Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs.

Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem-like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self-renewal and stemness. A nanotherapeutic strategy is developed using tumor-penetrating peptide iRGD-modified high-density lipoprotein (HDL)-mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide-a (Ppa), bis (2-hydroxyethyl) disulfide (S-S), and camptothecin (CPT) by synthesizing two amphiphilic drug-conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self-renewal and trigger differentiation of the CSCs, while S-S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti-cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC-enriched heterogeneous colon tumor mouse models.

High-Throughput Screening of pH-Dependent ß-sheet Self-Assembling Peptide.

pH-dependent peptide biomaterials hold tremendous potential for cell delivery and tissue engineering. However, identification of responsive self-assembling sequences with specified secondary structure remains a challenge. In this work, An experimental procedure based on the one-bead one-compound (OBOC) combinatorial library is developed to rapidly screen self-assembling ß-sheet peptides at neutral aqueous solution (pH 7.5) and disassemble at weak acidic condition (pH 6.5). Using the hydrophobic fluorescent molecule thioflavin T (ThT) as a probe, resin beads displaying self-assembling peptides show fluorescence under pH 7.5 due to the insertion of ThT into the hydrophobic domain, and are further cultured in pH 6.5 solution. The beads with extinguished fluorescence are selected. Three heptapeptides are identified that can self-assemble into nanofibers or nanoparticles at pH 7.5 and disassemble at pH 6.5. P1 (LVEFRHY) shows a rapid acid response and morphology transformation with pH modulation. Changes in the charges of histidine and hydrophobic phenyl motif of phenylalanine may play important roles in the formation of pH-responsive ß-sheet nanofiber. This high-throughput screening method provides an efficient way to identify pH-dependent ß-sheet self-assembling peptide and gain insights into structural design of such nanomaterials.

Novel antiviral discoveries for Japanese encephalitis virus infections through reporter virus-based high-throughput screening.

Japanese encephalitis (JE) caused by JE virus (JEV), remains a global public health concern. Currently, there is no specific antiviral drug approved for the treatment of JE. While vaccines are available for prevention, they may not cover all at-risk populations. This underscores the urgent need for prophylaxis and potent anti-JEV drugs. In this context, a high-content JEV reporter system expressing Nanoluciferase (Nluc) was developed and utilized for a high-throughput screening (HTS) of a commercial antiviral library to identify potential JEV drug candidates. Remarkably, this screening process led to the discovery of five drugs with outstanding antiviral activity. Further mechanism of action analysis revealed that cepharanthine, an old clinically approved drug, directly inhibited virus replication by blocking GTP binding to the JEV RNA-dependent RNA polymerase. Additionally, treatment with cepharanthine in mice models alleviated JEV infection. These findings warrant further investigation into the potential anti-JEV activity of cepharanthine as a new therapeutic approach for the treatment of JEV infection. The HTS method employed here proves to be an accurate and convenient approach that facilitates the rapid development of antiviral drugs.

Updated mechanisms of MASLD pathogenesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.

US Risk Stratification System for Follicular Thyroid Neoplasms.

