Decidual Cells Block Inflammation-Mediated Inhibition of 15-Hydroxyprostaglandin Dehydrogenase in Trophoblasts.

Chorioamnionitis generates prostaglandin (PG) E2 and F2α, promoting fetal membrane rupture, cervical ripening, and uterine contractions. 15-Hydroxyprostaglandin dehydrogenase (HPGD) contributes to pregnancy maintenance by inactivating PGs. The role of decidual cells in regulating HPGD expression at the maternal-fetal interface was investigated. HPGD immunostaining was primarily detected in anchoring villi and choriodecidual extravillous trophoblasts (EVTs) in the first, second, and third trimesters. Chorionic EVTs adjacent to decidua parietalis exhibited significantly higher HPDG levels than those adjacent to amnion. HPGD histologic score levels were significantly lower in choriodecidua from chorioamnionitis versus gestational age-matched controls (means ± SEM, 132.6 ± 3.8 versus 31.2 ± 7.9; P < 0.05). Conditioned media supernatant (CMS) from in vitro decidualized term decidual cells (TDCs) up-regulated HPGD levels in EVTs differentiated from human trophoblastic stem cells, primary trophoblasts, and HTR8/SVneo cells. However, CMS from 5 µg/mL lipopolysaccharide or 10 ng/mL IL-1ß pretreated TDC cultures down-regulated HPGD levels in HTR8/SVneo cultures. Similarly, direct treatment of HTR8/SVneo cultures with lipopolysaccharide or IL-1ß significantly reduced HPGD levels versus control (0.57 ± 0.1 or 0.47 ± 0.1 versus 1.03 ± 0.03; P < 0.05) but not in TDC-CMS pretreated HTR8/SVneo cultures. Collectively, the results uncover a novel decidual cell-mediated paracrine mechanism that stimulates levels of trophoblastic HPGD, whose function is to inactivate labor-inducing PGs, thereby promoting uterine quiescence during pregnancy. However, infectious/inflammatory stimuli in decidual cells cause a paracrine inhibition of trophoblastic HPGD expression, increasing PGE2/PGF2α levels, thereby contributing to preterm birth.

Clonotypic VDJ rearrangements in Mixed Phenotype Acute Leukemia can be Successfully Utilized to Track Minimal Residual Disease (MRD).

INTRODUCTION: Multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) can both be used to identify a neoplastic clonotype by targeting CDR3 and assessing rearrangements in IgH, IgK, IgL, TCR-ß, and TCR-gamma loci. The clonotypic sequence can be robustly used to track minimal residual disease (MRD). The ability to track MRD by NGS in mixed phenotype acute leukemia (MPAL) is unknown and warrants investigation. METHODS: Institutional Review Board (IRB) approval was obtained. Central Moffitt Cancer Center (MCC) database was searched to locate any patients with MPAL from over 600,000 entries. Patient charts were manually curated to identify those with clonoSEQ data, and clinical data was procured from the electronic medical record (EMR). RESULTS: Twenty-nine patients with MPAL were identified. Only 2 patients with clonoSEQ testing were found. Both demonstrated a B/myeloid phenotype, and both were bilineal. NGS (clonoSEQ) identified 4 dominant (IGH) (patient A; 8/2019) and 2 dominant sequences (patient B; 10/2019), respectively. In both patients, clonoSEQ testing successfully tracked minimal residual disease and mirrored clinical disease burden. CONCLUSIONS: This report is the first to confirm the utility of NGS-based MRD tracking in patients with MPAL and shows increased sensitivity of NGS over MRD flow cytometry.

Plasmablastic myeloma transformation of light-chain multiple myeloma.

Plasmablastic myeloma (PBM) is an uncommon and aggressive morphologic variant of multiple myeloma (MM). The neoplastic immature cells exhibit diverse morphology, posing a diagnostic challenge. The diagnostic criteria for PBM include the identification of ≥ 2% plasmablasts in the bone marrow aspirate. This case describes the incidental finding of a light-chain multiple myeloma (LCMM) transformed into PBM, a phenomenon not previously reported.

Chemical Complementarity of Breast Cancer Resident, T-Cell Receptor CDR3 Domains and the Cancer Antigen, ARMC3, is Associated With Higher Levels of Survival and Granzyme Expression.

