Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and ...repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to the ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), although some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naive ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of Prdm14 expression transiently elevated 5hmC, followed by the reduction of 5mC at pluripotency-associated genes, germline-specific genes and imprinted loci, but not across the entire genome, which resembles the second wave of DNA demethylation observed in gonadal PGCs. PRDM14 physically interacts with TET1 and TET2 and enhances the recruitment of TET1 and TET2 at target loci. Knockdown of TET1 and TET2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors of APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 takes place normally in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs.
Abstract
Background
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disorder characterized by asthma, eosinophilia, and systemic vasculitis. Renal involvement is not regarded as a ...prominent feature and the treatment is still under study.
Case presentation
A 68-year-old woman was admitted to our hospital because of fever, renal dysfunction, eosinophilia, and the presence of MPO-ANCA. Based on the renal pathological examination which showed extravascular eosinophilic-predominant inflammation and crescentic glomerulonephritis, EGPA was diagnosed. Considering the acute kidney injury, prominent eosinophilia, and strongly positive anti-MPO antibodies, pulse steroid therapy was administered, followed by intravenous rituximab. Plasmapheresis was also provided (9 sessions). The eosinophil count was normalized, and renal dysfunction was reversed. The patient no longer requires dialysis.
Conclusions
Renal involvement of EGPA is rare, and consensus on its treatment is still lacking, because of a lack of large-scale randomized controlled trials. We treated our patient as a case with high severity. For patients with severe disease, the addition of cyclophosphamide to glucocorticoid therapy is commonly used. However, rituximab and plasmapheresis combined with systemic glucocorticoid therapy were found to be beneficial because the renal function and other clinical conditions were almost fully recovered. Thus, our treatment is highly effective against renal involvement of eosinophilic granulomatosis with polyangiitis.
Thymine DNA glycosylase (TDG) is a base excision repair (BER) enzyme, which is implicated in correction of deamination‐induced DNA mismatches, the DNA demethylation process and regulation of gene ...expression. Because of these pivotal roles associated, it is crucial to elucidate how the TDG functions are appropriately regulated in vivo. Here, we present evidence that the TDG protein undergoes degradation upon various types of DNA damage, including ultraviolet light (UV). The UV‐induced degradation of TDG was dependent on proficiency in nucleotide excision repair and on CRL4CDT2‐mediated ubiquitination that requires a physical interaction between TDG and DNA polymerase clamp PCNA. Using the Tdg‐deficient mouse embryonic fibroblasts, we found that ectopic expression of TDG compromised cellular survival after UV irradiation and repair of UV‐induced DNA lesions. These negative effects on cellular UV responses were alleviated by introducing mutations in TDG that impaired its BER function. The expression of TDG induced a large‐scale alteration in the gene expression profile independently of its DNA glycosylase activity, whereas a subset of genes was affected by the catalytic activity of TDG. Our results indicate the presence of BER‐dependent and BER‐independent functions of TDG, which are involved in regulation of cellular DNA damage responses and gene expression patterns.
Abstract
Background and Aims
Glucocorticoids have been the standard treatment for anti-neutrophil cytoplasm autoantibody-associated vasculitis (AAV). Avacopan, a complement C5a receptor inhibitor, ...has been approved for the treatment of AAV in Japan, the USA, Germany, and Austria. The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids 1–3. Avacopan is a new, promising adjunctive agent for standard induction therapy for AAV and may potentially reduce steroid use.
Method
We assessed treatment responses of patients with AAV who did not require dialysis between 2018 and 2023. Group 1 consisted of six adult patients who were treated with avacopan (30 mg, twice daily) plus reduced-dose prednisone, and Group 2 consisted of 14 patients who received high-dose prednisone. We compared the mean dose of prednisone, Birmingham Vasculitis Activity Score (BVAS), creatinine, urine protein/creatinine ratio (UPCR), and C-reactive protein (CRP) at weeks 0 and 12 between the two groups.
Results
The mean total prednisone dose of oral glucocorticoids at both weeks 0 and 12 was much lower in Group 1 than in Group 2 (p<0.05). Mean BVAS, creatinine, UPCR, and CRP in Group 1 was comparable to Group 2. Steroid-related toxicity occurred in three of six (50%) patients in Group 1, and 5 of 14 (36%) patients in Group 2. Liver damage related to avacopan occurred in two of six (33%) patients in Group 1.
Conclusion
Herein, we describe practice observations on the use of avacopan in patients with AAV. While further studies are needed to confirm the efficacy of avacopan because the number of cases treated with avacopan is still lacking, our findings suggest that avacopan was beneficial in AAV patients because of the absence of steroid dependence.
