Refractory Type Research Articles

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

Erosion Behavior and Longevity Technologies of Refractory Linings in Blast Furnaces for Ironmaking: A Review

Erosion of the refractory materials in blast furnaces (BFs) greatly limits their campaign life, which seriously reduces the economic benefits of iron and steel plants and endangers workers. Therefore, it is important to detect and monitor the erosion process of refractory materials in the BF hearth. In this review, the mechanisms of physical damage, chemical corrosion, and mechanical erosion of BF hearths during BF operation are analyzed and summarized. In addition, the effects of hearth structure, refractory type, and protective layer on hearth erosion behavior and hearth life are analyzed and discussed. Some longevity technologies of BF hearths are analyzed and compared, such as reasonable hearth structure design, refractory selection, and technologies to form protective layers. Finally, some suggestions and prospects for the future development of long campaign life BF hearths are discussed.

CCL4 Functions as a Biomarker of Type 2 Airway Inflammation.

Eosinophilic airway inflammatory disease is associated with bronchial asthma, with eosinophilic chronic rhinosinusitis (ECRS) typical of refractory type 2 airway inflammation. CCL4 produced at local inflammatory sites is involved in them via the accumulation and activation of type 2 inflammatory cells, including eosinophils. The detailed mechanism of CCL4 production remains unclear, and also the possibility it could function as a biomarker of type 2 airway inflammation remains unresolved. In this study, we evaluated CCL4 mRNA expression and production via the TSLP receptor (TSLPR) and toll-like receptors (TLRs) or proteinase-activated receptor-2 (PAR2) in BEAS-2B bronchial epithelial cells co-incubated with purified eosinophils or eosinophil peroxidase (EPX). We examined serum chemokine (CCL4, CCL11, CCL26, and CCL17) and total IgE serum levels, fractionated exhaled nitrogen oxide (FENO), and CCL4 expression in nasal polyps in patients with severe ECRS and asthma. CCL4 was induced by TSLP under eosinophilic inflammation. Furthermore, CCL4 was released via TLR3 signaling, which was enhanced by TSLP. CCL4 was mainly located in nasal polyp epithelial cells, while serum CCL4 levels were reduced after dupilumab treatment. Serum CCL4 levels were positively correlated with FENO, serum IgE, and CCL17 levels. Thus, CCL4 released from epithelial cells via the innate immune system during type 2 airway inflammation may function as a useful biomarker for the condition.

Subcutaneous BoNT/A Injection for Intractable Pain and Disability in Complex Regional Pain Syndrome: A Case Report

We treated a 51-year-old woman with refractory Complex Regional Pain Syndrome type I (CRPS-I) involving her left hand and forearm with subcutaneous injections of BoNT/A. The injections were performed every 3 months, with a total of six treatments. Each treatment was able to effectively improve pain and motor impairment; however, the duration of the effect was limited to only a few months. BoNT/A could improve patients’ quality of life with CRPS; however, extensive clinical studies are needed to determine its role in clinical practice.

Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease.

Despite following a gluten-free diet, which is currently the only effective therapy for celiac disease, about 5% of patients can develop serious complications, which in the case of refractory type 2 could evolve towards intestinal lymphoma. In this study, we have identified a set of 15 microRNAs in serum discriminating between the two types of refractory disease. Upregulated miR-770-5p, miR-181b-2-3p, miR-1193, and miR-1226-3p could be useful for the better stratification of patients and the monitoring of disease development, while miR-490-3p was found to be dysregulated in patients with refractory type 1. Finally, by using bioinformatic tools applied to the analysis of the targets of dysregulated microRNAs, we have completed a more precise assessment of their functions. These mainly include the pathway of response to Transforming Growth Factor β cell–cell signaling by Wnt; epigenetic regulation, especially novel networks associated with transcriptional and post-transcriptional alterations; and the well-known inflammatory profiles.

Treatment Resistance in Severe Asthma Patients With a Combination of High Fraction of Exhaled Nitric Oxide and Low Blood Eosinophil Counts.

