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With the widespread adoption of ultrasound guidance, Seldinger puncture techniques, and intracardiac electrical positioning technology for the placement of peripherally inserted central catheters in recent years, an increasing number of medical staff and patients now accept peripheral placement of totally implantable venous access devices (TIVADs) in the upper arm. This approach has the advantage of completely avoiding the risks of hemothorax, pneumothorax, and neck and chest scarring. Medical specialties presently engaged in this study in China include internal medicine, surgery, anesthesiology, and interventional departments. However, command over implantation techniques, treatment of complications, and proper use and maintenance of TIVAD remain uneven among different medical units. Moreover, currently, there are no established quality control standards for implantation techniques or specifications for handling complications. Thus, this expert consensus is proposed to improve the success rate of TIVAD implantation via the upper-arm approach, reduce complication rates, and ensure patient safety. This consensus elaborates on the technical indications and contraindications, procedures and technical points, treatment of complications, and the use and maintenance of upper-arm TIVAD, thus providing a practical reference for medical staff.
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PURPOSE: To appraise the diagnostic performance of magnetic resonance imaging-guided percutaneous coaxial cutting needle biopsy of pancreatic lesions using a 0.4-T open magnetic resonance imaging scanner with optical tracking navigation. MATERIALS AND METHODS: This retrospective study included 158 patients who underwent magnetic resonance imaging-guided pancreatic lesion biopsy procedures from May 2019 to December 2020. Two to four specimens were collected from each patient. Pathological diagnosis and clinical follow-ups were conducted to establish the final diagnosis. The procedures were evaluated for sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and complications. The Cardiovascular and Interventional Radiological Society of Europe guidelines were used to classify complications. RESULTS: Biopsy pathology revealed 139 pancreatic tumor malignancies and 19 benign pancreatic lesions. Finally, 151 patients were diagnosed with pancreatic malignancy and 7 with benign disease confirmed by surgery, re-biopsy, and clinical follow-up. The sensitivity, specificity, positive and negative predictive value, and accuracy for diagnosis of pancreatic diseases were 92.1%, 100%, 100%, 36.8%, and 92.4%, respectively. The biopsy accuracy was significantly related to the size (≤ 2 cm, 76.2%; 2-4 cm, 94.0%; > 4 cm, 96.2%, P = .02) and not the lesion's location (head of pancreas, 90.7%; neck of pancreas, 88.9%; body of pancreas, 94.3%; tail of pancreas, 96.7%, P = .73). Minor complications included two patients experiencing mild abdominal pain and two with a minor occurrence of hemorrhage. CONCLUSIONS: Percutaneous magnetic resonance imaging-guided pancreatic lesion biopsy combined with optical navigation has high diagnostic accuracy and is safe for clinical practice. Level of Evidence Level 4, Case-series.
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Páncreas , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Sensibilidad y Especificidad , Páncreas/diagnóstico por imagen , Biopsia Guiada por Imagen/métodos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Biopsia con Aguja/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias PancreáticasRESUMEN
Connexins are membrane expressed proteins, which could assemble into hexamers to transfer metabolites and secondary messengers. However, its roles in pancreatic cancer metastasis remains unknown. In this study, by comparing the gene expression patterns in primary pancreatic cancer patients primary and liver metastasis specimens, we found that Gap Junction Protein Beta 3 (GJB3) significantly increased in Pancreatic ductal adenocarcinoma (PDAC) liver metastasis. Animal experiments verified that GJB3 depletion suppressed the hepatic metastasis of PDAC cancer cells. Further, GJB3 over expression increased the neutrophil infiltration. Mechanistic study revealed that GJB3 form channels between PDAC tumor cells and accumulated neutrophil, which transfer cyclic adenosine monophosphate (cAMP) from cancer to neutrophil cells, which supports the survival and polarization. Taken together, our data suggesting that GJB3 could act as a potential therapeutic target of PDAC liver metastasis.
