Cardiac allograft vasculopathy (CAV) is a transplant pathology, limiting graft survival after heart transplantation. CAV arteries are surrounded by ectopic lymphoid structures (ELS) containing B ...cells and plasma cells. The aim of this study was to characterize the antigenic targets of antibodies produced in ELS. Coronary arteries and surrounding epicardial tissue from 56 transplant recipients were collected during autopsy. Immunofluorescence was used to identify antibody‐producing plasma cells. Immunoglobulin levels in tissue lysates were measured by enzyme‐linked immunosorbent assay and analyzed for donor‐specific HLA antibodies by Luminex assay. Cytokine and receptor expression levels were quantified using quantitative polymerase chain reaction. Plasma cells in ELS were polyclonal and produced IgG and/or IgM antibodies. In epicardial tissue, IgG (p < 0.05) and IgM levels were higher in transplant patients with larger ELS than smaller ELS. In 4 of 21 (19%) patients with ELS, donor‐specific HLA type II antibodies were detected locally. Cytokine and receptor expression (CXCR3, interferon γ and TGF‐β) was higher in large ELS in the epicardial tissue than in other vessel wall layers, suggesting active recruitment and proliferation of T and B lymphocytes. ELS exhibited active plasma cells producing locally manufactured antibodies that, in some cases, were directed against the donor HLA, potentially mediating rejection with major consequences for the graft.
Ectopic lymphoid structures surrounding coronary arteries with allograft vasculopathy contain high levels of antibodies directed, in part, toward donor HLA class II.
Background
Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer ...categorizes tumours into four robust subtypes, which could guide subtype‐targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study.
Methods
Fresh‐frozen tissue samples from primary colorectal cancer and paired peritoneal metastases from patients who underwent cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy were collected. Histopathological features were analysed, and a reverse transcriptase–quantitative PCR test was used to assess CMS4 status of all collected lesions.
Results
Colorectal peritoneal carcinomatosis was associated with adverse histopathological characteristics, including a high percentage of stroma in both primary tumours and metastases, and poor differentiation grade and high‐grade tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched in primary tumours with peritoneal metastases, compared with unselected stage I–IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The majority of peritoneal metastases (75 per cent, 21 of 28) were also classified as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 15 of 16 patients with paired tumours had at least one CMS4‐positive tumour location.
Conclusion
Significant enrichment for CMS4 was observed in colorectal peritoneal carcinomatosis.
Surgical relevance
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC) improves survival of selected patients with colorectal peritoneal carcinomatosis, but recurrence is common. Histopathological and molecular analysis of colorectal peritoneal carcinomatosis could provide clues for development of novel therapies.
In this study, colorectal peritoneal carcinomatosis was found to be enriched for tumours with high stromal content and CMS4‐positive status.
To further improve prognosis for patients with colorectal peritoneal carcinomatosis, therapies that target tumour–stroma interaction could be added to CRS‐HIPEC.
Mesenchymal subtype predominates
The stromal vascular fraction (SVF) of adipose tissue contains an abundant population of multipotent adipose-tissue-derived stem cells (ASCs) that possess the capacity to differentiate into cells of ...the mesodermal lineage in vitro. For cell-based therapies, an advantageous approach would be to harvest these SVF cells and give them back to the patient within a single surgical procedure, thereby avoiding lengthy and costly in vitro culturing steps. However, this requires SVF-isolates to contain sufficient ASCs capable of differentiating into the desired cell lineage. We have investigated whether the yield and function of ASCs are affected by the anatomical sites most frequently used for harvesting adipose tissue: the abdomen and hip/thigh region. The frequency of ASCs in the SVF of adipose tissue from the abdomen and hip/thigh region was determined in limiting dilution and colony-forming unit (CFU) assays. The capacity of these ASCs to differentiate into the chondrogenic and osteogenic pathways was investigated by quantitative real-time polymerase chain reaction and (immuno)histochemistry. A significant difference (
P
= 0.0009) was seen in ASC frequency but not in the absolute number of nucleated cells between adipose tissue harvested from the abdomen (5.1 ± 1.1%, mean ± SEM) and hip/thigh region (1.2 ± 0.7%). However, within the CFUs derived from both tissues, the frequency of CFUs having osteogenic differentiation potential was the same. When cultured, homogeneous cell populations were obtained with similar growth kinetics and phenotype. No differences were detected in differentiation capacity between ASCs from both tissue-harvesting sites. We conclude that the yield of ASCs, but not the total amount of nucleated cells per volume or the ASC proliferation and differentiation capacities, are dependent on the tissue-harvesting site. The abdomen seems to be preferable to the hip/thigh region for harvesting adipose tissue, in particular when considering SVF cells for stem-cell-based therapies in one-step surgical procedures for skeletal tissue engineering.
