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Background: Bempedoic Acid (BA) is a novel drug that has a potential to serve as an alternative to statins to decrease lipid levels and improve cardiovascular disease (CVD) outcomes, particularly for statin-intolerant individuals. However, insufficient statistical power has limited our understanding of the efficacy and safety of BA. This meta-analysis utilizes the latest data to improve our knowledge of BA's effects on lipids and CVD with increased statistical power. Methods: MEDLINE, Embase, Cochrane Central, Clinicaltrials.gov, abstracts of national and international conferences, and reference lists of studies were searched for relevant studies. Rayyan was used to screen the search results, and Revman 5.3 was used for the meta-analysis and sensitivity analysis. Results: Our final analysis included seven randomized control trials (RCTs) with 17,782 participants, 53.6 % in the BA group (n = 9535) and 46.4 % in the placebo group (n = 8247). BA significantly decreased major adverse cardiovascular events (MACE) (OR: 0.86; 95 % CI 0.78-0.95; p = 0.03), non-fatal myocardial infarction (OR 0.72; 95 % CI 0.61-0.85; p = 0.0001), and new onset/worsening diabetes (OR:0.55; 95 % CI 0.30-0.98, p = 0.04), while reducing low-density lipoprotein cholesterol (LDL-C) levels by 22.5 % (MD: -22.53 %; 95 % CI -25.54 to -19.52, p < 0.00001). Conclusion: The findings of this meta-analysis suggest that BA is a promising and effective alternative to statin therapy, particularly for statin-intolerant and high CVD-risk patients. However, further studies with diverse populations are needed to quantify the long-term efficacy and safety endpoints.
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Hypertension is a highly prevalent chronic disease that leads to a significant number of deaths and disabilities as a consequence of cardiovascular complications. However, there is insufficient information regarding research trends and performance assessments from South Asian countries, including Pakistan. In this review, we analyzed research data related to hypertension from Pakistan over the last 20 years (2003-2022). We used the Web of Science (WoS) database to retrieve research data related to hypertension from Pakistan, and then applied scientometric analysis using the "R-Bibliometrix" package. An extensive range of indicators was studied to determine the quality and quantity of these hypertension-related publications. A total of 4,008 research articles from 891 sources were extracted through WoS over the last 20 years (2003-2022). There was a continuous growth in the number of research articles, with relatively more increase observed from 2012, and maximum output in 2021. Among 16,855 authors contributing from 67 countries, three authors had >50 publications and five had >1,500 citations. The country's leading affiliation was the Aga Khan University which showed networking trends with international institutes while the other national universities restricted their institutional partnerships to the provincial or city level. The Higher Education Commission was the only local sponsoring institute among the top funding sources. Pakistan Journal of Medical Sciences was the leading and most consistent source, whereas hypertension, diabetes mellitus, and obesity were the most frequently used keywords. This review provides a comprehensive account of hypertension-related research productivity from Pakistan. Some characteristic trends were detected for top authors' contributions, impact, productivity, international collaborations, funding sources, and institutional affiliations. Particularly, the funding sources and collaboration patterns of corresponding authors along with their affiliated institutes showed striking results. These findings can be very helpful for the relevant stakeholders in the accurate interpretation of trends and performance of hypertension-related research work from the region.
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Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-ß and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
Subject(s)
CRISPR-Cas Systems , Pancreatic Neoplasms , Animals , Humans , Mice , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Gemcitabine , Gene Expression Regulation, Neoplastic , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Ubiquitin-Specific Proteases/genetics , Ubiquitin-Specific Proteases/metabolismABSTRACT
A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Klatskin Tumor , Humans , Klatskin Tumor/therapy , Klatskin Tumor/surgery , Treatment Outcome , Hepatectomy/methods , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/therapy , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/therapy , Bile Ducts, Intrahepatic/pathology , Cholangiopancreatography, Endoscopic Retrograde , DrainageABSTRACT
Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Subject(s)
Mutation , Protein Stability , Tumor Suppressor Protein p53 , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Humans , Mice , Female , CRISPR-Cas Systems , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Gene Expression Regulation, Neoplastic , Clustered Regularly Interspaced Short Palindromic RepeatsABSTRACT
BACKGROUND: Neurosurgery is a rapidly advancing surgical specialty. Social media has significantly impacted the landscape of advancements in the field of neurosurgery. Research on the subject of neurosurgery and social media plays a vital role in combating disability and mortality due to neurological diseases, especially in trauma-affected individuals by increasing cooperation and sharing of clinical experiences between neurosurgeons via social media. This study aimed to evaluate the global neurosurgery and social media research performance from 2004 to 2023. METHODS: All the data for neurosurgery and social media-related research publications from 2004 to 2023 were extracted from the Web of Science database and a comprehensive analysis was performed on the R-bibliometrix package. RESULTS: An increasing number of publications with an annual growth rate of 22.04% was observed, with >91% of total articles published in the last decade. The United States, the United Kingdom, Italy, France, Canada, and India made up of more than 67% of the global contribution. Out of 1449 authors, Chaurasia B was the most productive with 14 publications and the most globally cited document was JEAN WC, 2020 with 117 citations. The University of Cambridge was the leading institutional affiliation. World Neurosurgery was the most productive with >60 articles. CONCLUSIONS: Exploring neurosurgery on social media enhances global collaboration, utilizing dynamic platforms for real-time knowledge exchange and holds immense potential for the field's global advancement.
