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1.
Genes (Basel) ; 11(10)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33066131

RESUMO

Stanford type A aortic dissection (TAAD) is one of the most dangerous diseases of acute aortic syndrome. Molecular pathological studies on TAAD can aid in understanding the disease comprehensively and can provide insights into new diagnostic markers and potential therapeutic targets. In this study, we defined the molecular pathology of TAAD by performing transcriptome sequencing of human ascending aortic tissues. Pathway analysis revealed that activated inflammation, cell death and smooth muscle cell degeneration are the main pathological changes in aortic dissection. However, autophagy is considered to be one of the most important biological processes, regulating inflammatory reactions and degenerative changes. Therefore, we focused on the pathological role of autophagy in aortic dissection and identified 10 autophagy-regulated hub genes, which are all upregulated in TAAD. These results indicate that exaggerated autophagy participates in the pathological process of aortic dissection and may provide new insight for further basic research on TAAD.

2.
Cytogenet Genome Res ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022677

RESUMO

The excessive production of inflammatory mediators by vascular endothelial cells (ECs) greatly contributes to the development of atherosclerosis. In this study, we explored the potential effect of lncRNA MALAT1 on endothelial inflammation. First, the EC inflammation model was constructed by treating human umbilical vein ECs (HUVECs) and human coronary artery ECs (HCAECs) with oxidized low-density lipoprotein (ox-LDL), which confirmed the role of MALAT1 in the inflammatory activity. Then MALAT1 was overexpressed in HUVECs and HCAECs, and the levels of inflammatory mediators and nitric oxide (NO) were examined by Western blotting, ELISA, and NO detection assay. The migration ability was confirmed by wound healing assay. The interactions among MALAT1, miR-590, and STAT3 were predicted by bioinformatics analysis and verified by qRT-PCR, Western blotting, or dual-luciferase reporter assay. MALAT1 was upregulated in ECs treated with ox-LDL, and knockdown of MALAT1 significantly inhibited ox-LDL-induced inflammation. MALAT1 overexpression potentiated the inflammatory activities of ECs, including enhanced production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and adhesion molecules (VCAM1 and ICAM1), and decreased NO level and cell migratory ability. Mechanistically, MALAT1 could directly downregulate miR-590, and miR-590 could bind to the 3'-UTR of STAT3 to repress its expression. Additionally, overexpression of MALAT1-mediated inflammation was largely abrogated by the concomitant overexpression of miR-590. miR-590 knockdown activated the inflammatory response, which was reversed by STAT3 inhibition. Thus, MALAT1 serves as a proinflammatory lncRNA in ECs through regulating the miR-590/STAT3 axis, suggesting that MALAT1 may be a promising therapeutic target during the treatment of atherosclerosis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33045183

RESUMO

PURPOSE: The purpose of this article is to study the effect of autologous platelet-rich plasma (PRP) injected into the upper cavity of the temporomandibular joint (TMJ) on the treatment of TMJ osteoarthritis. PATIENTS AND METHODS: We retrospectively analyzed the data of 27 patients with TMJ osteoarthritis treated at the China Medical University Hospital of Stomatology from September 2018 to September 2019. Maximal interincisal opening, pain intensity, and TMJ sounds were recorded and compared before treatment and at the 3rd and 6th months after the treatment. SPSS 24.0 software was used to analyze the data of each group, and the imaging changes in the condylar bone were compared before and 6 months after the treatment. The P-value was set at .05. RESULTS: Better results were observed in the group treated with PRP on maximal interincisal opening and pain intensity than in the group receiving chitosan treatment. Regarding TMJ sounds, relief was observed in both groups, with no significant difference. CONCLUSIONS: The effect of PRP on the improvement of the maximal interincisal opening and pain intensity of patients with TMJ osteoarthritis is better than that of chitosan. However, it should be noted that the incidence of complications associated with the injection of PRP may be higher than that with injection of chitosan.

4.
Biomed Eng Online ; 19(1): 76, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028306

RESUMO

Three-dimensional (3D) printing is widely used in medicine. Most research remains focused on forming rigid anatomical models, but moving from static models to dynamic functionality could greatly aid preoperative surgical planning. This work reviews literature on dynamic 3D heart models made of flexible materials for use with a mock circulatory system. Such models allow simulation of surgical procedures under mock physiological conditions, and are; therefore, potentially very useful to clinical practice. For example, anatomical models of mitral regurgitation could provide a better display of lesion area, while dynamic 3D models could further simulate in vitro hemodynamics. Dynamic 3D models could also be used in setting standards for certain parameters for function evaluation, such as flow reserve fraction in coronary heart disease. As a bridge between medical image and clinical aid, 3D printing is now gradually changing the traditional pattern of diagnosis and treatment.

