A case of oncocytic papillary cystadenocarcinoma of the parotid gland—Pathological and molecular features of a rare tumor

AbstractWe present histological, immunohistochemical and molecular features of oncocytic papillary cystadenocarcinoma, a rare neoplasm of the salivary and parotid glands, in an 82-year-old Japanese man. The resected tumor was solid nodular mass with fibrous capsule. The tumor was composed of papillary proliferation of tall columnar cells with thin vascular cores. The cytoplasm of the tumor cells was granular and eosinophilic. The tumor cells showed clear positive reaction for mitochondria and androgen receptor. GCDFP15 and HER2 were negative. Electron microscopy demonstrated numerous mitochondria in the cytoplasm of the tumor cells. Ki-67 index was 30%. Most of the tumor cells were positive for TP53, and single nucleotide polymorphism was found at codon 151. The invasion into the lymphatic spaces and capsule was noted. Although recurrence and metastasis were not noted at one and a half years after the resection, the patient needs to be followed up under careful observation

ARTADE2DB: Improved Statistical Inferences for Arabidopsis Gene Functions and Structure Predictions by Dynamic Structure-Based Dynamic Expression (DSDE) Analyses

Recent advances in technologies for observing high-resolution genomic activities, such as whole-genome tiling arrays and high-throughput sequencers, provide detailed information for understanding genome functions. However, the functions of 50% of known Arabidopsis thaliana genes remain unknown or are annotated only on the basis of static analyses such as protein motifs or similarities. In this paper, we describe dynamic structure-based dynamic expression (DSDE) analysis, which sequentially predicts both structural and functional features of transcripts. We show that DSDE analysis inferred gene functions 12% more precisely than static structure-based dynamic expression (SSDE) analysis or conventional co-expression analysis based on previously determined gene structures of A. thaliana. This result suggests that more precise structural information than the fixed conventional annotated structures is crucial for co-expression analysis in systems biology of transcriptional regulation and dynamics. Our DSDE method, ARabidopsis Tiling-Array-based Detection of Exons version 2 and over-representation analysis (ARTADE2-ORA), precisely predicts each gene structure by combining two statistical analyses: a probe-wise co-expression analysis of multiple transcriptome measurements and a Markov model analysis of genome sequences. ARTADE2-ORA successfully identified the true functions of about 90% of functionally annotated genes, inferred the functions of 98% of functionally unknown genes and predicted 1,489 new gene structures and functions. We developed a database ARTADE2DB that integrates not only the information predicted by ARTADE2-ORA but also annotations and other functional information, such as phenotypes and literature citations, and is expected to contribute to the study of the functional genomics of A. thaliana. URL: http://artade.org

Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS)

Abstract Background This study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS). Methods A Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician’s Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded. Results Overall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug. Conclusion Baricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities. Trial registration NLM clinicaltrials.gov, NCT04517253 . Registered 18 August 2020

Laz İsmail, Nazım abimi öldürmek istedi

Taha Toros Arşivi, Dosya Adı: Nazım Hikmetİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: A 52-week, randomized, single-blind, extension study

<p><b>Objectives:</b> The objective of this study is to evaluate the efficacy and safety of long-term (64 weeks; 52-week extension of a 12-week study) baricitinib treatment in Japanese patients with active rheumatoid arthritis (RA) despite methotrexate therapy.</p> <p><b>Methods:</b> Patients (<i>N</i> = 145) with active RA were randomized to placebo, 1mg, 2mg, 4mg, or 8mg baricitinib for the first 12 weeks. During the 52-week extension period, patients on 4mg or 8mg baricitinib remained on the same dose and all other patients were re-randomized to 4mg or 8mg baricitinib. Most patients on 8mg baricitinib were switched to 4mg by week 64 (protocol amendment); data analysis was based on the treatment group at the beginning of the extension period.</p> <p><b>Results:</b> Increases in the American College of Rheumatology (ACR) response rates (ACR20, ACR50, and ACR70) observed during the first 12 weeks were maintained during the extension period, accompanied by improvements in ACR core components. At week 64, a large proportion of patients (>40%) had low disease activity. Most treatment-related adverse events were mild or moderate; herpes zoster was the most common reason (11/27 patients) for discontinuation.</p> <p><b>Conclusions:</b> The efficacy and safety profile of baricitinib was maintained during long-term treatment of Japanese patients with RA and background methotrexate therapy.</p> <p>Clinicaltrials.gov NCT01469013; Funding: Eli Lilly and Incyte</p

Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

We report the identification and characterization of a potent regulator of genomic integrity, mouse and human FRAG1 gene, a conserved homolog of replication factor C large subunit that is homologous to the alternative replication factor C subunits Elg1, Ctf18/Chl12, and Rad24 of budding yeast. FRAG1 was identified in a search for key caretaker genes involved in the regulation of genomic stability under conditions of replicative stress. In response to stress, Atr participates in the down-regulation of FRAG1 expression, leading to the induction of apoptosis through the release of Rad9 from damaged chromatin during the S phase of the cell cycle, allowing Rad9-Bcl2 association and induction of proapoptotic Bax protein. We propose that the Frag1 signal pathway, by linking replication stress surveillance with apoptosis induction, plays a central role in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis