Higher Levels Of Markers Research Articles

GCT-64. TREATMENT RESULTS IN CHILDREN WITH LOCALIZED CNS NGGCT

BACKGROUND/OBJECTIVESTreatment of children with CNS NGGCT remains challenge: 5y OS is 60 – 80%; relapses are very aggressive.DESIGN/METHODSBetween 2003 and 2019, 14 children (median age 10.5, range 4 – 16 years) with localized intracranial NGGCT were treated with RT after induction chemotherapy (focal – 4, WVI+boost – 6, WBI+boost – 3, CSI+boost – 1). Tumor markers were elevated in 13 patients: 6 – AFP, 5 – HCG, 2 – both. One patient with level of HCG 72049 IU/l in serum and 121451 IU/l in CSF received 4 cycles of PEI + CSI 30 Gy with boost 54Gy.RESULTSAt a median follow-up of 4,7 years (range 1 – 16,25 years), 12 patients are alive. 5-year PFS and OS are 77,1% and 85,7%, respectively. Two patients (both AFP and HCG) progressed during RT (1 – focal, 1 – WBI+boost), both died. Two patients with high level of HCG recurred after therapy (WVI+boost – 1, focal – 1), both are alive. The first of them at recurrence (mts of lateral ventricle) received 4 cycles of PEI and RT (WBI+boost). The second patient had level of HCG 620IU/l and initially received focal irradiation 54Gy. At recurrence with distant spinal mts he received HD-CHT with auto-SCT, surgical resection of residual tumor and CSI with boost.CONCLUSIONSGood results of treatment of localized CNS NGGCT with CSI, WBI or WVI in compare with focal RT show advantages of extended irradiation field. CSI should be considered for patients with extremely high levels of tumor markers and respectively poor prognostic histology.

Could PCSO-524® be a potential adjuvant treatment to sleep therapy in the management of depression?

Sleep is essential in neural system homeostasis due to its regulation of the immunological system and inflammatory cytokines. Poor sleep quality can induce a pro-inflammatory state and aggravate depressive symptoms. Depression has been linked with high levels of peripheral and central pro-inflammatory markers. In this context, we highlight a possible role for PCSO-524®, a nutritional supplement extracted from the New Zealand green lipped mussel that has already been shown to have anti-inflammatory effects, as an adjuvant treatment for depression alongside sleep therapy. Although there are not as yet any studies on its use in treating depression, it has been demonstrated to be a promising treatment in another condition that has been linked with inflammation, attention deficit/hyperactivity disorder, and in some other neurodegenerative disorders. Therefore, PCSO-524®, associated with good sleep quality, could be an option to reinforce depression management.

Essential oils can cause false-positive results of medium-chain acyl-CoA dehydrogenase deficiency

Newborn screening is a public health care program worldwide to prevent patients from critical illness or conditions. Tandem mass spectrometry allows multiplex, inexpensive, and rapid newborn screening. However, mass spectrometry used for newborn screening to date is not able to separate peaks of compounds with similar m/z, which could lead to false-positive results without additional second-tier tests, such as fragmentation. We experienced three neonatal cases with high levels of markers, octanoylcarnitine and octanoylcarnitine/decanoylcarnitine ratio used to pick up possible cases of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. The babies were born consecutively in a maternity hospital. Their second acylcarnitine profiles were normal, and the genetic tests for ACADM were negative. Analysis of samples extracted from their first Guthrie cards where blood was not stained also showed peaks equivalent to octanoylcarnitine and decanoylcarnitine, indicating contamination. Environmental surveillance in the maternity ward suggested that essential oils used there might contain the contaminated compound. LC-HRMS/MS and in silico analysis revealed that false-positive results might be due to contamination with the essential oils in Guthrie cards, and causal agents were sphinganine (d17:0) and 2-[2-hydroxyethyl(pentadecyl)amino]ethanol. Thus, health care providers should be cautioned about use of essential oils when collecting blood samples on Guthrie cards. False-positive results can waste costly social resources and cause a physical and psychological burden for children and parents.

