Knowledge, Attitudes, and Practices of Physicians Regarding Targeted Drug Therapy for Lung Cancer.

Purpose: This study aimed to examine the KAP of physicians regarding targeted drug therapy for lung cancer in China. Methods: This cross-sectional study enrolled physicians working in hospitals in Nanyang. A self-administered questionnaire was developed (Cronbach's α=0.912) to collect the demographic information and KAP. Results: This study included 191 valid questionnaires. Most participants were male (70.2%) and aged 36-50 (55.5%). The median knowledge score was 29 (24-31) (/36, 80.6%), the mean attitude score was 42 (39-44) (/50, 84.0%), and the mean practice score was 28 (26-29) (/30, 93.3%), indicating sufficient knowledge, positive attitudes, and proactive practice. The female gender (OR=5.291, 95% CI: 1.426-19.634, P=0.013), working in non-public tertiary hospitals (OR=0.053, 95% CI: 0.008-0.360, P=0.003), and working in medical oncology (OR=10.764, 95% CI: 2.638-43.922, P=0.001) were independently associated with adequate knowledge. Only the knowledge scores (OR=1.121, 95% CI: 1.036-1.212, P=0.004) were independently associated with a positive attitude. Only the attitude scores (OR=1.895, 95% CI: 1.333-2.694, P<0.001) were independently associated with proactive practice. Conclusion: Physicians working in thoracic surgery, respiratory medicine, or medical oncology displayed sufficient knowledge, positive attitude, and proactive practice toward targeted therapy for lung cancer.

Knowledge, attitudes, and practice toward glioma of patients with neurological symptoms or diseases in henan, China.

Objective: To explore the knowledge, attitude, and practice (KAP) toward glioma of patients with neurological symptoms or diseases. Methods: This web-based cross-sectional study was conducted at two medical centers in Henan Province between January 2023 and April 2023 and enrolled patients with neurological symptoms or diseases. The demographic characteristics of the participants and their KAP toward glioma were collected using a self-administered questionnaire. A structural equation modeling (SEM) was used to examine the relationship among KAP dimensions. Results: The study included 442 valid questionnaires. The mean knowledge, attitude, and practice scores were 7.65 ± 1.62 (possible range: 0-9), 37.98 ± 3.17 (possible range: 9-45), and 40.16 ± 4.17 (possible range: 10-50), indicating good knowledge, favorable attitude, and active practice. The SEM analysis showed that knowledge directly affected attitudes (ß = 0.89, 95%CI: 0.73-1.06, P < 0.001) but not practice (ß = -0.08, 95%CI: -0.32-0.14, P = 0.487), while attitudes directly affected practice (ß = 0.35, 95%CI: 0.21-0.48, P < 0.001). Conclusion: Patients with neurological symptoms/diseases who had heard of gliomas had good knowledge, favorable attitudes, and active practice toward glioma. Specific knowledge items that would warrant improvements were identified in the specific population of patients with neurological symptoms/diseases who had heard of glioma. Future studies should also examine the general population.

Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery.

The dynamic protein corona formed on nanocarriers has been revealed to strongly affect their in vivo behaviors. Precisely manipulating the formation of protein corona on nanocarriers may provide an alternative impetus for specific drug delivery. Herein, we explore the role of glycosylated polyhydroxy polymer-modified nanovesicles (CP-LVs) with different amino/hydroxyl ratios in protein corona formation and evolution. CP-LVs with an amino/hydroxyl ratio of approximately 0.4 (CP1-LVs) are found to efficiently suppress immunoglobulin adsorption in blood and livers, resulting in prolonged circulation. Moreover, CP1-LVs adsorb abundant tumor distinctive proteins, such as CD44 and osteopontin in tumor interstitial fluids, mediating selective tumor cell internalization. The proteins corona transformation specific to the environment appears to be affected by the electrostatic interaction between CP-LVs and proteins with diverse isoelectric points. Benefiting from surface modification-mediated protein corona regulation, paclitaxel-loaded CP1-LVs demonstrate superior antitumor efficacy to PEGylated liposomes. Our work offers a perspective on rational surface-design of nanocarriers to modulate the protein corona formation for efficient drug delivery.

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury.

