Publications by authors named "Ahmed Nabil"

89 Publications

Temperature responsive smart polymer for enabling affinity enrichment of current coronavirus (SARS-CoV-2) to improve its diagnostic sensitivity.

Comput Struct Biotechnol J 2021 14;19:3609-3617. Epub 2021 Jun 14.

Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1Namiki, Tsukuba, Ibaraki 305-0044, Japan.

The current commercially available SARS-CoV-2 diagnostic approaches including nucleic acid molecular assaying using polymerase chain reaction (PCR) have many limitations and drawbacks. SARS-CoV-2 diagnostic strategies were reported to have a high false-negative rate and low sensitivity due to low viral antibodies or antigenic load in the specimens, that is why even PCR test is recommended to be repeated to overcome this problem. Thus, in anticipation of COVID-19 current wave and the upcoming waves, we should have an accurate and rapid diagnostic tool to control this pandemic. In this study, we developed a novel preanalytical strategy to be used for SARS-CoV-2 specimen enrichment to avoid misdiagnosis. This method depends on the immuno-affinity trapping of the viral target followed by in situ thermal precipitation and enrichment. We designed, synthesized, and characterized a thermal-responsive polymer poly (N-isopropylacrylamide-co-2-hydroxyisopropylacrylamide-co-strained alkyne isopropylacrylamide) followed by decoration with SARS-CoV-2 antibody. Different investigations approved the successful synthesis of the polymeric antibody conjugate. This conjugate was shown to enrich recombinant SARS-CoV-2 nucleocapsid protein samples to about 6 folds. This developed system succeeded in avoiding the misdiagnosis of low viral load specimens using the lateral flow immunoassay test. The strength of this work is that, to the best of our knowledge, this report may be the first to functionalize SARS-CoV-2 antibody to a thermo-responsive polymer for increasing its screening sensitivity during the current pandemic.
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http://dx.doi.org/10.1016/j.csbj.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200327PMC
June 2021

A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma.

Sci Transl Med 2021 05;13(592)

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αβ T cell receptor-expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8 T cell populations (CD8NK1.1) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8NK1.1 T cells. Adoptive transfer of CD8NK1.1 cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8NK1.1 cells. Freshly isolated human CD8CD61 T cells exhibited heightened allogeneic killing activity in comparison to CD8CD61 T cells or total peripheral blood mononuclear cells (PBMCs). To determine whether this subset might improve the antitumor efficacy of CAR T cell therapy against solid tumors, we compared bulk PBMCs, CD8CD161, and CD8CD161 T cells transduced with a human epidermal growth factor receptor-2 (HER2)-specific CAR construct. In vitro, CD8CD161 CAR-transduced T cells killed HER2 targets faster and with greater efficiency. Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2 pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.
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http://dx.doi.org/10.1126/scitranslmed.abc3196DOI Listing
May 2021

Conjugation of antibody with temperature-responsive polymer click reaction to enable biomarker enrichment for increased diagnostic sensitivity.

Biomater Sci 2021 Jul;9(14):4870-4879

Research Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-1Namiki, Tsukuba, Ibaraki 305-0044, Japan. and Department of Materials Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika, Tokyo 125-8585, Japan and Graduate School of Pure and Applied Sciences, University of Tsukuba, Ten-nodai, Tsukuba, Ibaraki 305-8577, Japan and Department of Bioengineering, University of Washington, USA.

Early diagnosis of infectious diseases is one of the current prevalent challenges, especially in low and limited resource settings where simple, fast, portable, cheap, and sensitive diagnostic approaches are needed. Lateral flow immunoassay (LFIA) is a common, rapid screening assay. However, the low assay sensitivity limits the utility of LFIA for specimens with low pathogenic loads (early infection stages). Antibodies conjugated with stimulus-responsive polymers have been previously utilized to improve assay sensitivity for detection of biomarkers at low concentrations. However, the loss of antibody affinity after polymer conjugation remains a significant challenge. In this study, we developed poly(N-isopropylacrylamide-co-N-(2-hydroxyisopropyl)acrylamide-co-strained alkyne-isopropylacrylamide), a novel polymer for biomarker enrichment, by polymer conjugation after antibody-antigen recognition. We employed and promoted the click chemistry in situ, to facilitate highly specific conjugation between novel temperature-responsive polymers and antibody-antigen complexes. This method could suppress the decrease in the binding constant associated with polymer conjugation (>20-fold). The conjugation was successfully demonstrated in body fluids such as urine and saliva. We achieved >5-fold antigen enrichment via thermal precipitation by conjugating polymers to the antibodies after antigen recognition. Concentrated biomarkers resulted in improved LFIA detection. This approach can potentially be utilized to improve diagnostic tests for infectious diseases in low and limited resource settings.
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http://dx.doi.org/10.1039/d1bm00349fDOI Listing
July 2021