Background Preoperative assessment of follicular thyroid neoplasms is challenging using the current US risk stratification systems (RSSs) that are applicable to papillary thyroid neoplasms. Purpose To develop a US feature-based RSS for differentiating between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC) in biopsy-proven follicular neoplasm and compare it with existing RSSs. Materials and Methods This retrospective multicenter study included consecutive adult patients who underwent conventional US and received a final diagnosis of follicular thyroid neoplasm from seven centers between January 2018 and December 2022. US images from a pretraining data set were used to improve readers' understanding of the US characteristics of the FTC and FTA. Univariable and multivariable logistic regression analyses were used to assess the association of qualitative US features with FTC in a training data set. Features with P < .05 were used to construct a prediction model (follicular tumor model, referred to as F model) and RSS for follicular neoplasms using the Thyroid Imaging Reporting and Data System (TI-RADS). Area under the receiver operating characteristic curve (AUC) was compared between follicular TI-RADS (hereafter, F-TI-RADS) and existing RSS (American College of Radiology [ACR] TI-RADS, Korean Society of Thyroid Radiology and Korean Society of Radiology TI-RADS [hereafter, referred to as K-TI-RADS], and Chinese TI-RADS [hereafter, referred to as C-TI-RADS]) in a validation data set. Results The pretraining, training, and validation data sets included 30 (mean age, 47.6 years ± 16.0 [SD]; 16 male patients; FTCs, 30 of 60 [50.0%]), 703 (mean age, 47.9 years ± 14.5; 530 female patients; FTCs, 188 of 703 [26.7%]), and 155 (mean age, 49.9 years ± 13.3 [SD]; 155 female patients; FTCs, 43 of 155 [27.7%]) patients. In the validation data set, the F-TI-RADS showed improved performance for differentiating between FTA and FTC (AUC, 0.81; 95% CI: 0.71, 0.86) compared with ACR TI-RADS (AUC, 0.74; 95% CI: 0.66, 0.80; P = .02), K-TI-RADS (AUC, 0.69; 95% CI: 0.61, 0.76; P = .002), and C-TI-RADS (AUC, 0.68; 95% CI: 0.60, 0.75; P = .002). Conclusion F-TI-RADS outperformed existing RSSs for differentiating between FTC and FTA. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Baumgarten in this issue.

A Multifunctional Asymmetric Fabric for Sustained Electricity Generation from Multiple Sources and Simultaneous Solar Steam Generation.

Harvesting electrical energy from water and moisture has emerged as a novel ecofriendly energy conversion technology. Herein, a multifunctional asymmetric polyaniline/carbon nanotubes/poly(vinyl alcohol) (APCP) that can produce electric energy from both saline water and moisture and generate fresh water simultaneously is developed. The constructed APCP possesses a negatively charged porous structure that allows continuous generation of protons and ion diffusion through the material, and a hydrophilicity-hydrophobic interface which results in a constant potential difference and sustainable output. A single APCP can maintain stable output for over 130 h and preserve a high voltage of 0.61 V, current of 81 µA, and power density of 82.4 µW cm-3 with 0.15 cm3 unit size in the water-induced electricity generation process. When harvesting moisture energy, the APCP creates dry-wet asymmetries and triggers the spontaneous development of electrical double layer with a current density of 1.25 mA cm-3 , sufficient to power small electronics. A device consisting of four APCP can generate stable electricity of 3.35 V and produce clean water with an evaporation rate of 2.06 kg m-2  h-1 simultaneously. This work provides insights into the fabrication of multifunctional fabrics for multisource energy harvesting and simultaneous solar steam generation.

Current distribution of two species of Chinese macaques (Macaca arctoides and Macaca thibetana) and the possible influence of climate change on future distribution.

Predicting the spatial distribution of species and suitable areas under global climate change could provide a reference for species conservation and long-term management strategies. Macaca thibetana and Macaca arctoides are two endangered species of Chinese macaques. However, limited information is available on their distribution, and their habitat needs lack proper assessment due to complicated taxonomy and less research attention. In recent years, scholars widely used the maximum entropy (MaxEnt) model to predict the impact of global climate and certain environmental factors on species distribution. Therefore, we used the MaxEnt model to predict the spatiotemporal distribution of both macaque species under six climate change scenarios using occurrence and high-resolution ecological data. We identified climatic factors, elevation, and land cover that shape their distribution range and determined shifts in their habitat range. The results demonstrated that temperature range, annual precipitation, forest land cover, and temperature seasonality, including the precipitation of the driest month are the main factors affecting their distribution. Currently, M. thibetana is mainly concentrated in central, eastern, southern, and southwestern China, and M. arctoides is mainly concentrated in three provinces (Yunnan, Guangxi, and Guangdong) in southern China. The MaxEnt model predicted that the suitable habitat for both species will increase with increased greenhouse emission scenarios. We also found that with the further increase in greenhouse emissions M. thibetana is expected to migrate to western China, and M. arctoides is expected to migrate to western or eastern China. This reinterpretation of the distribution of M. thibetana and M. arctoides in China, and predicted potential suitable habitat and possible migration direction, may provide new insights into the future conservation and management of these two species.