AIM: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS: ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION: Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

Elasticity regulates nanomaterial transport as delivery vehicles: Design, characterization, mechanisms and state of the art.

Nanobiotechnology and nanomedicine are rapidly growing fields, in which nanomaterials (NMs) can lead to enhanced therapeutic efficacy by achieving efficient transport and drug delivery in vivo. The physicochemical properties of NMs have a great impact on their interactions with biological environments and hence determine their biological fates and drug delivery efficiency. Despite rapid advances in understanding the significance of NM properties, such as shape, size, and surface charge, there is a pressing need to engineer and discover how elasticity shapes NM transport. Recently, advances in material synthesis and characterization have promoted investigations into the macroscopic roles and microscopic mechanisms of elasticity to modulate nano-bio interactions. This review will highlight (1) the basic definitions of elasticity and strategies for modulating NM elasticity; (2) advanced techniques for evaluating the effects of elasticity on nano-bio interactions; (3) the macroscopic role of elasticity in the biological fates of NMs, including blood circulation, biodistribution, biological hydrogel penetration, cellular uptake, and intracellular trafficking; and (4) the potential microscopic mechanisms probed by these advanced characterization techniques. Additionally, challenges and future prospects are included. The advanced research discussed in this review will provide guidance to extensively explore the effects and detailed mechanism of elasticity in nano-bio interactions for enhanced drug delivery and developed nanomedicines.

Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy.

Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving optimal drug-delivery efficacy. Here, we develop ligand-switchable nanoparticles which resemble viral unique surfaces, enabling them to fully display diverse functions. The nanoparticles are modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). Once orally administered, the acidic environments trigger the extension of Pep from surface in a virus-like manner, enabling Pep/Gal-PNPs to traverse intestinal barriers efficiently. Subsequently, Gal is exposed by Pep folding at physiological pH, thereby allowing the specific targeting of Pep/Gal-PNPs to the liver. As a proof-of-concept, insulin-loaded Pep/Gal-PNPs are fabricated which exhibit effective intestinal absorption and excellent hepatic deposition of insulin. Crucially, Pep/Gal-PNPs increase hepatic glycogen production by 7.2-fold, contributing to the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieving full potential of diverse ligands on multifunctional nanoparticles.

Ligand-modified nanocarriers for oral drug delivery: Challenges, rational design, and applications.

Ligand-modified nanocarriers (LMNCs) specific to their targets have attracted increasing interest for enhanced oral drug delivery in recent decades. Although the design of LMNCs for enhanced endocytosis and improved exposure of the loaded drugs through the oral route has received abundant attention, it remains unclear how the design influences their transcellular process, especially the key factors affecting their functions. This review discusses the extracellular and cellular barriers to orally administered LMNCs in the gastrointestinal (GI) tract and new discoveries regarding the GI protein corona and the sequential transport barriers that impede the preplanned movements of LMNCs after oral administration. Furthermore, innovative progress in considering key factors (including target selection, ligand properties, and other important factors) in the rational design of LMNCs for oral drug delivery is presented. In particular, some factors that endow LMNCs with efficient transcytosis rather than only endocytosis are highlighted. Finally, the prospects of orally administered LMNCs in disease therapy for the enhanced oral/local bioavailability of active pharmaceutical ingredients, as well as emerging delivery routes, such as lymphatic drug delivery and systemic location-specific drug release based on oral transcellular LMNCs, are discussed.

Characterizing the source apportionment of black carbon and ultrafine particles near urban roads in Xi'an, China.

