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Although the prognosis of advanced extramammary Paget’s disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient’s tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient’s tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.

Eccrine porocarcinoma, also known as porocarcinoma (PC) and malignant eccrine poroma, is very rare and is known to arise from the cutaneous intraepidermal ducts of the sweat glands. Its etiology is not well understood; however, some studies suggest that PC tumors originate from benign eccrine poroma. Recently, several gene alterations have been reported in PC that can reveal mechanisms of the oncogenic process. Since the clinical and histopathological findings of PC are variable, PC is difficult to diagnose precisely, especially when the histology resembles that of cutaneous squamous cell carcinoma or poroma. Immunohistochemical staining with carcinoembryonic antigen and epithelial membrane antigen may help to distinguish PC from other tumors. The standard treatment for local PC is wide local excision. The prognosis of patients with metastatic PC is poor, with mortality rates of approximately 60–70%. The efficacy of radiation and chemotherapy for metastatic PC is limited; however, immunotherapy with pembrolizumab, a programmed cell death protein 1 inhibitor, could be a promising treatment. This review focuses on the history, pathogenesis, pathological features, diagnosis, and treatment of eccrine porocarcinoma.

Extramammary Paget’s disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development of potential treatments has long been sought. Cyclin‐dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient‐derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor‐bearing NOD/Scid mice over a 3‐week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX. The Ki‐67‐positive ratio of the treated EMPD‐PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD. The therapeutic efficacy of cyclin‐dependent kinase 4/6 inhibitors was assessed using extramammary Paget’s disease patient‐derived xenografts (EMPD‐PDX).Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX.

Structural variations disrupting the 3′ region of PD-L1 are shown to aid immune evasion in a number of human cancers, including adult T-cell leukaemia/lymphoma, and in a mouse tumour model, CRISPR/Cas9-mediated deletion of the 3'-UTR of Pd-l1 is also shown to result in immune escape, suggesting that PD-L1 3′-UTR disruption could provide a diagnostic marker to identify patients who will benefit from anti-PD-1/PD-L1 therapy. A marker for responsiveness to anti-PD-1/PD-L1 therapy In some patients, cancer therapy with antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) is ineffective due to immune evasion. Here Seishi Ogawa and colleagues show that structural variations disrupting the 3′-region of PD-L1 lead to overexpression of the PD-L1 protein, promoting immune evasion in a number of human cancers, including adult T-cell leukaemia and diffuse large B-cell lymphoma. Crispr-Cas9-mediated deletion of the 3′-UTR of Pd-l1 is also shown to result in immune escape in a mouse tumour model, suggesting that PD-L1 3′-UTR disruption could provide a diagnostic marker to identify patients who will benefit from anti-PD-1/PD-L1 therapy. Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development 1 , 2 , 3 , 4 , 5 , 6 . However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma 6 , 7 , 8 , 9 , 10 . Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of the Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo , which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.

Atomic scale characterization of fine precipitates in an under-aged Cu added Al-Mg-Si alloy was carried out by combination of atomically-resolved annular dark-field scanning transmission electron microscopy and energy dispersive X-ray spectroscopy. Two types of precipitates were observed in the alloy. In the case of ordered β” precipitates, β” was proposed as Mg 5-x Al 2+x Si 4 (x ≈ 1) with solute Cu atoms replacing Al site of β” precipitate. In the case of disordered precipitates, the precipitates were found to consist of β” sub-unit cells, three-fold symmetric structure without Cu atoms, Cu containing structures termed as “Cu sub-unit cluster”, and Q’ sub-unit cells. Among these structures, the morphologies of three-fold symmetric structure without Cu atoms, Cu sub-unit cluster, and Q’ sub-unit cell were almost the same, so that these structures should be the clusters of Q’ phase. Since the areal density, length and diameter of precipitates were almost equal between Cu free Al-Mg-Si alloy and Cu added Al-Mg-Si alloy, the increase of hardness by Cu addition should be due to the precipitation of Cu related precipitates, such as Cu sub-unit clusters and Q’ sub-unit cells.

Key summary points Aim This study investigated the association of dysphagia with social isolation in community-dwelling older people. Findings Dysphagia was significantly associated with social isolation, even after adjusting for physical function, cognitive function, and confounding factors. Message Dysphagia should be evaluated in community-dwelling older people at risk of social isolation. Purpose This cross-sectional study aimed to clarify the relationship between dysphagia and social isolation among community-dwelling older people. Methods The study participants were 238 community-dwelling older people (168 women; mean age, 74.0 ± 5.2 years; independent in instrumental activities of daily living, 97%) who lived independently and didn’t have a history of cerebrovascular disease. Swallowing function was assessed using the Eating Assessment Tool-10, with a score of ≥ 3 defined as dysphagia. Tongue pressure and oral diadochokinesis (ODK) were assessed as swallowing-related functions. Social isolation was assessed using the 6-item Lubben Social Network Scale. Physical function, cognitive function, and basic attributes were investigated as confounding factors. The relationship between social isolation and dysphagia was examined by logistic regression analysis with social isolation as the dependent variable and swallowing function as the independent variable, adjusted for confounding factors. Results Twenty-one percent of the participants were classified as social isolation group. A significantly higher percentage of participants with dysphagia were in the social isolation group than in the nonsocial isolation group (odds ratio [OR]: 3.3, 95% confidence interval [CI] 1.4–7.9). No significant association was found between social isolation and either tongue pressure or ODK. Dysphagia was significantly associated with social isolation (OR: 2.8, 95% CI 1.1–6.9), even after adjusting for confounders (physical function, cognitive function, and basic attributes). Conclusion Dysphagia may be an independent risk factor for social isolation in community-dwelling older people. These findings suggest that dysphagia should be assessed in community-dwelling older people at risk of social isolation.

