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BACKGROUND AND STUDY AIMS: The limited angle of view of standard colonoscopes means that lesions can be missed. A multidirectional viewing system (OmniVision) has been developed recently and has been incorporated into the Aer-O-ScopeT (GI View Ltd., Ramat Gan, Israel), a disposable, self-propelling, and self-navigating colonoscope. The objectives of this study were to qualitatively assess the sensitivity of this viewing system in an ex vivo porcine polyp induction model, and to demonstrate its feasibility and safety in live pigs. MATERIALS AND METHODS: For the ex vivo part of the study, six red metal beads of various sizes were randomly sewn into the mucosa of an unfolded, 2-meter-long porcine colonic segment. Seven passages of the Aer-O-ScopeT were video-recorded separately and blindly reviewed by six experienced gastroenterologists. The sensitivity of the Aer-O-ScopeT to detect beads of various sizes was calculated. For the in vivo experiment, in a repeated-measure study, nine female domestic pigs were examined with the Aer-O-ScopeT with the OmniView optics, followed immediately by examination with standard optical colonoscopy in order to assess the integrity of the colonic mucosa. RESULTS: In the ex vivo study the sensitivity of the Aer-O-ScopeT was 97.6 % (CI 94.0 % - 100 %) for any bead (i. e. any "polyp"). The rate of polyp detection was similar for the six endoscopists, and was consistent for all bead sizes. The average false-positive rate was 0.3 % polyps per run (SD 0.61 %). The mean time taken for the video assessment was 8.0 minutes (SD 4.0 minutes). In the in vivo experiments with the Aer-O-ScopeT, both the front-viewing and omnidirectional-viewing systems were functional in all cases. The colon in front of the optical capsule was well distended and a complete and meticulous inspection of the entire colonic mucosa was performed in all the pigs. There were no adverse events. CONCLUSIONS: The OmniVision system allows for a highly sensitive inspection of the colonic mucosa without the need for tip manipulation. Clinical studies are warranted in order to validate these results in humans. [ABSTRACT FROM AUTHOR]

This article summarizes the expert discussion on the management of hepatocellular carcinoma (HCC), which took place during the 10th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, June 2008. A multidisciplinary approach to a patient with HCC is essential, to guarantee optimal diagnosis and staging, planning of surgical options and selection of embolisation strategies or systemic therapies. In many patients, the underlying cirrhosis represents a challenge and determines therapeutic options. There is now robust evidence in favour of systemic therapy with sorafenib in patients with advanced HCC with preserved liver function. Those involved in the care for patients with HCC should be encouraged to participate in well-designed clinical trials, to increase evidence-based knowledge and to make further progress. [ABSTRACT FROM AUTHOR]

The specificity and sensitivity of a simple non-invasive multi-cancer screening method in detecting breast, lung, prostate, and colorectal cancer in breath samples were evaluated in a double-blind study. Breath samples of 1386 participants (59.7% males, median age 56.0 years) who underwent screening for cancer using gold-standard screening methods, or a biopsy for a suspected malignancy were collected. The samples were analyzed using a bio-hybrid platform comprising trained detection canines and artificial intelligence tools. According to cancer screening/biopsy results, 1048 (75.6%) were negative for cancer and 338 (24.4%) were positive. Among the 338 positive samples, 261 (77.2%) were positive for one of the four cancer types that the bio-hybrid platform was trained to detect, with an overall sensitivity and specificity of 93.9% (95% confidence interval [CI] 90.3-96.2%) and 94.3% (95% CI 92.7%-95.5%), respectively. The sensitivity of each cancer type was similar; breast: 95.0% (95% CI 87.8-98.0%), lung: 95.0% (95% CI 87.8-98.0%), colorectal: 90.0% (95% CI 74.4-96.5%), prostate: 93.0% (95% CI 84.6-97.0%). The sensitivity of 14 other malignant tumors that the bio-hybrid platform was not trained to detect, but identified, was 81.8% (95% CI 71.8%-88.8%). Early cancer (0-2) detection sensitivity was 94.8% (95% CI 91.0%-97.1%). This bio-hybrid multi-cancer screening platform demonstrated high sensitivity and specificity and enables early-stage cancer detection., Competing Interests: Declarations Competing interests Milana Avdalimov and Assaf Rabinowicz are SpotitEarly Ltd. employees. Sharon Furman-Assaf and Ronit Shmuel received funding from SpotitEarly Ltd. All other authors have no competing interests to declare., (© 2024. The Author(s).)