COVID-19 Pneumonia in Patients with Chronic Myocarditis (HBV-Associated with InfarctLike Debute): Specifics of the Diseases Course, the Role of the Basic Therapy (Part II)

Chronic infectious-immune myocarditis of severe course can potentially be considered as a factor that aggravates the course of new coronavirus disease (COVID-19) and increases the risk of adverse outcomes. The interaction of chronic myocarditis and COVID-19 during long-term immunosuppressive therapy has not been studied. We present a description of a 35-year-old female patient with chronic infectious-immune myocarditis (morphologically confirmed, with a history of infarction-like onset and thromboembolic complications), who had continuous immunosuppressive therapy with methylprednisolone and mycophenolate mofetil. The patient also received new oral anticoagulants and tenofovir (for chronic HBV infection). COVID-19 (SARS-Cov-2 RNA+) was diagnosed in May 2020. Risk factors for the adverse course of coronavirus infection included severe obesity, heart failure, and life-threatening ventricular arrhythmias. Correction of immunosuppressive therapy (withdrawal of the cytostatic agent, administration of hydroxychloroquine) and therapy with levofloxacin, an interleukin-17 inhibitor (netakimab) were performed. The severity of pneumonia and respiratory failure was moderate despite high fever and high levels of inflammatory markers in the blood (including interleukin-6). Signs of exacerbation of myocarditis, increased levels of troponin T and anticardial antibodies (compared with the initial ones) were not found. It can be assumed that supportive immunosuppressive therapy for myocarditis has a positive effect on the course of coronavirus pneumonia and avoids exacerbation of myocarditis. Careful continuation of immunosuppressive therapy with temporary withdrawal of aggressive cytostatics can be recommended in chronic myocarditis. Further study of the features of the course of previous myocarditis and COVID-19 pneumonia is necessary.

Imperforate hymen mimicking malignancy in adolescence

Imperforate hymen is a rare congenital abnormality. It often presents with abdominal mass associated with pain. Differential diagnosis includes abdominal malignancies. A thirteen years-old female was referred to our center with abdominal distention and pain with the presumptive diagnosis of abdominal malignancy. Serum levels of tumor markers were extremely high. Abdominal CT scan without contrast revealed an extremely large, cystic mass (hematocolpos) with thickened walls. Gynecologic examination revealed imperforated hymen. A midline vertical hymenal incision was performed. This case is unique in terms of high suspicion of malignancy in light of physical examination, CT scan characteristics and high levels of tumor markers. It emphasizes that gynecologic examination should be a part of routine physical examination in adolescent females presenting with abdominal mass.

Is It the Missing Piece for Coronavirus Disease 2019, Acute Respiratory Distress Syndrome, and Venovenous Extracorporeal Membrane Oxygenation?

Is It the Missing Piece for Coronavirus Disease 2019, Acute Respiratory Distress Syndrome, and Venovenous Extracorporeal Membrane Oxygenation?

Genome diversity and population structure analysis of Iranian landrace and improved barley (Hordeum vulgare L.) genotypes using arbitrary functional gene-based molecular markers

