ResearchPad - Histology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Reduction of osteoarthritis severity in the temporomandibular joint of rabbits treated with chondroitin sulfate and glucosamine]]> https://www.researchpad.co/product?articleinfo=N10336f10-2066-4958-9182-9e228dac929f

Osteoarthritis is a degenerative disease that causes substantial changes in joint tissues, such as cartilage degeneration and subchondral bone sclerosis. Chondroitin sulfate and glucosamine are commonly used products for the symptomatic treatment of osteoarthritis. The aim of the present study was to investigate the effects of these products when used as structure-modifying drugs on the progression of osteoarthritis in the rabbit temporomandibular joint. Thirty-six New Zealand rabbits were divided into 3 groups (n = 12/group): control (no disease); osteoarthritis (disease induction); and treatment (disease induction and administration of chondroitin sulfate and glucosamine). Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate. Animals were killed at 30 and 90 days after initiation of therapy. The treatment was effective in reducing disease severity, with late effects and changes in the concentration of glycosaminoglycans in the articular disc. The results indicate that chondroitin sulfate and glucosamine may have a structure-modifying effect on the tissues of rabbit temporomandibular joints altered by osteoarthritis.

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<![CDATA[Detection of microbial cell-free DNA in maternal and umbilical cord plasma in patients with chorioamnionitis using next generation sequencing]]> https://www.researchpad.co/product?articleinfo=N85cfbb28-a074-423a-88cd-d5e05af52830

Background

Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms.

Objective

The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis.

Study design

Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28–41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma.

Results

Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma.

Conclusion

This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications.

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<![CDATA[Effect of moderate elevated intra-abdominal pressure on lung mechanics and histological lung injury at different positive end-expiratory pressures]]> https://www.researchpad.co/product?articleinfo=Nccafa6f6-e83a-4af1-be67-e451f21e0145

Introduction

Intra-abdominal hypertension (IAH) is a well-known phenomenon in critically ill patients. Effects of a moderately elevated intra-abdominal pressure (IAP) on lung mechanics are still not fully analyzed. Moreover, the optimal positive end-expiratory pressure (PEEP) in elevated IAP is unclear.

Methods

We investigated changes in lung mechanics and transformation in histological lung patterns using three different PEEP levels in eighteen deeply anesthetized pigs with an IAP of 10 mmHg. After establishing the intra-abdominal pressure, we randomized the animals into 3 groups. Each of n = 6 (Group A = PEEP 5, B = PEEP 10 and C = PEEP 15 cmH2O). End-expiratory lung volume (EELV/kg body weight (bw)), pulmonary compliance (Cstat), driving pressure (ΔP) and transpulmonary pressure (ΔPL) were measured for 6 hours. Additionally, the histological lung injury score was calculated.

Results

Comparing hours 0 and 6 in group A, there was a decrease of EELV/kg (27±2 vs. 16±1 ml/kg; p<0.05) and of Cstat (42±2 vs. 27±1 ml/cmH2O; p<0.05) and an increase of ΔP (11±0 vs. 17±1 cmH2O; p<0.05) and ΔPL (6±0 vs. 10±1 cmH2O; p<0.05). In group B, there was no significant change in EELV/kg (27±3 vs. 24±3 ml/kg), but a decrease in Cstat (42±3 vs. 32±1 ml/cmH20; p<0.05) and an increase in ΔP (11±1 vs. 15±1 cmH2O; p<0.05) and ΔPL (5±1 vs. 7±0 cmH2O; p<0.05). In group C, there were no significant changes in EELV/kg (27±2 vs. 29±3 ml/kg), ΔP (10±1 vs. 12±1 cmH2O) and ΔPL (5±1 vs. 7±1 cmH2O), but a significant decrease of Cstat (43±1 vs. 37±1 ml/cmH2O; p<0.05). Histological lung injury score was lowest in group B.

Conclusions

A moderate elevated IAP of 10 mmHg leads to relevant changes in lung mechanics during mechanical ventilation. In our study, a PEEP of 10 cmH2O was associated with a lower lung injury score and was able to overcome the IAP induced alterations of EELV.