Introduction: One of the most pressing goals for cancer immunotherapy at this time is the identification of actionable antigens. Methods: This study relies on the following considerations and approaches to identify potential breast cancer antigens: (i) the significant role of the adaptive immune receptor, complementarity determining region-3 (CDR3) in antigen binding, and the existence cancer testis antigens (CTAs); (ii) chemical attractiveness; and (iii) informing the relevance of the integration of items (i) and (ii) with patient outcome and tumor gene expression data. Results: We have assessed CTAs for associations with survival, based on their chemical complementarity with tumor resident T-cell receptor (TCR), CDR3s. Also, we have established gene expression correlations with the high TCR CDR3-CTA chemical complementarities, for Granzyme B, and other immune biomarkers. Conclusions: Overall, for several independent TCR CDR3 breast cancer datasets, the CTA, ARMC3, stood out as a completely novel, candidate antigen based on multiple algorithms with highly consistent approaches. This conclusion was facilitated by use of the recently constructed Adaptive Match web tool.

Genomic Landscape of Mixed-Phenotype Acute Leukemia.

Mixed-phenotype leukemia (MPAL) is a type of acute leukemia in which the blast population shows mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. MPALs are rare and carry a poor prognosis, thus, often pose both a diagnostic and therapeutic challenge. Conventionally, the diagnosis of MPAL requires either a single blast population with a lineage-defining phenotypic expression of multiple lineages (myeloid, B-cell and/or T-cell) (biphenotypic) or two distinct blast populations that each independently satisfy criteria for designation as AML, B-ALL, and/or T-ALL (bilineage). Given the rarity of MPAL, minimal studies have been performed to describe the genomic landscape of these neoplasms. IRB approval was obtained. Central MCC database was searched for any patient with a diagnosis of acute undifferentiated leukemia (AUL), acute leukemia of ambiguous lineage (ALAL), and MPAL. All patient diagnoses were manually reviewed by a hematopathologist to confirm the diagnosis of MPAL. Genomic and molecular data were collated from the EMR and bioinformatically from MCC genomics repositories. Twenty-eight patients with MPAL were identified. Thirteen were female and 15 were male. Average age was 56 years old (range = 28-81). Ten cases were biclonal and 18 were biphenotypic. Diagnoses were as follows: B/myeloid (n = 18), T/myeloid (n = 9), and T/B (n = 1). Cytogenetic analysis (Karyotype +/- FISH) was available for 27 patients. The most frequent recurrent abnormalities were complex karyotype (n = 8), BCR/ABL1 translocation (n = 6), Del 5q/-5 (n = 4), Polysomy 21 (n = 4). Mutational analysis was available for 18 patients wherein mutations were detected in 45 unique genes. The most frequently mutated genes were TP53 (7), RUNX1 (6), WT1 (4), MLL2 (3), FLT3 (3), CBL (2), ASXL1 (2), TET2 (2), MAP3K6 (2), MLL (2), and MAP3K1 (2). Targetable or potentially targetable biomarkers were found in 56% of cases. Overall survival was 19.5 months (range = 0-70 m). Ten patients were treated with an allogeneic stem cell transplant and had superior outcome (p = 0.0013). In one the largest series of MPAL cases to date, we corroborate previous findings with enriched detection of RUNX1 and FLT3-ITD mutations along with discovery of unreported mutations (MAP3K) that may be amenable to therapeutic manipulation. We also report the frequent occurrence of AML with MDS-related changes (AML-MRC)-defining cytogenetic abnormalities (26%). Finally, we show that those patients that received stem cell transplant had a better overall survival. Our findings support the need to genomically profile MPAL cases to exploit opportunities for targeted therapies in this orphan disease with dismal prognosis.

TRAV gene segments further away from the TRAJ gene segment cluster appear more commonly in human tumor and blood samples.