Background: Combining a fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (B-EOS) may be a useful strategy for administration of biologics such as anti-IgE or anti-IL-5 to patients with type 2 inflammatory-predominant severe asthma and is important to be elucidated considering the increasing use of biologics. Methods: This cross-sectional study analyzed the clinical data from 114 adult patients with severe asthma, who were treated at Saitama Medical University Hospital. The eligible patients were stratified into four subgroups defined by thresholds of FeNO and blood eosinophil (B-EOS) counts to detect sputum eosinophilia, using the receiver operating characteristic curve analysis. A total of 75 patients with optimal samples were stratified into four subtypes defined by thresholds of sputum eosinophilia and neutrophilia. Clinical characteristics, pattern of biologics, and distribution of sputum subtypes were analyzed in the stratified subclasses according to the FeNO and B-EOS thresholds. The asthma exacerbation (AE)-free time of the FeNO/B-EOS subgroups and any biologics treatment including anti-IgE or anti-IL-5 use were examined using the Kaplan–Meier method. The hazard ratios (HRs) for AE-free time were examined using the Cox proportional hazard model. Results: The optimal cutoff values for prediction of sputum eosinophilia were defined as ≥2.7% wherein for FeNO as ≥27 ppb and B-EOS as ≥265/µL were considered. The high-FeNO subgroups showed significant high total IgE, compared with the low FeNO. The high-FeNO/high-B-EOS and the high-FeNO/low-B-EOS subgroups showed the largest prevalence of mepolizumab and benralizumab use among the other FeNO/B-EOS, respectively. The high-FeNO/low-B-EOS showed the largest frequency of AEs, high HR, and the shortest AE-free time, among the other FeNO/B-EOS. The sputum eosinophil-predominant subtype was the great majority in the high FeNO/high B-EOS. A diverse distribution of sputum leukocyte-predominant subtype was observed in the other FeNO/B-EOS. The subsequent AE-free time and its HR were comparable among the biologics use groups. Conclusion: The strategy of classifying severe asthma based on the combination of FeNO and B-EOS proposes particular refractory type 2 severe asthma and underlying airway inflammation as a feasible trait for optimal biologics use.

Hemophagocytic Lymphohistiocytosis in Refractory Celiac Disease Type II Transformed into Enteropathy-Associated T-Cell Lymphoma

Celiac disease (CD) can lead to small intestinal damage from gluten exposure. Refractory celiac disease type II (RCD2), a complication of CD, can transform to enteropathy-associated T-cell lymphoma (EATL). Hemophagocytic lymphohistiocytosis (HLH) is a rare complication that has been reported in patients with CD, RCD2, and EATL. We report the case of a 61-year-old man with a history of CD complicated by RCD2 that transformed into EATL with HLH as its presenting syndrome.

Incidence and Fate of Refractory Type II Endoleak after EVAR: A Retrospective Experience of Two High-Volume Italian Centers.

Introduction: The aim of the present study is to report the outcome of patients presenting an isolated type II endoleak (TIIEL) requiring reintervention and to identify clinical and anatomical characteristics potentially implicated in refractory TIIEL occurrence and fate. Materials and Methods: A multicenter retrospective study on TIIEL requiring reintervention was conducted between January 2003 and December 2020. Demographic and clinical characteristics, procedural technical aspects, reinterventions, and outcomes were recorded. TIIEL determining sac expansion greater than 10 mm underwent a further endovascular procedure aiming to exclude aneurismal sac. Redo endovascular procedures were performed via endoleak nidus direct embolization and/or aortic side branches occlusion. TIIELs responsible for persisting aneurysmal sac perfusion 6 months after redo endovascular procedures were classified as “refractory” and submitted to open conversion. Results: A total of 102 TIIEL requiring reintervention were included in the final analysis. Eighty-eight (86.27%) patients were male, the mean age was 77.32 ± 8.08 years, and in 72.55% of cases the American Society of Anaesthesiologists (ASA) class was ≥3. The mean aortic diameter was 64.7 ± 14.02 mm, half of treated patients had a patent inferior mesenteric artery (IMA), and 44.11% ≥ 3 couples of patent lumbar arteries (LA). In 49 cases (48.03%) standard endovascular aneurysm repair (EVAR) procedure was completed without adjunctive maneuvers. All enrolled patients were initially submitted to a further endovascular procedure once TIIEL requiring reintervention was diagnosed; 57 patients underwent LAs or IMA embolization (55.87%), 42 transarterial aneurismal sac embolization (41.17%), and three (2.96%) laparoscopic ostial ligations of the inferior mesenteric artery. During a mean follow-up of 15.22 ± 7.57 months (7–48), a redo endovascular approach was able to ensure complete sac exclusion in 52 cases, while 50 patients presented a still evident refractory TIIEL and therefore a surgical conversion or semiconversion was conducted. At the univariate analysis refractory TIIEL patients were significantly different from those who did not develop the complication in terms of preoperative clinical, morphological characteristics, and initial EVAR procedures: coronary artery disease occurrence (p = 0.005, OR: 3.18, CI95%: 1.3–7.2); preoperative abdominal aortic aneurysm (AAA) sac diameter (p = 0.0055); IMA patency (p = 0.016, OR: 2.64, CI95%: 1.18–5.90); three or more patent LAs; isolated standard EVAR without adjunctive procedures (p > 0.0001; OR: 9.48, CI95%: 3.84–23.4). Conclusions: Our experience seems to demonstrate that it is reasonable to try to preoperatively identify those patients who will develop a refractory TIIEL after EVAR and those with a TIIEL requiring reintervention for whom a simple endovascular redo will not be enough, needing surgical conversion.