Background: Asymptomatic SARS-CoV-2 infection can significantly increase the spread of the COVID-19 pandemic. We aimed to investigate the epidemiological and clinical predictors of occult serologically confirmed SARS-CoV-2 cases among the general population during the fourth vaccination era in Israel. Methods: We conducted a cross-sectional study among individuals aged ≥18 years who had not been tested for COVID-19 in the preceding 5 months. Occult serologically confirmed cases were based on the presence of anti-N IgG antibodies. Potential risk factors were examined. Multivariable regression analysis identified independent predictors of subclinical SARS-CoV-2 infection. Results: This study included 504 participants. The prevalence of occult serologically confirmed SARS-CoV-2 was 12.5%. Chronic disease was found to be an independent predictor for the absence of occult disease (aOR) 0.4 [95% (CI): 0.18-0.87], p -value = 0.02). No significant differences were observed in age, sex, marital status, number of children, vaccination status, or exposure to COVID-19 infection between participants with and without SARS-CoV-2 sub-infection. Conclusions: We found a lower prevalence of occult serologically confirmed SARS-CoV-2 cases, compared to previous reports, and a negative correlation between chronic disease and occult SARS-CoV-2. Continued research, surveillance, and intervention strategies are needed to optimize long-term health outcomes and provide valuable insights for public health policymakers and clinicians.

Introduction: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier., Methods: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 10 9 or 10 10 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria., Results: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO 2 ) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group., Conclusions: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo., (© 2024. The Author(s).)

Acute Respiratory Distress Syndrome (ARDS) is a major health concern with urgent unmet need for treatment options. There are three million new ARDS cases annually, and the disease's mortality rate is high (35-46%). Cluster of differentiation 24 (CD24), a long-known protein with multifaceted functions, is a small, heavily glycosylated, membrane-anchored protein which functions as an immune checkpoint control. CD24 allows for immune discrimination between Damage-Associated Molecular Patterns and Pathogen-Associated Molecular Patterns derived from pathogens. Exosomes are intraluminal vesicles which play an important role in intercellular communication. Exosomes offer the advantage of targeted delivery, which improves safety and efficacy. The safety and efficacy of EXO-CD24 is promising, as was shown in >180 ARDS patients in phase 1b/2a, phase 2b, and compassionate use. CD24 binds Damage-associated molecular patterns (DAMPs) and inhibits the activation of the NF-ĸB pathway, a pivotal mediator of inflammatory responses. In contrast to anti-inflammatory therapies that are cytokine-specific or steroids that shut down the entire immune system, EXO-CD24 acts upstream, reverting the immune system back to normal activity. Herein, the safety and efficacy of mEXO-CD24 is shown in murine models of several pulmonary diseases (sepsis, allergic asthma, Chronic Obstructive Pulmonary Disease(COPD), fibrosis). EXO CD24 can suppress the hyperinflammatory response in the lungs in several pulmonary diseases with a significant unmet need for treatment options.

Introduction: CD24 is often overexpressed in human tumors as a regulator of cell migration, invasion and proliferation. It has been associated with poor prognosis and chemoresistance in laryngeal cancer. In oral cavity tumors, it was correlated with better overall survival. In this study, we aimed to evaluate the role of CD24 in peripheral blood leukocytes (PBLs) as a potential marker for head and neck malignancies., Materials and Methods: CD24/CD11b expression in peripheral blood leukocytes (PBLs) of head and neck cancer patients and matched healthy controls was analyzed via flow cytometry. Tumors and healthy tissues were immune-stained for CD24 expression and the intensity of stain was ranked. Clinical data including tumor site, size, locoregional or metastatic spread, histopathological characteristics and recurrence events were analyzed., Results: CD24 expression in PBLs was significantly higher in a cohort of 101 head and neck cancer patients compared with 101 matched healthy controls (26.9 ± 12.9 vs. 22.4 ± 13.8; p = 0.02). No significant differences in CD24 levels in PBLs were found between different head and neck subsites involved with malignancy. Higher CD24 levels did not correlate with any adverse feature, i.e., perineural invasion or lymphovascular invasion, advanced T stage or regional spread. Immunohistochemistry analysis demonstrated that CD24 was highly expressed in tumor tissue in comparison to healthy surrounding tissue., Conclusions: CD24 is a possible uprising marker for tumor identification, overexpressed in PBLs and is intensely stained in tumor tissue and pre-malignant lesions. Tumor-PBLs should be further studied.

