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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1749-1753, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839033

RESUMO

OBJECTIVE: To investigate the effect of BAX gene deletion on the sensitivity of BCR-ABL-induced B-ALL cells of mice to imatinib and the related mechanism. METHODS: The target gene-knock out (BAX-/-) mice were used as bone marrow cell donors; the wild type bone marrow cells(B6BM) and BAX-/- bone marrow cells(B6BM-BAX-/-) of mice were transfected by using reverse transcription virus, then the BCR-ABL transfected B6BM cells and B6BM-BAX-/- cells were treated with imatinib at different concentration (0,0.5, 1.0 and 2.0 µmol/L) for 48 hours. The number of viable cells was detected by trypan blue, the flow cytometry was used to detect the cell apoptosis, the Western blot was used to detect the changes of BAX, Caspase expression. RESULTS: In BCR-ABL transfected bone marrow cells treated with imatinib, the numbers of viable cells of BAX deletion group was significantly higher than that of wild type groups with statristcal difference(P<0.05), and effect- and dose-dependency(r=-0.9533 for BAX deletion group, and r=-0.9812 for wild type group). The flow cytometry showed that the cell apoptosis in BAX deletion group signifincantly decreased, compared with wild type group(P<0.05). The Western blot showed that the expression of apoptotic protein Caspase 3 in BAX deletion group was significantly higher than that in wild type group(P<0.05). CONCLUSION: BAX deletion can reduce the sensitivity of BCR-ABL-induced B-ALL cells to imatinib.

2.
Biosci Trends ; 13(5): 423-429, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31666440

RESUMO

In-stent restenosis is highly related to the deposition of inflammatory extracellular matrix and the migration of endothelial and vascular smooth muscle cells. The miR-17/TIMP-1/interleukin pathway regulates vascular matrix remodeling and plays an important role in the inflammatory reaction. This study identified miR-17 and its related biomarkers in serum that potentially indicated susceptibility to in-stent restenosis (ISR) after coronary artery stenting. Subjects were 42 patients with single de novo coronary artery lesions who underwent regular coronary angiography one year after percutaneous coronary intervention. The clinical baseline information was recorded. Serum levels of biomarkers (including miR-17, TIMP-1, IL-6, IL-8, IL-2R, TNF-alpha, IL-10, and IL-1beta) were measured with real-time PCR or ELISA. Intergroup comparisons were used to compare patients with or without ISR. Compared to levels in the non-restenosis group, the serum miR-17 level was significantly higher (3.13 ± 0.22 vs. 1.06 ± 0.04, p < 0.01) and the serum TIMP-1 and IL-6 levels were significantly lower in the ISR group (TIMP-1: 0.33 ± 0.04 vs. 1.00 ± 0.05, p < 0.01; IL-6: 1.64 ± 0.18 vs. 3.52 ± 0.11, p < 0.01). Moreover, the levels of TIMP-1 and IL-6 decreased as the level of miR-17 increased. Spearman's correlation analysis indicated that the miR-17 level was inversely correlated with TIMP-1 and IL-6 levels. Findings suggest that an elevated level of miR-17 and decreased levels of TIMP-1 and IL-6 may be associated with the risk of ISR, which is in accordance with vascular matrix remodeling and an inflammatory reaction during the pathologic process of ISR. This study highlighted the potential for miR-17, TIMP-1, and IL-6 to serve as biomarkers for ISR.