5.
Ann Plast Surg ; 85(4): 430-436, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32931683

RESUMO

PURPOSE: This study aimed to investigate the repair of bone defects in rabbits with tissue-engineered bones using cocultured endothelial progenitor cells (EPCs) and bone marrow mesenchymal stem cells (BMSCs) as seeding cells. METHODS: Endothelial progenitor cells and BMSCs were isolated and purified from the peripheral blood and bone marrow, respectively, of New Zealand rabbits. The third passage of BMSCs was cultured alone or with EPCs. Cells were characterized using specific markers and then seeded on partially deproteinized biologic bones from pigs as a scaffold. The engineered bones were used to repair bone defects in rabbits. Hematoxylin and eosin and Masson staining were performed to examine vascularization and osteogenesis in the engineered bone. RESULTS: The cocultured EPCs and BMSCs grew well on the surface of the scaffold. Compared with monocultured BMSCs, cocultured EPCs and BMSCs promoted the formation of blood vessels and bone on the scaffold, in addition to accelerating the repair of bone defects. The collagen content was significantly increased in the scaffold with cocultured EPCs and BMSCs, compared with the scaffold seeded with mono-cultured BMSCs. CONCLUSIONS: Tissue-engineered bones seeded with cocultured EPCs and BMSCs may be used effectively for the repair of bone defects.

6.
J Vasc Surg ; 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32891806

RESUMO

PURPOSE: To report 5-year results of the prospective, multicenter study designed to evaluate the Zenith Fenestrated AAA Endovascular Graft (William A. Cook Australia, Brisbane, Australia) for juxtarenal abdominal aortic aneurysms (AAAs). METHODS: Sixty-seven patients (54 male, mean age 74 ± 8 years) were prospectively enrolled at 14 U.S. centers from 2005 to 2012. Fenestrated stent grafts were used in patients with infrarenal aortic neck lengths of 4 to 14 mm to target 178 renal-mesenteric arteries with a mean of 2.7 vessels per patient. At 5 years, 42 of the 67 patients completed the final study follow-up, with clinical examination obtained in 41 and computed tomography imaging in 39. Outcomes adjudicated by a clinical events committee included all-cause and aneurysm-related mortality, major adverse events, renal stent occlusion/stenosis, renal function changes and renal infarcts, aneurysm sac enlargement (>5 mm), device migration (≥10 mm), type I/III endoleak, and secondary interventions. RESULTS: Median follow-up was 59.8 months (range, 0.1-67.5 months). There were seven deaths, including one (1.5%) within 30 days (procedure-related) and six beyond 30 days (not procedure-related in five, indeterminate in one). At 5 years, freedom from all-cause mortality was 88.8 ± 4.2% and freedom from aneurysm-related mortality was 96.8 ± 2.3%. There were no aneurysm ruptures or conversions to open surgery. Of the 129 renal arteries targeted by fenestrations, five (4%) occluded and 14 (11%) developed in-stent stenosis. Treatment included redo stenting/angioplasty in 13 vessels, renal artery bypass in 2 vessels, and failed thrombectomy in 1 vessel. Primary and secondary renal target patency was 82.7 ± 4.1% and 95.7 ± 2.1% at 5 years, respectively. Dialysis was required in one patient who had pre-existing chronic kidney disease. During the 5 years, there was 1 type IA endoleak (1.5%), 1 type IB endoleak (1.5%), 2 device migrations (3%), and 4 aneurysm sac enlargements (6%). Overall, 81% of patients had sac shrinkage at 5 years. Of 20 patients who underwent secondary interventions, 12 were for renal in-stent stenosis or occlusion, 7 were for endoleak, and 1 was for both indications. Freedom from secondary intervention was 63.5 ± 7.2% at 5 years. CONCLUSIONS: These 5-year results confirm the safety and effectiveness of the Zenith Fenestrated AAA stent graft with no late graft- or aneurysm-related deaths. In-stent stenosis of bare metal renal stents was the most frequent indication for secondary intervention. The low rate of type IA endoleak, sac enlargement, and device migration support its use in patients with juxtarenal AAAs.

