Aryl hydrocarbon receptor activation by diesel exhaust particles mediates epithelium-derived cytokines expression in severe allergic asthma.

BACKGROUND: Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium-derived thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma. METHODS: Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR-mediated IL-33, Il-25, and TSLP synthesis and release. RESULTS: Primary bronchial epithelial cells exposed to DEP showed upregulation of IL-33, IL-25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL-33, IL-25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL-33, IL-25, and TSLP. These patients derived clinical benefit from anti-IgE treatment. CONCLUSION: Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL-33, IL-25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.

Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only.

Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.

In situ investigation of the surface morphology evolution of the bulk ceramic Y2Mo3O12 during crystal water release.

The surface morphology evolution of the bulk ceramic Y2Mo3O12 during the release of crystal water is followed in situ for the first time using atomic force microscopy. It is found that both the shape and size of individual grains and the integration morphology of the sample exhibit dynamic changes with increasing temperature. We believe that the surface morphology evolution of the sample with increasing temperature is closely correlated with the forces induced by the contraction and expansion of the lattice during crystal water release in two different stages.

Consensus of German transplant centers on hematopoietic stem cell transplantation in Fanconi anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10-15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings.

Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes.

Peters plus syndrome (PPS) is a rare autosomal-recessive disorder characterized by Peters anomaly of the eye, short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable other systemic abnormalities. In this report, we describe screening of 64 patients affected with PPS, isolated Peters anomaly and PPS-like phenotypes. Mutations in the coding region of B3GALTL were identified in nine patients; six had a documented phenotype of classic PPS and the remaining three had a clinical diagnosis of PPS with incomplete clinical documentation. A total of nine different pathogenic alleles were identified. Five alleles are novel including one frameshift, c.168dupA, p.(Gly57Argfs*11), one nonsense, c.1234C>T, p.(Arg412*), two missense, c.1045G>A, p.(Asp349Asn) and c.1181G>A, p.(Gly394Glu), and one splicing, c.347+5G>T, mutations. Consistent with previous reports, the c.660+1G>A mutation was the most common mutation identified, seen in eight of the nine patients and accounting for 55% of pathogenic alleles in this study and 69% of all reported pathogenic alleles; while two patients were homozygous for this mutation, the majority had a second rare pathogenic allele. We also report the absence of B3GALTL mutations in 55 cases of PPS-like phenotypes or isolated Peters anomaly, further establishing the strong association of B3GALTL mutations with classic PPS only.

Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group study.

BACKGROUND: We evaluated the long-term results of radiotherapy for patients with gastric marginal zone lymphoma (GMZL). PATIENTS AND METHODS: We carried out a retrospective, multi-centre study of patients with low-grade GMZL treated by radiotherapy between 17 July 1981 and 25 March 2004. RESULTS: There were 102 eligible patients. Fifty-eight patients were previously untreated and 44 had recurrent/residual disease after prior treatment (HP eradication, chemotherapy and surgery in 35, 9 and 8 patients, respectively, and 7 had >1 prior therapy). Radiation fields included the stomach /involved nodes in 61 patients and whole abdomen in 41. The median radiotherapy dose to stomach was 40 Gy (range 26-46 Gy) in a median 22 fractions. With a median follow-up after radiotherapy of 7.9 years (range 0.3-24 years), 10- and 15-year freedom from treatment failure (FFTF) was 88% (95% CI 82%-95%). Risk factors for TF were a large-cell component (P = 0.036) and an exophytic growth pattern (P = 0.042). Radiotherapy field size, radiotherapy dose, and failure of prior therapy were not associated with inferior FFTF. Ten-year overall survival was 70% (95% CI 60%-82%). CONCLUSIONS: Radiotherapy achieves cure for the majority of patients with low-grade GMZL, including patients who have had prior therapy. Several features may predict a poorer outcome.

Decoherence cross-section in NO + Ar collisions: experimental results and a simple model.

Quantum decoherence can be viewed as the mechanism responsible for the quantum-to-classical transition as the initially prepared quantum state interacts with its environment in an irreversible manner. One of the most common mechanisms responsible for the macroscopically observed decoherence involves collisions of an atom or molecule, initially prepared in a coherent superposition of states, with gas particles. In this work, a coherent superposition of quantum internal states of NO molecules is prepared by the interaction between the molecule with both a static and a radiofrequency electric field. Subsequently, NO + Ar collision decoherence experiments are investigated by measuring the loss of coherence as a function of the number of collisions. Data analysis using a model based on the interaction potential of the collisional partners allowed to unravel the molecular mechanism responsible for the loss of coherence in the prepared NO quantum superposition of internal states. The relevance of the present work relies on several aspects. On the one hand, the use of radio-waves introduces a new way for the production of coherent beams. On the other hand, the employed methodology could be useful in investigating the Stereodynamics of chemical reactions with coherent reagents.