Barley (Hordeum vulgare L. subsp. vulgare) is one of the earliest domesticated crop plants, which originated in Fertile Crescent. Genetic diversity analysis in primary gene pool and landraces is an effective strategy for germplasm conservation and utilization in breeding programs. In this study, Eighty-two barley genotypes comprised 22 Iranian improved cultivars and 60 landrace accessions collected from different zones of Iran were assumed for genetic diversity analysis using three gene targeted markers, start codon targeted (SCoT) polymorphism, conserved DNA-derived polymorphism (CDDP) and CAAT box-derived polymorphism (CBDP) in comparison with sequence-related amplified polymorphism (SRAP) markers. A total of 40 primers (10 primers from each marker) detected genetic polymorphism among barley genotypes. Four different marker types showed high level of polymorphism and SRAP markers produced higher number of polymorphic bands (67) in comparisons with SCoT, CDDP and CBDP. Average PIC values for SCoT, CDDP, CBDP and SRAP were 0.33, 0.37, 0.37 and 0.31, respectively. Marker index (MI) in SRAP and CBDP markers was higher than SCoT and CDDP markers. Cluster analysis using CDDP, CBDP and SRAP markers grouped barley genotypes in three distinct groups, while SCoT markers divided genotypes in four clusters. There were positive correlations between similarity matrixes obtained by each marker types. The results from cluster analysis and STRUCTURE analysis using combined data grouped barley genotypes in three clusters and the grouping of genotypes was strongly in agreement with their origins. Results showed that genotypes from west and north-west of Iran grouped in distinct clusters from those originated from north-east and center of Iran. To our knowledge, this is the first detailed report of using gene targeted molecular marker for genetic diversity analysis in barley. Our results showed the efficiency of these markers for genetic diversity analysis in barley and their potential for genome diversity and germplasm conservation.

MutT Homolog1 has multifaceted role in glioma and is under the apparent orchestration by Hypoxia Inducible factor1 alpha

AimsThe study focused on the expression and role of a recent potential cancer therapeutic target protein, MutT Homolog1 (MTH1). MTH1 gets activated in an increased reactive oxygen species (ROS) environment and removes the oxidized nucleotides from the cell. The study aimed to check the role of MTH1 in DNA damage and apoptosis, migration and angiogenesis and also to examine its regulation in glioma. Main methodsThe experiments were carried out in human glioma tissue samples and brain tissues of epilepsy patients (non-tumor control). We used two human glioblastomas cell lines, U87MG and U251MG cells. In order to study the role of MTH1 in glioma and to analyze the relation of MTH1 with Hif1α, we have used MTH1 siRNA and Hif1α siRNA respectively. Key findingsWe found an increased expression of MTH1 in glioma tissues compared to the non-tumor brain tissues. Correlation analysis revealed that those samples showing reduced expression of MTH1 also had high levels of DNA damage and apoptotic markers, while diminished expression of angiogenesis regulators and levels of migration. MTH1 knockdown in vitro by siRNA in tumor cell lines corroborates the above observation. This justifies the emergence of MTH1 inhibitors as potential first-in-class drugs. Mechanistically, our observations suggest that Hif1α may modulate MTH1 expression. SignificanceWe found elevated MTH1 expression in glioma irrespective of their grades, while its inhibition affects multiple tumor progression pathways, and that targeting Hif1α could simulate the same.

The incidence and clinical features of PEGylated filgrastim-induced acute aortitis in patients with breast cancer

Although PEGylated filgrastim-induced aortitis is very rare and unknown clinically, some cases were reported and increasing, especially in breast cancer patients. The present study investigated the prevalence, clinical features and treatment of aortitis induced by PEGylated filgrastim in patients with breast cancer. A total of 2068 consecutive patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were enrolled. From the medical record, clinical, laboratory, medication, and imaging evaluation findings were collected. PEGylated filgrastim-induced aortitis was established in 0.3% of the study population. Common clinical presentations included extremely high fever and chest/back pain with high levels of inflammatory markers without any signs of infection. Contrast-enhanced computed tomography scans revealed typical enhancing wall thickening and periaortic soft tissue infiltration at various levels of aorta. All patients improved rapidly after treatment with modest doses of prednisolone (0.5 mg/kg/day) without any complications. Clinicians should be aware of aortitis as a possible complication of granulocyte-colony stimulating factor therapy, especially PEGylated filgrastim, given the frequent misdiagnoses in neutropenic patients undergoing chemotherapy.