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<![CDATA[Validation of risk factors for recurrence of renal cell carcinoma: Results from a large single-institution series]]> https://www.researchpad.co/product?articleinfo=Ne7ebe4b8-b927-4fd1-a438-3fd04efc5df6

Purpose

To validate prognostic factors and determine the impact of obesity, hypertension, smoking and diabetes mellitus (DM) on risk of recurrence after surgery in patients with localized renal cell carcinoma (RCC).

Materials and methods

We performed a retrospective cohort study among patients that underwent partial or radical nephrectomy at Weill Cornell Medicine for RCC and collected preoperative information on RCC risk factors, as well as pathological data. Cases were reviewed for radiographic evidence of RCC recurrence. A Cox proportional-hazards model was developed to determine the contribution of RCC risk factors to recurrence risk. Disease-free survival and overall survival were analyzed using the Kaplan-Meier method and log-rank test.

Results

We identified 873 patients who underwent surgery for RCC between the years 2000–2015. In total 115 patients (13.2%) experienced a disease recurrence after a median follow up of 4.9 years. In multivariate analysis, increasing pathological T-stage (HR 1.429, 95% CI 1.265–1.614) and Nuclear grade (HR 2.376, 95% CI 1.734–3.255) were independently associated with RCC recurrence. In patients with T1-2 tumors, DM was identified as an additional independent risk factor for RCC recurrence (HR 2.744, 95% CI 1.343–5.605). Patients with DM had a significantly shorter median disease-free survival (1.5 years versus 2.6 years, p = 0.004), as well as median overall survival (4.1 years, versus 5.8 years, p<0.001).

Conclusions

We validated high pathological T-stage and nuclear grade as independent risk factors for RCC recurrence following nephrectomy. DM is associated with an increased risk of recurrence among patients with early stage disease.

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<![CDATA[Oral toxicity of arjunolic acid on hematological, biochemical and histopathological investigations in female Sprague Dawley rats]]> https://www.researchpad.co/product?articleinfo=N47cc57d4-7cfc-45d0-a7c8-7d1bec05d222

Background

Arjunolic acid (AA) is a potent phytochemical with wider pharmacological activities. Despite potential medicinal properties on various in vitro and in vivo studies, there is still a dearth of scientific data related to its safety profile and toxicological parameters. The current study aimed to investigate acute toxicity of AA in normal female Sprague Dawley rats.

Methods

In this study, AA was administered orally at an individual dose of 300 and 2000 mg/kg body weight to group 1 and 2 respectively, while group 3 served as normal control. All the animals were observed for 2 weeks to determine any behavioral and physical changes. On day 15, blood was collected for hematological and biochemical investigation, later animals from all the three groups were euthanized to harvest and store essential organs for histopathological analysis. Four different staining techniques; hematoxylin and eosin, Masson trichrome, Periodic acid Schiff and Oil O Red were used to investigate any alterations in different tissues through microscopical observation.

Results

The results of the study showed no morbidity and mortality at two different dosage of AA treatment. Daily food & water intake, body weight, relative organ weight, hematological and biochemical parameters were detected to be normal with no severe alteration seen through microscopical investigation in the structure of harvested tissues. Our findings support the safety profile of AA, which was well tolerated at higher dose. Thus, an in-detail study on the subacute disease model is warranted.

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<![CDATA[Hematological convergence between Mesozoic marine reptiles (Sauropterygia) and extant aquatic amniotes elucidates diving adaptations in plesiosaurs]]> https://www.researchpad.co/product?articleinfo=N0f16665b-e98b-4c32-a97a-d8161ec3cf0a

Plesiosaurs are a prominent group of Mesozoic marine reptiles, belonging to the more inclusive clades Pistosauroidea and Sauropterygia. In the Middle Triassic, the early pistosauroid ancestors of plesiosaurs left their ancestral coastal habitats and increasingly adapted to a life in the open ocean. This ecological shift was accompanied by profound changes in locomotion, sensory ecology and metabolism. However, investigations of physiological adaptations on the cellular level related to the pelagic lifestyle are lacking so far. Using vascular canal diameter, derived from osteohistological thin-sections, we show that inferred red blood cell size significantly increases in pistosauroids compared to more basal sauropterygians. This change appears to have occurred in conjunction with the dispersal to open marine environments, with cell size remaining consistently large in plesiosaurs. Enlarged red blood cells likely represent an adaptation of plesiosaurs repeated deep dives in the pelagic habitat and mirror conditions found in extant marine mammals and birds. Our results emphasize physiological aspects of adaptive convergence among fossil and extant marine amniotes and add to our current understanding of plesiosaur evolution.

