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1.
Glob Chang Biol ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479577

RESUMO

Subsoil contains more than half of soil organic carbon (SOC) globally and is conventionally assumed to be relatively unresponsive to warming compared to the topsoil. Here we show substantial changes in carbon allocation and dynamics of the subsoil but not topsoil in the Qinghai-Tibetan alpine grasslands over 5 years of warming. Specifically, warming enhanced the accumulation of newly synthesized (14 C-enriched) carbon in the subsoil slow-cycling pool (silt-clay fraction) but promoted the decomposition of plant-derived lignin in the fast-cycling pool (macroaggregates). These changes mirrored an accumulation of lipids and sugars at the expense of lignin in the warmed bulk subsoil, likely associated with shortened soil freezing period and a deepening root system. As warming is accompanied by deepening roots in a wide range of ecosystems, root-driven accrual of slow-cycling pool may represent an important and overlooked mechanism for a potential long-term carbon sink at depth. Moreover, given the contrasting sensitivity of SOC dynamics at varied depths, warming studies focusing only on surface soils may vastly misrepresent shifts in ecosystem carbon storage under climate change. This article is protected by copyright. All rights reserved.

2.
ACS Nano ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31487452

RESUMO

We report a solution for the challenge of having luminescence and metal conductivity from the same material. The fabrication of a hybrid metal-conductive luminescent film that manifests this dual property is described: the conductivity arising from a continuous gold thin film structure and luminescence originating from the embedded fluorescent emitters (nanoparticles of silica-coated CdSe/CdS quantum dots (QD/SiO2 NPs)). The embedding of the QD/SiO2 NPs is performed via a self-templating gold electroless process. The presence of the insulating silica layer on the QDs avoids quenching and enables luminescence, while still allowing plasmonic coupling of the QDs, as observed by luminescence lifetime analysis and by surface-enhanced Raman scattering. The potential applications of this special dual functionality are demonstrated by its used as a temperature probe: Passing current (heating the gold thin film) affects the emission intensity and induces a spectral red-shift of the QD/SiO2 NPs. All properties of this metal-conductive luminescent film required the special embedding architecture and are not observed with simple adsorption of QD/SiO2 NPs on a continuous Au film.

3.
Hum Mutat ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373411

RESUMO

Intermediate Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.

4.
Medicine (Baltimore) ; 98(33): e16789, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415384

RESUMO

To investigate the efficacy of lacrimal endoscopy in the diagnosis and treatment of primary canaliculitis.This is a retrospective, interventional study. Fifteen patients diagnosed as primary canaliculitis were investigated, who underwent surgery with lacrimal endoscopy from January 2015 to December 2017 at Zhejiang Provincial People's Hospital. Patients were subsequently followed post-operatively for at least 6 months. Pre- and post-operative main measurement included ocular surface symptoms, signs of canaliculitis, intraoperative images, treatment response and complications.Twelve patients (12 eyes) were enrolled. Endoscopy was successful in revealing the residual concretion and pathological change of lacrimal duct. With its unique direct vision and micro drill, all concretions got removed and lacrimal ducts got patent. On postoperative month 6, all of the patients got cured with no signs of redness, swelling of the punctum and eyelid, epiphora with discharge and pain. None serious complications such as false canalicular passage were observed.Lacrimal endoscopy is indispensable in diagnosis, treatment and follows up of primary canaliculitis. With less iatrogenic injury, higher resolution rate and direct observation of canalicular mucosa, lacrimal endoscopy should be widely applied in the management of lacrimal diseases.


Assuntos
Canaliculite/diagnóstico , Endoscopia/instrumentação , Aparelho Lacrimal , Adulto , Idoso , Canaliculite/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
5.
Ann Surg ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31449138

RESUMO

MINI: An international survey of high-volume pancreas cancer surgeons revealed wide variations in management preferences, attitudes regarding contraindications to surgery, and the propensity to offer exploration. When presented with 6 hypothetical clinical vignettes using details from real patients that have received R0 resection, only 14% to 53% of participating surgeons were willing to offer exploration following neoadjuvant therapy. OBJECTIVE: The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC). BACKGROUND: Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear. METHODS: An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, management preferences, attitudes regarding contraindications to surgery, and 6 clinical vignettes of patients that ultimately received a margin negative resection (with detailed videos of post-neoadjuvant imaging) to assess propensity for surgical exploration if resection status is not known. RESULTS: A total of 153 eligible responses were received from 4 continents. Median duration of practice is 12 years (interquartile range 6-20) and 77% work in a university setting. Most surgeons (86%) are considered high volume (>10 resections/yr), 33% offer a minimally-invasive approach, and 50% offer arterial resections in select patients. Most (72%) always recommend neoadjuvant chemotherapy, and 65% prefer FOLFIRINOX. Preferences for the duration of chemotherapy varied widely: 39% prefer ≥2 months, 43% prefer ≥4 months, and 11% prefer ≥6 months. Forty-one percent frequently recommend neoadjuvant radiotherapy, and 53% prefer 5 to 6 weeks of chemoradiation. The proportion of surgeons favoring exploration following neoadjuvant varied extensively across 5 vignettes of LAPC, from 14% to 53%. In a vignette of oligometastatic liver metastases, 31% would offer exploration if a favorable therapy response is observed. CONCLUSIONS: In an international cohort of pancreas surgeons, there is substantial variation in management preferences, perceived contraindications to surgery, and the propensity to consider exploration in LAPC. These results emphasize the importance of a robust and nuanced multidisciplinary discussion for each patient, and suggest an evolving concept of "resectability."