Subject(s)
Bibliometrics , Neurosurgery , Social Media , Social Media/trends , Neurosurgery/trends , HumansABSTRACT
Post-liver transplantation biliary complications remain a serious concern and are associated with reduced patient and graft survival. Among various biliary complications, anastomotic stricture (AS) is the most frequent and challenging one. The frequency of AS after living donor liver transplantation (LDLT) is higher as compared to deceased donor liver transplantation. The management involves endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic biliary drainage, but refractory cases necessitate surgical revision. We present a case of complex biliary AS in a 63-year-old man after LDLT. The conventional approaches including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and cholangioscope-guided interventions remained unsuccessful. An innovative approach using a wire-guided sphincterotome through percutaneous transhepatic route successfully managed the complex post-LDLT AS. This is perhaps the first reported case of novel utilization of sphincterotome through transhepatic route for the management of AS in LDLT, averting major surgical interventions with related morbidity and mortality.
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Retained surgical sponge is a relatively rare medical condition with potential serious medicolegal implications. The term "gossypiboma" is frequently used to describe this condition. We present a case of a 40-cm-long retained surgical sponge in a 43-year-old woman who presented with unexplained chronic abdominal pain for several years. She had a history of open cholecystectomy, hepaticojejunostomy, and enteroenterostomy. Computed tomography scan revealed a large cotton sponge anchored within the large bowel. Surgical exploration is usually required for the retrieval of gossypiboma. However, it was successfully removed endoscopically using a diathermic needle knife with no immediate complications. The patient was discharged after 48 hours with marked improvement in her abdominal pain. This case emphasizes the emerging role of novel endoscopic interventions, resulting in excellent clinical outcomes, avoiding major surgical interventions, and providing cost-effective benefits.
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Background and Objective: Patient safety is a major concern in health care. Research is an important tool to minimize preventable errors. Research performance and trends evaluation need to be identified for future guidance. Our objective was to evaluate the research performance in Arab World countries related to patient safety so that real picture is available to all stake holders for future application. Methods: This was a descriptive exploratory study carried at King Abdulaziz University Jeddah, using Bibliometric analyses on Web of Science extracted data, exploring the research publications related to Patient Safety from the Arab World in last two decades (2001-2020). Digital resources were used. Data collected was further explored to see the trends. Results: Only 2% of total worldwide publications on Patient Safety were from Arab World. A positive trend, however, has emerged since 2015. Out of 5940 documents identified, only 383 had single authorship. Egypt and Saudi Arab were the major contributors. Other countries had less or even zero publications. Researchers are coordinating with others in Western countries to enhance the research productivity. Cairo University with 734 publications had most affiliations. Publications on safety culture and medication safety were frequent. Hospital Acquired Infections and error reporting had limited research. Conclusion: Researches on patient safety in the Arab World are not sufficient. Countries other than Egypt and Saudi Arabia also need to contribute more frequently. Critical problems, like Hospital Acquired Infections, should have regular research from all countries to assist those treating patients and those making health related policies.
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Thorax disease is a life-threatening disease caused by bacterial infections that occur in the lungs. It could be deadly if not treated at the right time, so early diagnosis of thoracic diseases is vital. The suggested study can assist radiologists in more swiftly diagnosing thorax disorders and in the rapid airport screening of patients with a thorax disease, such as pneumonia. This paper focuses on automatically detecting and localizing thorax disease using chest X-ray images. It provides accurate detection and localization using DenseNet-121 which is foundation of our proposed framework, called Z-Net. The proposed framework utilizes the weighted cross-entropy loss function (W-CEL) that manages class imbalance issue in the ChestX-ray14 dataset, which helped in achieving the highest performance as compared to the previous models. The 112,120 images contained in the ChestX-ray14 dataset (60,412 images are normal, and the rest contain thorax diseases) were preprocessed and then trained for classification and localization. This work uses computer-aided diagnosis (CAD) system that supports development of highly accurate and precise computer-aided systems. We aim to develop a CAD system using a deep learning approach. Our quantitative results show high AUC scores in comparison with the latest research works. The proposed approach achieved the highest mean AUC score of 85.8%. This is the highest accuracy documented in the literature for any related model.