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<![CDATA[Renal injury after uninephrectomy in male and female intrauterine growth-restricted aged rats]]> https://www.researchpad.co/product?articleinfo=5c8acce7d5eed0c48499029e

Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.

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<![CDATA[Is there a reliable size cut-off for splenic involvement in lymphoma? A [18F]FDG-PET controlled study]]> https://www.researchpad.co/product?articleinfo=5c8c1956d5eed0c484b4d428

Purpose

Aim of present study was to determine whether the currently recommended 13-cm cranio-caudal diameter cut-off on CT for assessment of splenic involvement in lymphoma offers adequate sensitivity and specificity.

Materials and Methods

Patients with histologically proven lymphoma who had undergone [18F]FDG-PET/CT before therapy were included. Cranio-caudal diameters of the spleen were measured on the CT component of PET/CT, and ROC analyses with calculation of respective areas under the curve (AUC) were used to determine cut-off values of cranio-caudal measurements with their respective sensitivities and specificities, using [18F]FDG-PET as the reference standard.

Results

In 93 patients, we found a sensitivity of 74.1% and a specificity of 47% for the 13-cm splenic diameter cut-off.

Conclusions

Our results show reasonable, though far from perfect sensitivities and specificities for the currently recommend 13-cm splenic diameter cut-off.

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<![CDATA[Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome]]> https://www.researchpad.co/product?articleinfo=5c8accc2d5eed0c48498ff04

Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7–27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.

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<![CDATA[Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage]]> https://www.researchpad.co/product?articleinfo=5c76fe30d5eed0c484e5b699

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

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<![CDATA[Early-stage serrated adenocarcinomas are divided into several molecularly distinct subtypes]]> https://www.researchpad.co/product?articleinfo=5c76fdead5eed0c484e5b080

Serrated adenocarcinoma (SAC) is considered the end stage of the serrated neoplasia pathway. Although SAC prognosis is not widely recognized, the serrated pathway-associated subtype consistently exhibits unfavorable prognosis in genetic studies. Herein, we classified molecularly distinct subtypes of serrated adenocarcinomas and clarified their associated clinicopathological characteristics and genetic changes. We examined 38 early-stage colorectal SACs. Of these, 24 were classified into three molecularly distinct groups by colon cancer subtyping (CCS). The clinicopathological characteristics, Ki 67 labeling index (LI), and SAC epithelial serration were assessed. The DNA from carcinomas and normal tissue/adenoma was extracted by laser microdissection and sequenced by next-generation sequencing, and mutation numbers and patterns of a 15-oncogene panel were determined. The CCS groups included CCS1 (CDX2+, HTR2B-, FRMD6-, ZEB1-, and microsatellite instable-low [MSI-L]/microsatellite stable [MSS]; 14 cases), CCS2 (microsatellite instable-high [MSI-H], 5 cases), and CCS3 (CDX2-, HTR2B+, FRMD6+, ZEB1+, and MSI-L/MSS; 5 cases). Invasive cancer was significantly more frequent in CCS3 than in CCS1 (5/5 versus 3/14, respectively). Ki67 LI and epithelial serration were higher in CCS3 than in CCS1 (83.0 ± 5.8 versus 65.4 ± 4.0 and 5/5 versus 3/14, respectively; p = 0.031 and 0.0048). CCS2 showed the highest mutation number, whereas KRAS and BRAF mutation numbers were higher in CCS3 than in CCS1. Early-stage SACs were classified into three molecularly distinct subtypes with different clinicopathological and genetic characteristics.

