Summary CD70 is up-regulated in several malignancies, where it induces cytotoxic effects on B and T lymphocytes, leading to immune escape. Novel therapeutic agents targeting CD70 have entered ...clinical trials. We characterized expression of CD70 protein in renal cell carcinoma specimens of various histologic subtypes and assessed their prognostic value and association with clinical/pathologic variables. We used tissue microarrays containing 330 cases using a novel fluorescent immunohistochemistry-based method of Automated Quantitative Analysis of in situ protein expression. The mean expression of CD70 was almost twice as high in tumors relative to normal tissue ( P < .0001). When broken into subsets, CD70 was higher in sarcomatoid and clear cell tumors ( P < .0001) and was variably elevated in oncocytomas and some papillary tumors. No association was found between CD70 expression and stage or grade. High CD70 expression was associated with decreased survival on univariate analysis in the clear cell subset of renal cell carcinoma; however, it did not retain significance on multivariate analysis. Given the elevated expression of CD70 in clear cell, sarcomatoid, and some papillary tumors, our findings suggest that CD70 might be a good drug target in renal cell carcinoma. Additional studies are warranted to assess the association between expression of CD70 and response to therapy with CD70-targeting drugs in renal cell carcinoma.
Summary Background Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with ...untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). Methods In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov , number NCT02085070. Findings Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3–4 adverse events were grade 3 elevated aminotransferases (n=1 6%) in the melanoma cohort, and grade 3 colitis (n=1 6%), grade 3 pneumonitis (n=1 6%), grade 3 fatigue (n=1 6%), grade 4 hyperkalemia (n=1 6%), and grade 2 acute kidney injury (n=1 6%) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1–2 seizures (n=3 17%) in the melanoma cohort. Interpretation Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.
Highlights • When children go to sleep has been demonstrated to be important for their physical health, but this relationship has not been examined for other important outcomes such as child ...learning, cognition, behaviour and parent mental health • Cross-sectionally, late-to-sleep timing is a driver of children's quality of life and maternal depression, especially when children at aged 6-7 years • Longitudinally, there is a cumulative and adverse association between late-to-sleep profiles and poorer child and maternal outcomes at age 8-9 years
Background
In the present study, we examined the effect of a two‐herb traditional Chinese medicine (NF3), comprised of Astragali Radix and Radix Rehmanniae, on the healing of diabetic foot ulcer and ...the possible molecular mechanisms involved.
Methods
This was a prospective randomized double‐blind placebo‐controlled study. Sixteen diabetic patients were randomized to receive either placebo or NF3 for 6 months. Ulcer healing and sensory changes were examined. Molecular studies included measurement of serum tumor necrosis factor (TNF)‐α and RNA microarray investigation.
Results
The daily rate of reduction in ulcer area was 3.55% in the NF3 group and 1.52% in the placebo group (P = 0.062). In the index limb, the number of negative tests for sensory neuropathy using monofilament was reduced from 27% to 7% in the NF3 group and from 37% to 35% in the placebo group (P < 0.001). In addition, NF3 significantly decreased serum TNF‐α levels (P = 0.034). Microarray studies revealed concerted changes following NF3 treatment in the expression of genes implicated in fibroblast regeneration, angiogenesis, and anti‐inflammation.
Conclusions
In this proof‐of‐concept study, 6‐month treatment with NF3 was associated with improved wound healing and sensation accompanied by concerted changes in gene expression.
摘要
背景
在本研究中，我们调查了包括两种传统草本中药（包含黄芪与地黄）的配方（NF3）对糖尿病足部溃疡的治疗作用，探讨其中可能存在的分子学机制。
方法
这是一项前瞩性随机双盲安慰剂对照研究。16名糖尿病患者随机化之后分别接受安慰剂或者NF3治疗6个月。我们调查了患者的溃疡愈合以及感觉变化情况。分子学方面的研究包括血清肿瘤坏死因子（TNF）‐α的测定以及RNA微阵列研究。
结果
在NF3组与安慰剂组中每日的溃疡面积缩小率分别为3.55%与1.52%（P = 0.062）。使用单纤丝检测患肢的感觉神经病变，测试结果为阴性的患者比例在NF3组中从27%降到了7%，而安慰剂组从37%降到了35%（P < 0.001）。另外，NF3可以显著地降低血清TNF‐α水平（P = 0.034）。微阵列研究结果显示，使用NF3治疗后与成纤维细胞再生、血管生成以及抗炎作用相关的基因表达出现了一致的变化。
结论
在这项验证概念的研究中，6个月的NF3治疗与患者的创伤愈合以及感觉神经病变的改善相关，伴随着与之对应的相关基因表达的变化。
Testicular volume measurements obtained with the Prader and Rochester orchidometers were compared to those obtained using scrotal ultrasound. The ability of each orchidometer versus ultrasound in ...detecting volume differential between 2 testes and the accuracy of orchidometer measurement by a less experienced examiner to that of a urologist were compared.
