Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia

In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.Peer reviewe

A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia

Leukocytes that lack HLA allelic expression are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy (IST), although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at position 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to 4 HLA supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%,

Clonal hematopoiesis in adult pure red cell aplasia

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients

SHISA6 Confers Resistance to Differentiation-Promoting Wnt/β-Catenin Signaling in Mouse Spermatogenic Stem Cells

In the seminiferous tubules of mouse testes, a population of glial cell line-derived neurotrophic factor family receptor alpha 1 (GFRα1)-positive spermatogonia harbors the stem cell functionality and supports continual spermatogenesis, likely independent of asymmetric division or definitive niche control. Here, we show that activation of Wnt/β-catenin signaling promotes spermatogonial differentiation and reduces the GFRα1+ cell pool. We further discovered that SHISA6 is a cell-autonomous Wnt inhibitor that is expressed in a restricted subset of GFRα1+ cells and confers resistance to the Wnt/β-catenin signaling. Shisa6+ cells appear to show stem cell-related characteristics, conjectured from the morphology and long-term fates of T (Brachyury)+ cells that are found largely overlapped with Shisa6+ cells. This study proposes a generic mechanism of stem cell regulation in a facultative (or open) niche environment, with which different levels of a cell-autonomous inhibitor (SHISA6, in this case) generates heterogeneous resistance to widely distributed differentiation-promoting extracellular signaling, such as WNTs

Sucrose Metabolism for the Development of Seminal Root in Maize Seedlings

The objective of this study was to elucidate the roles of sugar in the formation of root systems. Several parts of theseminal root were investigated to determine their sucrose, glucose and fructose contents, and the activity and the in situ localization of the activities of two kinds of metabolic enzymes, invertase and sucrose synthase, whichhydrolyze sucrose. The sucrose, glucose and fructose concentrations in the 0-1 cm section from the root apex were three to five times those in the other sections. The invertase and sucrose synthase activities were also higher in the apical section. The in situ localization of invertase activity was detected in the cell elongation zone of the seminal root using histochemical method. The sucrose synthase activity was detected in the cell elongation zone of the seminal root and the root apices of lateral roots. These results suggested that sucrose is transported to the root elongation zone and the surrounding tissue of the lateral root primordia, and is cleaved into glucose, fructose, and UDP-glucose by invertase or sucrose synthase. This suggested that sucrose contributes to root formation by serving as the energy source, the carbon source for cell wall synthesis, and as a compatible solute for cell elongation

Metachronous rectal metastasis from primary transverse colon cancer: a case report

Abstract Background Colorectal metastases from primary colorectal cancers are very rare, and little is known about their epidemiological aspects or the best diagnostic and therapeutic strategies. Herein, we report a case of a 65-year-old woman with suspected metachronous metastasis to the rectum from primary transverse colon cancer. Case presentation The patient underwent a laparoscopic extended right hemicolectomy for primary transverse colon cancer. Histopathological examination showed moderately differentiated adenocarcinoma, and the tumor was diagnosed as stage IIA (T3, N0, M0). Fifteen months after her colectomy, a computed tomography scan demonstrated a rectal tumor and a right ovarian tumor. Colonoscopy revealed a superficial elevated lesion in the middle rectum, and histological analysis showed moderately differentiated adenocarcinoma. Laparoscopic low anterior resection preserving the left colic artery and bilateral adnexectomy were performed. Histological examination of the rectal tumor showed that adenocarcinoma was mainly present in the submucosa and muscularis propria, while the carcinoma-involved region of the mucosal layer had mucosal colonization representing the spread of metastatic tumor cells along the basement membrane of preexisting crypts and/or villi. The right ovarian tumor proved to be moderately differentiated adenocarcinoma that was positive for cytokeratin 20 and negative for cytokeratin 7 staining, indicating metastasis from the colorectal cancer. The rectal and ovarian tumors were similar to transverse colon cancer in architectural and cytological atypia. Both adenocarcinomas of the transverse colon and rectum were negative for p53 in immunohistochemical staining and RAS wild type in genetic assessment. These findings support a possible diagnosis of rectal and ovarian metastasis from the primary transverse colon cancer. The patient recovered well after surgery, and neither relapse nor metastasis was observed 18 months after surgery. Conclusion Distinguishing primary from metastatic colorectal cancer can be challenging, but a comprehensive evaluation of histological features, clinical history, and tumor distribution can enable making a correct diagnosis and implementing optimal treatment

Association of obesity paradox with prognosis of veno‐venous‐extracorporeal membrane oxygenation in patients with coronavirus disease 2019

Abstract Aim Although the obesity paradox is known for various diseases, including cancer and acute respiratory distress syndrome, little is known about veno‐venous extracorporeal membrane oxygenation (VV‐ECMO) in patients with coronavirus disease 2019 (COVID‐19). In this study, we aimed to investigate the association between body mass index (BMI) and prognosis in critical patients with COVID‐19 requiring VV‐ECMO. Methods We conducted a retrospective observational single‐center study at Yokohama City University Civic General Medical Center between March 2020 and October 2021. Participants were patients with COVID‐19 who required VV‐ECMO. They were classified into two groups: BMI ≤30 kg/m2 and >30 kg/m2. Results In total, 23 patients were included in the analysis, with a median BMI of 28.7 kg/m2. Overall, 22 patients were successfully weaned from the ECMO. When comparing the two groups, there was a trend toward fewer days from onset to ECMO induction in the BMI >30 kg/m2 group. Moreover, the two groups had a similar prognosis. There were no statistically significant differences in the number of days from onset to hospitalization or the duration of ECMO induction between the groups. Conclusion VV‐ECMO induction for patients with COVID‐19 may lead to earlier indications in patients with BMI >30 kg/m2 than in those with BMI ≤30 kg/m2