We considered the possibility that the greater the distance between an immune receptor V and J, the more likely the V usage. Such a hypothesis is supported by results from mouse experiments. And, such a hypothesis is consistent with the fundamental nature of recombination and genomic distance: the further the distance, the greater the chance of a DNA break. Thus, we exploited the vast dataset of V and J recombination reads available for the human TRA gene, particularly from cancer and blood specimens, to assess the frequency of TRAV usage with respect to distance from the TRAJ cluster. Results indicated that, indeed, over the entire TRAV cluster, there is a greater chance of V usage the further the distance from the J cluster. These results do not address causation, and are not consistent for certain individual V gene segments, but the results do indicate that overall, the larger the distance between the V and J gene segment cluster, the more likely the appearance of at least a subset of TRAV segments, particularly among tumor infiltrating lymphocytes. With a similar approach, the distal TRAV gene segments were also found to be more commonly associated with a subset of distal TRAJ segments. These results have implications for restrictions on the apparent TRA repertoire in disease settings.

PREVALENCE, ANTIBIOTIC AND PULSED-FIELD GEL ELECTROPHORESIS PATTERNS OF STAPHYLOCOCCUS AUREUS SMALL-COLONY VARIANTS IN CYSTIC FIBROSIS PATIENTS.

Staphylococcus aureus is the most common pathogen isolated from respiratory tract samples in cystic fibrosis (CF) cases. Rate of infection with S. aureus small-colony variants (SCVs) also is increasing in CF patients. In this study, we aimed to determine the prevalence, antibiotic susceptibility and genotypic property of S. aureus SCVs in respiratory tract samples of CF patients admitted to Istanbul Faculty of Medicine Hospital, Turkey. Among 305 respiratory tract samples from 84 CF patients, normal S. aureus isolates were present in 71% of the CF patients and S. aureus SCVs in 21%. The highest antibiotic resistance was against penicillin (82%) followed by clarithromycin (21%) in S. aureus SCVs, while resistance to levofloxacin was low (2%) in normal S. aureus isolates but was 16% in S. aureus SCVs. No mecA and mecC were detected. The S. aureus strains constituted 24 different genotypes based on pulsed field gel-electrophoresis assay. The possible existence of S. aureus SCVs that are more resistant to antibiotis than normal S. aureus should be taken into considerstion when treating CF patients for this pernicious bacterial infection.

Alzheimer disease, inflammation, and novel inflammatory marker: resistin.

BACKGROUND/AIM: Inflammation may play an important role in Alzheimer disease (AD) pathogenesis. A growing amount of evidence indicates that resistin has hallmark regulatory functions such as inflammatory states. The aim of this study was to determine whether plasma resistin levels would be useful in the diagnosis of patients with AD and to investigate the relationships between resistin and other inflammatory markers such as hs-CRP and TNF-α. Materials and methods: In this cross-sectional study, 38 AD patients and 32 control subjects with normal cognitive function aged 65 years and over were included. The diagnosis of AD was made according to DSM-IV and NINCDS-ADRDA criteria. Serum levels of resistin were measured with an enzyme-linked immunosorbent assay method using the human resistin E50 kit. Results: The median resistin level of AD patients was significantly higher than in the control group (86.3 vs. 70.8 pg/mL, P = 0.002). Overall accuracy of resistin in determining AD was 70.66%, with sensitivity, specificity, PPV, and NPV of 75.0%, 65.5%, 73.0%, and 67.9%, respectively. There was no statistically significant difference between AD patients and control subjects with respect to hs-CRP and TNF-α levels. Conclusion: Resistin levels may be considered as a predictor of AD and it may predict activation of the immune system in AD pathophysiology.

Detection and spread of oxa-48-producing Klebsiella oxytoca isolates in Istanbul, Turkey.

Five OXA-48 producing Klebsiella oxytoca strains isolated in April-July 2010 were analyzed. Antibiotic susceptibility tests were performed using disc diffusion method and VITEK 2 system. Carbapenemase activity was investigated using the Modified Hodge test. Beta-lactamase genes were detected by PCR and blaOXA-48 was sequenced. Genetic relatedness between K. oxytoca isolates was investigated by pulse-field gel electrophoresis (PFGE). Carbapenemase activity was detected in 5 isolates by Modified Hodge test. Although all strains were resistant to ertapenem and imipenem, only one strain was also resistant to meropenem. BlaOXA-48 in 4 isolates harbored 2 or 3 other ESBL types, namely, blaTEM, blaSHV, blaCTX-M, or blaVEB. PFGE revealed 3 different pulso-types among the K. oxytoca isolates. The presence of OXA-48 carbapenemase in other species of clinical isolates should also be considered.