Abstract BACKGROUND: Blood test has a better uptake for colorectal cancer screening than stool test and colonoscopy but suboptimal detection of early-stage colorectal neoplasia (CRN), including advanced adenoma and stage I cancer, limits its application. The present study aimed to evaluate whether clonal hematopoiesis (CH) from peripheral blood can be used as a biomarker for early-stage CRN screening and improve the detection of blood tests by machine-learning approach. METHODS: The CH profile was evaluated in 63 early-stage CRNs and 32 controls by error-corrected sequencing and classified by machine-learning method. Diagnostic performance was measured by receiver operator characteristic analysis. Additional 20 early-stage CRNs and 10 controls were used to validate the machine-learning model. We simultaneously used mutational signature analysis to study predictors based on CH. RESULTS: We identified 1,446 variants and clarified the uniqueness of variants from the peripheral bloods of early-stage CRNs. The machine learning model identified early-stage CRNs from controls and its AUC, sensitivity and specificity were 0.988, 94.2% and 99.3%, respectively. The CH-based CRN detection model was further verified. The accuracy, sensitivity, and specificity were 0.933 ( p =0.00065), 95.0%, and 90.0%, respectively. Furthermore, the mutational signature analysis of those unique variants in CRNs revealed the influence of genetic architecture on DNA damages. CONCLUSIONS: Our results reveal the potential of CH to a mark produced by the carcinogenesis in early-stage CRN. We developed a CH-based blood test with machine learning approach, which not only increase screening uptake but also improve the detection rate of early-stage CRN.
Patient participation in colorectal cancer (CRC) screening via a stool test and colonoscopy is suboptimal, but participation can be improved by the development of a blood test. However, the suboptimal detection abilities of blood tests for advanced neoplasia, including advanced adenoma (AA) and CRC, limit their application. We aimed to investigate the proteomic landscape of small extracellular vesicles (sEVs) from the serum of patients with colorectal neoplasia and identify specific sEV proteins that could serve as biomarkers for early diagnosis.We enrolled 100 patients including 13 healthy subjects, 12 non-AAs, 13 AAs, and 16 stage-I, 15 stage-II, 16 stage-III, and 15 stage-IV CRCs. These patients were classified as normal control, early neoplasia, and advanced neoplasia. The sEV proteome was explored by liquid chromatography-tandem mass spectrometry. Generalized association plots were used to integrate the clustering methods, visualize the data matrix, and analyze the relationship. The specific sEV biomarkers were identified by a decision tree via Orange3 software. Functional enrichment analysis was conducted by using the Ingenuity Pathway Analysis platform.The sEV protein matrix was identified from the serum of 100 patients and contained 3353 proteins, of which 1921 proteins from 98 patients were finally analyzed. Compared with the normal control, subjects with early and advanced neoplasia exhibited a distinct proteomic distribution in the data matrix plot. Six sEV proteins were identified, namely, GCLM, KEL, APOF, CFB, PDE5A, and ATIC, which properly distinguished normal control, early neoplasia, and advanced neoplasia patients from each other. Functional enrichment analysis revealed that APOF+ and CFB+ sEV associated with clathrin-mediated endocytosis signaling and the complement system, which have critical implications for CRC carcinogenesis.Patients with colorectal neoplasia had a distinct sEV proteome expression pattern in serum compared with those patients who were healthy and did not have neoplasms. Moreover, the six identified specific sEV proteins had the potential to discriminate colorectal neoplasia between early-stage and advanced neoplasia. Collectively, our study provided a six-sEV protein biomarker panel for CRC diagnosis at early or advanced stages. Furthermore, the implication of the sEV proteome in CRC carcinogenesis via specific signaling pathways was explored.
Chronic kidney disease with azotemia and proteinuria are prominent features of classical Fabry disease. Fabry disease is an X-linked recessive lysosomal storage disorder caused by α-galactosidase A deficiency. We report a 42-year-old Taiwanese male, who received check-up for the possibility of renal disease in a renal clinic, with the complaints of proteinuria and edema of bilateral lower legs for years. Symptoms as acroparesthesia, angiokeratoma and hypohidrosis have bothered him since childhood but have been neglected by many physicians. The percutaneous renal biopsy showed vacuolated podocytes on light microscopy and myeloid bodies in podocytes on electron microscopy. α-galactosidase A enzyme assay revealed 0.166 nmol/mg prot/hr (0.43% of normal value). Thus, Fabry disease was confirmed. The patient was treated with enzyme replacement therapy. Fabry disease might be rare and easily overlooked without highly clinical suspicion. Herein, we review the literature on clinical manifestations, course, and outcome of Fabry disease.