Single-Cell Analysis of Refractory Celiac Disease Demonstrates Inter- and Intra-Patient Aberrant Cell Heterogeneity.

Background & AimsRefractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII.MethodsPaired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39–cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell–cell interactions in duodenal biopsy specimens of RCDII patients.ResultsWe provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells.ConclusionsNovel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles.

Steroid Refractory Type 2 Autoimmune Liver Failure Complicated by HSV Induced leukoencephalopathy

Steroid Refractory Type 2 Autoimmune Liver Failure Complicated by HSV Induced leukoencephalopathy

Use of dilatometer to screen refractory raw materials

AbstractSudden shortage of a particular raw material due to freight disruptions, competitive market, and COVID restrictions have frequently forced the refractory industry to rapidly develop alternative formulations using available low‐cost materials. These alternative ingredients might cursorily appear to have similar total impurity content, but the presence of certain impurity combinations depending on the refractory type can produce more fluid liquid phase at high temperature, thereby drastically reducing hot strength. Undetected by the commonly used X‐ray fluorescence (XRF) analysis, the low‐cost material might differ in mineral‐phase content, whose phase transformations during firing might create excessive expansion producing warpage of the refractory along with a high porosity reducing strength and corrosion resistance. Finally, those cheap raw materials might have similar sieve analysis to that of the standard ingredient but might have much lower tapped density, which would introduce detrimental porosity into the resulting refractory. Hence, time‐consuming trials are often performed. Dilatometer studies on pressed or cast samples in a single test can identify reaction temperatures of spinel or mullite formation, which expand during firing, along with the amount of expansion and exact times at which firing needs to be done. It can also compare relative shrinkage due to liquid‐phase formation among impure raw materials like recycled grogs or low‐grade ores. Finally, dilatometric step scan is shown as a fast technique to prepare in‐house, low‐cost reactive spinel powder, which can also work for mullite.

Fungal keratitis: A review of clinical presentations, treatment strategies and outcomes

Infectious keratitis is a significant cause of corneal blindness worldwide. Although less prevalent in the developed world, cases of fungal keratitis account for almost half of all keratitis cases, occurring in the developing countries. These cases are one of the most refractory types of infectious keratitis and present various challenges to the treating physician such as delayed presentation, long waiting time for culture positivity, limited availability effective antifungal drugs, prolonged duration for response to therapy, a highly variable spectrum of anti-fungal drug sensitivity and a high recurrence rate following keratoplasty. The advent of rapid diagnostic tools, molecular methods, in vitro anti-fungal drug sensitivity testing, alternatives to natamycin, targeted drug delivery and most importantly the results of large randomized controlled trials have significantly improved our understanding and approach towards the diagnosis and management of cases with fungal keratitis.Overall, Aspergillus and Fusarium species are the most common causes ones of fungal keratitis. History of antecedent trauma is a significant predisposing factor. Corneal scrapings for microscopic evaluation and culture preparation, is the standard of care for establishing the diagnosis of fungal keratitis. Molecular identification of cultures offers accurate identification of fungal pathogens, especially the rare species. Natamycin is an approved first-line drug. Voriconazole is the best alternative, especially for non-fusarium cases. Management involves administration of drugs usually by a combination of various routes, the treatment regimen being individualized depending upon the response to therapy. Photodynamic therapy is a newer treatment modality, being tried for non-responsive cases, before resorting to a therapeutic graft.

Fused-cast chrome-containing refractories and prospects for their industrial production

Information is given on various types of fused-cast chrome-containing refractories ― chromalumozircon and chromium spinelids. It is shown that the chromium spinelids refractories HPL-85 and HMG are at the same level with the ceramic refractories made of chromium oxide in terms of corrosion resistance in melts of alkali- free borosilicate glass E, mineral wool, basalt fiber, etc. The problems of the presence and formation of hexavalent chromium in the production of chrome- containing materials are discussed. It is shown that the production of fused-cast chrome-containing refractories is possible under safe production conditions. The necessity of creating an industrial production of fused chromium-containing refractories based on domestic developments, taking into account the best foreign achievements, is noted.

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.

Effect of particle grading on fracture behavior and thermal shock resistance of MgO-C refractories

Two types of MgO-C refractories with tight particle grading and non-tight particle grading were prepared according to Andreasen's continuous packing theory. Fracture behaviors were investigated using wedge splitting tests combined with digital image correlation method and acoustic emission techniques. The results indicated that MgO-C refractory with non-tight particle grading treated at 1400 ℃ had more in situ phases (e.g., AlN and MgAl2O4) and exhibited less brittleness than specimens with tight particle grading even though they had similar nominal tensile strengths. In contrast, specimens with non-tight particle grading had greater horizontal strain under various loading stages, reflecting their better ability to resist rupture deformation. In addition, more microcracks were initiated earlier in the pre-peak region, and more energy was consumed. The decrease in coarse particles and corresponding increase in fine powder content increased the interface between particles, benefiting for reducing the local stress concentration and improving the thermal shock resistance of refractories.