6.
Aging (Albany NY) ; 11(16): 6385-6397, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454331

RESUMO

Hemorrhagic transformation (HT) is a severe complication occurring in acute ischemic stroke (AIS) patients. We explored the association between low triiodothyronine (T3) syndrome and HT in AIS patients. A total of 208 consecutive participants with HT and 208 age- and sex-matched stroke patients without HT were enrolled in this study. HT was diagnosed by follow-up imaging assessment, and was radiologically classified as hemorrhagic infarction (HI) type 1 or 2 or parenchymal hematoma (PH) type 1 or 2. HT was also classified into asymptomatic or symptomatic. The incidence of low T3 syndrome was significantly higher among patients who developed HT than among those without HT. Moreover, the more severe the HT, the lower the detected T3 levels. Multivariate-adjusted binary logistic regression showed that low T3 syndrome was an independent risk factor for HT and symptomatic HT in AIS patients. Low T3 syndrome was also significantly associated with a higher risk of PH, but not with the risk of HI. Thus, low T3 syndrome was independently associated with the risk of HT, symptomatic HT, and severe HT (PH) in AIS patients, which suggests monitoring T3 could be a useful means of preventing HT in patients with ischemic stroke.

7.
Ann Surg ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31389831

RESUMO

OBJECTIVE: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status. BACKGROUND: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors. METHODS: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status. RESULTS: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38). CONCLUSIONS: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.

8.
J Biomed Opt ; 24(12): 1-12, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31411010

RESUMO

Abdominal surgeries carry considerable risk of gastrointestinal and intra-abdominal hemorrhage, which could possibly cause patient death. Photoacoustic imaging is one solution to overcome this challenge by providing visualization of major blood vessels during surgery. We investigate the feasibility of in vivo blood vessel visualization for photoacoustic-guided liver and pancreas surgeries. In vivo photoacoustic imaging of major blood vessels in these two abdominal organs was successfully achieved after a laparotomy was performed on two swine. Three-dimensional photoacoustic imaging with a robot-controlled ultrasound (US) probe and color Doppler imaging were used to confirm vessel locations. Blood vessels in the in vivo liver were visualized with energies of 20 to 40 mJ, resulting in 10 to 15 dB vessel contrast. Similarly, an energy of 36 mJ was sufficient to visualize vessels in the pancreas with up to 17.3 dB contrast. We observed that photoacoustic signals were more focused when the light source encountered a major vessel in the liver. This observation can be used to distinguish major blood vessels in the image plane from the more diffuse signals associated with smaller blood vessels in the surrounding tissue. A postsurgery histopathological analysis was performed on resected pancreatic and liver tissues to explore possible laser-related damage. Results are generally promising for photoacoustic-guided abdominal surgery when the US probe is fixed and the light source is used to interrogate the surgical workspace. These findings are additionally applicable to other procedures that may benefit from photoacoustic-guided interventional imaging of the liver and pancreas (e.g., biopsy and guidance of radiofrequency ablation lesions in the liver).

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9.
J Mater Chem B ; 7(32): 4953-4962, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411627

RESUMO

Malignant solid tumors are composed of tumor cells, stromal cells and the complex networks of the tumor microenvironment (TME), which is the underlying cause of the unsatisfactory outcome of conventional chemotherapy approaches only aimed at cancer cell killing. In this study, a novel TME-responsive polymeric micelle has been developed for the programmed site-specific delivery of the angiostatin sunitinib and chemotherapeutic paclitaxel (PTX). The pH-sensitive micelle core encapsulates PTX, while ß-cyclodextrin molecules being conjugated to the micelle shell via matrix metalloproteinase 2 (MMP-2) sensitive peptides include sunitinib. Following the pH and MMP-2 dual sensitive structure design, the micelle may sequentially release sunitinib inside the tumor extracellular matrix and PTX into cancer cells through responding to enriched MMP-2 levels and decreased pH, respectively. Consequently, the anti-angiogenesis effect of sunitinib and tumor cell-killing effect of PTX synergize, resulting in highly efficient tumor treatment.