The Potential Safe Antifibrotic Effect of Stem Cell Conditioned Medium and Nilotinib Combined Therapy by Selective Elimination of Rat Activated HSCs.

Biomed Res Int 2021 28;2021:6678913. Epub 2021 Mar 28.

Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt.

Hepatic fibrosis is a progressive disease with serious clinical complications that arise from abnormal propagation and activation of multiple inflammatory pathways. Nilotinib is an oral tyrosine kinase inhibitor with antifibrotic activity. Mesenchymal stem cells (MSCs) are blank cells and can differentiate into specific cell types. They have the potential to repair and regenerate cells. MSCs have a special paracrine fashion where they produce special exosomes, microvesicles, and cytokines like IL-6, transforming growth factor-beta (TGF-), and HGF as well as hepatic stellate cell suppressors. This paracrine fashion can decrease collagen deposition, enhance antifibrotic, anti-inflammatory, and angiogenic activity in vitro and in vivo. In our study, the rat's hepatic stellate cells (HSCs) in addition to different normal cell lines were treated with Nilotinib alone and in combination with liver mesenchymal stem cells conditioned medium (LMSCs-CM) for 24 h. Mono and combined therapy antifibrotic and cytotoxicity effects were evaluated using different parameters including -SMA, cytochrome c, P53 expression, collagen deposition, DNA content, oxidative stress parameters, cell viability, and apoptosis by flow cytometry analysis. Our results showed that Nilotinib and LMSCs-CM in combination had a significantly potent antifibrotic and anti-inflammatory effect on activated hepatic stellate cells than Nilotinib alone; otherwise, this combination showed the best safety with minimal cytotoxicity on different normal cell lines.
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http://dx.doi.org/10.1155/2021/6678913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021473PMC
May 2021

Coronavirus (SARS-CoV-2) in gastroenterology and its current epidemiological situation: An updated review until January 2021.

EXCLI J 2021 16;20:366-385. Epub 2021 Feb 16.

Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1Namiki, Tsukuba, Ibaraki 305-0044, Japan.

Coronaviruses are positive-sense single-strand RNA viruses that infect amphibians, birds, and mammals. Coronavirus Disease 2019 (COVID-19) has become a major health problem caused by one of the coronaviruses called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread fast throughout the globe since its first identification in Wuhan, China, in December 2019. Although COVID-19 is principally defined by its respiratory symptoms, it is now clear that the virus can also affect the digestive system causing gastrointestinal (GI) symptoms like diarrhea, loss of appetite, nausea/vomiting, and abdominal pain as a major complaint. GI symptoms could be the initial signs of preceding respiratory signs, carrying a potential for slowed investigation and raised disease transmission opportunities. Various studies recognized the COVID-19 RNA in stool specimens of infected patients, and its viral receptor angiotensin-converting enzyme-2 (ACE-2) is highly expressed in GI epithelial cells. Many cases were reported negative using nasopharyngeal/oropharyngeal swabs and finally, SARS-CoV-2 RNA was detected in their anal/rectal swabs and stool specimens. These suggest that COVID-19 can actively infect and replicate in the GI tract. In this review, we elaborate on the close relationship between SARS-CoV-2 and the digestive system, focusing on the current status in the field of COVID-19 in gastroenterology, liver injury, endoscopy, inflammatory bowel disease, imaging, and the potential underlying mechanisms with illustrating the current epidemiological status regarding this pandemic.
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http://dx.doi.org/10.17179/excli2021-3417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975638PMC
February 2021

COVID-induced pancreatitis: case report.

Egypt J Intern Med 2021 8;33(1):10. Epub 2021 Mar 8.

Department of General Surgery, Kasr Al-Ainy School of Medicine, Cairo University, Cairo, Egypt.