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<![CDATA[The role of Virus "X" (Tortoise Picornavirus) in kidney disease and shell weakness syndrome in European tortoise species determined by experimental infection]]> https://www.researchpad.co/product?articleinfo=5c75ac17d5eed0c484d08133

Tortoise Picornavirus (ToPV) commonly known as Virus "X" was recently discovered in juvenile European tortoises suffering from soft carapace and plastron as well as kidney disease. Therefore, this virus was a potential candidate to be a causative agent for these disease patterns. Spur thighed tortoises (Testudo graeca) seemed to be more susceptible to establish clinical symptoms than other European species like T. hermanni. Thus this trial investigated the role of ToPV in the described syndrome. Two groups of juvenile European tortoises (T. graeca and T.hermanni) each of 10 animals, were cloacally, oronasally and intracoelomically inoculated with an infectious dose (~ 2000 TICD) of a ToPV strain isolated from a diseased T. graeca. A control group of two animals of each species received non-infected cell culture supernatant. The tortoises were examined daily and pharyngeal and cloacal swabs for detection of ToPV-RNA by RT-PCR were taken from each animal every six days for a period of 6 months. At the end of the study the remaining animals were euthanised and dissected. Bacteriological and parasitological tests were performed and organ samples of all tortoises were investigated by RT-PCR for the presence of ToPV and histopathology. Animals that were euthanised at the end of the experiment, were examined for presence of specific anti-ToPV antibodies. Several animals in both inoculated groups showed retarded growth and a light shell weakness, in comparison to the control animals. Three animals were euthanised during the trial, showing reduced weight gain, retarded growth, severe shell weakness and apathy, in parallel to clinical observations in naturally infected animals. In all inoculated animals of both species an intermittent virus shedding, starting from 18 days post inoculation (d.p.i.), till 164 d.p.i. was detected, while the control animals remained negative. The virus was successfully reisolated in terrapene heart cell culture in 16 of 20 inoculated animals of both species. Histopathology of most inoculated animals revealed a lack of bone remodeling and vacuolisation in kidney tubuli which supports the described pathogenesis of nephropathy and osteodystrophy. Anti- ToPV antibody titres ranged from 1:2 to >1:256 in 13 of 20 animals, whereas all control animals were seronegative. The study proofed the Henle Koch`s postulates of ToPV as causative agent for shell dystrophy and kidney disease in both testudo species. The proposed species specific sensitivity towards clinical disease was not observed.

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<![CDATA[Ornithine decarboxylase antizyme inhibitor 2 (AZIN2) is a signature of secretory phenotype and independent predictor of adverse prognosis in colorectal cancer]]> https://www.researchpad.co/product?articleinfo=5c70673fd5eed0c4847c6c9d

Ornithine decarboxylase (ODC) is the rate-limiting enzyme of polyamine synthesis. The two ODC antizyme inhibitors (AZIN1) and (AZIN2) are regulators of the catalytic activity of ODC. While AZIN1 is a regulator of cell proliferation, AZIN2 is involved in intracellular vesicle transport and secretion. There are no previous reports on the impact of AZIN2 expression in human cancer. We applied immunohistochemistry with antibodies to human AZIN2 on tissue micro- arrays of colorectal cancers (CRC) from 840 patients with a median follow-up of 5.1 years (range 0–25.8). The 5-year disease-specific survival rate was 58.9% (95% Cl 55.0–62.8%). High AZIN2 expression was associated with mucinous histology (p = 0.002) and location in the right hemicolon (p = 0.021). We found no association with age, gender, stage, or histological tumor grade. High tumor expression of AZIN2 predicted an unfavorable prognosis (p<0.0001, log-rank test), compared to low AZIN2 expression. Cox multivariable analysis identified AZIN2 as an independent factor of an unfavorable prognosis in CRC. The strongest AZIN2 expression was seen in invasive tumor cells having morphological features of epithelial-mesenchymal transition (EMT). Induction of EMT in HT-29 CRC cells lead to upregulated expression of endogenous AZIN2. Given that AZIN2 is a regulator of vesicle transport and secretion, we overexpressed human AZIN2 cDNA in T84 CRC cells, and found strongly enhanced accumulation of CD63-positive exosomes in the culture medium. These findings indicate that AZIN2 expression is a signature of EMT-associated secretory phenotype that is linked to an adverse prognosis in CRC.