7.
J Thorac Oncol ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32916309

RESUMO

INTRODUCTION: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging due to intratumor heterogeneity. We aimed to explore a refined stratification mode based on the integrated analysis of ctDNA tracking. METHODS: ctDNA was prospectively collected at baseline and every eight weeks in advanced treatment-naïve EGFR-mutant LUAD patients under gefitinib treatment enrolled in a phase II trial, and analyzed using next-generation sequencing of a 168-gene panel. RESULTS: Three subgroups categorized by baseline co-mutations: EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%) and EGFR-sensitizing mutations with other driver mutations (24, 13.3%), exhibited distinct progression-free survival (PFS) and overall survival (OS) [PFS 13.2 (11.3-15.2) vs. 9.3 (7.6-10.5) vs. 4.0 (2.4-9.3) months; OS 32.0 (29.2-41.5) vs. 21.7 [(19.3-27.0) vs. 15.5 (10.5-33.7) months], providing evidence for initial stratification. 63.7% of the patients achieved week-8 ctDNA-clearance, with significant difference among three subgroups (74.5% vs. 64.0% vs. 29.4%, P=0.004, fisher's exact test). Patients without week-8 ctDNA-clearance had worse PFS [clearance vs. non-clearance 11.2 (9.9-13.2) vs. 7.4 (5.6-9.6) months, P=0.016, cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, with significant difference in non-p.T790M mutations among three subgroups (7.5% vs. 15.7% vs. 80.0%, P<0.001, fisher's exact test), giving clues to post-line treatment. CONCLUSIONS: The patients with baseline co-mutations and ctDNA non-clearance at first visit might require combined therapy due to limited survival benefit of EGFR-TKI monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

8.
J Med Virol ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32915476

RESUMO

Severe acute respiratory syndrome coronavirus 2 is responsible for the coronavirus disease 2019 (COVID-19) epidemic, which has severely affected global public health security. However, the diagnosis and treatment of the disease need further exploration. Therefore, this retrospective analysis was conducted on multiple indicators of peripheral blood in patients with COVID-19 to determine the role of leukocytes, lymphocytes, and eosinophils in the diagnosis and prognostic evaluation of COVID-19. Baseline information and clinical records of 40 patients were collected, including demographic data, disease status, medication, and laboratory routine. The correlation between the inspection indicators and disease classification, as well as prognostic factors, was analyzed. Decreased eosinophils were detected in 33 out of 40 patients with COVID-19 on admission, while lymphocytes and eosinophils were inversely related to the severity of the disease, according to the Spearman's correlation coefficient. Thus, it could be deduced that eosinophils have better sensitivity for the diagnosis of COVID-19 and play a major role similar to lymphocytes in assessing the prognosis of patients.

9.
ESMO Open ; 5(5)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32967919

RESUMO

OBJECTIVE: Precision oncology depends on translating molecular data into therapy recommendations. However, with the growing complexity of next-generation sequencing-based tests, clinical interpretation of somatic genomic mutations has evolved into a formidable task. Here, we compared the performance of three commercial clinical decision support tools, that is, NAVIFY Mutation Profiler (NAVIFY; Roche), QIAGEN Clinical Insight (QCI) Interpret (QIAGEN) and CureMatch Bionov (CureMatch). METHODS: In order to obtain the current status of the respective tumour genome, we analysed cell-free DNA from patients with metastatic breast, colorectal or non-small cell lung cancer. We evaluated somatic copy number alterations and in parallel applied a 77-gene panel (AVENIO ctDNA Expanded Panel). We then assessed the concordance of tier classification approaches between NAVIFY and QCI and compared the strategies to determine actionability among all three platforms. Finally, we quantified the alignment of treatment suggestions across all decision tools. RESULTS: Each platform varied in its mode of variant classification and strategy for identifying druggable targets and clinical trials, which resulted in major discrepancies. Even the frequency of concordant actionable events for tier I-A or tier I-B classifications was only 4.3%, 9.5% and 28.4% when comparing NAVIFY with QCI, NAVIFY with CureMatch and CureMatch with QCI, respectively, and the obtained treatment recommendations differed drastically. CONCLUSIONS: Treatment decisions based on molecular markers appear at present to be arbitrary and dependent on the chosen strategy. As a consequence, tumours with identical molecular profiles would be differently treated, which challenges the promising concepts of genome-informed medicine.