Better knowledge of the sources of black carbon (BC) and ultrafine particles (UFPs) in urban roadway region will provide helpful information for improving road air pollution caused by vehicle emissions. For this purpose, we conducted daily observation of BC and UFPs at two trafficked sites (intersection and roadside), and a background site in Xi'an, China. The concentration data of BC and UFPs measured were combined with Aethalometer model and UFPs source apportion model, to determine and analyze the sources of BC in an urban road region. Further, the source and variation characteristics of primary and secondary UFPs at the roadside sites were clarified. The results showed that average BC concentrations at the intersection, roadside, and background were respectively 3577 ± 2771, 3078 ± 2343, and 1914 ± 1229 ng/m3. The BC source apportionment results revealed contribution rates of on-board fossil fuel combustion (BCff) at the intersection and near the road of ca. 78.7% and 73.6%, respectively. Moreover, the proportion of particles number concentrations directly emitted from vehicles and nucleated upon emission (47%) was lower than that of particles formed during the dilution and cooling of vehicle emissions and by in-situ new particle formation (53%) at the roadside site. At 49%, the proportion of primary particles number was slightly higher at the intersection. The impacts of new particle-formation events on the diurnal variation of secondary particles were explored. Generally, the majority of BC originated from traffic exhausts, while the secondary particles from non-traffic sources are dominant at the road intersections. By providing a better understanding of near-road pollution issues, this study's findings can be useful for taking effective regulatory efforts to improve air quality and reduce people's exposure to traffic-pollutants in an urban environment.

Shape-directed drug release and transport of erythrocyte-like nanodisks augment chemotherapy.

Nanoparticle shape has been recognized as a crucial parameter to affect the transport across various biological barriers, but its impact on drug release and the resulting therapeutic efficacy is less understood. Inspired by erythrocytes with shape-facilitated oxygen-carrying and penetrating abilities, we constructed artificial erythrocyte-like nanoparticles (RNDs) by wrapping discoidal mesoporous silica nanoparticles with red blood cell membrane. We observed that, compared with their spherical and rod-shaped counterparts with monotonic drug release profiles, RNDs displayed an on-demand drug release pattern mimicking natural erythrocytes, that is, they could rapidly release loaded oxygen and doxorubicin (DOX) in hypoxic condition but were relatively stable in high oxygen areas. Besides, the discoidal shape also endowed RNDs with facilitated transport capability in tumor extracellular matrix, contributing to increased tumor permeability. In tumor models, systemically administrated RNDs efficiently infiltrate throughout tumor tissue, successfully relieve tumor hypoxia, and further altered the cancer cell cycle status from G1 to G2 phase, enhancing cancer cell sensitivity to DOX correlated with improved chemotherapy efficacy. In contrast, nanospheres show hampered permeability, and nanorods suffer from insufficient intratumoral drug accumulation. These findings can offer guidelines for the use of particle shape as a design criterion to control drug release, transportation, and therapeutics delivery.

Cell Membrane-Camouflaged Nanocarriers with Biomimetic Deformability of Erythrocytes for Ultralong Circulation and Enhanced Cancer Therapy.

Despite considerable advancements in cell membrane-camouflaged nanocarriers to leverage natural cell functions, artificial nanocarriers that can accurately mimic both the biological and physical properties of cells are urgently needed. Herein, inspired by the important effect of the stiffness and deformability of natural red blood cells (RBCs) on their life span and flowing through narrow vessels, we report the construction of RBC membrane-camouflaged nanocarriers that can mimic RBCs at different life stages and study how the deformability of RBC-derived nanocarriers affects their biological behaviors. RBC membrane-coated elastic poly(ethylene glycol) diacrylate hydrogel nanoparticles (RBC-ENPs) simulating dynamic RBCs exhibited high immunocompatibility with minimum immunoglobulin adsorption in the surface protein corona, resulting in reduced opsonization in macrophages and ultralong circulation. Furthermore, RBC-ENPs can deform like RBCs and achieve excellent diffusion in tumor extracellular matrix, leading to improved multicellular spheroid penetration and tumor tissue accumulation. In mouse cancer models, doxorubicin-loaded RBC-ENPs demonstrated superior antitumor efficacy to the first-line chemotherapeutic drug PEGylated doxorubicin liposomes. Our work highlights that tuning the physical properties of cell membrane-derived nanocarriers may offer an alternative approach for the bionic design of nanomedicines in the future.

Transfersomes improved delivery of ascorbic palmitate into the viable epidermis for enhanced treatment of melasma.