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<![CDATA[Changes in the spatial distribution of the Purkinje network after acute myocardial infarction in the pig]]> https://www.researchpad.co/product?articleinfo=5c6b267bd5eed0c484289b76

Purkinje cells (PCs) are more resistant to ischemia than myocardial cells, and are suspected to participate in ventricular arrhythmias following myocardial infarction (MI). Histological studies afford little evidence on the behavior and adaptation of PCs in the different stages of MI, especially in the chronic stage, and no quantitative data have been reported to date beyond subjective qualitative depictions. The present study uses a porcine model to present the first quantitative analysis of the distal cardiac conduction system and the first reported change in the spatial distribution of PCs in three representative stages of MI: an acute model both with and without reperfusion; a subacute model one week after reperfusion; and a chronic model one month after reperfusion. Purkinje cells are able to survive after 90 minutes of ischemia and subsequent reperfusion to a greater extent than cardiomyocytes. A decrease is observed in the number of PCs, which suffer reversible subcellular alterations such as cytoplasm vacuolization, together with redistribution from the mesocardium—the main localization of PCs in the heart of ungulate species—towards the endocardium and perivascular epicardial areas. However, these changes mainly occur during the first week after ischemia and reperfusion, and are maintained in the chronic stages. This anatomical substrate can explain the effectiveness of endo-epicardial catheter ablation of monomorphic ventricular tachycardias in the chronic scar after infarction, and sets a basis for further electrophysiological and molecular studies, and future therapeutic strategies.

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<![CDATA[Serum Axl predicts histology-based response to induction therapy and long-term renal outcome in lupus nephritis]]> https://www.researchpad.co/product?articleinfo=5c6b261bd5eed0c484289315

Axl is a receptor tyrosine kinase with important functions in immune regulation. We investigated serum levels of soluble (s)Axl in lupus nephritis (LN) in association with renal disease activity, tissue damage and treatment response. We surveyed 52 patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III/IV LN and 20 healthy controls. Renal biopsies were performed at the time of active LN and post-treatment. Patients were classified as clinical responders (CRs) or clinical non-responders based on the American College of Rheumatology (ACR) criteria. Improvement by ≥50% in renal activity index scores defined histological responders (HRs). sAxl levels were elevated in patients compared to controls (median: 18.9 ng/mL), both at baseline (median: 45.7; P<0.001) and post-treatment (median: 41.2 ng/mL; P<0.001). Baseline sAxl levels were higher in patients with class IV (median: 47.7 ng/mL) versus class III (median: 37.5 ng/mL) nephritis (P = 0.008), and showed moderate correlations with albuminuria (r = 0.30, P = 0.030) and creatinine (r = 0.35, P = 0.010). Baseline sAxl levels decreased in CRs (P = 0.002) and HRs (P<0.001), but not in non-responders; levels ≥36.6 ng/mL yielded a >5 times higher probability of histology-based response (odds ratio, OR: 5.5; 95% confidence interval, CI: 1.2–25.1). High post-treatment sAxl levels were associated with worsening in chronicity index scores (P = 0.025); low levels predicted favourable renal outcome (creatinine ≤88.4 μmol/L) 10 years after the baseline renal biopsy (area under the curve: 0.71; 95% CI: 0.54–0.89). In conclusion, sAxl may prove useful as a marker of renal activity, histological response to immunosuppression, and renal damage progression in LN. Persistently high sAxl levels after completion of treatment may be indicative of a need for treatment intensification.

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<![CDATA[Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats]]> https://www.researchpad.co/product?articleinfo=5c67306cd5eed0c484f37ad3

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 μg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.