10.
J Agric Food Chem ; 68(40): 11242-11252, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32936624

RESUMO

The effects of TiO2 and ZnO nanoparticles on soil bacteria and enantioselective transformation of racemic-metalaxyl (rac-metalaxyl) in agricultural soil with or without Lolium perenne were investigated in an outdoor greenhouse. After a 70-day exposure to 2‰ ZnO, microbial biomass carbon decreased by 66% and bacterial community composition significantly changed. Meanwhile, ZnO decreased chlorophyll cumulation in L. perenne by 34%. ZnO also inhibited the enantioselective transformation of metalaxyl enantiomers and changed the enantiomer fraction of metalaxyl. TiO2 showed similar effects but to a lesser extent. L. perenne promoted the transformation of rac-metalaxyl and ingested TiO2 and ZnO. L. perenne changed the bacterial co-occurrence networks and biomarkers in native soil and soil exposed to TiO2 and ZnO. L. perenne reduced the inhibition effects of TiO2 and ZnO on the transformation of rac-metalaxyl. The decrease in the relative abundance of soil keystone taxa such as Acidobacteria and Gemmatimonas might respond to the corresponding slow transformation of rac-metalaxyl in soils exposed to TiO2 and ZnO, regardless of L. perenne. Our results demonstrated the existence of mutual interactions among the impact of engineered nanoparticles on different components (microbes, plants, and coexisting pollutants) in the terrestrial ecosystem.

11.
Sci Total Environ ; 752: 141470, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889255

RESUMO

Many traditional drinking water treatment processes have limited removal efficiencies on natural organic matter (NOM) and organic micropollutants (OMPs), and thus may lead to the production of harmful disinfection byproducts (DBPs). We examined four kinds of anion exchange resins (D205, D213, NDMP-3, and M80) in conjunction with chlorination in the treatment of drinking water. Five categories including 40 OMPs at environmentally relevant concentrations were analyzed. M80 showed the best performance to remove OMPs in water. However, it was vulnerable to the presence of humic acid (HA), indicating its limitation on removing OMPs and NOM at the same time. In contrast, D205, D213, NDMP-3 resins were less affected by HA. Besides, D205, D213 and NDMP-3 provided higher efficiencies on the reduction of DBPs than M80. The amount of trihalomethanes (THMs) lowered by 42.7%, 37.6%, 32.1%, and 0%, whereas haloacetic acids (HAAs) were decreased by 34.0%, 31.2%, 23.0%, and 17.9% by D205, D312, NDMP-3, and M80. Notably, D205 showed the highest removal effects on the bromide ion, brominated THMs, and HAAs, supporting that D205 can be a selective resin for the treatment of drinking water in high bromide-containing areas.

12.
Sci Total Environ ; 753: 141962, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32890875

RESUMO

Arsenic (As) is a known human carcinogen with a hitherto unknown mechanism of action. Dimethylarsinic acid (DMAV) is a methylated metabolite of arsenicals found in most mammals, and long-term exposure to DMAV can lead to bladder cancer in rats. Human epidermal growth factor receptor 2 (HER2) is an oncogenic factor that is overexpressed in bladder cancer, but its role in the initiation and progression of As-induced bladder cancer has not been elucidated. We found that HER2 was up-regulated in human uroepithelial cells treated with arsenite as well as in the bladder tissues of DMAV-exposed rats. HER2 overexpression correlated to increased cell proliferation, epithelial-to-mesenchymal transition (EMT), migration and angiogenesis in vitro. The anti-HER2 monoclonal antibody trastuzumab significantly decreased serum vascular endothelial-derived growth factor (VEGF) levels and that of proliferation-related proteins in the bladder tissues of DMAV-exposed rats. Furthermore, inhibition of HER2, as well as that of the MAPK, AKT and STAT3 pathways, attenuated arsenite-induced proliferation, migration and angiogenesis of human uroepithelial cells, and increased apoptosis rates in vitro. These findings indicate that HER2 mediates the oncogenic effects of As on bladder epithelial cells by activating the MAPK, PI3K/AKT and Src/STAT3 signaling pathways, and is therefore a promising biomarker.