To compare the effects of two free radical scavengers, dimethylsulfoxide 50% (DMSO) and N-acetylcysteine (NAC), for treatment of complex regional pain syndrome I (CRPS I), a randomized, double-dummy ...controlled, double-blind trial was conducted. Two outpatient clinics of two university hospitals in The Netherlands participated in the study and 146 patients, were included over a period of 24 months. Patients were randomized into two treatment groups, one was instructed to apply DMSO 50% five times daily to the affected extremity, the second was treated with NAC 600mg effervescent tablets three times daily, both combined with placebo. Interventions were accompanied by pain medication, occupational therapy for upper extremity CRPS I and physical therapy for lower extremity CRPS I in specific circumstances. Treatment was given for 17 weeks, with a possibility to continue or switch medication after this period, up to 1 year following the onset of treatment. An impairment level sum score was the primary outcome measure. Upper and lower extremity skills and functions, and general health status were also evaluated. Overall, no significant differences were found between NAC and DMSO after 17 and 52 weeks on impairment level and general health status. Significant differences were found for subscores of lower extremity function, in favor of DMSO-treatment. Subgroup analysis showed more favorable results for DMSO for warm CRPS I and significantly better performance of NAC for patients with a cold CRPS I. Results tended to be negatively influenced if the duration of the complaint was longer. Treatment with DMSO and NAC are generally equally effective in treatment of CRPS I. Strong indications exist for differences in effects for subgroups of patients with warm or cold CRPS I: for warm CRPS I, DMSO-treatment appears more favorable, while for cold CRPS I, NAC-treatment appears to be more effective.
Summary The purpose of the research was to evaluate postoperative complications, functional outcome and survival after salvage laryngectomy. Second, to evaluate the management of the neck in ...combination with a laryngectomy in this group of patients. A retrospective analysis of all patients who underwent total laryngectomy for residual or recurrent squamous cell laryngeal carcinoma after (chemo)radiotherapy between November 1990 and June 2007 was performed. Of the 120 patients that were included, the complication rate was 56% (33% major and 23% minor). In univariate analyses, T-stage ( p = 0.05), bilateral neck dissection ( p = 0.09) and ASA score ( p = 0.08) showed a trend for postoperative major complications. Lymph node metastases were found in 26% of the neck dissection specimens, with a trend towards more regional disease at higher initial N-stage ( p = 0.06) and T-stage ( p = 0.08). Five-year disease specific survival was 58%. In univariate analyses pre-operative chemoradiation (vs. radiation) ( p = 0.0001), N3 neck ( p = 0.001) and positive surgical margins ( p = 0.02) were significant predictors for a worse disease specific survival, but only positive surgical margins ( p < 0.001) maintained significance in multivariate analysis. Eighty-seven percent of the patients were able to produce speech using a voice prosthesis, and 84% of the patients were able to have a ‘normal’ or ‘soft’ diet. There was an almost significant increase in mean body mass index (BMI) 6–12 months postoperative ( p = 0.057). Laryngectomy after radiotherapy offers good survival, with a substantial risk of complications and good functional outcome.
