Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be ...representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).
Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of ...the MLH1 gene, characterized by soma‐wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss‐of‐heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation‐associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair–deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.
Summary
Background Our group recently reported a randomized and placebo‐controlled clinical trial on the efficacy of a twice‐daily concoction of five herbal ingredients (Pentaherbs formulation, PHF) ...in treating children with atopic dermatitis (AD).
Objectives To investigate the immunomodulatory effects that may be induced by PHF treatment.
Methods We investigated the effects of PHF on cytotoxicity and proliferation of phytohaemagglutinin (PHA)‐ and staphylococcal enterotoxin B (SEB)‐stimulated peripheral blood mononuclear cells (PBMC) isolated from buffy coat of blood donors. PHF‐induced immunomodulation for five inflammatory mediators in cultured PBMC was measured by reverse transcription–polymerase chain reaction and enzyme‐linked immunosorbent assay. The effects of a 3‐month, open‐label study of PHF on circulating inflammatory mediators in children with AD were also assessed.
Results PHF at up to 1 mg mL−1 dose‐dependently suppressed PBMC proliferation. The addition of PHF to cultured PBMC reduced supernatant concentrations of brain‐derived neurotrophic factor (BDNF), interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α in response to PHA, and BDNF and thymus and activation‐regulated chemokine (TARC) following SEB stimulation. PHF increased epithelial cell‐derived neutrophil activating peptide‐78 levels in culture supernatants. At the RNA level, PHF suppressed the transcription of BDNF, TARC, IFN‐γ and TNF‐α. Twenty‐eight children with AD were treated with PHF for 3 months, and their mean plasma concentrations of BDNF and TARC decreased significantly from 1798 pg mL−1 and 824 pg mL−1 at baseline to 1378 pg mL−1 and 492 pg mL−1 (P = 0·002 and 0·013, respectively) upon study completion.
Conclusions PHF possesses in vitro and in vivo immunomodulatory properties that may mediate the clinical efficacy observed in AD treatment.
Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma ...biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis.
In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio RR 1.7, 95% confidence interval CI 1.2%-2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%-2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%-0.8%).
The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma.
According to the general catalog of variable stars, AL Cas was classified as an EW-type eclipsing binary with a spectral type of B and an orbital period of P = 0.5005555 days. The first photometric ...light curves of the close binary in the B, V, R, and I bands are presented. New low-resolution spectra indicate that its spectral type is about F7 rather than B-type. A photometric analysis with the Wilson-Devinney method suggests that it is a contact binary (functionof = 39.3%) with a mass ratio of 0.61. Using 17 newly determined eclipse times together with those collected from the literature, we found that the observed-calculated (O - C) curve of AL Cas shows a cyclic change with a period of 86.6 yr and an amplitude of 0.0181 days. The periodic variation was analyzed for the light-travel time effect via the presence of a third body. The mass of the third body was determined to be M sub(3) sin i' = 0.29(+ or -0.05) M sub(middot in circle) when a total mass of 2.14 M sub(middot in circle) for AL Cas is adopted. It is expected that the cool companion star may have played an important role in the origin and evolution of the system by removing angular momentum from the central binary system during early dynamical interaction and/or late dynamical evolution. This causes the original detached system to have a low angular momentum and a short initial orbital period. Then it can evolve into the present contact configuration via a case A mass transfer.
Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal ...castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three
, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome.
depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently,
depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. SIGNIFICANCE: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
Objectives
The FlowTriever All‐Comer Registry for Patient Safety and Hemodynamics (FLASH) is a prospective multi‐center registry evaluating the safety and effectiveness of percutaneous mechanical ...thrombectomy for treatment of pulmonary embolism (PE) in a real‐world patient population (NCT03761173). This interim analysis reports outcomes for the first 250 patients enrolled in FLASH.
Background
High‐ and intermediate‐risk PEs are characterized by high mortality rates, frequent readmissions, and long‐term sequelae. Mechanical thrombectomy is emerging as a front‐line therapy for PE that enables immediate thrombus reduction while avoiding the bleeding risks inherent with thrombolytics.
Methods
The primary endpoint is a composite of major adverse events (MAE) including device‐related death, major bleeding, and intraprocedural device‐ or procedure‐related adverse events at 48 h. Secondary endpoints include on‐table changes in hemodynamics and longer‐term measures including dyspnea, heart rate, and cardiac function.
Results
Patients were predominantly intermediate‐risk per ESC guidelines (6.8% high‐risk, 93.2% intermediate‐risk). There were three MAEs (1.2%), all of which were major bleeds that resolved without sequelae, with no device‐related injuries, clinical deteriorations, or deaths at 48 h. All‐cause mortality was 0.4% at 30 days, with a single death that was unrelated to PE. Significant on‐table improvements in hemodynamics were noted, including an average reduction in mean pulmonary artery pressure of 7.1 mmHg (22.2%, p < 0.001). Patient symptoms and cardiac function improved through follow‐up.
Conclusions
These interim results provide preliminary evidence of excellent safety in a real‐world PE population. Reported outcomes suggest that mechanical thrombectomy can result in immediate hemodynamic improvements, symptom reduction, and cardiac function recovery.
Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations.
To determine the relationship ...between hypogammaglobulinemia and the risk of hospitalization in patients with COPD.
Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status.
The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001.
Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.
ZnO tetrapod nanowires were prepared by thermal evaporation of Zn in the flow of different carrier gases (argon, nitrogen, humidified argon and humidified nitrogen). The optical properties of the ...tetrapod nanowires were investigated by low-temperature photoluminescence measurements, reflectance measurements and X-ray photoelectron spectroscopy (XPS). It was found that the type of gas significantly affects the optical properties of the fabricated tetrapod nanowires. The origin of the differences in the photoluminescence spectra of tetrapod nanowires fabricated with different carrier gases is discussed. The addition of water vapor to the carrier gas affected the photoluminescence and XPS spectra for both N
2 and Ar carrier gases, and the changes observed in the XPS spectra indicated possible incorporation of hydrogen in these samples.
An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a ...wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (−)-amphidinolide K.
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