EVI1, respectively. The prognostic value of pretreatment WT1 levels was heterogeneous while subgroup analyses unveiled that overexpressed WT1 may correlate with a favorable outcome (summary hazard ratio [SHR] for OS = 0.42). Both WT1 and BAALC played a role in prognosis assessment at post-induction and the diagnostic performance of WT1 transcript reduction was superior to the absolute WT1 level. Post-consolidation WT1 overexpression consistently indicated an increased risk of relapse, while the combined HR for RFS was statistically insignificant (SHR = 4.22). CONCLUSION: These findings confirm the application of BAALC and EVI1 at diagnosis, WT1 after induction chemotherapy in AML patients throughout conventional chemotherapy.

[Values of MCV,MCH,ROFT and HbA2 for Screening α-Thalassemia in Guangdong Area].

OBJECTIVE: To investigate the values of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell osmotic fragility test(ROFT) and hemoglobin A2(HbA2) in screening of α-thalassemia in Guangdong area. METHODS: A total of 285 peripheral blood samples in patients treated in our hospital from January 2017 to December 2017 were collected. The detection of thalassemia gene was used as the gold standard, while blood routine examination, hemoglobin electrophoresis, and red cell osmotic fragility test were simultaneously performed. The optimal cut-off values in MCV, MCH, ROFT and HbA2 in α-thalassemia were determined by receiver operator characteristic curve (ROC curve). RESULTS: The most common types of α-thalassemia gene was --SEA/αα (54.59%). Compared with the control group, the differences in MCV, MCH, ROFT and HbA2 showed statistically significantce between different types of α-thalassemia (P<0.05). The best cut-off values of MCV, MCH, ROFT, and HbA2 in the diagnosis of α-thalassemia were 81.45 fl, 27.35 pg, 79.95%, and 2.55% respectively. CONCLUSION: For different laboratories, the cut-off values need to be established for screening α-thalassemia suitable in their own local region．The values of MCV, MCH, ROFT and HbA2 shows higher accuracy and sensitivity in the diagnosis of α-thalassemia. It is recommended to use MCV<81.45fl, MCH<27.35 pg, ROFT<79.95% and HbA2<2.55% as the standards for screening α-thalassemia in Guangdong area.

Efficacy of traditional Chinese medicine for chronic gastritis: A meta-analysis of randomized controlled trials.

BACKGROUND: To systematically evaluate efficacy of traditional Chinese medicine (TCM) in treating chronic gastritis (CG). METHODS: Data sources from PubMed, Embase, Springer Link, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Chinese Biomedicine Database, and Wan-fang database were searched up to July 5, 2018. Review Manager software version 5.3, the Cochrane Collaboration's risk of bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation profiler software were conducted for this meta-analysis. RESULTS: Sixteen studies involving 1673 participants (906 vs 767) were included in this study. Pooled data showed significant statistical differences between TCM groups and current routine pharmacotherapy (RP) groups in overall clinical efficacy (odds ratio [OR] 4.65; 95% confidence interval [CI] 3.29, 6.56; P < .00001), efficacy under endoscopy (OR 2.46; 95% CI 1.12, 5.43; P = .03), stomach distension (mean difference [MD] -0.37; 95% CI -0.56, -0.19; P < .0001), stomachache (standardized MD [SMD] -0.80; 95% CI -1.45, -0.14; P = .02), and belching (SMD -2.00; 95% CI -3.80, -0.20; P = .03). However, acid regurgitation (SMD -0.71; 95% CI -1.69, 0.28; P = .16) and anorexia (SMD -0.75; 95% CI -2.30, 0.80; P = .35) showed no significant statistical differences between 2 groups. In addition, incidence of adverse reactions of TCM groups was lower than that of RP groups. CONCLUSION: Evidence from this meta-analysis suggests that TCM could be more efficacious than current RP in treating CG. But further standardized research of rigorous design should be needed to further validate its efficacy.

Manganese(II), lead(II) and cadmium(II) coordination complexes containing a tetrazole-based acylamide ligand: synthesis and the influence of the metal ions on the structures.

Three new manganese(II), lead(II) and cadmium(II) coordination complexes have been prepared by reaction of N-(1H-tetrazol-5-yl)cinnamamide (HNTCA) with divalent metal salts (MnCl2, PbCl2 and CdCl2) in a mixed-solvent system, affording mononuclear to trinuclear structures namely, bis(methanol-κO)bis[5-(3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido-κ2N1,O]manganese(II), [Mn(C10H8N5O)2(CH3OH)2], (1), bis[µ-5-(3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido]-κ3N1,O:N2;κ3N2:N1,O-bis{aqua[5-(3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido-κ2N1,O]lead(II)}, [Pb2(C10H8N5O)4(H2O)2], (2), and hexakis[µ2-5-(3-phenylprop-2-enamido)-1H-1,2,3,4-tetrazol-1-ido-κ3N1,O:N2]tricadmium(II), [Cd3(C10H8N5O)6], (3). The structures of these three compounds reveal that the nature of the metal ions and the side groups of the organic building blocks have a significant effect on the structures of the coordination compounds formed. Intermolecular hydrogen bonds link the molecules into two-dimensional [complex (1)] and three-dimensional hydrogen-bonded networks. Complexes (2) and (3) show significant fluorescence, while complex (1) displays no fluorescence.

[Role of Hepatocyte Growth Factor in Wound Repair].

Hepatocyte growth factor (HGF) is a multifunctional cytokine that is related to many diseases. HGF mainly contributes to cell migration,proliferation,and survival and regulates vascular angiogenesis,matrix deposition,and degradation of wound healing. HGF also promotes wound reepithelialization and reduces scar formation. This review article summarizes the role of HGF in wound repair and the relationship between HGF and other growth factors,especially when applied for the clinical treatment of chronic skin ulcers.

Prenatal diagnosis and perinatal outcome of congenital dacryocystocele: a large case series.

OBJECTIVE: To describe the incidence, prenatal diagnosis, and perinatal outcome in fetuses with congenital dacryocystocele. METHODS: All cases of congenital dacryocystocele diagnosed by prenatal ultrasound were identified using an established perinatal database. Prenatal ultrasound images were reviewed, and perinatal outcome was abstracted from the medical records. The correlation between the cyst size, gestational age, and prenatal and neonatal outcome was analyzed. RESULTS: The overall incidence of fetal dacryocystocele was 0.016% (75/456,202). Fifty-three cases (70.7%) had unilateral, and 22 (29.3%) had bilateral lesions. Lesions were seen more commonly among female fetuses with a female : male ratio 1.48 : 1. The average diameter of cysts size was 6.9 ± 1.9 mm (3.3-11 mm). There was a direct correlation between cyst size and gestational age. Among the 75 cases, 8 were lost to follow-up, 3 underwent elective termination of pregnancy. 58 resolved spontaneously before birth, and 6 were confirmed at birth. Two developed neonatal infection requiring antibiotic treatment. All 6 cases confirmed at birth resolved without surgical resection. CONCLUSIONS: Congenital dacryocystocele can be diagnosed by prenatal ultrasound. Such lesions typically resolve spontaneously in utero or in the early neonatal period. Thus, it should be considered as a developmental variant rather than a structural birth defect.