Nonadverse effects on allergenicity of isopentenyltransferase-transformed broccoli.

BACKGROUND: Genetically modified organisms (GMOs) provide modern agriculture with improvements in efficiency and the benefits of enhanced food production; however, the potential impact of GMOs on human health has not yet been clarified. OBJECTIVE: To investigate the allergenicity of isopentenyltransferase (ipt)-transformed broccoli compared with non-GM broccoli. METHODS: Sera from allergic individuals were used to identify the allergenicity of GM and non-GM broccoli. Immunoglobulin (Ig) binding of different lines of GM and non-GM broccoli was identified using immunoblotting, enzyme-linked immunosorbent assay, and the histamin release assay. RESULTS: Positive reactions to broccoli (Brassica Oleracea) were observed in 7.02% of individuals. Specific IgE to broccoli and total IgE fro allergic individuals were well correlated. The different tests performed showed no significant differences in the allergenicity of conventionally raised and GM broccoli, indicating the absence of unexpected effects on allergenicity in ipt-transformed plants. Using Western blot analysis we detected heterogeneous IgE-reactive allergenic components in broccoli-allergic sera, but no significant differences between GM an non-GM broccoli were observed in serum from the same patients. CONCLUSIONS: Our study demonstrates that there are no differences between GM (ipt-transformed) broccoli and non-GM broccoli, as determined by specific IgE in sera from broccoli-allergic patients. This indicates that there were no unexpected effects on allergenicity in this GM broccoli.

Risk factors of bone metastasis in patients with newly diagnosed prostate cancer.

OBJECTIVE: The current study aimed to explore the risk factors for bone metastasis (BMT) in patients with newly diagnosed prostate cancer (PCa). PATIENTS AND METHODS: The clinical data of 322 patients newly diagnosed with PCa following transrectal prostate biopsy at our hospital from October 2016 to March 2021 were analyzed. According to the results of whole-body bone emission computed tomography (ECT) scanning, patients were divided into the following two groups: bone metastasis group (BMT) and none-bone metastasis group (None-BMT). Univariate and multivariate logistic regression analyses were performed to assess the BMT-related factors associated with PCa. A receiver operating characteristic curve was also used to compare the diagnostic value of total prostate-specific antigen (TPSA), prostate-specific antigen density (PSAD), Gleason score and alkaline phosphatase (ALP) for prostate cancer bone metastasis (PCBM). RESULTS: The results revealed that the incidence of BMT in newly diagnosed patients with PCa was ~22.05% (71/322). Univariate analysis demonstrated that Gleason score, clinical T stage, TPSA, PSAD and ALP were associated with PCBM (p<0.001). Furthermore, the results of multivariate regression analysis revealed that TPSA, PSAD, Gleason score and ALP were independent risk factors for BMT (p <0.05). The cutoff values for TPSA, PSAD, ALP and Gleason score were 39.58 ng/ml, 1.489 ng/(ml/cm3), 93.15 U/l and 7.5, respectively. Additionally, the respective sensitivities for TPSA, PSAD, ALP and Gleason score were 67.6, 62.0, 57.7 and 46.5%, and the respective specificities were 88.4, 98.0, 100 and 98.8%. CONCLUSIONS: The current study determined that TPSA, PSAD, Gleason score and ALP were predictors of PCBM. In patients with PSA levels >39.58 ng/ml, PSAD levels >1.489 ng/(ml/cm3), Gleason scores >7.5 and ALP levels >91.0 U/l, a whole-body bone ECT scan is recommended.

Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis.

A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

Quality, proximate composition, and sensory characteristics of Dorper, domestic commercial crossbred, and Australian sheep meat: a comparative study.