Background: Clinical trials show different effects of remdesivir on clinical outcomes relative to COVID-19 severity at hospital admission; in Europe, there are few real-world data., Methods: A multicentre, multinational retrospective cohort study in adult patients hospitalised with PCR-confirmed COVID-19 was conducted to understand remdesivir clinical use in different countries and to describe outcomes for patients receiving remdesivir stratified by oxygen use. Primary endpoints were all-cause mortality at day 28 and hospitalisation duration. Patients were categorised by baseline disease severity: no supplemental oxygen (NSO); low flow oxygen ≤ 6 litres (l)/minute (LFO); high flow oxygen > 6 l/minute (HFO)., Results: Four hundred and forty-eight (448) patients (72 [16.1%] HFO; 295 [65.8%] LFO; 81 (18.1%] NSO) were included; median age was 65 years and 64% were male. Mortality was higher in patients on HFO (rate 23.6%) compared to LFO (10.2%; p = 0.001) or NSO (6.2%; p = 0.002). Duration of hospitalisation was longer in patients on HFO (13 days) compared to LFO (9 days; p = 0.003) and NSO (9 days; p = 0.021). Patients who initiated remdesivir ≥ 2 days compared to within a day of hospitalisation had a 4.2 times higher risk of death, irrespective of age, sex, comorbidities, and oxygen support at baseline. Requirement for mechanical ventilation/ECMO and readmission within 28 days of discharge was similar across groups. Remdesivir use and outcomes differed by country., Conclusions: A higher mortality rate and duration of hospitalisation was seen in remdesivir-treated COVID-19 patients on HFO compared to LFO and NSO. Initiation of remdesivir upon admission as opposed to delayed initiation has a mortality benefit., Clinical Trials Registration: NCT04847622., Competing Interests: Declaration of Competing Interest EM, RH, and PH are employees of Gilead Sciences Inc and own stock/stock options. CR received grants from ViiV, Gilead Sciences, Aidsfonds, Dutch Federation Medical Specialist, Erasmus MC, ZonMW, Health∼Holland. AC has received grants/research support, and honoraria or consultation fees from Gilead Sciences, Janssen, MSD, and ViiV. LM has received consultation fees from Gilead Sciences, Angelini and MSD. AS has received honoraria for lectures and advisory boards from Pfizer, MSD, Menarini, Shionogi, Angelini, Roche, and Gilead Sciences. AS has also received a grant from Pfizer and Gilead Sciences., (Copyright © 2023. Published by Elsevier Masson SAS.)

Rationale: Acute respiratory distress syndrome (ARDS) is a major global health concern with a significant unmet need. EXO-CD24 is delivered via inhalation-reduced cytokines and chemokine secretion and lung injury in ARDS and improved survival in mice models of ARDS, influenza, and sepsis., Objectives: This clinical paper aims to evaluate the potential of EXO-CD24, a novel immunomodulatory treatment, in the compassionate care of critically ill, intubated patients with post-infection-induced acute respiratory distress syndrome (ARDS)., Methods: Eleven critically ill patients diagnosed with post-infection ARDS (10 with COVID-19 and one with an adenovirus-associated infection) were administered EXO-CD24 in four medical centers across Israel. The patients had multiple co-morbidities, including cancer, hypertension, diabetes, and ischemic heart disease, and met the criteria for severe ARDS according to the Berlin classification. EXO-CD24 was administered via inhalation, and adverse events related to its use were carefully monitored., Measurements and Main Results: The administration of EXO-CD24 did not result in any recorded adverse events. The median hospitalization duration was 11.5 days, and the overall mortality rate was 36%. Notably, patients treated at the Tel Aviv Medical Center (TASMC) showed a lower mortality rate of 12.5%. The WBC and CRP levels decreased in comparison to baseline levels at hospitalization, and rapid responses occurred even in patients with kidney transplants who were off the ventilator within a few days and discharged shortly thereafter. The production of cytokines and chemokines was significantly suppressed in all patients, including those who died. Among the patients at TASMC, four had kidney transplants and were on immunosuppressive drugs, and all of them fully recovered and were discharged from the hospital., Conclusions: EXO-CD24 holds promise as a potential therapeutic agent for all stages of ARDS, even in severe intubated cases. Importantly, EXO-CD24 demonstrated a favorable safety profile without any apparent side effects with promising efficacy. Furthermore, the potential of EXO-CD24 as a platform for addressing hyper-inflammatory states warrants exploration. Further research and larger-scale clinical trials are warranted to validate these preliminary findings.

Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in mice. A single Intraperitoneal (IP) injection of folic acid induced AKI in WT and CD24 -/- mice. Renal function tests, histological analysis, immunohistochemistry, Western blot analysis, and ELISA were performed to assess the severity of renal damage and the intensity of the inflammatory response. FA-AKI induced CD24 in the distal tubular epithelial cells. Compared to WT mice, FA-AKI CD24 -/- mice exhibited an attenuated reduction in renal function and histological injury, lower serum IL-10 and interferon γ, and decreased expression of renal TNFα. In contrast, renal and systemic IL-33 upregulation were augmented. CD24 -/- FA-AKI animals exhibited increased splenic margination and renal infiltration of regulatory T cells (Tregs). At day 7, FA-AKI CD24 -/- mice exhibited increased expression of tubular pro-apoptotic and decreased anti-apoptotic proteins compared to WT animals. Anti-CD24 antibody administration to FA-AKI mice attenuated the decrease in renal function as well as the histological injury. Renal biopsies from patients with ATN stained strongly for CD24 in the distal tubules. In conclusion, during AKI, upregulation of CD24 promotes renal inflammation through inhibition of Treg infiltration and diversion of cell death towards necrosis rather than apoptosis. Neutralization of CD24 may prove a target for future therapies in AKI.

