RESUMEN
Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological subtype and accounts for 85% of esophageal cancer cases worldwide. Traditional treatment for ESCC involves chemotherapy, radiotherapy, and surgery. However, the overall prognosis remains unfavorable. Recently, immune checkpoint blockade (ICB) therapy using anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) antibodies have not only achieved remarkable benefits in the clinical management of ESCC but have also completely changed the treatment approach for this cancer. In just a few years, ICB therapy has rapidly advanced and been added to standard first-line treatment regimen in patients with ESCC. However, preoperative immunotherapy is yet to be approved. In this review, we summarize the ICB antibodies commonly used in clinical immunotherapy of ESCC, and discuss the advances of immunotherapy combined with chemotherapy and radiotherapy in the perioperative treatment of ESCC, aiming to provide reference for clinical management of ESCC patients across the whole course of treatment.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/terapia , Neoplasias Esofágicas/terapia , Receptor de Muerte Celular Programada 1 , Inmunoterapia , Radioinmunoterapia , AnticuerposRESUMEN
The development of biodegradable Fe-based bone implants has rapidly progressed in recent years. Most of the challenges encountered in developing such implants have been tackled individually or in combination using additive manufacturing technologies. Yet not all the challenges have been overcome. Herein, we present porous FeMn-akermanite composite scaffolds fabricated by extrusion-based 3D printing to address the unmet clinical needs associated with Fe-based biomaterials for bone regeneration, including low biodegradation rate, MRI-incompatibility, mechanical properties, and limited bioactivity. In this research, we developed inks containing Fe, 35 wt% Mn, and 20 or 30 vol% akermanite powder mixtures. 3D printing was optimized together with the debinding and sintering steps to obtain scaffolds with interconnected porosity of 69%. The Fe-matrix in the composites contained the γ-FeMn phase as well as nesosilicate phases. The former made the composites paramagnetic and, thus, MRI-friendly. The in vitro biodegradation rates of the composites with 20 and 30 vol% akermanite were respectively 0.24 and 0.27 mm/y, falling within the ideal range of biodegradation rates for bone substitution. The yield strengths of the porous composites stayed within the range of the values of the trabecular bone, despite in vitro biodegradation for 28 d. All the composite scaffolds favored the adhesion, proliferation, and osteogenic differentiation of preosteoblasts, as revealed by Runx2 assay. Moreover, osteopontin was detected in the extracellular matrix of cells on the scaffolds. Altogether, these results demonstrate the remarkable potential of these composites in fulfilling the requirements of porous biodegradable bone substitutes, motivating future in vivo research. STATEMENT OF SIGNIFICANCE: We developed FeMn-akermanite composite scaffolds by taking advantage of the multi-material capacity of extrusion-based 3D printing. Our results demonstrated that the FeMn-akermanite scaffolds showed an exceptional performance in fulfilling all the requirements for bone substitution in vitro, i.e., a sufficient biodegradation rate, having mechanical properties in the range of trabecular bone even after 4 weeks biodegradation, paramagnetic, cytocompatible and most importantly osteogenic. Our results encourage further research on Fe-based bone implants in in vivo.