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BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe upper respiratory tract infections known as COVID-19. This single-center study aimed to investigate the demographics, comorbidities, symptoms, and disease severity of COVID-19 patients in Pakistan. METHODS: A retrospective descriptive study was conducted at the Pakistan Kidney and Liver Institute and Research Center from April 2020 to August 2020. A total of 430 PCR-positive COVID-19 patients were categorized into symptomatic and asymptomatic groups. The symptomatic group was further classified into severe and non-severe subgroups. Patients' demographics, comorbid conditions, presenting symptoms, laboratory parameters, and clinical outcomes were assessed in these two subgroups. Statistical tests were applied to determine significant differences. RESULTS: A total of 430 patients with COVID-19 presented in our center, of whom 334 (78%) were symptomatic and included in the study. Severe disease was observed in 83 (24.8%) symptomatic patients, with a male predominance (75.9%) and higher mean age (61.7 ± 13.2). Travel to high-risk destinations (p < 0.002) and close contact with COVID-19 patients (p < 0.001) were significant risk factors. Major comorbid conditions included diabetes mellitus (30.5%) and hypertension (39.8%). Frequent symptoms included fever (71.8%), cough (68.8%), dyspnea (53.8%), and myalgias (35.9%). Higher C-reactive protein (median = 12.76 vs. 1.45, p = 0.001), ferritin (median = 996.70 vs. 628, p = 0.004), and D-dimers (median = 1121 vs. 439.50, p = 0.009) were noted in severe vs non-severe disease. Lymphopenia was more prevalent in severe vs. non-severe disease (83.1% vs. 14.3% p-value = 0.033). More deaths (28.9%) and ICU admissions (53%) with a prolonged hospital stay (median = 25 days, IQR = 16.0-31.0) were noted in the severe group. CONCLUSION: This retrospective study provides insights into the clinical characteristics and outcomes of COVID-19 patients. Age, male gender, comorbidities, and specific symptoms were associated with disease severity. Inflammatory markers, including D-dimers, ferritin, and CRP, were elevated in severe cases. These findings contribute to a better understanding of COVID-19 and may aid in clinical management and decision-making for patients affected by the disease.
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The COVID-19 pandemic has brought vaccination to the forefront of global attention. The Pfizer-BioNTech vaccine, an mRNA vaccine that encodes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) glycoprotein spike, has emerged as a significant player in global vaccination efforts. It is generated from lipid nanoparticles and has been subject to various regulatory approvals and authorizations. The United Kingdom became the first country to approve the Pfizer vaccine on December 2, 2020. The World Health Organization (WHO) authorized the emergency use of the Pfizer vaccine on December 31, 2020, facilitating its production and distribution worldwide. In Saudi Arabia, as well as globally, concerns about the safety and effectiveness of vaccines have been raised. Several studies have reported side effects of the Pfizer vaccine, including rare conditions such as myocarditis. In our study, we aimed to systematically investigate the symptoms experienced after vaccination, considering the administration of three doses. We also explored the duration of these symptoms and whether they necessitated hospital visits, primary healthcare interventions, or resolved on their own. Our study employed an online cross-sectional design conducted in Jeddah, Saudi Arabia, utilizing an online self-reported survey. A total of 332 participants who met the predefined criteria were recruited for the study. The rate of COVID-19 infection after 1st and 2nd doses of Pfizer and AstraZeneca vaccines was significantly lower in middle-age subgroups (31-45 years), in comparison to young (18-30 years) and upper middle-age subgroups (46-60 years). For the AstraZeneca vaccine, the infection rate in the middle-aged group was higher after 2nd dose as compared to its 1st dose. Overall, greater infection rates were observed in upper-middle-aged subgroups with all doses of Pfizer and AstraZeneca vaccines. Fatigue and fever were the most common generalized side effects while redness/swelling/pain at the injection site, muscle pain, and joint pain were the most important local side-effects. Fatigue, fever, muscle pain, and joint pain were significantly common after 1st dose of Pfizer and fever was a significant side effect after 2nd dose of Pfizer in comparison to AstraZeneca doses. Understanding the spectrum of side effects associated with the vaccine is crucial for healthcare professionals and individuals receiving the vaccine, as it enables informed decision-making and appropriate management of potential adverse reactions.