Background: Although the frequent respiratory affection in COVID-19, it is well established that it could be presented with a wide variation of gastrointestinal symptoms; however, it is the effect on the pancreas remains unclear.

Case Presentation: We report a case of female patient, who was diagnosed with COVID-19 infection. A week later, the patient developed an attack of acute pancreatitis. Other causes of acute pancreatitis were excluded. Therefore, this was attributed to SARS-COV2 infection.

Conclusion: The case raises awareness about the possibility of acute pancreatitis in COVID-19. Also emphasize the importance of measuring serum amylase and lipase in patients with COVID-19.
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http://dx.doi.org/10.1186/s43162-021-00039-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937440PMC
March 2021

Immunogenicity of CAR T cells in cancer therapy.

Nat Rev Clin Oncol 2021 06 25;18(6):379-393. Epub 2021 Feb 25.

Berlin Center for Advanced Therapies (BeCAT) and Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Patient-derived T cells genetically reprogrammed to express CD19-specific chimeric antigen receptors (CARs) have shown remarkable clinical responses and are commercially available for the treatment of patients with certain advanced-stage B cell malignancies. Nonetheless, several trials have revealed pre-existing and/or treatment-induced immune responses to the mouse-derived single-chain variable fragments included in these constructs. These responses might have contributed to both treatment failure and the limited success of redosing strategies observed in some patients. Data from early phase clinical trials suggest that CAR T cells are also associated with immunogenicity-related events in patients with solid tumours. Generally, the clinical implications of anti-CAR immune responses are poorly understood and highly variable between different CAR constructs and malignancies. These observations highlight an urgent need to uncover the mechanisms of immunogenicity in patients receiving CAR T cells and develop validated assays to enable clinical detection. In this Review, we describe the current clinical evidence of anti-CAR immune responses and discuss how new CAR T cell technologies might impact the risk of immunogenicity. We then suggest ways to reduce the risks of anti-CAR immune responses to CAR T cell products that are advancing towards the clinic. Finally, we summarize measures that investigators could consider in order to systematically monitor and better comprehend the possible effects of immunogenicity during trials involving CAR T cells as well as in routine clinical practice.
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http://dx.doi.org/10.1038/s41571-021-00476-2DOI Listing
June 2021

Antioxidative Capacity of Liver- and Adipose-Derived Mesenchymal Stem Cell-Conditioned Media and Their Applicability in Treatment of Type 2 Diabetic Rats.

Oxid Med Cell Longev 2021 2;2021:8833467. Epub 2021 Feb 2.

Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.

Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance and impaired insulin secretion, which cannot be reversed with existing therapeutic strategies. Using mesenchymal stem cells (MSCs), cell-based therapy has been demonstrated in displaying therapeutic effects in T2DM for their self-renewable, differentiation potential, and immunosuppressive properties and higher levels of angiogenic factors. Stem cell therapies are complicated and have a serious adverse effect including tumor formation and immunogenicity, while using mesenchymal stem cell-conditioned media (MSC-CM) significantly reduces stem cell risk, maintaining efficacy and showing significantly higher levels of growth factors, cytokines, and angiogenic factors that stimulate angiogenesis and promote fracture healing in diabetes. In the present study, we investigated the therapeutic potential of the liver and adipose MSC-CM in diabetic endothelial dysfunction compared with standard insulin therapy. Fifty adult male Sprague Dawley rats were divided equally into 5 groups as follows: control, diabetic, diabetic+insulin, diabetic+liver MSC-CM, and diabetic+adipose MSC-CM; all treatments continued for 4 weeks. Finally, we observed that liver MSC-CM therapy had the most apparent improvement in levels of blood glucose; HbA1c; AGEs; lipid panel (cholesterol, TG, LDL, HDL, and total lipids); renal function (urea, uric acid, creatinine, and total protein); liver function (AST, ALT, ALP, bilirubin, and albumin); CPK; C-peptide; HO-1; inflammatory markers including IL-6, TNF-, and CRP; growth factors (liver and serum IGF-1); amylase; histopathological changes; pancreatic cell oxidative stress; and antioxidant markers (MDA, GSH, ROS, CAT, SOD, HO-1, and XO) toward the normal levels compared with insulin and adipose MSCs-CM. Moreover, both the liver and adipose MSC-CM relieved the hyperglycemic status by improving pancreatic islet cell regeneration, promoting the conversion of alpha cells to beta cells, reducing insulin resistance, and protecting pancreatic tissues against oxidative stress-induced injury as well as possessing the ability to modulate immunity and angiogenesis. These results indicated that MSC-CM infusion has therapeutic effects in T2DM rats and may be a promising novel therapeutic target.
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http://dx.doi.org/10.1155/2021/8833467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875634PMC
September 2021

Targeting hydrogen sulphide signaling in breast cancer.