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Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Animales , Neutrófilos/metabolismo , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Proteínas de la Membrana , Neoplasias PancreáticasRESUMEN
OBJECTIVES: Placenta accreta spectrum (PAS) can induce severe life-threatening obstetric hemorrhage. Herein, we conducted a Bayesian network meta-analysis of previous studies to evaluate the relative benefits of different prophylactic balloon occlusion (PBO) procedures. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to July 2021. Blood loss volume, blood transfusion volume, and hysterectomy rate were regarded as the primary endpoints. The data were pooled using a Bayesian network and traditional pairwise meta-analysis. RESULTS: Fifty-nine articles with a total sample size of 5150 patients were included. Compared with no PBO (non-PBO) intervention, PBO of the abdominal aorta (PBOAA, mean difference(MD) - 1.02, 95% credible interval (CrI) - 1.4 to - 0.67), common iliac artery (PBOCIA, MD - 0.84; 95%CrI - 1.36 to - 0.06) and internal iliac artery (PBOIIA, MD - 0.42; 95%CrI - 0.72 to - 0.13) significantly lowered blood loss volume, with PBOAA being more effective than PBOIIA (MD - 0.60; 95%CrI - 1.05 to - 0.17). PBOAA and PBOIIA also significantly decreased blood loss volume (MD - 2.33; 95%CrI - 3.74 to - 0.94, MD - 1.57; 95%CrI - 2.77 to - 0.47 respectively) and hysterectomy rate (OR 0.31; 95%CrI 0.16 to 0.54, OR 0.53; 95%CrI 0.29 to 0.92 respectively). PBOAA has the highest probability of being more effective in reducing the blood loss volume, blood transfusion volume, and hysterectomy rate. CONCLUSIONS: Performing PBOAA, PBOCIA, or PBOIIA in PAS patients is an effective way to minimize blood loss volume, while PBOAA and PBOIIA also reduce blood transfusion volume and hysterectomy rate. PBOAA is a notably more effective strategy to reduce blood loss volume than PBOIIA. KEY POINTS: ⢠PBOAA, PBOCIA, and PBOIIA procedures can significantly reduce the blood loss volume compared to non-PBO intervention in PAS patients, of which PBOAA was more effective than the PBOIIA procedure. ⢠PBOAA and PBOIIA could significantly reduce the blood transfusion volume and hysterectomy rate in contrast to the non-PBO intervention in patients with PAS. ⢠According to our statistical treatment ranking, PBOAA was statistically superior in reducing blood transfusion volume, blood transfusion volume, and hysterectomy rate than other PBO procedures.
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Oclusión con Balón , Placenta Accreta , Hemorragia Posparto , Oclusión con Balón/métodos , Teorema de Bayes , Pérdida de Sangre Quirúrgica/prevención & control , Femenino , Humanos , Histerectomía , Arteria Ilíaca , Metaanálisis en Red , Placenta Accreta/cirugía , Hemorragia Posparto/terapia , Embarazo , Estudios RetrospectivosRESUMEN
OBJECTIVES: The aim of this study is to evaluate the efficacy of prophylactic internal iliac artery balloon occlusion combined with Pituitrin intra-arterial infusion in the control of postpartum hemorrhage in women with placenta accreta spectrum (PAS). METHODS: This is a prospective and non-randomized controlled study. The participants were assigned into three groups: without balloon catheterization (non-BC) group, balloon catheterization (BC) group, and Pituitrin combined with balloon catheterization (PBC) group. The primary outcomes were estimated blood loss (EBL) and the units of transfused packed red blood cells (PRBC). The secondary outcome was the incidence of hysterectomy. RESULTS: A total of 100 participants were recruited between August 2013 and November 2018 and assigned into the respective groups as follows: 27 in the non-BC group, 22 in the BC group, and 51 in the PBC group. No statistical differences were found in demographic characteristics among the three groups. There was a trend of lower EBL, PRBC, and hysterectomy rate in the BC group than those in the non-BC group, while all values showed no significant differences (all p > 0.05). Patients in the PBC group had significantly lower EBL, PRBC, and hysterectomy rate compared with those in the non-BC group (all p < 0.05). Linear regression analysis revealed that the PBC (vs. others) was negatively correlated with EBL and the non-BC (vs. others) independently predicted more EBL. CONCLUSIONS: Balloon occlusion combined with Pituitrin infusion is an effective treatment method which significantly reduced EBL, PRBC, and hysterectomy rate in patients with PAS. KEY POINTS: ⢠Internal iliac artery balloon occlusion combined with Pituitrin intra-arterial infusion can significantly decrease EBL, PRBC, and hysterectomy rate during cesarean section in patients with PAS. ⢠Cesarean section without balloon occlusion and placenta accreta depth are two independent risk factors for EBL in patients with PAS.