Purpose: Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit., Methods: Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate., Results: Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10)., Conclusion: We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].

Introduction: Lung cancer remains the leading cause of death from cancer, worldwide. Developing early detection diagnostic methods, especially non-invasive methods, is a critical component to raising the overall survival rate and prognosis for lung cancer. The purpose of this study is to evaluate two protocols of a novel in vitro cellular immune response test to detect lung cancer. The test specifically quantifies the glycolysis metabolism pathway, which is a biomarker for the activation level of immune cells. It summarizes the results of two clinical trials, where each deploys a different protocol's version of this test for the detection of lung cancer. In the later clinical trial, an improved test protocol is applied., Method: The test platform is based on changes in the metabolic pathways of the immune cells following their activation by antigenic stimuli associated with Lung cancer. Peripheral Blood Mononuclear Cells are loaded on a multiwell plate together with various lung tumor associated antigens and a fluorescent probe that exhibits a pH-dependent absorption shift. The acidification process in the extracellular fluid is monitored by a commercial fluorescence plate reader device in continuous reading for 3 h at 37 °C to document the fluorescent signal received from each well., Results: In the later clinical trial, an improved test protocol was applied and resulted in increased test accuracy. Specificity of the test increased to 94.0% and test sensitivity increased to 97.3% in lung cancer stage I, by using the improved protocol., Conclusion: The improved protocol of the novel cellular immune metabolic response based test detects stage I and stage II of lung cancer with high specificity and sensitivity, with low material costs and fast results., (© 2023. The Author(s).)

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes., (©2022 American Association for Cancer Research.)

Cluster of differentiation (CD) 24, a long-known protein with multifaceted functions, has gained attention as a possible treatment for Coronavirus Disease 19 (COVID-19) due to its known anti-inflammatory action. Extracellular vesicles (EVs), such as exosomes and microvesicles, may serve as candidate drug delivery platforms for novel therapeutic approaches in COVID-19 and various other diseases due to their unique characteristics. In the current review, we describe the physiology of CD24 and EVs and try to elucidate their role, both independently and as a combination, in COVID-19 therapeutics. CD24 may act as an important immune regulator in diseases with complex physiologies characterized by excessive inflammation. Very recent data outline a possible therapeutic role not only in COVID-19 but also in other similar disease states, e.g., acute respiratory distress syndrome (ARDS) and sepsis where immune dysregulation plays a key pathophysiologic role. On the other hand, CD24, as well as other therapeutic molecules, can be administered with the use of exosomes, exploiting their unique characteristics to create a novel drug delivery platform as outlined in recent clinical efforts. The implications for human therapeutics in general are huge with regard to pharmacodynamics, pharmacokinetics, safety, and efficacy that will be further elucidated in future randomized controlled trials (RCTs).

A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO-CD24 was produced and purified from CD24-expressing 293-TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO-CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo. In a phase Ib/IIa study, 35 patients with moderate-high severity COVID-19 were recruited and given escalating doses, 10 8 -10 10 , of EXO-CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443-575 days. EXO-CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO-CD24 may be a treatment strategy to suppress the hyper-inflammatory response in the lungs of COVID-19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Some of the most significant medical achievements in recent history are the development of distinct and effective vaccines, and the improvement of the efficacy of previously existing ones, which have contributed to the eradication of many dangerous and life-threatening diseases. Immunization depends on the generation of a physiological memory response and protection against infection. It is therefore crucial that antigens are delivered in an efficient manner, to elicit a robust immune response. The recent approval of COVID-19 vaccines containing lipid nanoparticles encapsulating mRNA demonstrates the broad potential of lipid-based delivery systems. In light of this, the present review article summarizes currently synthesized lipid-based nanoparticles such as liposomes, lipid-nano particles, or cell-derived exosomes.