Asunto(s)
Sustitutos de Huesos , Sustitutos de Huesos/farmacología , Porosidad , Osteogénesis , Impresión Tridimensional , Andamios del Tejido/químicaRESUMEN
The treatment of femoral nonunion with large segmental bone defect is still challenging. Although magnesium alloys have been considered potential materials for such a treatment, their application is limited by their fast degradation. Adding bioceramic particles into magnesium to form Mg-matrix composites is a promising strategy to adjust their biodegradation rates and to improve their mechanical properties and cytocompatibility further. Here, we developed an extrusion-based additive manufacturing technique to fabricate biodegradable Mg-Zn/bioceramic composite scaffolds ex-situ. Inks carrying a Mg-Zn powder and 5, 10 and 15% ß-tricalcium phosphate (TCP) powder particles were investigated regarding the dispersion of ß-TCP particles in the inks and viscoelastic properties. Optimally formulated inks were then employed for subsequent 3D printing of porous composite scaffolds. The in vitro biodegradation rate of the scaffolds containing 5% ß-TCP decreased to 0.5 mm/y, which falls within the range desired for critical-sized bone substitution. As compared to the monolithic Mg-Zn scaffolds, the elastic moduli and yield strengths of the composite scaffolds were much enhanced, which remained in the range of the cancellous bone properties even after 28 d of in vitro degradation. The Mg-Zn/5TCP and Mg-Zn/10TCP scaffolds also exhibited improved biocompatibility when cultured with preosteoblasts, as compared to Mg-Zn scaffolds. In addition, the ALP activity and mineralization level of the composite scaffolds were much enhanced in the extracts of the composite scaffolds. Taken together, this research marks a great breakthrough in fabricating porous Mg-matrix composite scaffolds that meet several design criteria in terms of appropriate biodegradation rate, mechanical properties, and bioactivity. STATEMENT OF SIGNIFICANCE: The treatment of posttraumatic femoral nonunion with large segmental bone defect is still challenging. In this study, we developed a multi-material extrusion-based additive technique to fabricate porous Mg/bioceramic composite scaffolds for such a treatment. The technique allowed for the fine-tuning of printable inks to optimize the dispersion of micro-sized particles. The relative densities of the struts of the fabricated composite scaffolds reached 99%. The added bioceramic particles (ß-TCP) exhibited proper interfacial bonding with the Mg alloy matrix. The porous Mg-based composite possessed desired biodegradability, bone-mimicking mechanical properties throughout the in vitro biodegradation period and improved bioactivity to bone cells. These results demonstrated great prospects of extrusion-based 3D printed porous Mg materials to be developed further as ideal biodegradable bone-substituting materials.
Asunto(s)
Magnesio , Andamios del Tejido , Aleaciones/farmacología , Materiales Biocompatibles , Fosfatos de Calcio , Magnesio/farmacología , Porosidad , Polvos , Impresión Tridimensional , ZincRESUMEN
Advanced additive manufacturing techniques have been recently used to tackle the two fundamental challenges of biodegradable Fe-based bone-substituting materials, namely low rate of biodegradation and insufficient bioactivity. While additively manufactured porous iron has been somewhat successful in addressing the first challenge, the limited bioactivity of these biomaterials hinder their progress towards clinical application. Herein, we used extrusion-based 3D printing for additive manufacturing of iron-matrix composites containing silicate-based bioceramic particles (akermanite), thereby addressing both of the abovementioned challenges. We developed inks that carried iron and 5, 10, 15, or 20 vol% of akermanite powder mixtures for the 3D printing process and optimized the debinding and sintering steps to produce geometrically-ordered iron-akermanite composites with an open porosity of 69-71%. The composite scaffolds preserved the designed geometry and the original α-Fe and akermanite phases. The in vitro biodegradation rates of the composites were improved as much as 2.6 times the biodegradation rate of geometrically identical pure iron. The yield strengths and elastic moduli of the scaffolds remained within the range of the mechanical properties of the cancellous bone, even after 28 days of biodegradation. The composite scaffolds (10-20 vol% akermanite) demonstrated improved MC3T3-E1 cell adhesion and higher levels of cell proliferation. The cellular secretion of collagen type-1 and the alkaline phosphatase activity on the composite scaffolds (10-20 vol% akermanite) were, respectively higher than and comparable to Ti6Al4V in osteogenic medium. Taken together, these results clearly show the potential of 3D printed porous iron-akermanite composites for further development as promising bone substitutes. STATEMENT OF SIGNIFICANCE: Porous iron matrix composites containing akermanite particles were produced by means of multi-material additive manufacturing to address the two fundamental challenges associated with biodegradable iron-based biomaterials, namely very low rate of biodegradation and insufficient bioactivity. Our porous iron-akermanite composites exhibited enhanced biodegradability and superior bioactivity compared to porous monolithic iron scaffolds. The murine bone cells proliferated on the composite scaffolds, and secreted the collagen type-1 matrix that stimulated bony-like mineralization. The results show the exceptional potential of the developed porous iron-based composite scaffolds for application as bone substitutes.