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Oclusión con Balón/métodos , Hormonas Neurohipofisarias/uso terapéutico , Placenta Accreta/fisiopatología , Hemorragia Posparto/terapia , Adulto , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión de Eritrocitos/estadística & datos numéricos , Femenino , Humanos , Histerectomía/estadística & datos numéricos , Arteria Ilíaca/diagnóstico por imagen , Infusiones Intraarteriales , Imagen por Resonancia Magnética , Hormonas Neurohipofisarias/administración & dosificación , Placenta Accreta/diagnóstico por imagen , Hemorragia Posparto/tratamiento farmacológico , Hemorragia Posparto/fisiopatología , Embarazo , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Objective: To establish the technique of intratumoral combination therapy of radiofrequency hyperthermia (RFH) with herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy for rat ovarian cancers.Material and methods: This study consisted of three parts: (1) in vitro experiments to establish the 'proof of principal' that combination of RFH and HSV-TK gene therapy has the synergistic effect on human ovarian cancer cells; (2) creation of bioluminescence imaging-detectable rat ovarian cancer model; and (3) in vivo experiments using this rat model to validate the technical feasibility of the combination therapy. Cells and nude rats were divided into four groups: (i) combination therapy (HSV-TK/GCV + RFH); (ii) RFH; (iii) HSV-TK/GCV; and (iv) phosphate-buffered saline (PBS). Data were analyzed using Dunnett t-test or Kruskal-Wallis test.Results: Cell proliferation assay demonstrated significantly greater reduction in viable cells with the combination therapy [0.52 (0.43, 0.61)] compared to other treatments [RFH 0.90 (0.84, 0.96), HSV-TK/GCV 0.71 (0.53, 0.88), PBS 1 (1, 1); p < .05]. For 24 rat models with bioluminescence imaging-detectable orthotopic ovarian cancer (n = 6 per group), optical imaging demonstrated significantly decreased relative bioluminescence signal with the combination therapy [0.81 (0.52, 1.08)] compared to other treatments [RFH 3.60 (2.34, 4.86), HSV-TK/GCV 2.21 (1.71, 2.71), PBS 3.74 (3.19, 4.29); p < .001]. Ultrasound imaging demonstrated the smallest relative tumor volume with the combination therapy [0.78 (0.45, 1.11) versus 3.50 (2.67, 4.33), 2.10 (0.83, 3.37), 3.70 (1.79, 5.61); p < .05].Conclusion: The feasibility of intratumoral RFH-enhanced HSV-TK/GCV gene therapy was established on a unique rat model with molecular imaging-detectable orthotopic ovarian cancer.
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Terapia Genética/métodos , Hipertermia Inducida/métodos , Imagen Molecular/métodos , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/radioterapia , Simplexvirus/efectos de los fármacos , Timidina Quinasa/uso terapéutico , Animales , Femenino , Humanos , Ratas , Ratas Desnudas , Timidina Quinasa/farmacologíaRESUMEN
PURPOSE: Hepatic ischemia-reperfusion (IR) injury is a serious complication of many clinical conditions, which may lead to liver or multiple organ failure. Hyperoside, a flavonoid compound, has been reported to protect against myocardial and cerebral injury induced by IR. This study aimed to investigate the protective effects of hyperoside on hepatic IR injury in rats. METHODS: Using the 70% hepatic IR injury model, we divided 32 male Wistar rats into 4 groups (n = 8): sham-operated, IR+saline (saline/p.o.), IR+vehicle (carboxy methyl cellulose/p.o.), and IR+hyperoside (50 mg/kg/d/p.o.). At 24 hours after reperfusion, blood and liver tissue were collected. The effects of hyperoside on hepatic IR injury were assessed through tests of serum transaminase, hepatic histopathology, and measurement of markers of oxidative stress and apoptosis. RESULTS: Pretreatment with hyperoside protected the liver from IR injury by a reduction in serum aspartate aminotransferase/alanine aminotransferase levels and a decrease in the severity of histologic changes. Hyperoside treatment also decreased the activity of malondialdehyde, increased the activities of superoxide dismutase and glutathione peroxidase, up-regulated the expression of heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1, and reduced the apoptotic index after IR injury. A decrease in the expression of caspase-3 and an increase in the ratio of B cell lymphoma 2 to B cell lymphoma 2-associated X also were observed. CONCLUSION: Hyperoside has a protective effect on hepatic IR injury in rats, which may be due to its antioxidant and antiapoptotic properties.