Deep targeted sequencing technologies are still not widely used in clinical practice due to the complexity of the methods and their cost. The Molecular Inversion Probes (MIP) technology is cost effective and scalable in the number of targets, however, suffers from low overall performance especially in GC rich regions. In order to improve the MIP performance, we sequenced a large cohort of healthy individuals ( n  = 4417), with a panel of 616 MIPs, at high depth in duplicates. To improve the previous state-of-the-art statistical model for low variant allele frequency, we selected 4635 potentially positive variants and validated them using amplicon sequencing. Using machine learning prediction tools, we significantly improved precision of 10-56.25% ( P  < 0.0004) to detect variants with VAF > 0.005. We further developed biochemically modified MIP protocol and improved its turn-around-time to ∼4 h. Our new biochemistry significantly improved uniformity, GC-Rich regions coverage, and enabled 95% on target reads in a large MIP panel of 8349 genomic targets. Overall, we demonstrate an enhancement of the MIP targeted sequencing approach in both detection of low frequency variants and in other key parameters, paving its way to become an ultrafast cost-effective research and clinical diagnostic tool., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Background: Activity and safety of the SARS-CoV-2 BNT162b2 vaccine in actively treated patients with solid tumors is currently unknown., Methods: We conducted a retrospective study of 326 patients with solid tumors treated with anticancer medications to determine the proportion of cancer patients with immunogenicity against SARS-CoV-2 following 2 doses of the BNT162b2 vaccine. The control group comprised 164 vaccinated healthy adults. Anti-SARS-CoV-2 S immunoglobulin G antibodies were measured using a level greater than 50 AU/mL as a cutoff for seropositivity. Information on adverse effects was collected using a questionnaire. All statistical tests were 2-sided., Results: Most patients (205, 62.9%) were treated with chemotherapy either alone or with additional therapy; 55 (16.9%) were treated with immune checkpoint inhibitors and 38 (11.7%) with targeted therapy alone; 28 (8.6%) received other combinations. The vaccine was well tolerated, and no severe side effects were reported. Among patients with cancer, 39 (11.9%) were seronegative compared with 5 (3.0%) of the control group (P = .001). Median immunoglobulin G titers were statistically significantly lower among patients with cancer compared with control (931 AU/mL vs 2817 AU/mL, P = .003). Seronegativity proportions were higher in the chemotherapy-treated group (n = 19; 18.8%) compared with the immune checkpoint inhibitor-treated patients (n = 5; 9.1%) and with those treated with targeted therapy (n = 1; 2.6%) (P = .02). Titers were also statistically significantly different among treatment types (P = .002)., Conclusions: The BNT162b2 vaccine is safe and effective in actively treated patients with cancer. The relatively lower antibody titers and lower proportion of seropositive patients, especially among chemotherapy-treated patients, call for continuing the use of personal protective measures in these patients, even following vaccination., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The CD24 gene has raised considerable interest in tumor biology as a new prognostic factor and a biomarker for the early detection of cancer. There are currently no studies that assess predictors of CD24 in blood tests among healthy individuals. Our aims were (1) to evaluate predictors of the CD24/CD11b biomarker among healthy subjects and (2) to assess CD24/CD11b levels of participants with and without benign tumors. Our cohort included 1640 healthy subjects, aged 20-85, recruited at the Health Promotion and Integrated Cancer Prevention Center (ICPC) in the Tel Aviv Medical Center. Eligible subjects completed a detailed questionnaire on medical history and other epidemiologic information. CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results showed that the average levels of CD24/CD11b in healthy patients (22.8 ± 9.3) was statistically significant lower compared to subjects with benign cancers (26.1 ± 10.5, p < 0.001). Our multivariable analysis demonstrated that elevated levels of CRP (coefficient β: 1.98, p = 0.011) were significantly associated with high levels of CD24/CD11b expression among healthy participants. Other risk factors of cancer were not associated with elevated CD24 levels among healthy subjects. In conclusion, our findings may assist in further development and optimization of the CD24/CD11b biomarker to serve as a cancer screening test for early detection of cancer among the healthy population.

The inactivation of p53, a tumor suppressor, and the activation of the RAS oncogene are the most frequent genetic alterations in cancer. We have shown that a unique E. coli MazF-MazE toxin-antitoxin (TA) system can be used for selective and effective eradication of RAS-mutated cancer cells. This out of the box strategy holds great promise for effective cancer treatment and management. We provide proof of concept for a novel platform to selectively eradicate cancer cells using an adenoviral delivery system based on the adjusted natural bacterial system. We generated adenoviral vectors carrying the mazF toxin (pAdEasy-Py4-SV40mP-mCherry-MazF) and the antitoxin mazE (pAdEasy-RGC-SV40mP-MazE-IRES-GFP) under the regulation of RAS and p53, resp. The control vector carries the toxin without the RAS-responsive element (pAdEasy-ΔPy4-SV40mP-mCherry-MazF). In vitro, the mazF-mazE TA system (Py4-SV40mP-mCherry-MazF+RGC-SV40mP-MazE-IRES-GFP) induced massive, dose-dependent cell death, at 69% compared to 19% for the control vector, in a co-infected HCT116 cell line. In vivo, the system caused significant tumor growth inhibition of HCT116 (KRAS mut /p53 mut ) tumors at 73 and 65% compared to PBS and ΔPY4 control groups, resp. In addition, we demonstrate 65% tumor growth inhibition in HCT116 (KRAS mut /p53 wt ) cells, compared to the other two control groups, indicating a contribution of the antitoxin in blocking system leakage in WT RAS cells. These data provide evidence of the feasibility of using mutations in the p53 and RAS pathway to efficiently kill cancer cells. The platform, through its combination of the antitoxin (mazE) with the toxin (mazF), provides effective protection of normal cells from basal low activity or leakage of mazF., (© 2021. The Author(s).)