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<![CDATA[CENPE expression is associated with its DNA methylation status in esophageal adenocarcinoma and independently predicts unfavorable overall survival]]> https://www.researchpad.co/product?articleinfo=5c61e918d5eed0c48496f7f8

Centrosome-associated protein E (CENPE) is a plus end-directed kinetochore motor protein, which plays a critical role in mitosis. In this in silico study, using data from the Cancer Genome Atlas-Esophageal Carcinoma (TCGA-ESCA), we analyzed the expression profile of CENPE mRNA in esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EA), its independent prognostic value and the potential mechanisms of its dysregulation in EA. Results showed that both ESCC and EA tissues had significantly elevated CENPE expression compared with their respective adjacent normal tissues. However, Kaplan-Meier survival curves showed that high CENPE was associated with unfavorable OS in EA. Univariate and multivariate analysis confirmed that CENPE expression was an independent indicator of unfavorable OS in EA patients, as a continuous variable (HR: 1.861, 95%CI: 1.235–2.806, p = 0.003) or as categorical variables (HR: 2.550, 95%CI: 1.294–5.025, p = 0.007). However, CENPE expression had no prognostic value in ESCC. Compared with the methylation status in normal samples, 3 CpG sites were hypomethylated (cg27388036, cg27443373, and cg24651824) in EA, among which two sites (cg27443373 and cg24651824) showed moderately negative correlation with CENPE expression. In addition, we also found that although heterozygous loss (-1) was frequent in EA (50/88, 56.8%), it was not necessarily associated with decreased CENPE expression compared with the copy neutral (0) cases. The methylation of the -1 group was significantly lower than that of the +1/0 group (p = 0.04). Based on these findings, we infer that CENPE upregulation in EA might serve as a valuable indicator of unfavorable OS. The methylation status of cg27443373 and cg24651824 might play a critical role in modulating CENPE expression.

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<![CDATA[Anatomical location-based nodal staging system is superior to the 7th edition of the American Joint Committee on Cancer staging system among patients with surgically resected, histologically low-grade gastric cancer: A single institutional experience]]> https://www.researchpad.co/product?articleinfo=5c63395fd5eed0c484ae6576

Background

A hybrid topographic and numeric lymph node (LN) staging system for gastric cancer, which was recently proposed by Japanese experts as a simple method with a prognostic predictive power comparable to the N staging of the American Joint Committee on Cancer (AJCC) Tumor-node-metastasis classification, has not yet been validated in other Asian countries. This study aimed to examine the prognostic predictability of the hybrid staging system with the current AJCC staging system in gastric cancer.

Methods

Overall, 400 patients with gastric cancer who underwent surgery at Changhua Christian Hospital from January 2007 to December 2017 were included in the study. Univariate and multivariate analyses were performed to identify prognostic factors for gastric cancer-related death. Homogeneity and discrimination abilities of the two staging systems were compared using likelihood ratio chi-square test, linear trend chi-square test, Harrell’s c-index, and bootstrap analysis.

Results

One-third of the LN-positive patients were reclassified into the new N and Stage system. The concordance rates of the two staging systems and the N staging between the two staging systems were 0.810 and 0.729, respectively. Harrell’s c-indices for the stage and N staging were higher in the 7th AJCC staging system than the hybrid staging system (c-index for stage, 0.771 vs 0.764; c-index for nodal stage, 0.713 vs 0.705). Stratification of the patients according to the histological grade revealed that Harrell’s c-indices for the stage and N stage of the hybrid staging system were comparable with those of the 7th AJCC staging system (c-index for AJCC stage vs hybrid stage, 0.800 vs 0.791; c-index for AJCC N stage vs hybrid N stage, 0.746 vs 0.734) among patients with histologically lower grade gastric cancer. The performance of the new nodal staging system was better than that of the 7th AJCC staging system by likelihood ratio and linear trend tests and bootstrap analysis in the low-grade group.

Conclusions

The hybrid anatomical location-based classification may have better prognostic predictive ability than the 7th AJCC staging system for LN metastasis of low-grade gastric cancer. Further studies involving different ethnic populations are necessary for the validation of the new staging system.