J Adv Res 2021 Jan 16;27:177-190. Epub 2020 Jul 16.

Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt.

Introduction: Hydrogen sulphide (HS) has been established as a key member of the gasotransmitters family that recently showed a pivotal role in various pathological conditions including cancer.

Objectives: This study investigated the role of HS in breast cancer (BC) pathogenesis, on BC immune recognition capacity and the consequence of targeting HS using non-coding RNAs.

Methods: Eighty BC patients have been recruited for the study. BC cell lines were cultured and transfected using validated oligonucleotide delivery system. Gene and protein expression analysis was performed using qRT-PCR, western blot and flow-cytometry. analysis for BC hallmarks was performed using MTT, BrdU, Modified Boyden chamber, migration and colony forming assays. HS and nitric oxide (NO) levels were measured spectrophotometrically. Primary natural killer cells (NK cells) and T cell isolation and chimeric antigen receptor transduction (CAR T cells) were performed using appropriate kits. NK and T cells cytotoxicity was measured. Finally, computational target prediction analysis and binding confirmation analyses were performed using different software and dual luciferase assay kit, respectively.

Results: The HS synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), exhibited elevated levels in the clinical samples that correlated with tumor proliferation index. Knock-down of CBS and CSE in the HER2+ BC and triple negative BC (TNBC) cells resulted in significant attenuation of BC malignancy. In addition to increased susceptibility of HER2+ BC and TNBC to the cytotoxic activity of HER2 targeting CAR T cells and NK cells, respectively. Transcriptomic and phosphoprotein analysis revealed that HS signaling is mediated through Akt in MCF7, STAT3 in MDA-MB-231 and miR-155/ NOS2/NO signaling in both cell lines. Lastly, miR-4317 was found to function as an upstream regulator of CBS and CSE synergistically abrogates the malignancy of BC cells.

Conclusion: These findings demonstrate the potential role of HS signaling in BC pathogenesis and the potential of its targeting for disease mitigation.
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http://dx.doi.org/10.1016/j.jare.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728592PMC
January 2021

Endoscopic intervention in a case proven latterly to be a COVID-19.

Egypt J Intern Med 2020 25;32(1):28. Epub 2020 Nov 25.

Internal Medicine, Hepatogastroenterology Unit, Kasr Al-Ainy School of Medicine, Cairo University, Kasr Al-Aini Street, Cairo, 11451 Egypt.

Background: COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the newly developed worldwide outbreak of coronavirus disease with a high rate of mortality especially among elderly and multiple co-morbid personnel. Asymptomatic COVID-19-infected patients are a well-known source of transmission of infection. The risk of exposure to respiratory secretions and/or feces is hardly avoidable during the endoscopic procedure; also, the aerosol and droplets take up to an hour disperse, so they remain a risk to staff and other patients after they leave the room; therefore, strict infectious precautions should be taken by all health care workers to limit the virus spread.

Main Body: We present an endoscopic trial of duodenal stent insertion in non-operable gastric carcinoma that is proven 2 days later to be a COVID-19-positive case. Fortunately, no one of the health care workers that came in contact with the case becomes infected owing to the proper infection control measures.

Conclusion: We recommended that the endoscopy examination and procedures should be strictly limited to urgent cases to minimize the risk of virus infection among health care workers.
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http://dx.doi.org/10.1186/s43162-020-00029-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686812PMC
November 2020

Current coronavirus (SARS-CoV-2) epidemiological, diagnostic and therapeutic approaches: An updated review until June 2020.

EXCLI J 2020 20;19:992-1016. Epub 2020 Jul 20.

Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt.