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Apoptosis/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Quercetina/análogos & derivados , Daño por Reperfusión/patología , Animales , Antioxidantes/farmacología , Hígado/patología , Masculino , Quercetina/farmacología , Ratas , Ratas WistarRESUMEN
AIMS: The study aimed to evaluate the safety and efficacy of navigated magnetic resonance imaging (MRI)-guided celiac plexus neurolysis (CPN) using a 0.4 T open magnetic resonance system. MATERIALS AND METHODS: A retrospective analysis was performed on 23 patients with unresectable pancreatic cancer who underwent MRI-guided CPN between January 2013 and October 2017. Clinical outcomes were evaluated by recording the complications, the opioid intake, and questionnaire before the intervention and at the time point of 1 day, 1 month, and 3 months postprocedure using a numerical visual analog scale (VAS). RESULTS: Navigated MRI guidance allowed the precise placement of needle in the targeted area and the visualization of the injected neurolysis agents for all cases. The VAS scores decreased from 8.8 ± 1.0 to 2.9 ± 0.9, 4.2 ± 1.7, and 4.7 ± 1.8 at 1 day, 1 month, and 3 months postprocedure (P < 0.05). This intervention reduced the dosage of opioid consumption 1 month after the procedure (52.3 ± 10.4 mg before the treatment vs. 28.2 ± 4.9 mg after the treatment; P < 0.001). Treatment-related side effects included hematoma in one patient, short episodes of diarrhea in three patients, and hypotension in four patients. CONCLUSIONS: With the assistance of the navigation system, MRI-guided CPN is a safe and effective treatment approach for managing the upper abdominal pain in patients with unresectable pancreatic cancer.
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Dolor Abdominal/prevención & control , Dolor en Cáncer/prevención & control , Plexo Celíaco/patología , Imagen por Resonancia Magnética/métodos , Bloqueo Nervioso/métodos , Neoplasias Pancreáticas/complicaciones , Cirugía Asistida por Computador/métodos , Dolor Abdominal/etiología , Dolor Abdominal/patología , Anciano , Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/etiología , Dolor en Cáncer/patología , Plexo Celíaco/cirugía , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Manejo del Dolor , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pronóstico , Estudios RetrospectivosRESUMEN
The aim of this study was to develop an interventional oncologic technique, "Image-guided intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus-thymidine kinase (HSV-TK) gene therapy of ovarian cancer. This study consisted of three portions: (1) serial in-vitro experiments to establish "proof-of-principle" of this novel technique using human ovarian cancer cells; (2) serial in-vivo experiments to validate technical feasibility using animal models with the same orthotopic ovarian cancers; and (3) serial investigations into the underlying bio-molecular mechanisms of this technique. We included four subject groups: (i) combination therapy with RFH+HSV-TK gene therapy; (ii) gene therapy-only; (iii) RFH-only; and (iv) Phosphate-buffered saline (PBS). For in-vitro experiments, confocal microscopy and MTS assays were performed to quantify HSV-TK gene expression and assess cell viability. For in-vivo experiments, bioluminescence optical and ultrasound imaging were used to assess therapeutic effectiveness. These results were correlated with subsequent pathologic/laboratory studies to further elucidate the biologic mechanisms of this technique. In in-vitro experiments, combination therapy resulted in the lowest cell proliferation and greatest increase in HSV-TK gene expression among four subject groups. In in-vivo experiments, combination therapy lead to significant decreases of bioluminescence signals and sizes of tumors in combination therapy by optical and ultrasound imaging. Pathology/laboratory examinations confirmed the significantly increased expression of Bax, Caspase-3, HSP70, IL-2, and CD94 in cancer tissues subjected to combination therapy. "Image-guided intratumoral RFH-enhanced direct gene therapy" is an effective interventional oncologic technique which functions through apoptotic/anti-tumor immunity pathways. This technical development may open new avenues for treating ovarian cancer.
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OBJECTIVE: To evaluate pre-cesarean prophylactic balloon placement (PBP) in the internal iliac artery among women with pernicious placenta previa. METHODS: The present retrospective study included women with pernicious placenta previa who underwent cesarean delivery at Shanghai Renji Hospital, Shanghai, China, between March 1, 2011, and June 30, 2017. Data were compared between patients who did and did not undergo PBP. RESULTS: Among 42 patients included, 20 underwent PBP and 22 did not. Mean ± SD estimated blood loss was 2900.00 ± 2352.21 mL in the PBP group, and 4549.77 ± 2366.67 mL in the non-PBP group (P=0.025). The amount of transfused red blood cells was 8.40 ± 7.14 U and 13.00 ± 7.93 U (P=0.018), respectively. No patients in the PBP group developed postoperative disseminated intravascular coagulopathy, compared with 3 (14%) in the non-PBP group (P=0.087). In the PBP and non-PBP groups, the hospital stay duration was 7.40 ± 3.07 and 8.68 ± 2.58 days (P=0.029), and there were 1 and 7 patients who had obstetric hysterectomies (P=0.027), respectively. Two patients experienced PBP-related adverse events, including thrombosis and re-bleeding. There were no deaths. CONCLUSION: Pre-cesarean PBP in the internal iliac artery was a safe and effective treatment that could reduce the incidence of both postpartum hemorrhage and hysterectomy among women with pernicious placenta previa.