10.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336824

RESUMO

Microbial biofilms are communities of aggregated microbial cells embedded in a self-produced matrix of extracellular polymeric substances (EPS). Biofilms are recalcitrant to extreme environments, and can protect microorganisms from ultraviolet (UV) radiation, extreme temperature, extreme pH, high salinity, high pressure, poor nutrients, antibiotics, etc., by acting as "protective clothing". In recent years, research works on biofilms have been mainly focused on biofilm-associated infections and strategies for combating microbial biofilms. In this review, we focus instead on the contemporary perspectives of biofilm formation in extreme environments, and describe the fundamental roles of biofilm in protecting microbial exposure to extreme environmental stresses and the regulatory factors involved in biofilm formation. Understanding the mechanisms of biofilm formation in extreme environments is essential for the employment of beneficial microorganisms and prevention of harmful microorganisms.

11.
Brain ; 142(9): 2845-2859, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31312839

RESUMO

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.

12.
Virology ; 535: 171-178, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31306912

RESUMO

Human respiratory syncytial virus (RSV) is one of the predominant pathogens causing lower respiratory tract infection in infants and young children worldwide, whereas there is so far no vaccine or drug against RSV infection for clinical use. In this work, we developed and validated a fluorescence-based high-throughput screening (HTS) assay to identify compounds active against RSV, using RSV-mGFP, a recombinant RSV encoding enhanced green fluorescent protein (EGFP). Thereafter, among 54,800 compounds used for our screen, we obtained 62 compounds active against RSV. Among these hits, azathioprine (AZA) and 6-mercaptopurine (6-MP) were identified as RSV inhibitors with half maximal inhibitory concentration (IC50) values of 6.69 ±â€¯1.41 and 3.13 ±â€¯0.98 µM, respectively. Further experiments revealed that they functioned by targeting virus transcription or/and genome replication. In conclusion, the established HTS assay is suitable to screen anti-RSV compounds, and the screened two hits of AZA and 6-MP, as potential anti-RSV agents targeting RSV genome replication/transcription, are worthy of further investigation on their anti-RSV activity in vivo.

13.
Mod Pathol ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285527

RESUMO

Germline pathogenic variants in the ATM serine/threonine kinase (ATM) gene are associated with an increased risk of pancreatic ductal adenocarcinoma. It is important to identify germline ATM pathogenic variants in pancreatic cancer patients because these alterations are potentially targetable with chemotherapeutic drugs and/or radiation and have implications for other family members. As germline pathogenic variants in other genes have been associated with distinct histologic subtypes of pancreatic cancer, we studied the histomorphology of pancreatic cancer in 23 patients with germline ATM pathogenic variants. The histologic subtype was ductal adenocarcinoma in 19/23 (83%) of the patients, adenosquamous carcinoma in 1/23 (4%), and colloid (mucinous non-cystic) carcinoma in 3/23 (13%). The percentage of colloid (mucinous non-cystic) carcinomas is higher than we have previously observed in patients with familial and sporadic pancreatic cancer (1 and 2% in prior reports, p < 0.01 and p < 0.01, respectively). Three carcinomas (2 colloid carcinomas, 1 ductal adenocarcinoma) arose in association with intraductal papillary mucinous neoplasms. Among the resected pancreata, non-invasive precursor lesions, including pancreatic intraepithelial neoplasia and incipient intraductal papillary mucinous neoplasms, were identified in 83%. We conclude that pancreatic cancers in patients with germline ATM pathogenic variants are more frequently of colloid (mucinous non-cystic) morphology but are overall morphologically diverse supporting the utility of universal germline genetic testing for patients with pancreatic cancer.

14.
Phys Chem Chem Phys ; 21(29): 15940-15948, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31263809

RESUMO

Reversible intermolecular interactions play critical roles in nature. However, it is still challenging to monitor the dynamic intermolecular interactions at the single-molecule level in aqueous solution. Here, we studied the dynamic changes of intermolecular interactions at the carboxyl/carboxyl interfaces between a pair of molecules trapped in a plasmonic nanocavity formed between a gold nanoparticle (GNP) and a gold nanoelectrode (GNE). The development of intermolecular interactions, including the appearance of hydrogen bonds (h-bonds), during and after single GNP collision events on the GNE, was monitored by time-resolved surface-enhanced Raman spectroscopy at a tens of milliseconds time resolution. Spectral fingerprints of the carboxyl group corresponding to non-specific intermolecular interactions and h-bonds are identified. Furthermore, we demonstrated that the strength of intermolecular interaction could be mechanically modulated by changing the applied bias at the GNE, which resulted in small and controllable changes in the nanogap distance. Unlike non-specific intermolecular interactions, the intermolecular h-bonds can only be formed stochastically and are more sensitive to the gap distance modulation. This report demonstrates a new approach to modulate and probe intermolecular interactions within nanogaps.