An estimated 1.24 million blood cancer cases occur annually worldwide, accounting for approximately 6% of all cancer cases. Currently, there are no standardized hematology cancer screening tests that are recommended for the general population. CD24 is a mucin-like cell surface molecule and P-selectin ligand, which plays a significant role in the maturation of B-lymphocytes and was found to be overexpressed in a number of hematological malignancies. Our primary aim was to assess the sensitivity and specificity of the CD24/CD11b-based blood test for the detection of hematological malignancies. Our cohort included 488 subjects with positive hematological cancer diagnosis ( n = 122) and healthy subjects ( n = 366). CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results demonstrated that the average levels of CD24/CD11b in healthy patients (21.7 ± 9.0) were statistically significantly lower compared to levels of CD24/CD11b in cancer patients (29.5 ± 18.7, p < 0.001). The highest levels of CD24/CD11b were found in multiple myeloma (39.1 ± 23.6), followed by chronic myeloid leukemia (33.0 ± 13.7) and non-Hodgkin lymphoma (32.3 ± 13.3). The test had an overall sensitivity for hematologic cancers of 78.5% (95% CI, 70.7-86.3%) and specificity of 80.2% (95% CI, 76.1-84.3%). In conclusion, our findings indicate the feasibility of a CD24/CD11b-based blood test as a screening test of hematological malignancies.

The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surface protein expressed mostly in cancer cells and is very rarely found in normal cells. Here, we propose a novel targeted cancer therapeutic platform based on the lentiviral integrase, stimulated by integrase-derived peptides, that are specifically delivered to cancerous cells via CD24 antigen-antibody targeting. INS and INR were synthesized and humanized and anti-CD24 antibodies were fused to the lentivirus envelope. The activity, permeability, stability, solubility, and toxicity of these components were analyzed. Cell death was measured by fluorescent microscopy and enzymatic assays and potency were tested in vitro and in vivo. Lentivirus particles, containing non-functional DNA led to massive cell death (40-70%). Raltegravir, an antiretroviral drug, inhibited the induction of apoptosis. In vivo, single and repeated administrations of INS/INR were well tolerated without any adverse effects. Tumor development in nude mice was significantly inhibited (by 50%) as compared to the vehicle arm. In summary, a novel and generic therapeutic platform for selective cancer cell eradication with excellent efficacy and safety are presented.

CD24 is a small, glycophosphatidylinositol-anchored cell surface protein, mostly investigated with respect to cancer, inflammation, and autoimmune diseases. CD24 knockdown or inhibition has been used to test various biochemical mechanisms and neurological conditions; however, the association between CD24 and behavioral phenotypes has not yet been examined. This study aims to characterize cognitive and emotional functions of CD24 knockout mice (CD24 -/- ) compared with CD24 wild-type mice at three time-points: adolescence, young adulthood, and adulthood. Our results show that CD24 -/- mice exhibited better cognitive performance and less anxiety-like behavior compared with WT mice, with no effect on depression-like behavior. This phenotype was constant from childhood (2 months old) to adulthood (6 months old). The results from our study suggest that CD24 may influence important behavioral aspects at the whole-organism level, which should be taken into consideration when using CD24 knockout models., Competing Interests: The authors declare no conflict of interest.

Background: The heat-stable HSA/CD24 gene encodes a protein that shows high expression levels in adipocyte precursor cells but low levels in terminally differentiated adipocytes. Its high expression in many types of human cancer suggests an association between cancer, diabetes, and obesity, which is currently unclear. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) is a regulator of adipogenesis that plays a role in insulin sensitivity, lipid metabolism, and adipokine expression in adipocytes., Aim: To assess gender-dependent changes in CD24 KO and its association with PPARγ expression., Experimental Approach: WT and CD24 KO mice were monitored from birth up to 12 months, and various physiological and molecular characteristics were analysed. Mean body weight and adipose mass were higher in KO mice than in WT mice. Male, but not female, KO mice showed increased insulin sensitivity, glucose uptake, adipocyte size, and PPARγ expression than WT mice. In addition, enteric bacterial populations, assessed through high-throughput sequencing of stool 16S rRNA genes, were significantly different between male KO and WT mice., Conclusions: CD24 may negatively regulate PPARγ expression in male mice. Furthermore, the association between the CD24 and insulin sensitivity suggests a possible mechanism for diabetes as a cancer risk factor. Finally, CD24 KO male mice may serve as a model of obesity and insulin hyper-sensitivity.