13.
J Cardiovasc Pharmacol ; 76(3): 360-366, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32902944

RESUMO

Warfarin is the most widely prescribed oral anticoagulant and is recommended for patients recovering from coronary artery bypass graft (CABG) with atrial fibrillation. Increasing evidence suggested that warfarin increased arterial stiffness in those patients. We aimed to examine the effect of warfarin therapy on aortic stiffness in patients who underwent CABG with or without postoperative warfarin treatment and explored the potential relationships of warfarin therapy with ABCA1 polymorphisms. This was a retrospect observational study of 24 patients who were continuously treated with warfarin were selected as the warfarin group and matched them by age (±3 years) and gender to 48 patients with nonuse of warfarin as the control group. The aortic stiffness, cholesterol efflux capacity, and plasma level of PIVKA-II were measured. Two ABCA1 polymorphisms were genotyped. Compared with baseline, treatment with warfarin for 1 year significantly increased the plasma level of PIVKA-II and aortic stiffness in pulse pressure and pulse wave velocity in patients after CABG. The increase of pulse wave velocity and plasma PIVKA-II level in the TT genotype was significantly greater than the CC genotype when comparing the -565C/T genotypes. The capacity of cholesterol efflux was significantly lower in the TT genotype at baseline and 1-year follow-up than the CC genotype. Postoperative treatment of warfarin for 1 year significantly increased aortic stiffness in patients who underwent CABG. ABCA1 -565C/T polymorphisms affected the cholesterol efflux capacity and were associated with the vitamin K status and the increased aortic stiffness after warfarin treatment in those patients.

14.
Spectrochim Acta A Mol Biomol Spectrosc ; 244: 118845, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32882656

RESUMO

A functional ratio fluorescence sensor based on the molecularly imprinted polymer (MIP) coated double quantum dots (QDs) being composited of Mn-ZnS QDs and silica-coated graphene quantum dots (GQDs@SiO2) had been established for the sensitive, selective and visual detection of sinapic acid (SA). MIPs@Mn-ZnS/GQDs@SiO2 was synthesized through a simple one-pot sol-gel reaction, and it exhibited two fluorescence emission peaks with yellow fluorescence of Mn-ZnS QDs at 580 nm and the blue fluorescence of GQDs at 445 nm. SA can selectively enhance the fluorescence of GQDs but quench the Mn-ZnS QDs fluorescence to the MIPs@Mn-ZnS/GQDs@SiO2. The ratio of fluorescence enhancement to fluorescence reduction is linear with the concentration of SA from 9 to 81 nM with the detection limits of 0.8388 nM (S/N = 3). And the constructed fluorescent probe can also be used to visually detect SA according to the change of color. More importantly, molecular imprinting technique enables the sensors to selectively recognize the SA while other similar structure molecules hardly interfere with the SA determination in the measurement environment. Meanwhile, the fluorescence sensors have the advantages of fast response time and long duration of fluorescence intensity. These excellent performances made the proposed method to be applied for the determination of SA in Semen Sinapis and Descurainiae Semen.

15.
J Headache Pain ; 21(1): 111, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928098

RESUMO

BACKGROUND: Resting-state functional magnetic resonance imaging (Rs-fMRI) has confirmed sensorimotor network (SMN) dysfunction in migraine without aura (MwoA). However, the underlying mechanisms of SMN effective functional connectivity in MwoA remain unclear. We aimed to explore the association between clinical characteristics and effective functional connectivity in SMN, in interictal patients who have MwoA. METHODS: We used Rs-fMRI to acquire imaging data in 40 episodic patients with MwoA in the interictal phase and 34 healthy controls (HCs). Independent component analysis was used to profile the distribution of SMN and calculate the different SMN activity between the two groups. Subsequently, Granger causality analysis was used to analyze the effective functional connectivity between the SMN and other brain regions. RESULTS: Compared to the HCs, MwoA patients showed higher activity in the bilateral postcentral gyri (PoCG), but lower activity in the left midcingulate cortex (MCC). Moreover, MwoA patients showed decreased effective functional connectivity from the SMN to left middle temporal gyrus, right putamen, left insula and bilateral precuneus, but increased effective functional connectivity to the right paracentral lobule. There was also significant effective functional connectivity from the primary visual cortex, right cuneus and right putamen to the SMN. In the interictal period, there was positive correlation between the activity of the right PoCG and the frequency of headache. The disease duration was positively correlated with abnormal effective functional connectivity from the left PoCG to right precuneus. In addition, the headache impact scores were negatively correlated with abnormal effective functional connectivity from the left MCC to right paracentral lobule, as well as from the right precuneus to left PoCG. CONCLUSIONS: These differential, resting-state functional activities of the SMN in episodic MwoA may contribute to the understanding of migraine-related intra- and internetwork imbalances associated with nociceptive regulation and chronification.