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OBJECTIVES: The present study investigated osteoprotegerin (OPG) genetic polymorphisms and their influence on the therapeutic response to ibandronate in postmenopausal osteoporotic females. METHODS: This case-control study included 135 postmenopausal females (89 osteoporotic females and 46 non-osteoporotic females). Each osteoporotic patient received a monthly 150 mg ibandronate tablet for six months, and blood samples were taken before and after treatment. Bone mineral density (BMD) was measured using DEXA Scan. Three SNPs (A163G, T245G, and G1181C) of the OPG gene were selected for analysis. RESULTS: Serum OPG levels were significantly lower in osteoporotic subjects than in the control group. The percentage changes in OPG levels in the osteoporotic group before and after treatment with ibandronate were significant (p < .001). After six months of therapy with ibandronate, the percentage changes in OPG levels with AA, TT, TC, GC, and GG genotypes were significant. Following six months of ibandronate treatment, the AA genotype of rs3134069, TT, TC genotypes of rs3102735, GG, and GC genotypes of rs2073618 SNP showed a significant increase in OPG levels. Age, BMI, and GC polymorphism (rs2073618 (G/C) G1181C) were inversely associated with low BMD. Adjusted odds ratios (OR) showed that BMI, GC, GG polymorphism (rs2073618 (G/C) G1181C) and TC polymorphism (rs3102735 (T/C) A163G) were inversely associated with low BMD. CONCLUSION: The inverse association of rs2073618 and rs3102735 with low BMD indicates the protective role of these SNPs in our population. More research is needed to replicate these results in another cohort and to determine the molecular processes by which such SNPs may influence BMD.
Subject(s)
Bone Diseases, Metabolic , Osteoprotegerin , Humans , Female , Ibandronic Acid , Osteoprotegerin/genetics , Case-Control Studies , Postmenopause/genetics , Polymorphism, Single NucleotideABSTRACT
Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational "Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease"-LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD (n = 114) and further subdivided into mild (n = 66) and severe type 1 GD (n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.
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Coronaviruses are a well-established and deadly group of viruses that cause illness in both humans and animals. The novel type of this virus group, named COVID-19, was firstly reported in December 2019, and, with the passage of time, coronavirus has spread to almost all parts of the world. Coronavirus has been the cause of millions of deaths around the world. Furthermore, many countries are struggling with COVID-19 and have experimented with various kinds of vaccines to eliminate the deadly virus and its variants. This survey deals with COVID-19 data analysis and its impact on human social life. Data analysis and information related to coronavirus can greatly help scientists and governments in controlling the spread and symptoms of the deadly coronavirus. In this survey, we cover many areas of discussion related to COVID-19 data analysis, such as how artificial intelligence, along with machine learning, deep learning, and IoT, have worked together to fight against COVID-19. We also discuss artificial intelligence and IoT techniques used to forecast, detect, and diagnose patients of the novel coronavirus. Moreover, this survey also describes how fake news, doctored results, and conspiracy theories were spread over social media sites, such as Twitter, by applying various social network analysis and sentimental analysis techniques. A comprehensive comparative analysis of existing techniques has also been conducted. In the end, the Discussion section presents different data analysis techniques, provides future directions for research, and suggests general guidelines for handling coronavirus, as well as changing work and life conditions.
Subject(s)
COVID-19 , Social Media , Humans , COVID-19/epidemiology , Artificial Intelligence , SARS-CoV-2 , Machine LearningABSTRACT
BACKGROUND: Hepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. OBJECTIVE: Our study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. METHODS: This is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at -80 °C until the end of recruitment. Gas chromatography-mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis-mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. RESULTS: The recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. CONCLUSIONS: There is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44264.
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How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.
Subject(s)
Antineoplastic Agents , Fertilins , Lung Neoplasms , Serpins , Animals , Humans , Male , Mice , Antigens, Neoplasm , Fertilins/genetics , Immunotherapy , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Membrane Proteins/genetics , Serpins/genetics , T-Lymphocytes, Cytotoxic , Tumor MicroenvironmentABSTRACT
Impaction of Dormia basket while extracting common bile duct (CBD) stones during endoscopic retrograde cholangiopancreatography is a well-known but relatively rare complication. Its management could be very challenging and may require percutaneous, endoscopic, or major surgical intervention. In this study, we present a case of a 65-year-old man with a history of obstructive jaundice secondary to a large CBD stone. For stone extraction, mechanical lithotripsy with a Dormia basket was attempted resulting in its entrapment within CBD. Subsequently, the entrapped basket and large stone were retrieved using a novel technique of cholangioscope-guided electrohydraulic lithotripsy with excellent clinical outcomes.
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Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.