Coronaviruses are a group of enveloped viruses with non-segmented, single-stranded, and positive-sense RNA genomes. In December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Wuhan City, China. The World Health Organization (WHO) declared the coronavirus outbreak as a global pandemic in March 2020. Fever, dry cough and fatigue are found in the vast majority of all COVID-19 cases. Early diagnosis, treatment and future prevention are keys to COVID-19 management. Currently, the unmet need to develop cost-effective point-of-contact test kits and efficient laboratory techniques for confirmation of COVID-19 infection has powered a new frontier of diagnostic innovation. No proven effective therapies or vaccines for SARS-CoV-2 currently exist. The rapidly increasing research regarding COVID-19 virology provides a significant number of potential drug targets. Remdesivir may be the most promising therapy up till now. On May 1, 2020, Gilead Sciences, announced that the U.S. Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for the investigational Remdesivir as a potential antiviral for COVID-19 treatment. On May 7, 2020, Gilead Sciences, announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted regulatory approval of Veklury® (Remdesivir) as a treatment for SARS-CoV-2 infection, the virus that causes COVID-19 acute respiratory syndrome, under an exceptional approval pathway. Also, Corticosteroids are recommended for severe cases only to suppress the immune response and reduce symptoms, but not for mild and moderate patients where they are associated with a high-risk side effect. Based on the currently published evidence, we tried to highlight different diagnostic approaches, side effects and therapeutic agents that could help physicians in the frontlines.
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http://dx.doi.org/10.17179/excli2020-2554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415934PMC
July 2020

Protective Effect of DPPD on Mercury Chloride-Induced Hepatorenal Toxicity in Rats.

J Toxicol 2020 15;2020:4127284. Epub 2020 Jul 15.

Zoology Department, Faculty of Science, Ain-Shams University, Cairo, Egypt.

Mercury is a global environmental pollutant, accumulating mainly in the kidney and liver inducing hepatorenal toxicity, oxidative stress, and tissue damage. Oxidative stress is caused by an imbalance between free radicals' production and cellular antioxidant defense systems. In the present study, we investigated the effect of N N'-diphenyl-1, 4-phenylenediamine (DPPD) antioxidant activity against mercury chloride- (HgCl-) induced renal and hepatic toxicity. Thirty adult female Sprague Dawley rats were divided into three equal groups: the first group was injected with saline only and served as a control, the second group was injected with HgCl, and the third group received DPPD + HgCl rats injected with HgCl without treatment showing a significant increase in alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, and uric acids compared to control. Moreover, the second group showed a significant reduction in the activity of the antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH)) in addition to a marked increase in the malondialdehyde (MDA) content, histopathological alterations, collagen deposition, CD8%, CD4%, and TGF-% in kidney and liver tissues compared with the control group. Treatment with DPPD showed significant recovery ( ≤ 0.001) in all previous parameters and histopathological examination. In conclusion, we suggested that DPPD may have a promising antioxidant capacity, gives it the applicability to be used as a prophylactic agent against mercury-induced hepatorenal cytotoxicity in the future.
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http://dx.doi.org/10.1155/2020/4127284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378606PMC
July 2020

Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.

Nat Commun 2020 07 15;11(1):3549. Epub 2020 Jul 15.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.
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http://dx.doi.org/10.1038/s41467-020-17175-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363864PMC
July 2020

Zinc Oxide Nanoparticle Synergizes Sorafenib Anticancer Efficacy with Minimizing Its Cytotoxicity.

Oxid Med Cell Longev 2020 28;2020:1362104. Epub 2020 May 28.

Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.