High Expression of microRNA-371a-3p in Cystic Fluid of Post-Chemotherapy Teratoma with Concurrent Normal Serum Levels in Patients with Non-Seminomatous Testicular Germ Cell Tumours

Background: MicroRNA-371a-3p (miR-371), the novel serum biomarker of testicular germ cell tumours (GCTs), is produced by undifferentiated subtypes of GCTs but not by teratoma. Cystic teratoma developing from retroperitoneal metastases of GCT subsequent to chemotherapy had been shown to contain high levels of classical serum tumour markers of GCT in the presence of normal marker levels in serum. To date, no information is available regarding the presence of miR-371 in the cystic fluid of residual teratoma after chemotherapy. Methods: Four patients (age 18–26 years) undergoing retroperitoneal lymph node dissection (RPLND) for cystic residual masses resulting from chemotherapy of bulky retroperitoneal GCT had measurements of miR-371 in both serum and cystic fluid aspirated from surgical specimens. Measurement of the miR was performed with quantitative real-time PCR using miR-30b-5p as reference. Results were tabulated and analysed in a descriptive manner. Results: Histologically, all of the surgical specimens involved teratoma only with no evidence of vital undifferentiated GCT tissue. All patients were cured. Prior to RPLND, miR-371 serum levels were not measurable or close to zero in all of the patients. Cystic fluid revealed elevated levels of miR-371 in 3 patients and traces of miR in one. Conclusions: The detection of miR-371 in the cystic fluid of teratoma is somewhat enigmatic since this GCT subtype usually does not express the miR. Two hypotheses may explain the finding: First, miR-371 molecules were released into the cystic fluid by active GCT tissue prior to chemotherapy. High levels were kept after regression of vital GCT tissue because the cystic lumen is without a specific drainage system. Second, teratoma cells lining the interior cyst wall may shed small amounts of miR-371 into the lumen. Because of the lacking drainage system, even small levels may accumulate. The present finding adds to the understanding of the biology of the novel biomarker of GCT.

A peripheral inflammatory signature discriminates bipolar from unipolar depression: A machine learning approach

BackgroundMood disorders (major depressive disorder, MDD, and bipolar disorder, BD) are considered leading causes of life-long disability worldwide, where high rates of no response to treatment or relapse and delays in receiving a proper diagnosis (~60% of depressed BD patients are initially misdiagnosed as MDD) contribute to a growing personal and socio-economic burden. The immune system may represent a new target to develop novel diagnostic and therapeutic procedures but reliable biomarkers still need to be found. MethodsIn our study we predicted the differential diagnosis of mood disorders by considering the plasma levels of 54 cytokines, chemokines and growth factors of 81 BD and 127 MDD depressed patients. Clinical diagnoses were predicted also against 32 healthy controls. Elastic net models, including 5000 non-parametric bootstrapping procedure and inner and outer 10-fold nested cross-validation were performed in order to identify the signatures for the disorders. ResultsResults showed that the immune-inflammatory signature classifies the two disorders with a high accuracy (AUC = 97%), specifically 92% and 86% respectively for MDD and BD. MDD diagnosis was predicted by high levels of markers related to both pro-inflammatory (i.e. IL-1β, IL-6, IL-7, IL-16) and regulatory responses (IL-2, IL-4, and IL-10), whereas BD by high levels of inflammatory markers (CCL3, CCL4, CCL5, CCL11, CCL25, CCL27, CXCL11, IL-9 and TNF-α). ConclusionsOur findings provide novel tools for early diagnosis of BD, strengthening the impact of biomarkers research into clinical practice, and new insights for the development of innovative therapeutic strategies for depressive disorders.