16.
Biomed Pharmacother ; 131: 110665, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32920510

RESUMO

Hypopharyngeal cancer is squamous cell carcinoma (SCC) with the worst prognosis among the head and neck cancers. Overall, the 5-year survival rate remains poor although diagnostic imaging, radiation, chemotherapy, and surgical techniques have been improved. The mortality of patients with hypopharyngeal cancer is partly due to an increased likelihood of developing a second primary malignancy and metastasis. In this study, we found that MLCK expression, compared to healthy tissue, was up-regulated in hypopharyngeal tumor tissue. Of particular interest, a low 5-year survival rate was positively correlated with MLCK expression. We hypothesized that MLCK might be a target for hypopharyngeal cancer prognosis and treatment. In order to explore the function of MLCK in the development of cancer, we knockdown MLCK in hypopharyngeal cancer FaDu cells. The results showed that MLCK knockdown reduced the migration and invasion of FaDu cells. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) is the derivative of all-trans retinoic acid (ATRA), which was able to reduce both MLCK expression and activity in FaDu cells. ATPR induced FaDu cells apoptosis in a dose-dependent manner and also inhibited cell growth both in vivo and in vitro. Further experiments showed that overexpression of MLCK reduced ATPR induced-migration inhibition while increase of ATPR induced apoptosis, which suggested that MLCK was involved in ATPR's anti-cancer function. In conclusion, MLCK is a novel prognostic marker and therapeutic target for hypopharyngeal cancer. By targeting MLCK, ATPR exhibits its potential application in the treatment of this type of cancer.

18.
Int J Cancer ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32949150

RESUMO

The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of this study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 out of 14 KRAS positive tumors, in three patients without KRAS mutation in the respective tumor acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (p=0.022; HHR 3.110 (95%CI: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations (SCNA) in advanced cancer patients.

19.
Arthritis Rheumatol ; 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32892503

RESUMO

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure and immunodeficiency. Most cases are diagnosed by paediatric care providers given the typical early age of disease onset. We aim to describe the clinical phenotypes and treatment response of adults as well as paediatric DADA2 patients in India. METHODS: We conducted a retrospective analysis of DADA2 patients diagnosed at various rheumatology centres across India. The clinical characteristics, diagnostic findings and treatment response of all the subjects were analysed. RESULTS: We confirmed 33 cases of DADA2 between April 2017 and March 2020. Unlike previous studies, nearly half of the cases presented during adulthood. All symptomatic patients exhibited features of vasculitis while constitutional symptoms and anaemia were more common in paediatric patients. Cutaneous and neurologic involvement were common and 18 subjects had at least one stroke. In addition, we expand the clinical spectrum of DADA2 by describing novel features including pancreatic infarction, focal myocarditis and diffuse alveolar haemorrhage. Tumour necrosis factor inhibitors (TNFi) were initiated for 25 patients. All measured disease manifestations showed marked improvement after initiation of TNFi and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection and two deaths were reported. CONCLUSIONS: We present the first case series of DADA2 patients from India. We highlight the presentation of DADA2 in adults and raise awareness of this syndrome for both adult and paediatric care providers.

20.
FASEB J ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32954572

RESUMO

This study was designed to clarify whether the irradiation of carotid baroreceptor (CB) with low-intensity pulsed ultrasound (LIPUS) protects against obesity by rebalancing the autonomic nervous system (ANS). Obesity was induced using a high-fat diet (HFD) for 8 weeks in Sprague-Dawley rats. Irradiation with LIPUS was daily (20 minutes a day) applied to the right CB. In our study, LIPUS significantly ameliorated metabolic disorders in obese rats. LIPUS partly restored norepinephrine (NE) and acetylcholine (ACH) levels in the perirenal white adipose tissue (PWAT), epididymal white adipose tissue (EWAT), interscapular brown adipose tissue (IBAT), and plasma of obese rats. LIPUS partially rectified the dysregulated AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor (PPAR) α/É£ pathway in the PWAT, EWAT, and IBAT of obese rats. PPARγ and PPARγ target genes respond more sensitively to HFD and LIPUS in PWAT and EWAT than in IBAT. NE, ACH, uncoupling protein-1, phosphorylated AMPK, PPARα, and PPARα target genes respond more sensitively to HFD and LIPUS in IBAT than in PWAT and EWAT. Conclusion: LIPUS irradiation of CB exerts different metabolic protection in PWAT, EWAT, and IBAT by rebalancing the ANS and rectifying the AMPK/PPARα/É£ pathway in obese rats.

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