TP53 variants in p53 signatures and the clonality of STICs in RRSO samples

ObjectivePrecursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.MethodsWe analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease.Results TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer.ConclusionThe sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.     

Total arch replacement using frozen elephant trunk technique with Frozenix for distal aortic arch aneurysms

Open in a separate window OBJECTIVESTotal arch replacement (TAR) using an endovascular approach has been initially introduced as the frozen elephant trunk technique (FET). In our institute, TAR using the FET with Frozenix has been used as the first-line treatment for distal aortic arch aneurysms since 2014. This study aimed to evaluate the early and long-term outcomes and demonstrate the efficacy of this procedure.METHODSBetween 2014 and 2021, 121 consecutive patients were treated with TAR using the FET with Frozenix for distal aortic arch aneurysms. Early and long-term outcomes were retrospectively analysed.RESULTSThe 30-day mortality rate was 2.5% (3/121). Of postoperative complications, paraplegia due to spinal cord injury occurred in 2 (1.7%) patients, stroke in 12 (9.9%) and acute renal failure in 10 (8.3%). At follow-up, 23 secondary aortic interventions were required and 8 (6.6%) patients underwent intended secondary thoracic endovascular aortic repair for residual descending aortic aneurysm. Late and aortic-related deaths occurred in 16 (13.2%) and 4 (3.3%) patients, respectively. The overall long-term survival rates at 1, 3 and 5 years were 87.6%, 83.1% and 65.4%, respectively, while the rates of freedom from aortic-related death at 1, 3 and 5 years were 95.7%, 95.7% and 84.8%, respectively.CONCLUSIONSTAR using the FET with Frozenix for distal aortic arch aneurysms has acceptable early mortality and morbidity. Spinal cord injury and paraplegia occur less frequently than previously reported. The technique has satisfactory long-term survival and freedom from aortic-related death.     

Effect of carbon disulfide on the anticholinesterase action of several organophosphorus insecticides in mice

Effect of carbon disulfide (CS2) on toxic action of 11 organophosphorus (OP) insecticides were examined by determining the plasma cholinesterase activity in mice. CS2 pretreatment potentiated the anticholinesterase action of parathion and EPN, but suppressed that of dimethoate and diazinon. CS2 had no significant effect or a slightly suppressive effect on the other compounds. Some of these effects were contrasted with the reported alteration of the toxicity following phenobarbital pretreatment. CS2 administration suppressed both detoxification and activation of parathion and EPN by liver microsomes in vitro, as measured by p-nitrophenol production and cholinesterase inhibition, respectively. Causal relationship between the in vitro and in vivo observations, however, remains to be clarified.     

Urinary Transthyretin as a Biomarker in ATTRv Val50Met Amyloidosis

Transthyretin (TTR), the precursor protein for amyloidogenic TTR (ATTR) amyloidosis, forms tetramers and escapes glomerular filtration by binding with thyroxine and retinol-binding protein. However, variant TTRs are unstable as tetramers, so monomeric TTR has become the precursor protein of amyloid deposits, via protein misfolding. The aim of the study was to evaluate the utility of urinary TTR in the diagnosis of ATTRv amyloidosis. Urinary samples from healthy volunteers, ATTRv V50M amyloidosis patients, and asymptomatic carriers of the ATTRv V50M gene were analysed using ELISA. To analyse the different forms of TTR secreted to the urine, we performed Western blotting and mass spectrometry. Urinary TTR concentrations were significantly higher in the ATTRv V50M amyloidosis patients than they were in the healthy volunteers and asymptomatic carriers of the gene. Although the TTR concentrations were negligible in the healthy volunteers, they were correlated with disease progression and urinary albumin concentrations in the ATTRv V50M amyloidosis patients. The Western blotting and mass spectrometry revealed the presence of monomeric wild-type and variant TTRs in the urine. Urinary TTR concentrations may become a more sensitive biomarker of ATTRv progression than albumin.     

Reorganization of brain activity for multiple internal models after short but intensive training