Cancer, as a group, represents the most important cause of death worldwide. Unfortunately, the available therapeutic approaches of cancer including surgery, chemotherapy, radiotherapy, and immunotherapy are unsatisfactory and represent a great challenge as many patients have cancer recurrence and severe side effects. Methotrexate (MTX) is a well-established (antineoplastic or cytotoxic) chemotherapy and immunosuppressant drug used to treat different types of cancer, but its usage requires high doses causing severe side effects. Therefore, we need a novel drug with high antitumor efficacy in addition to safety. The aim of this study was the evaluation of the antitumor efficacy of zinc oxide nanoparticle (ZnO-NPs) and sorafenib alone or in combination on solid Ehrlich carcinoma (SEC) in mice. Sixty adult female Swiss-albino mice were divided equally into 6 groups as follows: control, SEC, MTX, ZnO-NPs, sorafenib, and ZnO-NPs+sorafenib; all treatments continued for 4 weeks. ZnO-NPs were characterized by TEM, zeta potential, and SEM mapping. Data showed that ZnO-NPs synergized with sorafenib as a combination therapy to execute more effective and safer anticancer activity compared to monotherapy as showed by a significant reduction ( < 0.001) in tumor weight, tumor cell viability, and cancer tissue glutathione amount as well as by significant increase ( < 0.001) in tumor growth inhibition rate, DNA fragmentation, reactive oxygen species generation, the release of cytochrome c, and expression of the apoptotic gene caspase-3 in the tumor tissues with minimal changes in the liver, renal, and hematological parameters. Therefore, we suggest that ZnO-NPs might be a safe candidate in combination with sorafenib as a more potent anticancer. The safety of this combined treatment may allow its use in clinical trials.
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http://dx.doi.org/10.1155/2020/1362104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275957PMC
January 2021

Efficacy of DAAs in the Treatment of Chronic HCV: Real-World Data from the Private Health-Care Sector of the Kingdom of Saudi Arabia.

J Epidemiol Glob Health 2020 06;10(2):178-183

Department of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

Background And Aim: The hepatitis C virus (HCV) is considered a global health challenge that requires urgent interventions for prevention and control. In this study, we aimed to evaluate the effectiveness of direct-acting antiviral agents (DAAs) for HCV-infected patients in the Kingdom of Saudi Arabia (KSA).

Patients And Methods: In this retrospective cohort study, we ascertained data of patients treated with DAA-based regimens for chronic HCV in the private health-care sector hospitals of KSA between April 2015 and December 2017. Data regarding presence or absence of liver cirrhosis, virus genotype, quantitative HCV RNA test, fibrosis stage, and history of liver disease were included. The primary end point of the study was the overall cure rate, defined as the number of patients achieving sustained viral response (SVR) rate at least 12 weeks following completion of treatment, divided by the total number of patients included in the study.

Results: A total of 262 patients fulfilled the study inclusion criteria. Adult patients were enrolled, of which 114 (44%) were females and 148 (56%) were males. About 105 of the patients (40%) were cirrhotic and 156 were treatment-naïve patients (60%), 84 patients were interferon (INF) experienced, and 22 patients had previously received new DAAs but failed to achieve SVR. The majority of patients received ledipasvir-sofosbuvir±RBV (57%) with SVR rate of approximately 97%.

Conclusions: Our local real-world data indicate an overall HCV cure rate of 97% following treatment with DDA#x2019;s when prescribed in the private sector. This estimate is acquiescence with previously reported global cure rates.
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http://dx.doi.org/10.2991/jegh.k.200117.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310777PMC
June 2020

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

BMC Med Genomics 2020 05 13;13(1):68. Epub 2020 May 13.

Departments of Neurosciences and Pediatrics, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA.

Background: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.

Methods: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.

Results: Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).

Conclusions: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.
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http://dx.doi.org/10.1186/s12920-020-0714-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218834PMC
May 2020

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Nat Med 2020 05 27;26(5):720-731. Epub 2020 Apr 27.

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
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http://dx.doi.org/10.1038/s41591-020-0827-2DOI Listing
May 2020

Salvage Free Tissue Transfer for Clival Osteoradionecrosis After Repeat Proton Beam Therapy.

World Neurosurg 2020 06 27;138:485-490. Epub 2020 Mar 27.

Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.

Background: Craniocervical junction chordoma treated with surgery and Proton Beam Therapy evolved with Osteonecrosis and CSF leak. As the vascularization of the head was compromised, we harvested an Anterolateral thigh musculofascial flap to seal the leak.

Case Description: A 56-year-old man presented with a history of chronic headaches and dysarthria with tongue deviation to the right. Magnetic resonance imaging showed a lesion at the craniocervical junction with imaging characteristics compatible with chordoma. Endoscopic endonasal resection was followed by proton beam therapy. Recurrence of the chordoma was subsequently resected via far lateral approach again followed by proton beam therapy accumulating a total dose of 75 Gy. Unfortunately, this led to osteoradionecrosis of the skull base resulting in a cerebrospinal fluid (CSF) leak more than 1 year after treatment. After multiple failed attempts to seal the defect using local vascularized tissue and free fat grafts, the defect was reconstructed with a vastus lateralis free tissue transfer. Six weeks later, the flap had mucosalized, the patient was pain free, and there was no evidence of a CSF leak.