3.
Ann Transl Med ; 7(18): 435, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31700871

RESUMO

Background: Triple negative breast cancer (TNBC), as defined by ER, PR and HER2 negative expression in tumor, has limited treatment options beyond conventional chemotherapy. JS001, a humanized IgG4 antibody for PD-1, has demonstrated acceptable safety profile and preliminary anti-tumor activity in solid tumors. Methods: This phase I open-label study is designed to evaluate the safety, tolerability, and antitumor activity of JS001 in advanced TNBC patients who are refractory to standard systemic therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg Q2W followed by a dose expansion cohort at 3 mg/kg. (Clinical Trial ID: NCT02838823). Results: From August 04, 2016 to October 26, 2017, 20 heavily-pretreated advanced TNBC patients were enrolled into three dose cohorts (6 in 1 mg/kg, 8 in 3 mg/kg and 6 in 10 mg/kg). As of August 30, 2018, no DLT was observed and no MTD was reached. No AEs were grade 4 or 5. The most common treatment related AEs were all grade 1/2. Treatment related grade 3 AEs (15%) included 1 hyponatremia, 1 rash and 1 bronchospasm (infusion related reaction). Among 20 evaluable subjects, the ORR was 5%. One patient in 10 mg/kg group obtained PR, who was PD-L1 strong positive (>50%) in tumor biopsy, with treatment duration of 12.8 months as of data cutoff. As of follow-up on July 15, 2019, the patient continued PR with treatment duration of 24 months and still ongoing. Six patients achieved SD, for a DCR of 35%. The median PFS of all subjects was 1.8 months (95% CI, 1.4 to 4.6). 45% subjects are PD-L1 positive (≥1% cutoff), among whom a 11.1% ORR and a 22.2% DCR were observed. Conclusions: JS001 exhibited a favorable safety profile in advanced TNBC patients who are refractory to multi-line systemic therapy. JS001 also showed a moderate response in these TNBC patients who had limited treatment options.

4.
Biomed Res Int ; 2019: 1524908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772932

RESUMO

Objective: This study aimed to determine the accuracy and safety of the "blunt end" Kirschner wire (KW) technique for the minimally invasive treatment of unstable pelvic fractures with the assistance of a 3D printed external template. Methods: Clinical data of 28 patients with unstable pelvic fractures between January 2016 and January 2018 were retrospectively analyzed. There were 6 cases of B1, 10 of B2, 8 of C1, and 4 of C2 fractures, all of which received surgical treatment. The "blunt end" KW technique with a 3D template was adopted for the minimally invasive placement of the iliosacral (IS) or superior ramus screws. The number of intraoperative fluoroscopies, surgical time, and complications were recorded. Postoperative reduction was assessed using the Matta criteria, and the Majeed score system was used to evaluate postoperative functional recovery. Results: The average number of fluoroscopies was 35 per patient, and the average surgical time was 85.2 min. A total of 19 S1 and 28 S2 IS screws were inserted. Eleven antegrade superior ramus screws and 4 retrograde screws were placed in 11 patients, and anterior subcutaneous internal fixation (INFIX) was used to fix the anterior pelvic ring in 17 patients. All patients were followed up for an average of 18 months. Postoperative reduction was evaluated by Matta's criteria: excellent in 16 cases, good in 9 cases, and fair in 3 cases. The Majeed score was used in the last follow-up to evaluate functional recovery: excellent in 13 cases, good in 10 cases, fair in 4 cases, and poor in 1 case. There were no cases of operative vascular injury. Conclusion: The "blunt end" KW technique with a 3D printed external template is a safe and effective method for the placement of IS and superior ramus screws in unstable pelvic fractures with minimized surgical duration and radiation exposure.

5.
Fitoterapia ; 139: 104378, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676395

RESUMO

Five previously undescribed lycodine-type alkaloids, named huperzine Y (1), 8,15-epoxy-N-demethylhuperzinine (2), 7-hydroxyl-huperzinine (3), huperzine Z (4), and huperzine D N-oxide (5), were isolated from the aerial parts and roots of Lycopodiastrum casuarinoides (Lycopodiaceae), along with ten known analogues. The structures of the new compounds were elucidated by means of spectroscopic technique (IR, UV, MS and NMR). The absolute configurations of the new compounds were established on the basis of comparison of their experimental and TD-DFT (time-dependent density functional theory) calculated ECD spectra. Moreover, all the isolates were evaluated for acetylcholinesterase (AChE) inhibitory activity. Only huperzine C showed moderate activity, with an IC50 value of 0.525 ±â€¯0.140 µM, which was comparable with the positive control, huperzine A (IC50 = 0.143 ±â€¯0.029 µM).