Ascorbic palmitate (AP) is widely used in the topical pharmaceutical or cosmetic formulations for melasma treatment. However, the presence of the skin barriers makes it difficult for the highly lipophilic drug molecules to traverse the stratum corneum (SC) and diffuse into the viable epidermis (EP) to reach the melanocytes, thereby exerting suboptimal antimelasma effects. Herein, AP was encapsulated into the transfersomes (TFs), yielding AP-TFs. AP-TFs utilized the deformability of TFs to squeeze through the skin pores in the SC under the transepidermal hydration gradient forces, leading to 14.1-fold increase in AP accumulation to the EP. AP-TFs could slowly release the encapsulated AP, while whether the released AP or transfersomal AP showed comparable uptake into the melanocytes, thereby exerting similar inhibitory effects on tyrosinase activity and melanogenesis. Ultimately, in the rat melasma model, AP-TFs showed superior antimelasma efficacy to free AP, with effective relief of oxidative stress and inflammation in the skin. Moreover, AP-TFs did not induce skin irritation. Therefore, the study provides a safe and effective approach to elevating the delivery of highly lipophilic drugs to the EP for enhanced treatment of melasma.

MT1-MMP-Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy.

Promoting tumor angiogenesis effectively and specifically to resolve tumor-associated hypoperfusion holds promise for improving pancreatic cancer therapy. Herein, a doxorubicin (DOX) loaded smart liposome, MC-T-DOX, is constructed, that carries appropriately low-density cilengitide, an αvß3 integrin-specific Arg-Gly-Asp (RGD)-mimetic cyclic peptide, via a membrane type 1-matrix metalloproteinase (MT1-MMP) cleavable peptide. After being administered systemically in a hypoperfused pancreatic cancer mouse model at a low dose of cilengitide, the proangiogenic activity of MC-T-DOX is specifically "turned on" in tumor vessels through cleavage by MT1-MMP on tumor endothelial cells to release cilengitide. This locally released cilengitide increases tumor blood perfusion, thereby improving the accumulation and distribution of MC-T-DOX in the tumor site. The loaded-DOX then displays enhanced penetration and increased cellular uptake upon heat-triggered release from MC-T-DOX in the tumor interstitium, contributing to the improved tumor therapy efficacy. Therefore, the strategy of combining the modulation of tumor vascular promotion with smart nanodrug delivery represents a promising approach to improving drug delivery and therapeutic efficacy in a wide range of hypoperfused tumors.

Rapid transport of germ-mimetic nanoparticles with dual conformational polyethylene glycol chains in biological tissues.

Polyethylene glycols (PEGs) can improve the diffusivity of nanoparticles (NPs) in biological hydrogels, while extended PEG chains severely impede cellular uptake of NPs. Inspired by invasive germs with flagellum-driven mucus-penetrating and fimbriae-mediated epithelium-adhering abilities, we developed germ-mimetic NPs (GMNPs) to overcome multiple barriers in mucosal and tumor tissues. In vitro studies and computational simulations revealed that the tip-specific extended PEG chains on GMNP functioned similarly to flagella, facilitating GMNP diffusion (up to 83.0-fold faster than their counterparts). Meanwhile, the packed PEG chains on the bodies of GMNP mediated strong adhesive interactions with cells similarly to the fimbriae, preserving cellular uptake efficiency. The in vivo results proved the superior tumor permeability and improved oral bioavailability provided by the GMNP (21.9-fold over administration of crystalline drugs). These findings offer useful guidelines for the rational design of NPs by manipulating surface polymer conformation to realize multiple functions and to enhance delivery efficacy.

Cancer-Cell-Membrane-Coated Nanoparticles with a Yolk-Shell Structure Augment Cancer Chemotherapy.