The objective of this study was to compare the proximate, quality, and sensory attributes of Dorper sheep meat (Dorper), domestic commercial crossbred (DCC) and Australian commercial crossbred (ACC). A total of 60 untrimmed loins from the three sheep sources were purchased (20 sheep loins/source) and processed. The objective color, objective tenderness [Warner-Bratzler Shear Force (WBSF)], and proximate composition of the sheep meat were evaluated. A consumer panel and a trained sensory panel were also conducted to evaluate the sensory attributes. Dorper had greater (P = 0.04) carbohydrate content compared to DCC, but was not (P = 0.86) different from ACC. In addition, Dorper had the greatest WBSF value, followed by DCC, with ACC having the least WBSF out of the three (P < 0.0001). For the consumer panel, Dorper was rated to be less tender than ACC (P = 0.01), but was not different from DCC (P = 0.76). Dorper was also rated with lower flavor acceptability compared to DCC (P = 0.02), but was not different from ACC (P = 0.86). In addition, Dorper had the lowest overall acceptance rating by the consumers (P = 0.01). Trained sensory panel results followed the same trend as the consumer panel results which rated Dorper to be less tender than ACC (P = 0.002), but was not different from DCC (P = 0.10). Dorper was also rated with greater off-flavor intensity compared to DCC (P = 0.009), but was not different from ACC (P = 0.53). Finally, no differences were found for all other attributes evaluated among the sheep sources. The results indicated that consumers did not prefer Dorper over ACC and DCC. However, additional research with a more controlled environment is needed to shed light on the true palatability traits of Dorper.

A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon.

A number of recent studies have demonstrated that cellular responses to tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF receptors are distinct. To evaluate the relative in vivo toxicities of wild-type TNF alpha (wtTNF alpha) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sp.) were infused with a near-lethal dose of either wtTNF alpha or a TNF alpha double mutant (dmTNF alpha) that binds specifically to the p55, but not to the p75, TNF receptor. Both wtTNF alpha and dmTNF alpha produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wtTNF alpha produced a marked granulocytosis and loss of granulocyte TNF receptors, whereas little if any changes in neutrophil number or cell surface TNF receptor density were seen after dmTNF alpha mutant administration. Infusion of dmTNF alpha resulted in a plasma endogenous TNF alpha response that peaked after 90-120 min. We conclude that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.

H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype.

BACKGROUND: About 1-5% of cancer patients suffer from significant normal tissue reactions as a result of radiotherapy (RT). It is not possible at this time to predict how most patients' normal tissues will respond to RT. DNA repair dysfunction is implicated in sensitivity to RT particularly in genes that mediate the repair of DNA double-strand breaks (DSBs). Phosphorylation of histone H2AX (phosphorylated molecules are known as gammaH2AX) occurs rapidly in response to DNA DSBs, and, among its other roles, contributes to repair protein recruitment to these damaged sites. Mammalian cell lines have also been crucial in facilitating the successful cloning of many DNA DSB repair genes; yet, very few mutant cell lines exist for non-syndromic clinical radiosensitivity (RS). METHODS: Here, we survey DNA DSB induction and repair in whole cells from RS patients, as revealed by gammaH2AX foci assays, as potential predictive markers of clinical radiation response. RESULTS: With one exception, both DNA focus induction and repair in cell lines from RS patients were comparable with controls. Using gammaH2AX foci assays, we identified a RS cancer patient cell line with a novel ionising radiation-induced DNA DSB repair defect; these data were confirmed by an independent DNA DSB repair assay. CONCLUSION: gammaH2AX focus measurement has limited scope as a pre-RT predictive assay in lymphoblast cell lines from RT patients; however, the assay can successfully identify novel DNA DSB repair-defective patient cell lines, thus potentially facilitating the discovery of novel constitutional contributions to clinical RS.

An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.

Vertebral Fractures Following Stereotactic Body Radiotherapy for Spine Oligometastases: A Multi-institutional Analysis of Patient Outcomes.

AIMS: Stereotactic body radiotherapy (SBRT) is a locally ablative therapy used for the treatment of patients with spine metastases. However, it is associated with higher rates of vertebral compression fractures (VCF) than conventionally fractionated palliative radiotherapy. The purpose of this study was to determine the rate of VCF following spine SBRT and to identify the risk factors associated with this outcome. MATERIALS AND METHODS: We retrospectively reviewed patients treated at two Australian institutions from January 2015 to March 2019. Descriptive statistics were used to assess patient, tumour and treatment factors. The Log-rank test and Cox proportional hazards model were applied in univariate and multivariable analyses to identify factors associated with VCF, local control and overall survival. RESULTS: We evaluated 113 spinal segments from 84 patients, with a median follow-up time of 11.9 months. The median dose and fractionation utilised was 30 Gy in three fractions (67.3%), with a single-fraction rate of 0.9%. The median Spinal Instability Neoplastic Score (SINS) of the lesions was 4/18, with most (84.1%) being SINS stable, scoring between 0 and 6. Five VCFs were observed (three progression of pre-existing fractures and two de novo), a cumulative VCF risk of 4.4%. Four of five fractures occurred within the first year after treatment, with a median time to VCF of 9.2 months. A pre-existing VCF (P = 0.011) was associated with subsequent fracture on multivariable analysis, whereas all VCF segments displayed lytic disease appearance. All fractures were managed conservatively with analgesia, without requirement for subsequent surgical intervention. CONCLUSION: SBRT to spine metastases is safe with respect to VCF, with rates around the lower limit observed in similar studies. Knowledge of factors that predispose to post-treatment fracture, such as pre-existing compression, lytic vertebral disease and SINS >6 will aid in the counselling and selection of patients for this therapy.