CYTOKERATIN-18 AS A MARKER OF NON-ALCOHOLIC FATTY LIVER DISEASE IN OBESE ADOLESCENTS

In parallel with the obesity epidemic in the world, the prevalence of non-alcoholic fatty liver disease among children and adolescents is growing. Current data suggest that insulin resistance is one of the main factors in the pathogenesis of non-alcoholic fatty liver disease, and the content of fragments of caspase-cleaved cytokeratin-18 in the blood serum may be one of the informative indicators of non-alcoholic fatty liver disease progression. The aim. To determine mechanisms of formation and progression of non-alcoholic fatty liver disease in obese children and adolescents by evaluating the level of cytokeratin-18. Materials and methods. The study involved 46 adolescents with obesity and non-alcoholic fatty liver disease aged 12–17 years: 19 boys (41.3 %) and 27 girls (58.7 %). Clinical (weight, height, waist and hip circumference), laboratory (glucose, immunoreactive insulin, lipid metabolism, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, cytokeratin-18) parameters were studied and instrumental examination (abdominal ultrasound) was performed. To assess insulin resistance the triglyceride-glucose index was calculated. Results. Depending on the presence of insulin resistance patients were divided into two groups: 21 (45.7 %) of adolescents with insulin resistance and 25 (54.3 %) of adolescents without insulin resistance. Blood tests in patients with insulin resistance revealed significantly higher levels of total cholesterol, triglycerides, very low-density lipoprotein cholesterol, fasting immunoreactive insulin, cytokeratin-18 and gamma-glutamyl transpeptidase. All adolescents were divided into 2 groups depending on the level of cytokeratin-18: patients with cytokeratin-18 >233 mIU/ml and <233 mIU/ml (15 (32.6 %) and 31 (67.4 %) respectively). It was found that there were significantly more patients with insulin resistance in the group with the level of cytokeratin-18 >233 mIU/ml. Conclusion. In obese adolescents with non-alcoholic fatty liver disease insulin resistance is associated with more pronounced disorders of lipid and carbohydrate metabolism and higher levels of markers that characterize the state of the liver such as cytokeratin-18 and gamma-glutamyl transpeptidase. Adolescents with obesity and non-alcoholic fatty liver disease with a threshold level of cytokeratin-18, which indicates the transformation of steatosis into steatohepatitis, two times more often have present insulin resistance.

Comparison of ameliorative effects of Taraxacum syriacum and N-acetylcysteine against acetaminophen-induced oxidative stress in rat liver and kidney.

Taraxacum syriacum (TS) with natural antioxidant and pharmacological activities may be considered for treatment of oxidative stress induced by acetaminophen (APAP). The aim of this study was to evaluate the ameliorative effects of the ethanol extract of TS root against hepatorenal toxicity induced by APAP in comparison to N-acetylcysteine (NAC) as a standard drug. Thirty male Wistar rats were randomly divided into five groups. Control group; APAP (1 g/kg) group; APAP-NAC (160 mg/kg) group and APAP-TS100 and APAP-TS200 groups: APAP plus 100 and 200 mg/kg of TS extract, respectively. After 7 days treatment, serum and liver and kidney tissues were prepared and evaluated. TS extract ameliorated the increased lipid peroxidation level and decreased antioxidant enzymes activities and glutathione level in liver and kidney of APAP-treated rats. Moreover, treatment with the TS extract caused significant reduction in the histopathological damages and high levels of serum biochemical markers of hepatic and renal functions after APAP treatment. This study suggests that the extract of TS roots has dose-dependent ameliorative effect against APAP-induced oxidative damage in liver and kidney due to its free radical scavenging and antioxidant properties. The overall efficacy of the extract at 200 mg/kg dose is comparable with NAC.

Multi-omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon

Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE-sequencing; combining surface proteomics with in-depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell findings. For the first time we show that human tendon harbours at least five distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T-cells, and monocytes. These consist of KRT7/SCX+ cells expressing microfibril associated genes, PTX3+ cells co-expressing high levels of pro-inflammatory markers, APOD+ fibro–adipogenic progenitors, TPPP3/PRG4+ chondrogenic cells, and ITGA7+ smooth muscle-mesenchymal cells. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro-inflammatory markers PTX3, CXCL1, CXCL6, CXCL8, and PDPN by microfibril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33.

Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus-specific CD8+ T cells after direct-acting antiviral therapies.

Chronic hepatitis C virus (HCV) infection impairs HCV CD8+ T-cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus-specific CD8+ T cells occurs after direct-acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow-up [FU] 12 and FU48) of virus-specific CD8+ T cells by multicolour flow cytometry in HCV-cirrhotic patients undergoing DAA therapy (n=26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA-A*02. HCV noncirrhotic patients (n=9) and healthy individuals (n=10) served as controls. We found that the proliferative capacity of HCV-specific CD8+ T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down-regulation of inhibitory co-regulatory receptors in HCV-cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV-specific CD8+ T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the 'exhausted' phenotype in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients did not associate with their functions. Larger studier with longer follow-up may elucidate whether this complex interplay influences the outcome of cirrhotic patients.

Abstract CT035: TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Abstract Background: Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. TP53 mutations and 17p (TP53) deletions occur in 37-46% of AML cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy approaches. Patients and Methods: We used the following transcriptomic data sets and patient cohorts (C) for in silico and wet-lab analyses: 1) The Cancer Genome Atlas (TCGA; 162 adult AML patients, 13 with TP53 mutations); 2) Beat AML Master Trial (281 adult AML patients, 17 with TP53 mutations); 3) HOVON (618 adult AML patients, 14 with TP53 mutations); 4) 24 diagnostic bone marrow (BM) samples from patients with TP53-wild-type AML (Bologna series); 5) 36 diagnostic BM samples from patients with TP53-mutated AML (Studien Allianz Leukämie [SAL] series); 6) 30 BM samples from patients with relapsed/refractory (R/R) AML (10 cases with TP53 mutations and/or 17p deletion) that received immunotherapy with flotetuzumab, a CD123×CD3 bispecific DART molecule (NCT02152956). Microenvironmental immune gene expression profiles (wet-lab cohorts, C4 and C5) were analyzed using the Pan-Cancer IO 360 Panel (NanoString Technologies, Seattle, WA). Immune cell type-specific and biological activity signature scores were computed as recently published (JITC 2017; 5: 18). Results: Compared with TCGA-AML cases (C1) with favorable-risk and intermediate-risk molecular features, all patients with TP53 mutations showed high levels of immune infiltration, including genes associated with adaptive immune responses and an interferon (IFN)-γ-dominant tumor microenvironment (TME), and a higher tumor mutational burden (14 versus 10 mutations on average in patients with TP53-mutated and TP53-wild-type AML, respectively; p=0.02). Similarly, 16 out of 17 (94%) TP53-mutated Beat AML cases (C2) expressed high levels of IFN signaling molecules, CD8 and markers of cytotoxicity (GZMB). Compared with patients with TP53-wild-type AML (C4), primary BM samples from patients with TP53-mutated AML (C5) showed higher levels of CD8A, markers of cellular senescence (EOMES, KLRD1, HRAS), IFN-γ-inducible genes (IRF1) and negative immune checkpoints including LAG3, IDO1, PDL1 and VSIR (VISTA). Interestingly, 10 patients with R/R AML (C6) had TP53 abnormalities and 5 of 6 patients evaluated for immune gene profiles had an immune-infiltrated TME. In patients with TP53 abnormalities, the overall response rate (ORR) was 40% to flotetuzumab (2 patients with CR, 1 patient with CRh, and 1 patient with morphologic leukemia-free state). The overall decrease of BM blasts averaged 42%. Stable disease was observed in 3 patients. Median overall survival (OS) was 3.5 months (range 1.25-21.25), which favorably compares with survival estimates for TP53-mutated cases with PIF in large AML series, such as HOVON (C3; median OS=1.16 months). Conclusions: This study provides evidence for a correlation between IFN-γ-dominant immune subtypes of AML and TP53 abnormalities. The ORR seen in this patient subgroup encourages further study of this immunotherapeutic approach. Citation Format: Jayakumar Vadakekolathu, Catherine Lai, Stephen Reeder, Sarah E. Church, Tressa Hood, John Muth, Heidi Altmann, Marilena Ciciarello, Antonio Curti, Peter J. Valk, Bob Löwenberg, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada, Sergio Rutella. TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT035.