Bioinspired Screening of Anti-Adhesion Peptides against Blood Proteins for Intravenous Delivery of Nanomaterials.

Nanomaterials (NMs) inevitably adsorb proteins in blood and form "protein corona" upon intravenous administration as drug carriers, potentially changing the biological properties and intended functions. Inspired by anti-adhesion properties of natural proteins, herein, we employed the one-bead one-compound (OBOC) combinatorial peptide library method to screen anti-adhesion peptides (AAPs) against proteins. The library beads displaying random peptides were screened with three fluorescent-labeled plasma proteins. The nonfluorescence beads, presumed to have anti-adhesion property against the proteins, were isolated for sequence determination. These identified AAPs were coated on gold nanorods (GNRs), enabling significant extension of the blood circulating half-life of these GNRs in mice to 37.8 h, much longer than that (26.6 h) of PEG-coated GNRs. In addition, such AAP coating was found to alter the biodistribution profile of GNRs in mice. The bioinspired screening strategy and resulting peptides show great potential for enhancing the delivery efficiency and targeting ability of NMs.

Single medium-sized hepatocellular carcinoma treated with sequential conventional transarterial chemoembolization (cTACE) and microwave ablation at 4 weeks versus cTACE alone: a propensity score.

BACKGROUND: Microwave ablation (MWA) is a potentially curative treatment for unresectable patients with hepatocellular carcinoma (HCC) ≤ 3 cm, while its therapeutic efficacy decreases significantly for HCC > 3cm. Previous studies have demonstrated that conventional transarterial chemoembolization (cTACE) combined with MWA (cTACE-MWA) may improve local tumor control rate and reduce the recurrence rate for HCC > 3cm. However, there have been few study designs to analyze the clinical efficacy of cTACE-MWA for medium-sized HCC (3-5cm). Therefore, this study aims to compare the clinical efficacy and safety of cTACE-MWA with cTACE alone for a single medium-sized HCC of 3-5 cm in diameter. METHODS: We retrospectively investigate the data of 90 patients with a single medium-sized HCC who were referred to our hospital and underwent cTACE-MWA or cTACE alone from December 2017 to March 2020. Then, patients were identified with propensity score-matched (1:1). The local tumor response to treatment and time to progression (TTP) were compared using mRECIST criteria between the cTACE-MWA group and the cTACE group. RESULTS: A total of 42 patients were included after matching (cTACE-MWA: 21; cTACE: 21). Comparing with cTACE, cTACE-MWA demonstrate significantly better local tumor control (ORR: 95.2% vs 61.9%, p = 0.02; DCR: 95.2% vs 66.7%, p = 0.045) and TTP (median 19.8 months vs 6.8 months, p < 0.001). The 1- and 2-year cumulative probabilities of OS were 100% and 95% in the cTACE-MWA group, which were significantly higher than those in the cTACE group (95% and 76%) (p = 0.032). Multivariate Cox regression analysis illustrates that cTACE-MWA was associated with better TTP (hazard ratio, 0.28; 95% CI: 0.1, 0.76; p = 0.012), but tumor size was associated with worse TTP (hazard ratio, 1.71; 95% CI: 1.01, 2.89; p = 0.045). CONCLUSIONS: cTACE followed by MWA improved TTP and OS in patients with a single medium-sized HCC, and no major complication was observed in this study.

Efficient Separation of Proteins and Polysaccharides from Dendrobium huoshanense Using Aqueous Two-Phase System with Ionic Liquids.