6.
J Neurol Sci ; 408: 116499, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31726383

RESUMO

BACKGROUND: Muscle pathology usually contributes to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS), even in patients without prominent muscle symptoms. We report a series of patients with MELAS without significant myopathic changes. METHODS: Twelve patients without ragged-red fibers (RRFs) on muscle pathology (RRF-negative group) and 99 patients with MELAS and RRFs and/or cytochrome c oxidase (COX)-deficient fibers (control RRF-positive group) were recruited. We analyzed clinical features, neuroimaging and pathological findings, gene mutation data, immunofluorescence assay of key respiratory chain subunits of complexes I and IV and mitochondrial DNA (mtDNA) mutation load in biopsied muscle samples. RESULTS: None of the RRF-negative patients had RRF or COX-negative fibers, but four patients had strongly succinate dehydrogenase-stained vessels (SSVs). There was a lower proportion of m.3243A>G and higher proportion of mitochondria-encoded ND gene mutations in RRF-negative than RRF-positive patients. The proportion of aphasia was relatively higher, while complex I and IV subunit abundance in muscle and mutation load were lower in RRF-negative than in RRF-positive patients. CONCLUSION: RRF-negative patients had a similar disease course, clinical symptoms, and neuroimaging results to RRF-positive patients with MELAS. SSV is a valuable diagnostic indicator for MELAS. For highly suspected MELAS yet without positive myopathological findings, combined immunofluorescence and genetic studies should be used to achieve final diagnosis.

7.
J Orthop Surg Res ; 14(1): 364, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727107

RESUMO

BACKGROUND: To compare the efficacy of the operative techniques, complications, reduction quality and hip functional recovery by using the supra-ilioinguinal approach and the modified Stoppa approach for the management of acetabular fractures. METHODS: A consecutive cohort of 60 patients from September 2014 to October 2017 with displaced acetabular fractures involving the quadrilateral plate were treated operatively with supra-ilioinguinal approach (group A) and modified Stoppa approach (group B), respectively. There were 36 patients in group A and 24 patients in group B. The surgical details, complications, radiographic and clinical results were recorded. The quality of reduction was assessed by measuring the residual step and gap displacement of postoperative CT with a standardized digital method. RESULTS: The complications, reduction quality (gaps and steps) and hip function recovery had no significant statistical difference in approaches. The mean operative time was shorter and the mean intraoperative haemorrhage was less in group A. There were statistical differences in the operative time (P = 0.025) and intraoperative haemorrhage (P = 0.003) between the supra-ilioinguinal approach and the modified Stoppa approach. CONCLUSION: Compared to the modified Stoppa approach, the supra-ilioinguinal approach provides a closer visualization to the quadrilateral plate, the operative time was shorter and the intraoperative haemorrhage was clearly less. It is at least equal to or could be a better choice to deal with complicated acetabular fractures especially involving the quadrilateral plate and the anterior one third of the iliac bone.

8.
Yi Chuan ; 41(10): 939-949, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31624056

RESUMO

Mutations in Hypoxanthine-guanine Phosphoribosyltransferase1 (HPRT1) gene can lead to metabolic disorder of hypoxanthine and guanine metabolism, and other severe symptoms such as hypophrenia, gout, and kidney stones, called the Lesch-Nyhan disease (LND). Although the mutations are widely distributed throughout the HPRT1 gene, there are some isolated hot spots. In this study, we aim to introduce two previously reported hot spots, c.508 C>T and c.151 C>T, which could lead to premature translational termination in HPRT1 gene. Through CRISPR/Cas9 mediated homology-directed repair (HDR) by using single-stranded oligo-deoxyribonucleotides (ssODN) as donor template, we obtained cell clones containing these two mutations in HEK293T or HeLa cells. Targeted mutation of c.508 C>T and c.151 C>T reached to 16.3% and 10%, respectively. We further detect HPRT1 protein levels with Western blot and enzyme activity with 6-TG in 5 different cell clones. HPRT1 protein and its enzymatic activity both was hardly detected in homozygous mutant cells, while reduced HPRT1 protein expression and enzymatic activity was detected in heterozygous mutant cells. Our study will be beneficial to those who working on generation of cell or animal models of HRPT1 mutations, and provides a basis for further investigations on the genetic mechanism of Lesch-Nyhan disease.