Asunto(s)
Sustitutos de Huesos , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Regeneración Ósea , Cerámica , Colágeno , Hierro/química , Hierro/farmacología , Ratones , Porosidad , Impresión Tridimensional , Andamios del Tejido/químicaRESUMEN
The role of biomaterials surface in controlling the interfacial biological events leading to implant integration is of key importance. In this study, the effects of NiTi surfaces treated by plasma electrolytic oxidation (PEO) on human umbilical vein endothelial cells (HUVECs) have been investigated. The changes in NiTi surface morphology and chemistry were assessed by SEM, XPS and cross-section TEM/EDX analyzes whereas the effects of the resultant surfaces on in vitro endothelialization and cell junction proteins have been evaluated by life/dead staining, SEM, cells counting, qPCR and immunofluorescence. The findings indicated that the PEO-treated NiTi, with a microporous morphology and oxide dominated surface chemistry, supports viability and proliferation of HUVECs. Numerous thin filopodia probing the microporous surface assisted cells attachment. In addition, claudin-5 and occludin have been upregulated and expression of vascular endothelial-cadherin was not suppressed on PEO-treated NiTi relative to the reference electropolished surfaces. The results of this study suggest that novel NiTi surfaces may be developed using the PEO process, which can be of benefit to atherosclerosis treatment.
Asunto(s)
Materiales Biocompatibles Revestidos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Níquel/farmacología , Titanio/farmacología , Aleaciones/química , Aleaciones/farmacología , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Claudina-5/genética , Claudina-5/metabolismo , Materiales Biocompatibles Revestidos/química , Electrólisis , Electrólitos/química , Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/ultraestructura , Humanos , Microscopía Confocal , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Níquel/química , Ocludina/genética , Ocludina/metabolismo , Oxidación-Reducción , Espectroscopía de Fotoelectrones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Propiedades de Superficie , Titanio/químicaRESUMEN
Cell manipulation is imperative to the areas of cellular biology and tissue engineering, providing them a useful tool for patterning cells into cellular patterns for different analyses and applications. This paper presents a novel approach to perform three-dimensional (3D) cell manipulation and patterning with a multi-layer engineered scaffold. This scaffold structure employed dielectrophoresis as the non-contact mechanism to manipulate cells in the 3D domain. Through establishing electric fields via this multi-layer structure, the cells in the medium became polarized and were attracted towards the interior part of the structure, forming 3D cellular patterns. Experiments were conducted to evaluate the manipulation and the patterning processes with the proposed structure. Results show that with the presence of a voltage input, this multi-layer structure was capable of manipulating different types of biological cells examined through dielectrophoresis, enabling automatic cell patterning in the time-scale of minutes. The effects of the voltage input on the resultant cellular pattern were examined and discussed. Viability test was performed after the patterning operation and the results confirmed that majority of the cells remained viable. After 7 days of culture, 3D cellular patterns were observed through SEM. The results suggest that this scaffold and its automated dielectrophoresis-based patterning mechanism can be used to construct artificial tissues for various tissue engineering applications.
Asunto(s)
Separación Celular , Andamios del Tejido/química , Células 3T3 , Animales , Separación Celular/instrumentación , Electrodos , Electroforesis/instrumentación , Fibroblastos/citología , Prepucio/citología , Células HEK293 , Humanos , Masculino , Ratones , Ingeniería de Tejidos/métodosRESUMEN
The purpose of this study was to generate hybrid micro/nano-structures on biomedical nickel-titanium alloy (NiTi). To achieve this, NiTi surfaces were firstly electrochemically etched and then anodized in fluoride-containing electrolyte. With the etching process, the NiTi surface was micro-roughened through the formation of micropits uniformly distributed over the entire surface. Following the subsequent anodizing process, self-organized nanotube structures enriched in TiO2 could be superimposed on the etched surface under specific conditions. Furthermore, the anodizing treatment significantly reduced water contact angles and increased the surface free energy compared to the surfaces prior to anodizing. The results of this study show for the first time that it is possible to create hybrid micro/nano-structures on biomedical NiTi alloys by combining electrochemical etching and anodizing under controlled conditions. These novel structures are expected to significantly enhance the surface biofunctionality of the material when compared to conventional implant devices with either micro- or nano-structured surfaces.