Chryseobacterium is an obligate aerobic, non-glucose-fermenting, Gram-negative bacillus belonging to the family Flavobacteriaceae . Chryseobacterium species have rarely been isolated from clinical samples. Chryseobacterium indologenes and Chryseobacterium gleum are the most frequently isolated species. Chryseobacterium taklimakanense was first reported in 2009. Reports of C. taklimakanense isolation from blood cultures are rare and no case reports exist, leaving no established susceptibility data. An 80-year-old man with multiple underlying conditions, including appendiceal cancer, chronic heart failure, and type 2 diabetes mellitus, visited our hospital with exertional dyspnea and orthopnea. Upon admission, the patient had low oxygen saturation, a fever, and diarrhea. Acute exacerbation of chronic heart failure was suspected to be due to bacteremia. Blood cultures revealed Gram-negative bacilli, which were identified as Chryseobacterium taklimakanense by an 16 S rRNA analysis. Whole-genome sequencing was performed later, but no resistance genes were detected. The patient was treated with piperacillin-tazobactam for two weeks, which led to symptom improvement. Since no other infection sources were identified, bacteremia was attributed to bacterial translocation from the gastrointestinal tract. The isolate in this case was susceptible to meropenem, levofloxacin, and piperacillin-tazobactam, but resistant to minocycline and sulfamethoxazole-trimethoprim. This susceptibility pattern was different from that commonly observed in C. indologenes and C. gleum . This case highlights the antimicrobial susceptibility profile and treatment approach for infections caused by the rare bacterium C. taklimakanense .

Background/objectives Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab’s effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy. Methods/subjects In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours. Results Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan). Conclusions This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

Background Klebsiella variicola and K. quasipneumoniae are new species distinguishable from K. pneumoniae but they are often misidentified as K. pneumoniae in clinical settings. Several reports have demonstrated the possibility that the virulence factors and clinical features differ among these three phylogroups. In this study, we aimed to clarify whether there were differences in clinical and bacterial features between the three phylogroups isolated from patients with bloodstream infections (BSIs) in Japan. Methods Isolates from all patients with BSIs caused by K. pneumoniae admitted to two hospitals between 2014 and 2017 ( n  = 119) were included in the study. Bacterial species were identified via sequence analysis, and their virulence factors and serotypes were analyzed via multiplex PCR results. Clinical data were retrieved from medical records. Results Of the 119 isolates, 21 (17.7%) were identified as K. variicola and 11 (9.2%) as K. quasipneumoniae ; K1 serotype was found in 16 (13.4%), and K2 serotype in 13 (10.9%). Significant differences in the prevalence of rmpA , iutA , ybtS , entB and kfu ( p  < 0.001), and allS genes ( p  < 0.05) were found between the three phylogroups. However, there were no significant differences in clinical features, including the 30-day mortality rate, between the three organisms, although K. variicola was more frequently detected in patients over 80 years old compared with other Klebsiella species ( p  < 0.005), and K. quasipneumoniae more frequently occurred in patients with malignancy ( p  < 0.05). Conclusions Our findings demonstrated the differences in bacterial pathogenicity and clinical features among these three phylogroups. Further epidemiological studies into BSI caused by Klebsiella species are warranted.

Aortic stenosis (AS) is an important prognostic cardiovascular disease. However, there are few reports investigating the factors contributing to AS progression in patients with hemodialysis (HD). Because human arterial tissue can be easily harvested during arteriovenous fistula (AVF) surgery, we focused on the association between arterial calcification and AS progression. This is the first study with the aimed to establish a link between radial artery calcification (RAC) level and AS progression in patients with end-stage kidney disease (ESKD). All segments of the radial artery were collected during AVF surgery and stained with the Von Kossa stain. Changes in peak flow velocity (ΔVmax) were calculated based on two echocardiographic findings, and the relationship between RAC level and ΔVmax was analyzed. In the univariate analysis, RAC level, baseline peak aortic jet velocity (Vmax), and age were found to contribute to ΔVmax. After adjusting for age, sex, presence of diabetes, and Vmax at HD initiation, RAC level emerged as an independent factor contributing to ΔVmax. In conclusion, a high RAC level may be a predictor of subsequent development and progression of AS after HD initiation. Our findings may help identify this high-risk group and provide targeted healthcare interventions.