Assuntos
Sistemas CRISPR-Cas , Hipoxantina Fosforribosiltransferase/genética , Mutação Puntual , Células HEK293 , Células HeLa , Humanos , Síndrome de Lesch-Nyhan/genética
9.
Kaohsiung J Med Sci ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633298

RESUMO

Endoscopic retrograde cholangiopancreatography (ERCP)-related perforation leads to high morbidity and mortality. The Stapfer classification divides patients with different perforation locations and suggests management accordingly. The classification may be unknown if perforation is not detected during endoscopy. We classified patients with ERCP-related perforation (ERP) through computed tomography (CT) and observed the clinical outcomes with varyingly invasive management. Fifty-two cases of ERP between July 2009 and December 2017 were retrospectively reviewed. Of them, 41 who underwent CT for ERCP were included. According to their CT findings, we divided patients into air-alone (n = 16), air-fluid (n = 18), and fluid-alone (n = 7) groups. Perforation severity was graded using the Clavien-Dindo classification for surgical complications. Demographic data and clinical outcomes among different groups were analyzed. Fifteen patients (37%) had an unknown Stapfer classification. More than half of the patients in the air-fluid group had a Clavien-Dindo complication grade of >3. Four patients underwent surgical repair; all of them were from the air-fluid group. All patients in the air- and fluid-alone groups underwent medical treatment without need for subsequent salvage surgery. The air-fluid group had the longest mean hospital stay (25.1 ± 21.9 days) and the exclusive two mortality cases in this study. Patients with ERCP can be divided into groups with different outcomes according to the presence of air or fluid on CT images. Because patients with both air and fluid have the worst clinical outcome, they may require more aggressive treatment than patients with either air or fluid alone.

10.
Clin Neuropathol ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31661069

RESUMO

Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder. Abnormally high signals of diffusion-weighted image (DWI) along the corticomedullary junction are a useful diagnostic indicator for patients with adult-onset NIID. However, the DWI abnormalities usually were observed in the late stage of disease; further study might be helpful to elucidate some clinical indicators regarding the early awareness of NIID. In this study, we summarized 9 patients with NIID from multiple centers. The mean age was 60.0 ± 6.2 years. The mean duration of disease was 4.4 ± 3.2 years. The most common symptoms included cognitive impairment, episodic encephalopathy, and bladder dysfunction. Among the 6 patients with bladder dysfunction, 3 patients had the symptom prior to the development of other neurological symptoms; 5 patients needed permanent cystostomy. Isolated high DWI signals on the splenium of corpus callosum were observed in 2 patients at the early stage. The characteristic intranuclear inclusions in the skin were identified in all patients and confirmed by electron microscopy. Episodic encephalopathy or bladder dysfunction prior to other neurological symptoms were valuable diagnostic indicators for adult-onset NIID. High DWI signals on the splenium of corpus callosum might be an early indicator for the diagnosis of NIID. The immunostain of anti-ubiquitin or anti-p62 antibody was a convenient and sensitive biomarker for NIID with the background of typical phenotype with cognitive impairment and autonomic dysfunctions.
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11.
Phytomedicine ; 65: 153100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31648127

RESUMO

BACKGROUND: The incidence of non-small cell lung cancer (NSCLC) accounts for approximately 85-90% of lung cancer, which has been shown to be challenging for treatment owing to poorly understanding of pathological mechanisms. Natural products serve as a source of almost all pharmaceutical preparations or offer guidance for those chemicals that have entered clinical trials, especially in NSCLC. PURPOSE: We investigated the effect of B10G5, a natural products isolated from the Croton tiglium, in human non-small cell lung canceras as a protein kinase C (PKC) activator. METHODS: The cell viability assay was evaluated by the MTT assay. The apoptosis and cell cycle distribution were assessed by flow cytometry. Reactive oxygen species (ROS) production was determined by using the fluorescent probe DCFDA. Cell migration ability of H1975 cells was analyzed by using the wound healing assay. The inhibiting effect of B10G5 against the phosphorylation level of the substrate by PKCs was assessed by using homogeneous time-resolved fluorescence (HTRF) technology. The correlation between PKCs and overall survival (OS) of Lung Adenocarcinoma (LUAD) patients was analysis by TCGA portal. The binding mode between B10G5 and the PKC isoforms was explored by molecular docking. Protein expression was detected by western blotting analysis. RESULTS: B10G5 suppressed cell proliferation and colony formation, as well as migration ability of NSCLC cells, without significant toxic effect on normal lung cells. B10G5 induced the cell apoptosis through the development of PARP cleavage, which is evidenced by means of the production of mitochondrial ROS. In addition, the B10G5 inhibitory effect was also related to the cell cycle arrest at G2/M phase. Mechanistically, molecular modelling technology suggested that the potential target of B10G5 was associated with PKC family. In vitro PKC kinase assay indicated that B10G5 effectively activated the PKC activity. Western blotting data revealed that B10G5 upregulated PKC to activate PKC-mediated RAF/MEK/ERK pathway. CONCLUSION: Our results showed that B10G5, a naturally occurring phorbol ester, considered to be a potential and a valuable therapeutic chemical in the treatment of NSCLC.