Asunto(s)
Nanotubos/química , Níquel/química , Titanio/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Técnicas Electroquímicas , Humanos , Ensayo de Materiales , Nanotecnología , Nanotubos/ultraestructura , Prótesis e Implantes , Propiedades de SuperficieRESUMEN
OBJECTIVE: To investigate the protective effect of angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats (SHRs). METHODS: A cohort of male SHRs were randomly divided into three groups (n = 10 for each group): pseudo-experimental group, enalapril-treated group as a positive control group, ACE-inhibitory peptide LAP-treated group. After the experiment, the left common carotid artery from each rat was removed for morphological evaluation. RESULTS: It was observed that the vascular medial thickness, media thickness/lumen diameter, medial cross-sectional area and mean nuclear area of smooth muscle cells of the left common carotid artery in the LAP group or enalapril group were significantly lower than those in the pseudo-experimental group, while there was no significant difference in these parameters observed between the LAP group and enalapril group. Additionally, the vascular area percentage of collagen fibers of the left common carotid artery in the LAP group and enalapril group was significantly lower than that of the pseudo-experimental group. CONCLUSIONS: The protective vessel remodeling effect in SHRs was observed with ACE-inhibitory peptide LAP in SHRs by decreasing blood pressure, inhibiting smooth muscle cell hypertrophy and reducing the proliferation of collagen fibers.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Arteria Carótida Común/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Péptidos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Arteria Carótida Común/enzimología , Arteria Carótida Común/patología , Grosor Intima-Media Carotídeo , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Enalapril/farmacología , Colágenos Fibrilares/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/enzimología , Hipertensión/fisiopatología , Hipertrofia , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Ratas , Ratas Endogámicas SHRRESUMEN
BACKGROUND: For these patients with colorectal cancers, improving their quality of life is just as important as clearing them of their tumor burden. AIM: To assess the reference value to surgeons of magnetic resonance imaging (MRI) and endorectal ultrasound (EUS) in local staging of rectal cancer. PATIENTS AND METHODS: According to the criteria we set, 69 patients received MRI and 60 patients received EUS, all by senior doctors. We compared two groups in staging accuracy of depth of penetration (T), lymph nodes positive (N) and combined T and N (TN) result. Strategy one (Str1.) was chosen based on MRI or EUS staging. Strategy two (Str2.) took into account clinical parameters, such as computed tomography (CT) and colonoscopy. Strategy three (Str3.) was the best treatment strategy; this was, in part, based on analysis of patients' specimen pathological results. Compared to Str.1 and Str.2, the use of Str.3 as the reference standard separately reflected the reference values of MRI and EUS for surgeons and actual treatment accuracy. RESULTS: EUS had higher sensitivity in T1 (p = 0.044 < 0.05) and specificity in T2 (p = 0.039 < 0.05) than MRI. MRI had higher sensitivity in N staging (p = 0.046 < 0.05) and was more accurate in pT1~4N1~2 (p < 0.05) than EUS. Reference values for surgery (comparing appropriate rates of Str.1 with Str.3) of MRI and EUS were 79.7% vs. 76. 7%, respectively (p > 0.05). The actual treatment accuracy (comparing appropriate rates of Str.2 with Str.3) was increased up to 94.2% vs. 91.7%, respectively (p > 0.05). CONCLUSIONS: EUS is good for early-stage patients but MRI for local advanced ones. Strategies both could be improved by combining clinical factors that lead to similar reference values for surgery.