A total of 65 males were examined by the attending urologist and urology nurse using the Prader and Rochester orchidometers, and scrotal ultrasound was subsequently performed by an attending radiologist. Statistical analysis of the results was performed to determine the correlation of orchidometer measurements between examiners, as well as with ultrasound, and sensitivity and specificity of orchidometer and ultrasound in detecting defined volume differentials between testes of 10%, 15%, 20% and 25%.
There was a strong linear relationship between testicular volume measurements using either orchidometer and ultrasound. To detect a defined volume differential as determined by ultrasound orchidometer sensitivity was weak, whereas orchidometer specificity was better. There was a strong correlation between orchidometer measurements of the urology nurse and attending urologist.
Although the orchidometer remains valuable in assessing size of the individual testis, it is too insensitive to volume differentials relative to ultrasound to be used routinely to determine growth impairment. For this reason observation of an adolescent with varicocele should include an annual ultrasound assessment of testicular volume.
The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection ...in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams.
Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020.
Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6–15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79–104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease.
SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.
A second-harmonic TE21 gyrotron traveling-wave tube (gyro-TWT) amplifier with an axis-encircling electron beam is being constructed at the University of California-Davis that is predicted to double ...the efficiency of our previous 12%-efficient magnetron injection gun (MIG) TE(2)21 gyro-TWT. Both devices employ a sliced mode-selective circuit to suppress the odd-order azimuthal modes. The new device will avoid the loss in efficiency that is due to off-axis electrons interacting with the resulting linearly polarized mode. The amplifier is predicted by our large signal code to produce 50 kW in Ka-band with 20% efficiency, 30 dB saturated gain, and 3% bandwidth. The 70-kV 3.5-A axis-encircling electron beam with v perpendicular/vz = 1.2 and deltavz /vz = 7% will be produced by a Cusp electron gun delivered by Northrop Grumman. The amplifier has been designed using linear theory to provide a 30% safety margin from absolute instability. Distributed loss is added to the first 30.5 cm of the circuit to ensure the device is stable to harmonic gyro-BWO. The last 11.5 cm of the circuit is standard copper to avoid attenuating the wave at high power levels.
Island populations are an interesting dichotomy in conservation biology. On the one hand, they can be a refuge for species where mainland populations have been decimated by loss of habitat and ...predation by exotic predators. On the other hand, island populations usually have reduced genetic diversity and are more susceptible to extinction through genetic and demographic processes. Genetic variation and morphological characters were measured for island and mainland populations of Parantechinus apicalis, small dasyurid marsupials, restricted to southwest Australia. Genetic variation at seven microsatellite loci revealed low levels of heterozygosity (He = 0.20−0.44) and high levels of inbreeding (Fe = 0.40−0.72) in island populations compared with the mainland population (He = 0.73). A nested clade analysis revealed that allopatric fragmentation was probably responsible for the association between geographical location and control region haplotypes, which is consistent with the isolation of populations on islands and indicative of two main populations of P. apicalis representing separate conservation units for management. While these results are typical of many island populations, they have important implications in terms of the conservation of threatened species in Australia and around the world, where island populations are a common source of founders for captive breeding and translocation to mainland sites.
Objectives To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including ...known CF modifiers SLC26A9 , SLC6A14 , and SLC9A3 , would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels. Study design NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9 , SLC6A14 , and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT. Results In the Colorado sample, 3 SLC26A9 SNPs were associated with NBS IRT (min P = 1.16 × 10−3 ; rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated ( P > .05). The rs7512462 association replicated in the Wisconsin sample ( P = .03) but not in the French sample ( P = .76). Furthermore, rs7512462 was the top-ranked apical membrane constituent in the combined Colorado and Wisconsin sample. Conclusions NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This work suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease.
Low mass ambient exposure to airborne particles is associated with atherothrombotic events that may be a consequence of the combustion-derived nanoparticle content. There is concern also over the ...potential cardiovascular impact of manufactured nanoparticles. To better understand the mechanism by which toxic airborne particles can affect cardiovascular function we utilised zebrafish as a genetically tractable model. Using light and confocal fluorescence video-microscopy, we measured heart-rate and blood flow in the dorsal aorta and caudal artery of zebrafish larvae that had been exposed to a number of toxic and non-toxic microparticles and nanoparticles. Diesel exhaust particles (DEP), carboxy-charged Latex beads (carboxy-beads) and toxic alumina (Taimicron TM300), but not non-toxic alumina (Baikalox A125), were found to promote both skin and gut cell damage, increased leukocyte invasion into the epidermis, tail muscle ischaemia and haemostasis within the caudal artery of free swimming zebrafish larvae. The presence of sodium sulfite, a reducing agent, or warfarin, an anticoagulant, within the system water abrogated the effects of both toxic alumina and carboxy-beads but not DEP. Genetic manipulation of skin barrier function augmented skin damage and haemostasis, even for the non-toxic alumina. The toxic effects of carboxy-beads were still apparent after leukocyte numbers were depleted with anti-Pu.1 morpholino. We conclude that particle uptake across skin epithelium and gut mucosal barriers, or the presence of leukocytes, is not required for particle-induced haemostasis while a compromised skin barrier function accentuated tissue injury and haemostasis.
PDF