12.
Org Lett ; 21(20): 8211-8214, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31580688

RESUMO

Two guaianolide sesquiterpenoid tetramers named ainsliatetramers A and B were separated from Ainsliaea fragrans. Through spectroscopic analyses, especially the band-selective CT-HSQC and CT-HMBC techniques, the complex skeleton was constructed from four sesquiterpene units via three different linkages. A biosynthetic pathway was proposed featuring a Michael addition and a regular and a hetero-Diels-Alder cycloaddition. Both exhibited potent cytotoxicity against human cancer cell lines with IC50 values ranging from 2 to 15 µM.

13.
Ann Clin Transl Neurol ; 6(9): 1728-1738, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31429185

RESUMO

OBJECTIVE: To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. METHODS: Whole-exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. RESULTS: The clinical features of the patients showed late-onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co-segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense-mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. INTERPRETATION: Variants in the MME gene were associated with not only a Charcot-Marie-Tooth neuropathy phenotype but also with an autosomal-recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

14.
Eur Spine J ; 28(10): 2275-2282, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440894

RESUMO

PURPOSE: Treatment options for adult spinal cord injury without radiographic abnormality (ASCIWORA) varied. Compression of ASCIWORA may more likely result from spinal cord lesions such as edema and hemorrhage or contusion. This study aimed to explore the clinical effect of early durotomy with duroplasty decompression in the treatment of severe ASCIWORA. METHODS: Data of 16 patients with ASCIWORA who underwent early ( < 72 h) posterior laminectomy followed by durotomy with duroplasty decompression from June 2015 to January 2017 were retrospectively analyzed. Patients' prognosis was analyzed by American Spinal Injury Association Impairment Scale (AIS) grades and scores. In 3 patients, intraspinal pressure (ISP) was continuously monitored for 1 week. RESULTS: Cervical magnetic resonance imaging (MRI) revealed spinal cord edema in 9 patients and suspected hemorrhage or contusion in 7 cases. Pathological manifestations of spinal cord injury found during the operation were consistent with preoperative MRI findings. Of the 16 cases, AIS grade was improved by 1 grade in 3 cases, 2 grades in 11 cases, and 3 grades in 1 case. The AIS scores at the last follow-up were significantly higher than preoperative scores. There was a high level of ISP after laminectomy, whereas ISP continued to decrease steadily after durotomy. CONCLUSIONS: Durotomy helps thoroughly decompress the spinal cord and improve cerebrospinal fluid circulation in severe ASCIWORA cases. Cervical MRI and pathological investigation of the spinal cord can be used to evaluate and predict the prognosis of ASCIWORA patients. ISP monitoring is an effective method for evaluating intramedullary pressure and decompression. These slides can be retrieved under Electronic Supplementary Material.

15.
J Med Genet ; 56(11): 758-764, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31413119

RESUMO

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5'-untranslated region (5'UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients. METHODS: Fifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases. RESULTS: Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5'UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases. CONCLUSION: Our findings provided evidence that confirmed the GGC repeated expansion in the 5'UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

16.
J Clin Oncol ; 37(32): 2987-2999, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31403867

RESUMO

PURPOSE: Metastatic mucosal melanoma responds poorly to anti-programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone. PATIENTS AND METHODS: We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G4 monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers. RESULTS: Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION: The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.