Despite rapid advancements in antitumor drug delivery, insufficient intracellular transport and subcellular drug accumulation are still issues to be addressed. Cancer cell membrane (CCM)-camouflaged nanoparticles (NPs) have shown promising potential in tumor therapy due to their immune escape and homotypic binding capacities. However, their efficacy is still limited due to inefficient tumor penetration and compromised intracellular transportation. Herein, a yolk-shell NP with a mesoporous silica nanoparticle (MSN)-supported PEGylated liposome yolk and CCM coating, CCM@LM, was developed for chemotherapy and exhibited a homologous tumor-targeting effect. The yolk-shell structure endowed CCM@LM with moderate rigidity, which might contribute to the frequent transformation into an ellipsoidal shape during infiltration, leading to facilitated penetration throughout multicellular spheroids in vitro (up to a 23.3-fold increase compared to the penetration of membrane vesicles). CCM@LM also exhibited a cellular invasion profile mimicking an enveloped virus invasion profile. CCM@LM was directly internalized by membrane fusion, and the PEGylated yolk (LM) was subsequently released into the cytosol, indicating the execution of an internalization pathway similar to that of an enveloped virus. The incoming PEGylated LM further underwent efficient trafficking throughout the cytoskeletal filament network, leading to enhanced perinuclear aggregation. Ultimately, CCM@LM, which co-encapsulated low-dose doxorubicin and the poly(ADP-ribose) polymerase inhibitor, mefuparib hydrochloride, exhibited a significantly stronger antitumor effect than the first-line chemotherapeutic drug Doxil. Our findings highlight that NPs that can undergo facilitated tumor penetration and robust intracellular trafficking have a promising future in cancer chemotherapy.

Cancer Cell Membrane-Camouflaged Nanorods with Endoplasmic Reticulum Targeting for Improved Antitumor Therapy.

Cell membrane-coated nanocarriers have been developed for drug delivery due to their enhanced blood circulation and tissue targeting capacities; however, previous works have generally focused on spherical nanoparticles and extracellular barriers. Many living organisms with different shapes, such as rod-shaped bacilli and rhabdovirus, display different functionalities regarding tissue penetration, cellular uptake, and intracellular distribution. Herein, we developed cancer cell membrane (CCM)-coated nanoparticles with spherical and rod shapes. CCM-coated nanorods (CRs) showed superior endocytosis efficiency compared with their spherical counterparts (CCM-coated nanospheres, CSs) due to the caveolin-mediated pathway. Moreover, CRs can effectively accumulate in the endoplasmic reticulum (ER) region and ship the loaded DOX to the nucleus at a considerable concentration, resulting in ER stress and subsequent apoptosis. After intravenous injection into human pancreatic adenocarcinoma cell (BxPC-3) and pancreatic stellate cell (HPSC) hybrid tumor-bearing nude mice, CRs exhibited improved immune escape ability, rapid extracellular matrix (ECM) penetration (8.2-fold higher than CSs), and enhanced tumor accumulation, further contributing to the enhanced antitumor efficacy. These findings may actually suggest the significance of shape design in improving current cell membrane-based drug delivery systems for effective subcellular targets and tumor therapy.

Advances in particle shape engineering for improved drug delivery.

Spherical particles such as liposomes and microspheres are the most common and extensively applied drug vehicles. However, researchers have come to realize the superiority of nonspherical nanoparticles. Actually, in human bodies red blood cells, gut biotics and many well-known pathogens have distinct shapes. It can be reasonably inferred that particle shape plays a pivotal part in human bodies. In this review, we summarize the recent studies about the effect of shape on delivery processes such as cellular uptake, tissue penetration and biodistribution. The underlying mechanisms that are relevant to the phenomena revealed, owing to experimental and computational modern techniques, will be addressed, and we shall provide future perspectives on particle design to improve the efficacy of drug delivery.

Simvastatin ameliorates graft-vs-host disease by regulating angiopoietin-1 and angiopoietin-2 in a murine model.

Angiopoietins play an important role in vascular endothelial function. Endothelial damage is an important pathogenesis relating with acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), protecting endothelial cells (ECs) from damage may be a potent prophylaxis and therapeutic strategy of acute GVHD (aGVHD). In this study, we explored changes in Angiopoietin-1 (Ang-1) and Ang-2 expression in a aGVHD mouse model and determined whether simvastatin prevents GVHD through regulating Ang-1 and Ang-2 expression. In vitro simvastatin administration increased Ang-1 production and release but conversely inhibited Ang-2 release from EA.hy926 ECs. Simvastatin improved the survival of aGVHD mice, attenuated the histopathological GVHD grades and plasma levels of Ang-2, and elevated the plasma levels of Ang-1 as well as the aortic endothelial levels of Ang-1 and Ang-2. In summary, simvastatin represents a novel approach to combat GVHD by increasing Ang-1 production while suppressing Ang-2 release to stabilize endothelial cells.

Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD.

Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-ß in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-ß promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.

Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations.

Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.