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<![CDATA[Medieval mummies of Zeleny Yar burial ground in the Arctic Zone of Western Siberia]]> https://www.researchpad.co/product?articleinfo=5c79afdad5eed0c4841e3874

Notwithstanding the pioneering achievements of studies on arctic mummies in Siberia, there are insufficient data for any comprehensive understanding of the bio-cultural details of medieval people living in the region. In the Western Siberian arctic, permafrost mummies have been found in 12th to 13th century graves located in the Zeleny Yar (Z-Y) burial ground (66°19'4.54"С; 67°21'13.54"В). In 2013–2016, we were fortunate to be able to excavate that cemetery, locating a total of 47 burials, including cases of mummification. Some of these mummies had been wrapped in a multi-layered birch-bark cocoon. After removal of the cocoon, we conducted interdisciplinary studies using various scientific techniques. Gross anatomical examination and CT radiography showed that the internal organs were still well preserved inside the body cavities. Under light and electron microscopy, the histological findings were very similar to those for naturally mummified specimens discovered in other countries. Ancient DNA analysis showed that the Z-Y mummies’ mtDNA haplotypes belong to five different haplogroups, namely U5a (#34), H3ao (#53), D (#67–1), U4b1b1 (#67–2), and D4j8 (#68), which distinguish them for their unique combination of Western- and Eastern Siberia-specific mtDNA haplogroups. Our interdisciplinary study obtained fundamental information that will form the foundation of successful future investigations on medieval mummies found in the Western Siberian arctic.

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<![CDATA[The findings of optical coherence tomography of retinal degeneration in relation to the morphological and electroretinographic features in RPE65−/− mice]]> https://www.researchpad.co/product?articleinfo=5c59ff13d5eed0c484135aa6

Purpose

Mutations of the gene encoding RPE65 cause Leber congenital amaurosis (LCA) retinitis pigmentosa (RP). The optical coherence tomography (OCT) is increasingly utilized to noninvasively evaluate various types of retinal diseases, including RP. The present study was conducted to characterize the OCT findings of the RPE65−/− mice—an animal model of LCA and RP—in relation to the morphological features based on histological and electron microscopic findings as well as electroretinography (ERG) features.

Materials and methods

RPE65−/− mice were employed as a model of retinal degeneration. C57BL/6J mice were used as a wild-type control. OCT was performed on the RPE65−/− mice from postnatal day (P) 22 to 170. The longitudinal changes in the OCT images and fundus pictures were analyzed both qualitatively and quantitatively in comparison to those of C57BL/6J mice. The OCT images were also compared to the histological and electron microscopic findings. Full field combined rod and cone ERG was performed to analyze the relationship between morphology based on OCT and the amplitudes of the a- and b-waves.

Results

In the RPE65−/− mice, the photoreceptor rod and cone layer appeared as a diffuse hyperreflective zone contiguous with the inner segment ellipsoid zone (IS-EZ) on OCT, even on P22, whereas the IS-EZ and interdigitation zone were clearly identified in the age-matched C57BL/6J mice. The histological analyses revealed that the regular arrangement of the photoreceptor inner and outer segments was gradually lost in the RPE65-/- mice. On electron microscopy, most of the rod outer segments were degenerated from P21 to P35, whereas outer segments became variably shorter after P49 although ultrastructure appeared to normalize. The thickness of the outer nuclear layer of RPE65−/− mice was slowly and progressively reduced in comparison to C57BL/6J mice. Although the thickness of the inner and outer segment layer of RPE65−/− mice was significantly decreased in comparison to C57BL/6J mice, the change was not progressive, at least until P170. Even at P35, the amplitudes of both a- and b-waves on ERG were severely deteriorated in comparison to those of C57BL/6J mice. Mottled depigmented spots appeared throughout the fundus in RPE65−/− mice after P72, and were detected as hyperreflective deposits under the retinal pigment epithelium on OCT.

Discussion

The pathological changes in the inner and outer segments layer of RPE65−/− mice were identified as diffuse hyperreflective changes on OCT. The rod outer segments showed degeneration in the early postnatal periods but became morphologically normalized in the disc structure after P49, although the sizes of the length of the rod outer segments were variable. OCT could not qualitatively differentiate the early degeneration of rods from the late variability in size of rods. Although the morphology of the photoreceptor outer segments was relatively preserved in the RPE65−/− mice, the amplitudes of ERG were severely disturbed. These structural and functional deficits may be derived from the defective supply of 11-cis-retinol to the photoreceptors.

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