S2951 Hemophagocytic Lymphohistiocytosis as a Complication of Refractory Celiac Disease Type II That Transforms into a T-cell Lymphoma: A Case Report

S2951 Hemophagocytic Lymphohistiocytosis as a Complication of Refractory Celiac Disease Type II That Transforms into a T-cell Lymphoma: A Case Report

Correlation between Vitamin A Deficiency and the Severity of Mycoplasma Pneumoniae Pneumonia in Children

Mycoplasma pneumoniae pneumonia is a problem that has attracted the attention of children’s respiratory department in recent years. The relationship between vitamin A deficiency (VA) and the severity of Mycoplasma disease (MPP) in children was studied. In this paper, the hospitalized children with Mycoplasma pneumoniae pneumonia (MPP) in our hospital were selected as the research objects, and they were divided into common type and refractory type (RMPP) for comparative experiment. The VA and immunoglobulin levels of the two groups were compared. Attention should be paid to the normal ratio of VA deficiency (CVAD) and sub deficiency (svad) in the two groups. In this paper, the relationship between infection, immunoglobulin level and VA level was analyzed. The results showed that CVAD was 27.27% in MPP group and 63.75% in RMPP group. Comparison of immunoglobulin levels between the two groups: the levels of IgM, IgA and IgG in the normal MPP group were significantly lower than those in the RMPP group. On the other hand, the detection rate of CVAD was 81.48% in RMPP with infection and 54.72% in RMPP without infection. The detection rate of CVAD in patients with infection was significantly higher than that in patients without infection. There was a correlation between VA Deficiency and MPP classification.

Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center.

INTRODUCTION:Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center.METHODS:Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10).RESULTS:Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23–73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation.DISCUSSION:Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.

Effect of temperature on abrasion erosion in particle based concentrating solar powerplants

The use of solid particles as a heat transfer medium is being explored for concentrated solar power plants (CSP) to increase their efficiency by achieving operating temperature >700 °C. During operation, these hot particles are expected to move along the various components within the collector system, resulting in material degradation from a combination of high-temperature oxidation and erosion. In the present study, the performance of candidate materials was evaluated through a series of abrasion erosion experiments at room temperature as well as at 800 °C. Wear in metallic and refractory type materials was investigated using CarboBead® HSP 40/70 particles inside a resistance heated kiln. Cross-sectional scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS) analysis on the specimens tested at 800 °C determined that the specific wear rate in Inconel 740H and stainless steel 316 metallic specimens was influenced by the thermally grown oxide morphology. High chromium Inconel 740H specimens exhibited greater resistance to wear with a steady state specific wear rate of 1.92E-4 mm3N-1m−1 compared to 5.7E-3 mm3N-1m−1 for Stainless Steel 316.

Recent Advances in Implantation-Based Genetic Modeling of Biliary Carcinogenesis in Mice.

Simple SummaryBiliary tract cancer (BTC) is often refractory to conventional therapeutics and is difficult to diagnose in the early stages. In addition, the pathogenesis of BTC is not fully understood, despite recent advances in cancer genome analysis. To address these issues, the development of fine disease models is critical for BTC. Although still limited in number, there are various platforms for genetic models of BTC owing to newly emerging technology. Among these, implantation-based models have recently drawn attention for their convenience, flexibility, and scalability. To highlight the relevance of this approach, we comprehensively summarize the advantages and disadvantages of BTC models developed using diverse approaches. Currently available research data on intra- and extrahepatic cholangiocarcinoma and gallbladder carcinoma are presented in this review. This information will likely help in selecting the optimal models for various applications and develop novel innovative models based on these technologies.Epithelial cells in the biliary system can develop refractory types of cancers, which are often associated with inflammation caused by viruses, parasites, stones, and chemicals. Genomic studies have revealed recurrent genetic changes and deregulated signaling pathways in biliary tract cancer (BTC). The causal roles have been at least partly clarified using various genetically engineered mice. Technical advances in Cre-LoxP technology, together with hydrodynamic tail injection, CRISPR/Cas9 technology, in vivo electroporation, and organoid culture have enabled more precise modeling of BTC. Organoid-based genetic modeling, combined with implantation in mice, has recently drawn attention as a means to accelerate the development of BTC models. Although each model may not perfectly mimic the disease, they can complement one another, or two different approaches can be integrated to establish a novel model. In addition, a comparison of the outcomes among these models with the same genotype provides mechanistic insights into the interplay between genetic alterations and the microenvironment in the pathogenesis of BTCs. Here, we review the current status of genetic models of BTCs in mice to provide information that facilitates the wise selection of models and to inform the future development of ideal disease models.