A preliminary investigation of the contribution of different tenderness factors to beef loin, tri-tip and heel tenderness.

The objective of this study was to identify the relative contribution of tenderness factors for three beef muscles with similar tenderness ratings. Longissimus lumborum (LL), tensor fascia latae (TF) and gastrocnemius (GC) were collected from 10 USDA low Choice beef carcasses and assigned to a 5 or 21 days aging period (n = 60). Sarcomere length, troponin-T degradation, collagen content, mature collagen crosslink density, intramuscular lipid content and trained panel analysis were measured. Correlation and multivariate regression analysis indicated each muscle has a specific tenderness factor that contributed to the overall tenderness evaluated by trained panelists. The equations indicated LL tenderness was driven by lipid content (P < .05); TF tenderness was driven by collagen content (P < .05). GC tenderness was driven by proteolysis (P < .01), and only collagen content can be casually used as an overall tenderness predictor for all three cuts.

Characterizing membrane phospholipid hydrolysis of pork loins throughout three aging periods.

Three chops from 20 pork carcasses were aged for 1, 8, and 21 days. Electrospray ionization-tandem mass spectrometry was used to comprehensively analyze profiles of phospholipids from each sample (n = 60). Total phospholipid quantity decreased 4-folds (P < .01) from 1 to 21 days of aging in pork loins. Phosphatidylinositol (PI) and phosphatidylserine (PS) increased by 30% and 73%, respectively, from 1 to 21 days of aging in pork loins (P < .01). This increase was mainly due to relative percentage increase from PI 38:4 (18:0-20:4) and PS 36:2 (18:0-18:2; P < .01). The results also showed that the relative percentage of lysophosphatidylcholine increased by 35% after short term aging (8d), and phosphatidic acid increased by 10-folds after extended aging (21d; P < .01). These results documented that phospholipids undergo enzymatic hydrolysis during aging, but also indicated that lipid species containing 18:2 or 20:4 within PI and PS were slightly more resistant to enzymatic hydrolysis compared with the other phospholipids.

Assessment of Intrafraction Motion of the Urinary Bladder Using Magnetic Resonance Imaging (cineMRI).

AIM: To assess the intrafraction motion of the urinary bladder and delineate the appropriate margin size for radiotherapy planning, for both the full and empty bladder. MATERIALS AND METHODS: This was a single-site, single-arm study of 20 patients planned to undergo radical cystectomy for histologically confirmed muscle-invasive bladder cancer. Patients underwent magnetic resonance imaging (cineMRI) of the entire pelvis using a 3-Tesla system, prior to cystectomy. Patients first underwent a cineMRI with a full bladder, then voided and underwent a second MRI with an empty bladder. All MRI sequences were acquired over 18 min. We assessed the differences in bladder filling and subsequent bladder wall displacement, between the empty and full bladder, during a time period consistent with radiotherapy treatment delivery. RESULTS: Twenty patients underwent cineMRI of the entire pelvis. The maximum mean directional displacements of the bladder walls over the 18 min duration of the scan for the empty bladders were 9.8 mm superiorly, 1.1 mm inferiorly, 2.39 mm anteriorly, 3.73 mm posteriorly, 2.74 mm to the left and 2.48 mm to the right. The maximal mean displacements for the full bladders were 9.2 mm superiorly, 1.1 mm inferiorly, 2.28 mm anteriorly, 1.08 mm posteriorly, 1.85 mm to the left and 1.73 mm to the right. Statistically significant differences were seen in the posterior, left and right displacements but were quantitatively small. CONCLUSIONS: Intrafractional motion secondary to bladder filling showed minimal variation between the full and empty bladder. Similar clinical target volume to planning target volume margins can be applied for the delivery of radiotherapy for a full and empty bladder.