Long-term follow up after denosumab treatment for osteoporosis \u2013 rebound associated with hypercalcemia, parathyroid hyperplasia, severe bone mineral density loss, and multiple fractures: a case report

BackgroundThe rebound effect after stopping treatment with denosumab may be associated with rapid loss of the gains in bone mineral density achieved with treatment, high levels of bone remodeling markers, the occurrence of vertebral fractures, and even hypercalcemia.Case presentationA 64-year-old osteoporotic Caucasian woman suffered from a fracture of her second lumbar vertebra in 2004. From January 2005, she was treated with denosumab for 9 years, with good densitometry results for her hip and lumbar areas, and no fractures over the last 6 years of treatment. Ten months after the treatment with denosumab was stopped, a cascade of vertebral fractures, including some in unusual locations (third thoracic vertebra), and multiple rib fractures in a context of hypercalcemia, suggested possible malignancy. A complete evaluation, including systemic, biological, and biopsy analyses, ruled out this hypothesis. The hypercalcemia was associated with normal plasma phosphate and vitamin D concentrations, and a high parathyroid hormone level, with an abnormal fixation of the lower lobe of the thyroid on sesta-methoxy-isobutyl-isonitrile scintigraphy. Histological analysis of the excised parathyroid tissue revealed hyperplasia. The associated thyroidectomy (goiter) led to the discovery of a thyroid papillary microcarcinoma.ConclusionsWe consider the consequences of this rebound effect, not only in terms of the major loss of bone density (return to basal values within 3 years) and the multiple disabling fracture episodes, but also in terms of the hypercalcemia observed in association with apparently autonomous tertiary hyperparathyroidism. Several cases of spontaneous reversion have been reported in children, but the intervention in our patient precluded any assessment of the possible natural course. The discovery of an associated thyroid neoplasm appears to be fortuitous. Better understanding of the various presentations of the rebound effect after stopping treatment with denosumab would improve diagnostic management of misleading forms, as in this case. Bisphosphonates could partially prevent this rebound effect.

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors.

Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.

Generation of one iPSC line (IMEDEAi007-A) by Sendai Virus transduction of PBMCs from a Psoriasis donor.

Psoriasis is a chronic inflammatory skin disease that speeds up the life cycle of skin cells, forming scales and red patches that are itchy and sometimes painful. It is a complex disease of autoimmune origin and genetic predisposition with more than 10 different loci associated. Here we described the production of an iPSC line generated by Sendai Virus (Klf4, Oct3/4, Sox2 and c-Myc) reprogramming of Peripheral Blood Mononuclear Cells (PBMCs) from a Psoriasis patient. The iPSC line generated has normal 46XY karyotype, is free of SeV genome and transgenes insertions, express high levels of pluripotency markers and can differentiate into all three germ layers.

Generation of a human iPSC line (IMEDEAi008-A) derived from natural homozygous CCR5-Δ32 PBMCs enriched in the pro-erythroblast population.

A 32 base pair deletion in the C-C chemokine receptor type gene (CCR5-Δ32), the main Human Immunodeficiency Virus (HIV) co-receptor results in a non-functional protein. Individuals homozygous for the CCR5-Δ32 mutation are resistant to HIV infection. Here we report the generation, from pro-erythroblast enriched Peripheral Blood Mononuclear Cells (PBMCs) from a naturally occurring CCR5-Δ32/Δ32 individual, of the fully characterized iPSC line IMEDEAi008-A. The new line has normal karyotype, carry the Δ32 mutation in homozygosity, is free of plasmid integrations, express high levels of pluripotency markers and can differentiate into all three germ layers.