By applying the hydrophilic ionic liquid, 1-butyl-3-methylimidazolium chloride ([C4mim]Cl), and inorganic salts (K3PO4), an ionic liquid aqueous two-phase system (ILATPS) was established for the separation of Dendrobium huoshanense polysaccharides (DhPs) and proteins. The effects of inorganic salt concentration, IL quantity, crude DhPs concentration, pH value and temperature were studied to achieve the optimal condition. With the best combination of ILATPS (1.75 g K3PO4, 1.25 g [C4mim]Cl, 10 mg crude DhPs and 5.0 mL ddH2O at pH 7.0 under 25 °C), the extraction efficiency rates for DhPs and proteins were 93.4% and 90.2%, respectively. The processed DhPs retrieved from the lower salt-rich phase comprised mannose, glucose, galactose, arabinose, and galacturonic acid with a molar ratio of 185:71:1.5:1:1 and the molecular weight was 2.14 × 105 Da. This approach is fast, simple and environmentally friendly. It provides a new insight into purifying functional polysaccharides of plant origin.

Multienzyme-Mimic Ultrafine Alloyed Nanoparticles in Metal Organic Frameworks for Enhanced Chemodynamic Therapy.

Nanozyme-based chemodynamic therapy (CDT) has emerged as an effective cancer treatment because of its low side effects and without the requirement of exogenous energy. The therapeutic effect of CDT highlights the pivotal importance of active sites, H2 O2 supplement and the glutathione (GSH) depletion of a nanozyme. The construction of a single kind of catalyst with multiple functions for the enhanced CDT is still a big challenge. In this work, seven types of bimetallic nanoparticles are synthesized using a metal-organic framework (MOF) as a stable host instead of a Fenton or Fenton-like ions supplier. Among them, Cu-Pd@MIL-101 with an alloy loading of 9.5 wt% modified by PEG (9.5% CPMP) is found to exhibit the highest peroxidase (POD) like activity combined with a superoxide dismutase (SOD) mimic activity and the function of GSH depletion. The in vivo results suggest that the stable and ultrafine nanoparticles possess favorable CDT effect for tumor and good biosafety as well as biocompatibility. This work has provided a credible strategy to construct nanozymes with an excellent activity and may pave a new way for the design of enhanced tumor CDT treatment.

Correlation of CCL8 expression with immune cell infiltration of skin cutaneous melanoma: potential as a prognostic indicator and therapeutic pathway.

BACKGROUND: The tumor microenvironment (TME) is critical in the progression and metastasis of skin cutaneous melanoma (SKCM). Differences in tumor-infiltrating immune cells (TICs) and their gene expression have been linked to cancer prognosis. Given that immunotherapy can be effective against SKCM, we aimed to identify key genes that regulate the immunological state of the TME in SKCM. METHODS: Data from 471 SKCM patients in the The Cancer Genome Atlas were analyzed using ESTIMATE algorithms to generate an ImmuneScore, StromalScore, and EstimateScore for each patient. Patients were classified into low- or high-score groups based on median values, then compared in order to identify differentially expressed genes (DEGs). Then a protein-protein interaction (PPI) network was developed, and a prognostic model was created using uni- and multivariate Cox regression as well as the least absolute shrinkage and selection operator (LASSO). Key DEGs were identified using the web-based tool GEPIA. Profiles of TIC subpopulations in each patient were analyzed using CIBORSORT, and possible correlations between key DEG expression and TICs were explored. Levels of CCL8 were determined in SKCM and normal skin tissue using immunohistochemistry. RESULTS: Two scores correlated positively with the prognosis of SKCM patients. Comparison of the low- and high-score groups revealed 1684 up-regulated and 18 down-regulated DEGs, all of which were enriched in immune-related functions. The prognostic model identified CCL8 as a key gene, which CIBERSORT found to correlate with M1 macrophages. Immunohistochemistry revealed strong expression in SKCM tissue, but failed to detect the protein in normal skin tissue. CONCLUSIONS: CCL8 is a potential prognostic marker for SKCM, and it may become an effective target for melanoma in which M1 macrophages play an important role.