Conclusions: In select cases, vascularized free flaps offer a superior reconstruction for osteoradionecrosis because radiotherapy often compromises the blood supply of local tissues.
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http://dx.doi.org/10.1016/j.wneu.2020.03.108DOI Listing
June 2020

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.

Leukemia 2021 01 24;35(1):75-89. Epub 2020 Mar 24.

Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.

Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(-) disease. We report that CD19(-) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(-) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(-) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.
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http://dx.doi.org/10.1038/s41375-020-0792-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519582PMC
January 2021

Care Bundle Approach to Reduce Surgical Site Infections in Acute Surgical Intensive Care Unit, Cairo, Egypt.

Infect Drug Resist 2020 28;13:229-236. Epub 2020 Jan 28.

Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.

Introduction: Surgical site infections (SSIs) are one of the most frequently reported hospital acquired infections associated with significant spread of antibiotic resistance.

Purpose: We aimed to evaluate a bundle-based approach in reducing SSI at acute surgical intensive care unit of the Emergency Hospital of Cairo University.

Patients And Methods: Our prospective study ran from March 2018 to February 2019 and used risk assessment. The study was divided into three phases. Phase I: (pre-bundle phase) for 5 months; data collection, active surveillance of the SSIs, screening for OXA-48 producing and multidrug resistant colonizers using Chrom agars were carried out. Phase II: (bundle-implementation) a 6-S bundle approach included education, training and postoperative bathing with Chlorhexidine Gluconate in collaboration with the infection control team. Finally, Phase III: (post-implementation) for estimation of compliance, rates of colonization, and infection.

Results: Phase I encompassed 177 patients, while Phase III included 93 patients. A significant reduction of colonization from 24% to 15% (p<0.001) was observed. Similarly, a decrease of SSI from 27% to 15% (p=0.02) was noticed. A logistic regression was performed to adjust for confounding in the implementation of the bundle and we found a 70% reduction of SSI odd's ratio (OR's ratio = 0.3) confidence interval (95% CI 0.14-0.6) with significant Apache II (p=0.04), type of wound; type II (p=0.002), type III (p=0.001) and duration of surgery (p=0.04) as independent risk factors for SSI. was the most prevalent organism during phase I (34.7%). On the other hand, was the commonest organism to be isolated during phase III with (38.5%) preceding (30%).

Conclusion: Our study demonstrated that the implementation of a multidisciplinary bundle containing evidence-based interventions was associated with a significant reduction of colonization and SSIs and was met with staff approval and acceptable compliance.
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http://dx.doi.org/10.2147/IDR.S236814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995287PMC
January 2020

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl-Induced Liver Fibrosis.

Stem Cells Int 2020 3;2020:6574010. Epub 2020 Feb 3.

Biochemistry Department, Faculty of Science, Zagazig University, Egypt.

Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and anti-inflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl-induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone ( value < 0.001).
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http://dx.doi.org/10.1155/2020/6574010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023822PMC
February 2020

Isolating the entire pulmonary venous component versus isolating the pulmonary veins for persistent atrial fibrillation: A propensity-matched analysis.

Pacing Clin Electrophysiol 2020 01 23;43(1):68-77. Epub 2019 Dec 23.

Cardiology Clinical Academic Group, St. George's University Hospitals NHS Foundation Trust, St. George's University of London, London, UK.

Background: The outcomes of pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF) are suboptimal. The entire pulmonary venous component (PV-Comp), consisting of the pulmonary veins, their antra, and the area between the antra, provides triggers and substrate for AF. PV-Comp isolation is an alternative strategy for persistent AF ablation.

Methods: Among 328 patients with persistent AF who underwent a first radiofrequency ablation procedure, 200 patients (PVI, n = 100; PV-Comp isolation, n = 100) were selected by propensity score matching. Both groups were followed up for 1 year.