Asunto(s)
Endosonografía/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias del Recto/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/cirugía , Valores de ReferenciaRESUMEN
Zinc and zirconium were selected as the alloying elements in biodegradable magnesium alloys, considering their strengthening effect and good biocompatibility. The degradation rate, hydrogen evolution, ion release, surface layer and in vitro cytotoxicity of two Mg-Zn-Zr alloys, i.e. ZK30 and ZK60, and a WE-type alloy (Mg-Y-RE-Zr) were investigated by means of long-term static immersion testing in Hank's solution, non-static immersion testing in Hank's solution and cell-material interaction analysis. It was found that, among these three magnesium alloys, ZK30 had the lowest degradation rate and the least hydrogen evolution. A magnesium calcium phosphate layer was formed on the surface of ZK30 sample during non-static immersion and its degradation caused minute changes in the ion concentrations and pH value of Hank's solution. In addition, the ZK30 alloy showed insignificant cytotoxicity against bone marrow stromal cells as compared with biocompatible hydroxyapatite (HA) and the WE-type alloy. After prolonged incubation for 7 days, a stimulatory effect on cell proliferation was observed. The results of the present study suggested that ZK30 could be a promising material for biodegradable orthopedic implants and worth further investigation to evaluate its in vitro and in vivo degradation behavior.
Asunto(s)
Aleaciones , Técnicas In Vitro , Magnesio/química , Zinc/química , Circonio/químicaRESUMEN
Fistula formation to the inferior vena cava is a rare complication of aortic aneurysm which is often misdiagnosed clinically. In one hundred of reported arteriocaval fistulae, none was originating from the right common iliac artery. We report a case of ileo-caval fistula due to a iatrogenic pseudoaneurysm. High resolution 3D imaging using breath-hold CT angiography is highly specific in identifying the location, extent of the aortocaval fistula as well as the neighbouring anatomic structures.
Asunto(s)
Aneurisma Falso/diagnóstico por imagen , Angiografía , Fístula Arteriovenosa/diagnóstico por imagen , Arteria Ilíaca/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Tomografía Computarizada por Rayos X , Vena Cava Inferior/diagnóstico por imagen , Adulto , Coledocostomía/efectos adversos , Femenino , Humanos , Enfermedad IatrogénicaRESUMEN
Using the hydrated adenosine intermediate (6R)-6-amino-1, 6-dihydro-6-hydroxy-9-(beta-D-ribofuranosyl)purine (2) produced by adenosine deaminase (ADA, EC 3.5.4.4) as a starting point, the active site probe and inhibitor platform 5-(formylamino)imidazole riboside (FAIRs, 4) was designed by removal of the-C6(OH)(NH2)-molecular fragment of 2 generated by the early events of the enzyme-catalyzed hydrolysis. FAIRs was synthesized directly from the sodium salt of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxylic acid (CAIR) along a reaction sequence involving a tandem N-formylation/decarboxylation that may have a mechanistic connection to the Escherichia coli purE-catalyzed constitutional isomerization of N5-CAIR to CAIR. The physical and spectral properties of FAIRs were elucidated, its X-ray crystal and NMR solution structures were determined, and its interaction with ADA was investigated. Crystalline FAIRs exists solely as the Z-formamide rotamer and exhibits many of the same intramolecular hydrogen bonding events known to contribute to the association of Ado to ADA. In water and various organic solvents, however, FAIRs exists as NMR-distinct, slowly interconverting Z and E rotamers. This truncated enzymatic tetrahedral intermediate analog was determined to be a competitive inhibitor of ADA with an apparent Ki binding constant of 40 microM, a value quite close to that (33 microM) of the natural substrate's K(m). The actual species selected for binding by ADA, though, is likely the minor hydroxyimino prototropic form of Z-FAIRs possessing a far lower true Ki value. As the structural features of FAIRs appear well-suited to support its use as a template for constructing active site probes of both ADA and AIR carboxylases, a variety of carbohydrate-protected versions of FAIRs suitable for facile aglycon elaborations were synthesized. The N3-alkylation, N3-borane complexation, and C4-iodination of some of these were investigated in order to assess physicochemical properties that may assist in the elucidation of mechanisms for the AIR carboxylases. The survey of these properties taken together with a reasonable mechanism for the model CAIRs-->FAIRs synthetic transformation is interpreted to support a mechanism for the purE-catalyzed N5-CAIR-->CAIR biosynthetic one that involves a carboxylative sp3-rehybridization of the imidazole C4 atom rather than one possessing a dipole-stabilized C4 sp2 carbanionic intermediate.