The NASA
Perseverance
rover Mast Camera Zoom (Mastcam-Z) system is a pair of zoomable, focusable, multi-spectral, and color charge-coupled device (CCD) cameras mounted on top of a 1.7 m Remote ...Sensing Mast, along with associated electronics and two calibration targets. The cameras contain identical optical assemblies that can range in focal length from 26 mm (
25.5
∘
×
19.1
∘
FOV
) to 110 mm (
6.2
∘
×
4.2
∘
FOV
) and will acquire data at pixel scales of 148-540 μm at a range of 2 m and 7.4-27 cm at 1 km. The cameras are mounted on the rover’s mast with a stereo baseline of
24.3
±
0.1
cm and a toe-in angle of
1.17
±
0.03
∘
(per camera). Each camera uses a Kodak KAI-2020 CCD with
1600
×
1200
active pixels and an 8 position filter wheel that contains an IR-cutoff filter for color imaging through the detectors’ Bayer-pattern filters, a neutral density (ND) solar filter for imaging the sun, and 6 narrow-band geology filters (16 total filters). An associated Digital Electronics Assembly provides command data interfaces to the rover, 11-to-8 bit companding, and JPEG compression capabilities. Herein, we describe pre-flight calibration of the Mastcam-Z instrument and characterize its radiometric and geometric behavior. Between April 26
t
h
and May 9
t
h
, 2019, ∼45,000 images were acquired during stand-alone calibration at Malin Space Science Systems (MSSS) in San Diego, CA. Additional data were acquired during Assembly Test and Launch Operations (ATLO) at the Jet Propulsion Laboratory and Kennedy Space Center. Results of the radiometric calibration validate a 5% absolute radiometric accuracy when using camera state parameters investigated during testing. When observing using camera state parameters not interrogated during calibration (e.g., non-canonical zoom positions), we conservatively estimate the absolute uncertainty to be
<
10
%
. Image quality, measured via the amplitude of the Modulation Transfer Function (MTF) at Nyquist sampling (0.35 line pairs per pixel), shows
MTF
Nyquist
=
0.26
−
0.50
across all zoom, focus, and filter positions, exceeding the
>
0.2
design requirement. We discuss lessons learned from calibration and suggest tactical strategies that will optimize the quality of science data acquired during operation at Mars. While most results matched expectations, some surprises were discovered, such as a strong wavelength and temperature dependence on the radiometric coefficients and a scene-dependent dynamic component to the zero-exposure bias frames. Calibration results and derived accuracies were validated using a Geoboard target consisting of well-characterized geologic samples.
The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between HbA(1c) and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the ...association of several glucose variability indices and the MPG-HbA(1c) relationship.
Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-HbA(1c) relationship.
GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-HbA(1c) relationship in type 1 diabetic patients so that high GV led to a higher HbA(1c) level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the HbA(1c) level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency.
In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with HbA(1c). This effect is more pronounced at higher HbA(1c) levels. However, the impact of GV on the HbA(1c) level in type 1 diabetes is modest, particularly when HbA(1c) is close to the treatment target of 7%.
TP53 is a key gene in cellular homeostasis and is frequently mutated in head and neck squamous cell carcinoma (HNSCC). There is a variety of TP53 mutations, each with its own biological and clinical ...implication. Aim of the study was to assess the prognostic significance of TP53 mutations in HNSCCs and to identify the most relevant mutation.
TP53 mutation status was investigated in 141 consecutive HNSCCs treated by surgery with radiotherapy when indicated and with a known human papilloma virus status. The type of mutation was correlated with overall and progression-free survival in a multivariate two-sided Cox regression analysis with wild type as reference.
A TP53 mutation was found in 88 (62.4%) of the carcinomas and was not significantly associated with overall survival (HR = 1.65, P = 0.11). Patients with a mutation resulting in a truncated protein (n = 36, 25.5%) had a significantly worse overall survival (HR = 2.54, P = 0.008) and progression-free survival (HR = 2.65, P = 0.002). Four of these mutations were at a splice site, 13 were nonsense mutations (produces stop codon), and 19 were insertions or deletions resulting in a frameshift. After multivariate analysis, a truncating mutation remained a significant prognosticator. A missense (i.e., nontruncating) mutation did not influence prognosis. Other ways of classification (disruptive vs. nondisruptive, hotspot vs. nonhotspot, and DNA binding vs. non-DNA binding) were less discriminative.
In HNSCCs, a truncating TP53 mutation is associated with a poor prognosis. This patient group seems as a target population for adjuvant therapy with chemoradiation or viral vector-mediated TP53 gene transfer.
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