Background: Global transmission from imported cases to domestic cluster infection is often the main route for the resultant community-acquired outbreaks facing the emerging SARS-CoV-2 variants. It is so important to monitor imported cases as to foretell outbreaks given various containment measures. Methods: We used Taiwanese COVID-19 epidemic data, mainly covering D614G and three VOCs (Alpha, Delta, and Omicron) from Jan 2020 to Jan 2022 to estimate the increased risk of domestic cluster infection per one imported case by type of variants given NPIs, test, and vaccination using an extra-Poisson regression model. The upper limit of predicted value one week before is used as the threshold for alerting community-acquired outbreak.Findings: An increase in one imported D614G case prior to one week led to 9·54% (95% CrI 6·44% to 12·59%) higher risk of domestic infection, yielding five clusters with the observed cases beyond the 95% upper limit but they did not lead to any outbreak due to effective contact tracing of infectives and the elevation to NPI level two. The risk of domestic cluster infections in Jan 2021 was gradually elevated to 14·14% (95% CrI 5·41% to 25·10%) until the end of April. The failure of timely contact tracing together with the loose of NPI led to the outbreak of Alpha VOC in mid-May 2021. After stamping out the outbreak with raising level three of NPI and rolling out of vaccination, surveillance of imported cases of Delta VOCs prevented any outbreak until Nov 2021. During Omicron pandemic from mid-Dec 2021 onwards, surveillance of imported cases found the observed cases exceeding the alert threshold around early Jan 2022, leading to a small-scale community-acquired outbreak.Interpretation: The proposed model for monitoring imported cases can be used as a global surveillance tool for forestalling large-scale community-acquired outbreak once SARS-CoV-2 VOCs emerges.Funding Information: This study was funded by Ministry of Science and Technology, Taiwan (MOST 108-2118-M-002-002-MY3; MOST 108-2118-M-038-001-MY3; MOST 108-2118-M-038 -002 -MY3; MOST 109-2327-B-002-009). Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study uses publicly available case line list without any private and identifiable information and does not require IRB approval.
Investigations of genetic alterations and correlations with histology or morphology could provide further insights into colorectal carcinogenesis. Nevertheless, such genetic changes were less investigated in adenoma stage and a comprehensive survey of oncogenic mutations in EGFR signaling pathway according to different morphologic subtypes has not been performed.A total of 94 neoplasms, including 34 polypoid adenoma, 16 lateral spreading tumors-granular (LST-G), 20 non-granular LST (LST-NG), and 24 depressed tumors, were subjected for mutational analysis of KRAS (exon 2), BRAF (exon 11 and 15), PIK3CA (exon 9 and 20), AKT (exon 4), EGFR (exon 18-24) and HER2 (exon18-24).KRAS mutation was noted more frequently in LST (13/36, 36.1%) than polypoid neoplasms (5/34, 14.7%, p = 0.041). When comparing with LST-NG, LST-G had a significantly higher frequency of KRAS mutation. (9/16, 56.3% vs. 4/20, 20.0%, p = 0.024). BRAF mutation (V600E) was found in 2 of 36 (5.6%)LSTs and 1 of 34 (2.9%) polypoid lesions. The two LST lesions with BRAF mutation were pathologically proven to be serrated adenoma. PIK3CA mutation (exon 9 E545K) was identified only in LST (5/36, 13.9%). Mutations in KRAS, BRAF or PIK3CA occurred in a mutually exclusive manner. All mutations were absent in the specimens obtained from depressed type neoplasms.Three different macroscopic subtypes of colorectal neoplasms display distinct carcinogenetic pathways in EGFR networking. Further molecular studies of CRCs should take macroscopic subtypes into consideration and highlight the importance of consensus and communication between endoscopic and pathologic diagnosis.
Recently, researchers have focused on the authentication and key agreement (AKA) approach to enable a secure vehicle-to-everything (V2X) interface. Often, these security measures are effective against passive snoopers who tap the links to decipher the conversation. Nevertheless, it has been noted that if the protocol were severely constructed, an active saboteur may mimic legal vehicles or change the broadcast message. In this paper, we cryptanalyze a recently proposed AKA protocol shown as lightweight compared to the state-of-the-art. We employ conventional and cutting-edge techniques to decipher algebraic systems while releasing many forgeries. Using cryptanalysis, we demonstrate that the algorithms and characterizations of this protocol are susceptible to a range of security concerns, such as insufficient anonymity, session-independent key agreement, exposing multiple keys, replay, and vehicle impersonation. In addition, this article provides remarks for developing a secure lightweight V2X authentication system.
Carbon dioxide (CO2) insufflation during colonoscopy can significantly decrease abdominal pain and bloating after the procedure, but its impact on the frequency and duration of toilet use remains unknown. The aim of this study was to assess the impact of CO2 insufflation on toilet use after screening colonoscopy.From 138 average-risk individuals who underwent screening colonoscopy during March to August 2013, 120 were enrolled and randomized to receive either CO2 or air insufflation at colonoscopy. Both the colonoscopist and participant were blinded to the type of gas used. Abdominal pain and distension were assessed using a visual analog scoring system. The frequency and duration of toilet visits during a 2-hour postcolonoscopy period were recorded using a radiofrequency identification system.Baseline characteristics were similar in both groups in terms of age, sex, and procedure time. In the 2 hours after colonoscopy, 50 participants (83 %) in the air group and 18 participants (30 %) in the CO2 group (P < 0.001) used the toilet at least once. The mean (± SD) duration of each toilet visit was 5.93 ± 4.65 minutes in the air group and 1.53 ± 2.84 minutes in the CO2 group (P < 0.001). The abdominal discomfort score was lower in the CO2 group than in the air group both at the end of the colonoscopy (P < 0.001) and 2 hours later (P < 0.001).Insufflation with CO2 can significantly reduce abdominal discomfort and toilet use after colonoscopy. Use of this technique may help reduce patient burden and allow more efficient use of space in the endoscopy unit.
'/%3e%3cuse xlink:href='%23a' transform='rotate(60)'/%3e%3ccircle r='17' fill='%23000095'/%3e%3ccircle r='15' fill='%23fff'/%3e%3c/svg%3e)