Internal models are neural mechanisms that can mimic the input-output properties of controlled objects. Our studies have shown that: 1) an internal model for a novel tool is acquired in the cerebellum (Imamizu et al., 2000); 2) internal models are modularly organized in the cerebellum (Imamizu et al., 2003); 3) their outputs are sent to the premotor regions after learning (Tamada et al., 1999); and 4) the prefrontal and parietal regions contribute to the blending of the outputs (Imamizu et al., 2004). Here, we investigated changes in global neural networks resulting from the acquisition of a new internal model. Human subjects manipulated three types of rotating joystick whose cursor appeared at a position rotated 60 degrees, 110 degrees, or 160 degrees around the screen's center. In a pre-test after long-term training (5 days) for the 60 degrees and 160 degrees joysticks, brain activation was scanned during manipulation of the three joysticks. The subjects were then trained for the 110 degrees for only 25 min. In a post-test, activation was scanned using the same method as the pre-test. Comparisons of the post-test to the pre-test revealed that the volume of activation decreased in most of the regions where activation for the three rotations was observed. However, there was an increase in volume at a marginally significant level (p < .08) only in the inferior-lateral cerebellum and only for the 110 degrees joystick. In the cerebral cortex, activation related to 110 degrees decreased in the prefrontal and parietal regions but increased in the premotor and supplementary motor area (SMA) regions. These results can be explained by a model in which outputs of the 60 degrees and 160 degrees internal models are blended by prefrontal and parietal regions to cope with the novel 110 degrees joystick before the 25-minute training; after the acquisition within the cerebellum of an internal model for the 110 degrees, output is directly sent to the premotor and SMA regions, and activation in these regions increases.     

Repeated Necrotizing Lymphadenitis with MEFV Gene Mutations

We herein report a 36-year-old man with repeated necrotizing lymphadenitis due to MEFV gene mutations. The patient''s chief complaints were a fever and painful cervical lymphadenopathy. We diagnosed him with necrotizing lymphadenitis based on the pathological findings of the lymph nodes and the exclusion of other differential diseases. The same episode recurred four times. We speculated the involvement of autoinflammatory backgrounds and detected MEFV gene mutations of E148Q (homo), P369S, and R408Q. Considering the elevation of interleukin-18, these mutations probably played roles in the repeated necrotizing lymphadenitis.     

Expression of parathyroid hormone/parathyroid hormone-related peptide receptor 1 in normal and diseased bladder detrusor muscles: a clinico-pathological study

Background

To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease.

Methods

PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome).

Results

Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH₂O (range 10–107 cmH₂O), and median compliance was 3.93 ml/cmH₂O (range 0.05–30.3 ml/cmH₂O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases.

Conclusions

Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.     

Late recurrence after resection of mass-forming intrahepatic cholangiocarcinoma: report of a case

The outcome after surgical resection for intrahepatic cholangiocarcinoma has not been satisfactorily evaluated due to its malignant behavior. Surgical resection, however, has the potential to improve the prognosis and may allow surgeons to experience rare cases with long survival. This report presents the case of a patient who developed recurrence 9?years after resection of intrahepatic cholangiocarcinoma. A 76-year-old female was diagnosed to have intrahepatic cholangiocarcinoma and underwent an extended right posterior subsegmentectomy. The gross appearance showed a mass-forming type tumor. The histopathological examination revealed well to moderately differentiated adenocarcinoma associated with portal vein invasion. Subcutaneous metastasis in the head as the first sign of relapse was diagnosed 9?years after hepatectomy. The histopathological findings of the subcutaneous tumor were similar to those of the intrahepatic cholangiocarcinoma, thus suggesting metastasis from intrahepatic cholangiocarcinoma. Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose was useful for detecting multiple metastases. Long-term follow-up for more than 5?years is recommended because the present case shows that late recurrence of intrahepatic cholangiocarcinoma occurs even 5?years after resection.     

Clinical Characteristics Associated with the Development of Diabetic Ketoacidosis in Patients with Type 2 Diabetes

Objective This study analyzed the clinical and laboratory parameters that might influence the clinical outcomes of patients with type 2 diabetes who develop diabetic ketoacidosis (DKA), which has not been well investigated. Methods We reviewed the clinical and laboratory data of 158 patients who were hospitalized due to DKA between January 2006 and June 2019 and compared the data of patients stratified by the type of diabetes. In addition, the patients with type 2 diabetes were subdivided according to age, and their clinical and laboratory findings were evaluated. Results Patients with type 2 diabetes had a longer symptom duration associated with DKA, higher body mass index (BMI), and higher C-peptide levels than those with type 1 diabetes (p＜0.05). Among patients with type 2 diabetes, elderly patients (≥65 years old) had a longer duration of diabetes, higher frequency of DKA onset under diabetes treatment, higher effective osmolarity, lower BMI, and lower urinary C-peptide levels than nonelderly patients (＜65 years old) (p＜0.05). A correlation analysis showed that age was significantly negatively correlated with the index of insulin secretory capacity. Conclusion Patients with DKA and type 2 diabetes had a higher BMI and insulin secretion capacity than those with type 1 diabetes. However, elderly patients with type 2 diabetes, unlike younger patients, were characterized by a lean body, impaired insulin secretion, and more frequent DKA development while undergoing treatment for diabetes.