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Cesárea , Histerectomía/estadística & datos numéricos , Placenta Previa/terapia , Hemorragia Posparto/prevención & control , Adulto , China , Femenino , Humanos , Arteria Ilíaca , Incidencia , Persona de Mediana Edad , Embarazo , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
We report on the fabrication of ion exchangeable microstructures by femtosecond laser direct writing of an ion exchange photopolymer, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPS). The resultant microstructures are negatively charged in aqueous solution, and can adsorb positively charged species, such as metal ions, nanoparticles, and proteins by electrostatic interaction, forming functional components for chip functionalization. In addition, it is possible to modify the microstructures with positively charged species that make the microstructures sensitive to negatively charged species. As a typical example, a crossed 3D microvessel functionalized with antibodies was fabricated, which reveals great potential for organ-on-a-chip systems. The fabrication of ion exchangeable microstructures holds great promise for flexible chip functionalization.
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Rayos Láser , Nanotecnología/métodos , Polímeros/química , Ácidos Sulfónicos/química , Escritura , Diseño de EquipoRESUMEN
BACKGROUND AND AIMS: The information about clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients is limited. We performed this study to assess the impact of age on potential differences in clinical characteristics, treatment patterns and outcome in HCC patients. METHODS: Clinical data of 164 "elderly" (≥70 years old) and 531 "younger" (<70 years old) HCC patients treated at a Chinese tertiary university-affiliated medical center between April 2004 and April 2012 were collected and compared using various parameters. RESULTS: Compared with younger patients, the elderly patients had a higher proportion of females (32.9 % vs. 18.1 %, p < 0.001), less hepatitis B virus (HBV) infection (40.9 % vs. 76.6 %, p < 0.001), more hepatitis C virus (HCV) infection (23.8 % vs. 5.6 %, p < 0.001), less liver cirrhosis (68.3 % vs. 76.8 %, p = 0.03) and massive tumors (12.8 % vs. 21.8 %, p = 0.01). There was no significant difference between the two groups in Child-Pugh class and tumor stages. The elderly patients received less surgical resection (14.6 % vs. 29.6 %, p < 0.001) and more supportive care (48.8 % vs. 37.9 %, p = 0.01) than younger patients. The overall survival was not significantly different between the two groups (26.2 mo. vs. 28.3 mo., p = 0.75). CONCLUSION: Characteristics that distinguish elderly from younger HCC patients included more female, less HBV infection, more HCV infection, less liver cirrhosis and massive tumors. Significant differences were observed in therapeutic strategies utilized with the two groups, but the overall survival was not significantly different.
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Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Adulto , Factores de Edad , Anciano , Carcinoma Hepatocelular/mortalidad , China/epidemiología , Comorbilidad , Femenino , Hepatitis B/epidemiología , Hepatitis C/epidemiología , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/patología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been shown to attenuate ischemia reperfusion (IR) injury in the heart, brain and kidney. However, their exact roles in the liver remain to be defined. Our objective was to investigate the potential effects of BM-MSCs on a hepatic IR rat model during the first 24 h after reperfusion, a crucial period for hepatic IR damage formation. A rat model of normothermic partial hepatic ischemia was obtained by vascular clamping for 60 min. BM-MSCs were transplanted via portal vein injection. Injury severity, oxidative stress response and apoptosis of liver cells were assessed at 2, 6, 12 and 24 h after reperfusion and cell transplantation was evaluated. At 12 and 24 h after reperfusion, rats transplanted with BM-MSCs had significantly lower serum levels of alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST), fewer damaged liver tissues, higher superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and lower malondialdehyde (MDA) levels compared to rats in the sham transplantation group. At 24 h after reperfusion, IR rats transplanted with BM-MSCs had significantly fewer apoptotic hepatocytes, higher levels of B-cell lymphoma 2 (Bcl-2) protein, and lower levels of Bcl-2-associated X (Bax) and caspase-3 (Casp3) proteins compared to sham transplantation rats. In conclusion, BM-MSCs transplanted via the portal vein partially prevent hepatic IR injury by suppressing oxidative stress and inhibiting apoptosis during the first 24 h after reperfusion.