15.
BMC Infect Dis ; 19(1): 615, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299911

RESUMO

BACKGROUND: China contributed 8.9% of all incident cases of tuberculosis globally in 2017, and understanding the spatiotemporal distribution of pulmonary tuberculosis (PTB) in major transmission foci in the country is critical to ongoing efforts to improve population health. METHODS: We estimated annual PTB notification rates and their spatiotemporal distributions in Sichuan province, a major center of ongoing transmission, from 2005 to 2017. Time series decomposition was used to obtain trend components from the monthly incidence rate time series. Spatiotemporal cluster analyses were conducted to detect spatiotemporal clusters of PTB at the county level. RESULTS: From 2005 to 2017, 976,873 cases of active PTB and 388,739 cases of smear-positive PTB were reported in Sichuan Province, China. During this period, the overall reported incidence rate of active PTB decreased steadily at a rate of decrease (3.77 cases per 100,000 per year, 95% confidence interval (CI): 3.28-4.31) that was slightly faster than the national average rate of decrease (3.14 cases per 100,000 per year, 95% CI: 2.61-3.67). Although reported PTB incidence decreased significantly in most regions of the province, incidence was observed to be increasing in some counties with high HIV incidence and ethnic minority populations. Active and smear-positive PTB case reports exhibited seasonality, peaking in March and April, with apparent links to social dynamics and climatological factors. CONCLUSIONS: While PTB incidence rates decreased strikingly in the study area over the past decade, improvements have not been equally distributed. Additional surveillance and control efforts should be guided by the seasonal-trend and spatiotemporal cluster analyses presented here, focusing on areas with increasing incidence rates, and updated to reflect the latest information from real-time reporting.

16.
Sci Transl Med ; 11(501)2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316009

RESUMO

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

17.
J Gastrointest Surg ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270718

RESUMO

BACKGROUND: Introduction of effective systemic therapies for pancreatic ductal adenocarcinoma (PDAC) has demonstrated survival benefit. However, chemotherapy remains underutilized in these patients. We sought to investigate the implications of disparities on the trends in utilization of chemotherapy. METHODS: A retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database identified patients who underwent surgical resection for PDAC from 1998 to 2014. Clinicopathologic, demographic, racial, and geographical factors were analyzed to assess associations with receipt of chemotherapy and disease-specific survival. RESULTS: A total of 15,585 patients were included in the study. A majority (N = 9953, 63.9%) received chemotherapy. Factors associated with poorer odds of receiving chemotherapy included older age (p < 0.001), African-American race (p = 0.003), and living in the Southwest region of the USA (p < 0.001). Married patients were at higher odds of receiving chemotherapy (all p < 0.001). Receipt of chemotherapy was independently associated with improved disease-specific survival (p < 0.001). CONCLUSIONS: Receipt of chemotherapy results in an improved survival in patients with resected PDAC. Demographic, racial, and geographic factors influence the rate of receipt of chemotherapy. Despite prior reports, these trends have not changed over the recent decades.

18.
Int Immunopharmacol ; 74: 105693, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203154

RESUMO

Metformin (Met) has been found to modify the methylation of H19 and to alter its expression. In addition, IL-27, one of the downstream factors in the H19 signaling pathway, plays an important role in the pathogenesis of pre-eclampsia (PE). In this study, we investigated the molecular mechanism underlying the therapeutic effect of Met in the management of PE both in vivo and in vitro. The role of H19 signaling pathway in PE was validated using online bioinformatics tools, luciferase assays, real-time PCR and Western Blot. A tail-cuff method was used to examine the blood pressures in PE rats with or without Met treatment. Cells exhibited a dose-dependent increase of H19 methylation, which inhibited the expression of H19. Additionally, upon the Met treatment, levels of miR-148-5p and miR-216-3p were both elevated in a dose-dependent manner while levels of p28 mRNA and EBI3 mRNA were both inhibited by Met treatment. Also, H19 was found to regulate the expression of miR-148a-5p and miR-216-3p, while P28 and EBI3 were respectively identified as target genes of miR-148a-5p and miR-216-3p. Therefore, the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways were implicated in the pathogenesis of PE. Met was implicated in the pathogenesis of PE via modulating the H19 signaling pathway. The methylation of H19 reduced H19 expression, which in turn could up-regulate the expression of miR-148-5p/miR-216-3p. And the expressions of subunits of IL-27, P28 and EBI3, were thus suppressed. Therefore, Met-induced inhibition of H19 also led to the reduction of IL-27 expression, TNF-α and IL-6 in vivo.

19.
Gastroenterology ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31175866

RESUMO

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

20.
Clin Cancer Res ; 25(17): 5351-5363, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31186314

RESUMO

PURPOSE: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. EXPERIMENTAL DESIGN: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. RESULTS: Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7- effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. CONCLUSIONS: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.

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