Results: At 6- and 12-month follow-up, atrial tachyarrhythmia (AF/atrial tachycardia) recurred in 41 and 61 patients in PVI group and 22 (P = .006) and 33 patients (P < .001) in PV-Comp isolation group, respectively. PV-Comp isolation was associated with longer mean time to recurrence (PVI: 8 months, PV-Comp isolation: 10 months, log-rank P < .001) and a lower probability of recurrence (odds ratio [OR] = 0.32; 95% confidence of interval [CI] = 0.18-0.56, P < .001), with no increase in procedural complications (PVI: 5 of 100, PV-Comp isolation: 6 of 100, P = .76). Procedure duration was longer in PV-Comp isolation group (PVI: 186 ± 42 min, PV-Comp isolation: 238 ± 44 min, P < .001), as well as fluoroscopy time (PVI: 22 ± 16 min, PV-Comp isolation: 31 ± 21 min, P = .001).

Conclusion: PV-Comp isolation for persistent AF reduced atrial tachyarrhythmia recurrence up to 1 year compared with PVI alone. While procedure and fluoroscopy time increased, there was no difference in procedural complications.
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http://dx.doi.org/10.1111/pace.13852DOI Listing
January 2020

Immunotherapy for pediatric brain tumors: past and present.

Neuro Oncol 2019 10;21(10):1226-1238

Division of Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

The field of cancer immunotherapy has progressed at an accelerated rate over the past decade. Pediatric brain tumors thus far have presented a formidable challenge for immunotherapy development, given their typically low mutational burden, location behind the blood-brain barrier in a unique tumor microenvironment, and intratumoral heterogeneity. Despite these challenges, recent developments in the field have resulted in exciting preclinical evidence for various immunotherapies and multiple clinical trials. This work reviews the history and advances in active immunotherapy, checkpoint blockade, and adoptive T-cell therapy for pediatric brain tumors, including ongoing clinical trials.
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http://dx.doi.org/10.1093/neuonc/noz077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784275PMC
October 2019

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Pediatr Blood Cancer 2019 10 21;66(10):e27869. Epub 2019 Jun 21.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.
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http://dx.doi.org/10.1002/pbc.27869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707829PMC
October 2019

Right ventricular function in patients presenting with non-ST-segment elevation myocardial infarction undergoing an invasive approach.

Egypt Heart J 2018 Sep 10;70(3):149-153. Epub 2018 May 10.

Department of Cardiology, Ain Shams University, Egypt.

Background: Right ventricular involvement in ST segment elevation myocardial infarction (STEMI) entails an increased morbidity and mortality. However, very scarce data is present on its affection in the setting of non-ST segment elevation myocardial infarction (NSTEMI).

Aim: To assess the affection of right ventricular function in patients presenting with NSTEMI undergoing an invasive procedure.

Subjects And Methods: One hundred and fifty patients admitted with a first NSTEMI and eligible for reperfusion therapy via invasive percutaneous coronary intervention. These patients were divided in two groups; group A including patients with normal RV function, and group B including patients with impaired RV function as diagnosed by tricuspid annular plane systolic excursion (TAPSE) cutoff value < 17 mm. All patients underwent angioplasty and were followed up in-hospital and for 3 months.

Results: RV dysfunction occurred in ninety-five (61.3%) patients of the study population. Significant improvement occurred to TAPSE after 3 months in comparison to TAPSE at baseline (15.45 ± 3.21 versus 17.09 ± 4.17 mm). Those with impaired RV function showed improvement of TAPSE after three months as compared to baseline (13.62 ± 2.58 vs 17.16 ± 3.64 p = 0.008). Multivariate analysis determined the independent predictors of RV dysfunction as RVEDD > 26 mm, RVFAC < 35%, RAA > 20 cm, and TAPSE < 17 mm.

Conclusion: RV dysfunction is not uncommon in NSTEMI when using the definition of TAPSE < 17 mm. Following up RV function by TAPSE, showed significant improvement after 3 months with successful PCI as compared to baseline. We recommend assessing and following up RV function in all patients admitted with a NSTEMI.
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http://dx.doi.org/10.1016/j.ehj.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123228PMC
September 2018

A homing system targets therapeutic T cells to brain cancer.

Nature 2018 09 5;561(7723):331-337. Epub 2018 Sep 5.

Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA.

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
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http://dx.doi.org/10.1038/s41586-018-0499-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402337PMC
September 2018
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