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Apoptosis , Hígado/metabolismo , Hígado/patología , Trasplante de Células Madre Mesenquimatosas , Estrés Oxidativo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/terapia , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Hígado/irrigación sanguínea , Masculino , Malondialdehído/metabolismo , Ratas , Superóxido Dismutasa/metabolismoRESUMEN
Hepatitis B virus (HBV)-specific T cells play a key role in the pathogenesis of hepatocellular carcinoma (HCC), but little is known about the regulation of HBV-specific CD8(+) T cells function in HCC patients. Lymphocyte activation gene-3 (LAG-3) is an inhibitory molecule with diverse biologic effects on T cell function, including direct effects on CD8(+) T cells. In this study, we assessed the frequency and function of HBV-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of HCC patients. Our data showed that compared with PBLs, LAG-3 expression is significantly up-regulated in tumor infiltrating CD8(+) T cells of HCC patients, and a severe functional defect were detectable in tumor infiltrating HBV-specific CD8(+) T cells at the tumor site. Since LAG-3 is an inhibitory molecule that plays a down-regulatory role on T cell responses, we found the correlation between LAG-3 expression and HBV-specific CD8(+) T cells dysfunction. Taken together, these results further provide a support for the role for LAG-3 in the suppression of HBV-specific cell-mediated immunity in HCC, and also provide a contribution to the potential cancer treatment.
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Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Virus de la Hepatitis B/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Adulto , Antígenos CD/genética , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/genética , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
BACKGROUND: Pancreatic islet cell transplantation is an effective approach to treat type 1 diabetes. However, this therapy is not widely used because of the severe shortage of transplantable donor islets. This study investigated whether mesenchymal stem cells (MSCs) derived from human umbilical cord blood (UCB) could be transdifferentiated into insulin producing cells in vitro and the role of extracellular matrix (ECM) gel in this procedure. METHODS: Human UCB samples were collected and MSCs were isolated. MSCs specific marker proteins were analyzed by a flow cytometer. The capacities of osteoblast and adipocyte to differentiate were tested. Differentiation into islet like cell was induced by a 15-day protocol with or without ECM gel. Pancreatic characteristics were evaluated with immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. Insulin content and release in response to glucose stimulation were detected with chemiluminescent immunoassay system. RESULTS: Sixteen MSCs were isolated from 42 term human UCB units (38%). Human UCB-MSCs expressed MSCs specific markers and could be induced in vitro into osteoblast and adipocyte. Islet like cell clusters appeared about 9 days after pancreatic differentiation in the inducing system with ECM gel. The insulin positive cells accounted for (25.2 +/- 3.4)% of the induced cells. The induced cells expressed islet related genes and hormones, but were not very responsive to glucose challenge. When MSCs were induced without ECM gel, clusters formation and secretion of functional islet proteins could not be observed. CONCLUSIONS: Human UCB-MSCs can differentiate into islet like cells in vitro and ECM gel plays an important role in pancreatic endocrine cell maturation and formation of three dimensional structures.
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Diferenciación Celular , Matriz Extracelular/fisiología , Sangre Fetal/citología , Células Secretoras de Insulina/citología , Células Madre Mesenquimatosas/citología , Péptido C/análisis , Separación Celular , Células Cultivadas , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Glucagón/análisis , Humanos , Insulina/análisis , Insulina/metabolismo , Secreción de Insulina , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
A major obstacle to successful islet transplantation for both type 1 and 2 diabetes is an inadequate supply of insulin-producing tissue. In vitro transdifferentiation of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) into insulin-producing cells could provide an abundant source of cells for this procedure. For this study, we isolated and characterized human UCB-MSCs and induced them in vitro to differentiate into islet-like cell clusters using a 15-day protocol based on a combination of high-glucose, retinoic acid, nicotinamide, epidermal growth factor, and exendin-4. These clusters appeared about 9 days after pancreatic differentiation; expressed pancreatic beta-cell markers, including insulin, glucagon, Glut-2, PDX1, Pax4, and Ngn3; and could synthesize and secrete functional islet proteins at the end of the inducing protocol. The insulin-positive cells accounted for (25.2-3.36)% of whole induced cells. Although insulin secretion of those insulin-producing cells did not respond to glucose challenge very well, human UCB-MSCs have the ability to differentiate into islet-like cells in vitro and may be a potential new source for islet transplantation.