17.
Bioorg Med Chem Lett ; 29(16): 2178-2181, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257084

RESUMO

Here we reported the development of a novel immuno-SPECT tracer, namely 99mTc-JS001, to non-invasively image PD-1 expression in mice. The JS001 antibody was directly labeled by the most widely used SPECT radionuclide 99mTc with a radiochemical yield of 90%, and the specific activity was ≤74 GBq/mmol. After the radiolabeling, 99mTc-JS001 exhibited a similar immnuoaffinity to PD-1 in vitro. 99mTc-conjugated JS001 maintained intact in 5% HSA system for 24 h. S180 sarcoma xenograft-bearing Kunming mice and BGC823 gastric cancer orthotopic tumor model were built. Bio-distribution and/or immuno-SPECT studies with 99mTc-JS001 showed the antibody maintained in the blood, liver, kidneys and tumors at 1.5 ID%/g, 1.4 ID%/g, 2.0 ID%/g and 0.5 ID%/g, respectively. Also, there was a higher uptake in the BGC823 orthotopic tumor than that in the adjunct stomach. These results demonstrated that 99mTc-JS001 might have capacity to monitor the PD-1 expression in vivo, which might facilitate the anti-PD-1 antibodies treatment in preclinical models.

18.
Orthop Traumatol Surg Res ; 105(5): 877-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31300239

RESUMO

INTRODUCTION: With the rapid development of three-dimensional (3D) printing and computer technology, adopting computer-assisted virtual surgical procedures and 3D printing of patient-specific pre-contoured plates can greatly reduce surgical invasiveness and operative time and simplify the procedure. HYPOTHESIS: Use of computer-assisted virtual surgical procedures and 3D printing of patient-specific pre-contoured plates reduce the operative time and blood loss in bicolumnar acetabular fracture fixation. METHODS: A retrospective analysis was performed for 52 bicolumnar acetabular fracture cases treated surgically in our department from January 2013 to January 2017. According to the patients' willingness to accept 3D printing services, 52 patients were divided into groups A and B. In group A (28 patients), computer-assisted virtual surgical procedures and 3D printing of patient-specific pre-contoured plates were adopted. In group B (24 patients), the conventional method was adopted. Fracture type, operative blood loss, surgical time, complications, radiographic quality of reduction, and hip function were compared between groups. All patients were operated by the same surgeon. RESULTS: The real surgical procedure of all patients in group A was almost identical to the preoperative virtual operation. Operative time and intraoperative blood loss were significantly reduced in group A than in group B (p<0.05), while the postoperative fracture reduction quality and hip function obtained slightly higher levels of satisfaction in group A. CONCLUSIONS: Computer-assisted virtual surgical procedures, 3D printing technology and patient-specific pre-contoured plates can reduce the operative time and blood loss with less surgical invasiveness and ensure completely satisfactory clinical outcomes. However, promotion of this technology requires additional work. LEVEL OF EVIDENCE: III, therapeutic study.

19.
Acta Pharmacol Sin ; 40(12): 1578-1586, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31201357

RESUMO

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy. In this study, we identified a natural compound 3-deoxy-2ß,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC50 of 0.2 µM. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyrosine kinases. Furthermore, B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3. Taken together, our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3.

20.
Acta Pharmacol Sin ; 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197246

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as a promising therapeutic target for the treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor efficacy of existing small-molecule IDO1 inhibitors is still unsatisfactory, and the underlying mechanism remains largely undefined. To identify novel IDO1 inhibitors, an in-house natural product library of 2000 natural products was screened for inhibitory activity against recombinant human IDO1. High-throughput fluorescence-based screening identified 79 compounds with inhibitory activity > 30% at 20 µM. Nine natural products were further confirmed to inhibit IDO1 activity by > 30% using Ehrlich's reagent reaction. Compounds 2, 7, and 8 were demonstrated to inhibit IDO1 activity in a cellular context. Compounds 2 and 7 were more potent against IDO1 than TDO2 in the enzymatic assay. The kinetic studies showed that compound 2 exhibited noncompetitive inhibition, whereas compounds 7 and 8 were graphically well matched with uncompetitive inhibition. Compounds 7 and 8 were found to bind to the ferric-IDO1 enzyme. Docking stimulations showed that the naphthalene ring of compound 8 formed "T-shaped" π-π interactions with Phe-163 and that the 6-methyl-naphthalene group formed additional hydrophobic interactions with IDO1. Compound 8 was identified as a derivative of tanshinone, and preliminary SAR analysis indicated that tanshinone derivatives may be promising hits for the development of IDO1 inhibitors. This study provides new clues for the discovery of IDO1/TDO2 inhibitors with novel scaffolds.

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