A cohort study of microwave ablation and surgery for low-risk papillary thyroid microcarcinoma.

BACKGROUND: The optimal treatment method for papillary thyroid microcarcinoma (PTMC) is lacking consensus. Here we aimed to compare the efficacy and safety of surgery and microwave ablation (MWA) for PTMC. METHODS: The clinical data of 644 patients with PTMC treated between July 2013 and June 2020 were retrospectively analyzed. A total of 320 and 324 patients underwent MWA and surgery, respectively. We observed lesion changes in the MWA group and compared the recurrence, metastasis, complications, and other health economic indicators between the 2 groups. RESULTS: The mean follow-up time was 890.7 ± 532.9 (187.9-2679.0) days in the MWA group and 910.9 ± 568.4 (193.8-2821.5) days in the surgery group. In the MWA group, lesion volume increased significantly after ablation and then gradually decreased. The final lesion volume reduction rate was 90.73% ± 7.94%, and 193 lesions (60.3%) disappeared completely. There were no significant intergroup differences in recurrence or metastasis. The incidence of main complications (temporary hypothyroidism, hypoparathyroidism, and temporary hoarseness) was significantly lower in the MWA group than in the surgery group (p < 0.001). The treatment time, intraoperative blood loss, and hospital stay were significantly lower in the MWA group than in the surgery group (p < 0.001). CONCLUSIONS: MWA is effective for treating PTMC, with a low incidence of complications and less trauma. The rates of post-treatment recurrence and metastasis are similar to those of surgery, indicating that MWA is a suitable alternative to surgery.

Marked decrease of tacrolimus blood concentration caused by compound Chinese herbal granules in a patient with refractory nephrotic syndrome.

WHAT IS KNOWN AND OBJECTIVE: The blood concentration of tacrolimus can be affected by co-administrated drugs. The objective is to draw more attention to herb-drug interactions in China, where herbal medicines are commonly used. CASE DESCRIPTION: The blood concentration of tacrolimus in a girl with refractory nephrotic syndrome decreased nearly a half despite no change in dose. Nebulizer therapy, cyclophosphamide and a compound Chinese herbal medicine were the only additional treatments than usual. WHAT IS NEW AND CONCLUSION: The most possible cause of the decrease in tacrolimus concentration was the administration of Radix Astragali among compound Chinese herbal medicine granules.

Acaricidal activity of the essential oil from Senecio cannabifolius and its constituents eucalyptol and camphor on engorged females and larvae of Rhipicephalus microplus (Acari: Ixodidae).

The objective of this experiment was to evaluate the acaricidal activity of Senecio cannabifolius essential oil, and two of its constituents, eucalyptol and camphor. Efficacy against females and larvae of Rhipicephalus (Boophilus) microplus was assessed by the adult immersion test (AIT) and the larval immersion test (LIT). The oil was analyzed by gas chromatography-flame ionization detection (GC-FID) and GC-mass spectrometry (MS) and in total 68 components were identified representing 99.2% of the essential oil. AIT revealed that the oil, eucalyptol, and camphor at the highest concentration presented efficacy of 68.9, 57.1, and 71.9%, respectively. LIT revealed that the essential oil and camphor achieved 100% mortality at concentration of 1.6% wt/vol, whereas eucalyptol showed moderate inhibitory activity. Biochemical assays indicated that the essential oil and camphor can reduce significantly overall detoxification enzyme activities in engorged females and larvae at high concentration (≥ 0.4% wt/vol), whereas the inhibitory effect of eucalyptol is weaker than that of the oil and camphor. Taken together our results indicated that the S. cannabifolius essential oil and its isolated constituent had potential for the development of a new and safe acaricide for the control of R. microplus ticks.

Transformable Dual-Inhibition System Effectively Suppresses Renal Cancer Metastasis through Blocking Endothelial Cells and Cancer Stem Cells.

Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual-inhibition system (TDS) based on a self-assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand-receptor interaction-induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human-derived CSCs, TDS inhibits stemness by reducing endogenic miR-19b and its transportation via CSCs-derived exosomes, which increases PTEN expression and consequently suppresses CSCs-mediated metastasis. In patient-derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0-fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer.

"French fries"-like luminescent metal organic frameworks for the fluorescence determination of cytochrome c released by apoptotic cells and screening of anticancer drug activity.

A luminescent metal organic framework was prepared by encapsulating Zn-Ag-In-S quantum dots into "French fries"-like MIL-68(In) metal organic frameworks (ZAISQDs@MIL-68(In)). The ZAISQDs@MIL-68(In) had a maximum excitation wavelength at 370 nm and maximum emission wavelength at 620 nm. It was found that the ZAISQDs@MIL-68(In) was efficiently quenched by cytochrome c (Cyt c), which is an important biomarker of early cell apoptosis. The quenching mechanism was ascribed to be an inner filter effect and dynamic quenching of Cyt c towards the ZAISQDs@MIL-68(In), and the enrichment effect of MIL-68(In). Benefiting from the multiple advantages, ZAISQDs@MIL-68(In) was developed as an assay strategy of Cyt c with logarithmic relation between signal quenching and concentration in the range 0.02 to 3.5 µM. The linear equation was (F0-F)/F0 = 0.5043 + 0.2678 × logcCyt c with a detection limit of 8 nM. Cyt c released by drug induced apoptotic cells was determined by ZAISQDs@MIL-68(In), and this strategy has been utilized for the screening of anticancer drug activity. Graphical abstract Schematic representation of the synthesis of ZAISQDs@MIL-68(In) and its application for Cyt c and screening anticancer drug activity.

MicroRNA-145 induces the senescence of activated hepatic stellate cells through the activation of p53 pathway by ZEB2.

Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA-145 (miR-145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E-box binding homeobox 2 (ZEB2). In addition, overexpression of miR-145 and p53 led to upregulation of the number of senescence-associated ß-galactosidase-positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α-smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR-145 specifically targeted the 3'-untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E-box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR-145-ZEB2-p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.

Tumor Microenvironmental pH and Enzyme Dual Responsive Polymer-Liposomes for Synergistic Treatment of Cancer Immuno-Chemotherapy.

Despite recent advances in tumor treatment through cancer immunotherapy, the efficacy of this approach remains to be improved. Looking forward to high rates of objective clinical response, cancer immunotherapy combined with chemotherapy has gained increasing attention recently. Here, we constructed liposomes with matrix metalloproteinases (MMPs) responsive moiety and PD-L1 inhibitor conjugate combine with low dose chemotherapy to achieve enhanced antitumor efficacy. Upon introduction of the pH-responsive polymer to LPDp, the coassembly could be almost stable in physiological conditions and tumor microenvironments and release the loaded cargos at the lysosome. MMP-2 enzyme extracellularly secreted by the B16F10 cells could cleave the cross-linker and liberate the PD-L1 inhibitor effectively disrupting the PD-1/PD-L1 interaction in vitro. Low dose DOX encapsulated in the LPDp was capable of sensitizing B16F10 cells to CTLs by inducing overexpression of M6PR on tumor cell membranes. In comparison with free PD-L1 inhibitor, LPDp improved the biodistribution and on-demand release of the peptide inhibitor in tumor regions following administration. LPDp achieved the optimal tumor suppression efficiency (∼78.7%), which demonstrated the significantly enhanced antitumor effect ( P < 0.01) than that of LPp (∼57.5%) as well as that of LD (<40%), attributing to synergistic contribution from the substantial increase in M6PR expression on tumor cells and the blockade of immune checkpoints. This strategy provides a strong rationale for combining standard-of-care chemotherapy with relative nontoxic and high specific immunotherapy.