While the incidence and prevalence of non-tuberculous mycobacterial-pulmonary disease (NTM-PD) are increasing and microscopic polyangiitis (MPA) is common in East Asian countries, case reports of MPA ...associated with NTM-PD are limited. A 72-year-old male receiving treatment for NTM-PD with antibiotics was referred to our hospital with fever and arthralgia that developed a few months previously. A blood test revealed the presence of the myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) and renal impairment. Based on a pathological examination of renal tissue, which showed crescentic glomerulonephritis, the patient was diagnosed with MPA. Due to acute kidney injury and strongly positive MPO-ANCA, pulse steroid therapy was initiated followed by intravenous rituximab (RTX). The patient also received plasmapheresis (14 sessions). Renal dysfunction was reversed. MPA associated with NTM-PD is extremely rare and, thus, there is currently no established treatment. Our patient was diagnosed with MPA based on the findings of renal biopsy while receiving treatment for NTM-PD. RTX and plasmapheresis combined with systemic glucocorticoid therapy were initiated before these clinical conditions had fully recovered. Although MPA secondary to NTM-PD may be more refractory to treatment than primary MPA in the presence of a very low interferon-gamma (IFN-γ) level, this case was successfully treated with steroids, RTX, and plasmapheresis.
A 47-year-old man who had cirrhosis exhibited bruising on his left abdominal wall. Upon arrival, his systolic blood pressure was 88 mmHg and pulse was 96 beats/min. CT showed laceration of the upper ...pole of the spleen and extravasation in the delayed phase. After he underwent angiographic embolization of the splenic artery, his systolic blood pressure rose to 100 mmHg. During conservative management in the ICU, his blood pressure dropped again. Therefore, he underwent emergency laparotomy. Ongoing bleeding from the splenic laceration was found and he underwent splenectomy. His spleen was AAST grade II . Twenty-two hours after his arrival at hospital, the patient died. We were not able to stop the bleeding because of the cirrhosis.
An 83-year-old man was brought to our hospital after a traffic accident. He exhibited respiratory failure, which was caused by an upper airway obstruction that occurred due to bilateral vocal cord ...paralysis. It was an emergency state and he underwent oral tracheal intubation. CT scan showed a thyroid cartilage fracture. Subsequently, he underwent tracheotomy and was transferred to another hospital to undergo conservative treatment. Laryngeal trauma is relatively uncommon, and treatment of the acute phase consists of airway management. We need to recognize laryngeal trauma based on the mechanism of injury or symptoms and perform reliable intubation or surgical airway management during airway emergency. Because tracheal intubation after laryngeal trauma may cause airway obstruction, we should prepare for emergency airway management.
Ruptured incisional hernia is a rare condition. Performing surgery may be challenging due to its high contamination. Our case involved a 41-year-old man who had two previous surgeries for chronic ...pancreatitis. Six months before being admitted, he presented to our hospital for an expansion of his incisional hernia. Ulcers and atrophy in the skin were observed; thus, we recommended surgery, but he refused. Further, he complained of a rupture of the incisional hernia. He underwent an emergency surgery using the bilateral anterior rectus abdominis sheath turnover flap method for hernia repair. On postoperative day four, there was recurrence of the incisional hernia; therefore he underwent another emergency surgery. The hernia was closed by using an absorbable mesh. Surgery should be recommended for patients with ulcers or atrophy in the skin. We do not perform tissue repair methods for ruptured large incisional hernias.
Objectives: The purpose of this study was to evaluate venous patency, valvular function, and freedom from re-thrombosis in patients with acute proximal deep vein thrombosis (DVT) who underwent ...catheter-directed thrombolysis (CDT). Material and methods: Fifty patients with acute proximal DVT between January 2003 and October 2010 underwent CDT. CDT was performed with temporally inferior vena cava filter and the infusion catheter was inserted through a sheath in popliteal vein by percutaneous puncture. A solution of urokinase was infused either continuously and using the pulse spray technique together with heparin and intermittent pneumatic compression. Results: The median CDT duration was 4.3 days, the median total dose of urokinase was 1,050,000 IU, mechanical thrombolysis was performed in 39 patients and a metallic stent was inserted in 5 limbs. At the time of completion venography, the median recanalizaion rate was 91% and there were thirty nine patients in complete recanalization. 51-month primary and secondary patencies, venous reflux free-rate, and freedom from re-thrombosis were 80%, 83%, 88.6%, and 93.9%. Conclusion: Treatment with CDT for acute proximal DVT achieved good patency, prevention of valvular function, and low freedom from re-thrombosis after 51-month of follow up in current study.
Ruptured incisional hernia is a rare condition. Performing surgery may be challenging due to its high contamination. Our case involved a 41-year-old man who had two previous surgeries for chronic ...pancreatitis. Six months before being admitted, he presented to our hospital for an expansion of his incisional hernia. Ulcers and atrophy in the skin were observed; thus, we recommended surgery, but he refused. Further, he complained of a rupture of the incisional hernia. He underwent an emergency surgery using the bilateral anterior rectus abdominis sheath turnover flap method for hernia repair. On postoperative day four, there was recurrence of the incisional hernia; therefore he underwent another emergency surgery. The hernia was closed by using an absorbable mesh. Surgery should be recommended for patients with ulcers or atrophy in the skin. We do not perform tissue repair methods for ruptured large incisional hernias.
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