Aim: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples., Methods: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively)., Results: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942., Conclusions: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations., Competing Interests: Conflict of interest: M. Gaga has nothing to disclose. Conflict of interest: J. Chorostowska-Wynimko reports grants, personal fees and non-financial support from Grifols, AstraZeneca, Pfizer, CSL Behring and CelonPharma, grants and personal fees from Boehringer Ingelheim, personal fees and non-financial support from MSD and BMS, personal fees from Amgen, GSK, Novartis, Chiesi, Roche and Lekam, outside the submitted work. Conflict of interest: I. Horváth reports personal fees from AstraZeneca, Novartis, CSL Behring, Boehringer Ingelheim, GSK and Berlin-Chemie, outside the submitted work. Conflict of interest: M.C. Tammemagi has served as consultant to Johnson & Johnson/Janssen, Medial EarlySign, Nucleix, bioAffinity Technologies and AstraZeneca. Conflict of interest: D. Shitrit has nothing to disclose. Conflict of interest: V.H. Eisenberg has nothing to disclose. Conflict of interest: H. Liang has nothing to disclose. Conflict of interest: D. Stav has nothing to disclose. Conflict of interest: D. Levy Faber has nothing to disclose. Conflict of interest: M. Jansen has nothing to disclose. Conflict of interest: Y. Raviv has nothing to disclose. Conflict of interest: V. Panagoulias has nothing to disclose. Conflict of interest: P. Rudzinski has nothing to disclose. Conflict of interest: G. Izbicki has nothing to disclose. Conflict of interest: O. Ronen has nothing to disclose. Conflict of interest: A. Goldhaber has nothing to disclose. Conflict of interest: R. Moalem has nothing to disclose. Conflict of interest: N. Arber has nothing to disclose. Conflict of interest: I. Haas has nothing to disclose. Conflict of interest: Q. Zhou has nothing to disclose., (Copyright ©ERS 2021.)

Background: CD24 is a sialoglycoprotein anchored to the cell surface via glycosylphosphatidylinositol and is involved in intracellular signaling processes. It plays an important role in the early stages of the multistep process of colorectal carcinogenesis. Several single nucleotide polymorphisms in the CD24 gene are reported to exert a diverse effect on cancer risk. We aimed to elucidate whether CD24 TG/del genetic variants are associated with susceptibility to colorectal cancer (CRC)., Methods: The study included 179 subjects, 36 with CRC (prior to surgery) and 143 healthy control subjects. Deoxyribonucleic acid was purified from peripheral blood leukocytes, and by using restriction fragment length polymorphism analysis, the CD24 gene was genotyped for the specific genetic variant, TG deletion. Additionally, CD24 protein expression levels were determined by Western blotting analysis., Results: The incidence of the TG/del was higher among the CRC patients compared with healthy controls, 14% and 10%, respectively ( P = .54). CD24 protein levels were significantly higher among CRC patients. There were no significant differences in CD24 expression between CRC patients at different stages of the disease or between patients who carry the mutation and those who did not., Conclusions: CD24 genetic variant might be of clinical value for risk assessment as part of cancer prevention programs. Further study on larger populations is needed to validate the importance of this dinucleotide deletion in CRC development. Overexpression of CD24 protein occurs early along the multistep process of CRC carcinogenesis, and a simple blood sample based on CD24 expression on peripheral blood leukocytes can contribute to early diagnosis.

Bloom syndrome is a rare autosomal recessive disorder characterized by distinct physical features, such as short stature, genomic instability, and predisposition to numerous cancers. The BLM gene encodes for the RecQ helicase that plays an important role in genome editing, maintenance, and stability. Mutations in the BLM gene cause genomic instability that exposes the carriers to a variety of cancers, and in particular hematological and gastrointestinal cancers. Herein, we report the first case of pancreatic cancer in a 32-year-old patient with bloom syndrome., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow-derived cells that have been largely studied in the context of allergic diseases and parasite infections. Although tumor-associated eosinophilia has been described in various solid tumors including colorectal cancer, knowledge is still missing regarding eosinophil activities and even the basic question of whether the TME promotes eosinophil recruitment without additional manipulation (e.g., immunotherapy) is unclear. Herein, we report that eosinophils are recruited into developing tumors during induction of inflammation-induced colorectal cancer and in mice with the Apc min /+ genotype, which develop spontaneous intestinal adenomas. Using adoptive transfer and cytokine neutralization experiments, we demonstrate that the TME supported prolonged eosinophil survival independent of IL5, an eosinophil survival cytokine. Tumor-infiltrating eosinophils consisted of degranulating eosinophils and were essential for tumor rejection independently of CD8 + T cells. Transcriptome and proteomic analysis revealed an IFNγ-linked signature for intratumoral eosinophils that was different from that of macrophages. Our data establish antitumorigenic roles for eosinophils in colorectal cancer. These findings may facilitate the development of pharmacologic treatments that could unleash antitumor responses by eosinophils, especially in colorectal cancer patients displaying eosinophilia., (©2019 American Association for Cancer Research.)

Despite a high remission rate after therapy, only 40-50% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of CD34 + CD38 - AML cells. In order to induce preferential cell death in CD34 + CD38 - AML cells, two separate events may be necessary: (1) inhibition of survival signals such as nuclear factor kappa-beta (NF-κB) and (2) induction of stress responses such as the oxidative stress response. Therefore, regimens that mediate both effects may be favorable. Deferasirox is a rationally designed oral iron chelator mainly used to reduce chronic iron overload in patients who receive long-term blood transfusions. Our study revealed that clinically relevant concentrations of deferasirox are cytotoxic in vitro to AML progenitor cells, but even more potent against the more primitive CD34 + CD38 - cell population. In addition, we found that deferasirox exerts its effect, at least in part, by inhibiting the NF-κB/hypoxia-induced factor 1-alpha (HIF1α) pathway and by elevating reactive oxygen species levels. We believe that, pending further characterization, deferasirox can be considered as a potential therapeutic agent for eradicating CD34 + CD38 - AML cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management., (© 2018 by the American Association for the Study of Liver Diseases.)

Aim: To use a micro-computed tomography (micro-CT) to quantify bone healing at maxillary first molar extraction sites, and test the hypothesis that bone healing is impaired in CD24-knockout mice as compared with wild-type C57BL/6J mice., Materials and Methods: Under ketamine-xylazine general anaesthesia, mice had either extraction of the right maxillary first molar tooth or sham operation. Mice were sacrificed 1 (n = 12/group), 2 (n = 6/group) or 4 (n = 6/group) weeks postoperatively. The right maxillae was disected. Micro-CT was used to quantify differences in bone microstructural features at extrction sites, between CD24-knockout mice and wild-type mice., Results: CD24-Knockout mice displayed impaired bone healing at extraction sites that was manifested as decreased trabecular bone density, and decreased number and thickness of trabeculae., Conclusions: This pilot study suggests that CD24 plays an important role in extraction socket bone healing and may be used as a novel biomarker of bone quality and potential therapeutic target to improve bone healing and density following alveolar bone injury.

Background: Curcumin, green tea polyphenols and selenium possess anti-inflammatory and anti-oxidant properties. Individually they have demonstrated some efficacy in animal models and human subjects with inflammatory bowel disease (IBD). To evaluate the efficacy and safety of Coltect [Curcumin (500 mg), green tea (250 mg) and selenium (100 µg)] in vivo and in patients with ulcerative colitis (UC)., Methods: Each component was compared to placebo in a DSS mice colitis model. The efficacy was validated in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) rat colitis model. Twenty patients with mild-to-moderate UC received two Coltect tablets twice daily for 8 weeks. Enrollees underwent sigmoidoscopy at study entrance and closure, and physical and laboratory evaluation at baseline, 4 and 8 weeks., Results: Coltect showed a synergistic therapeutic effect in the DSS and TNBS models. Disease activity was significantly higher in the placebo versus the treated group ( p < 0.05). Selenium was the more active component. The contribution of green tea was minor. In the TNBS model, the Wallace scores for macroscopic lesions were 4.8 ± 1.5 (treatment) and 8.2 ± 0.5 (placebo) ( p = 0.01). In humans, Coltect was well tolerated and effective. Fourteen subjects (70%) improved: nine (45%) went into complete remission, four (20%) experienced marked improvement and one (5%) experienced moderate improvement at the end of the trial. Clinical activity index decreased significantly at 4 and 8 weeks ( p < 0.001). Two patients had no change in their symptoms, and one withdrew after 4 weeks. Flare-up in four subjects caused three to withdraw from the study after less than 4 weeks. Endoscopic improvement was observed in 11 (69%) patients, and four patients (25%) achieved complete remission., Conclusions: Coltect may serve as a first-line or add-on therapy in patients with mild-to-moderate UC., Competing Interests: Conflict of interest statement: Drs. Arber and Katz have a patent issued for Coltect. Drs. Arber and Katz were part of the development team of Coltect, but did not receive any payment or other benefits for the present study. The other authors have no conflicts of interest to disclose.

Background and Objective: KRAS mutation is an early event in colorectal cancer carcinogenesis. We previously reported that a recombinant adenovirus, carrying a pro-apoptotic gene (PUMA) under the regulation of Ets/AP1 (RAS-responsive elements) suppressed the growth of cancer cells harboring hyperactive KRAS. We propose to exploit the hyperactive RAS pathway, rather than to inhibit it as was previously tried and failed repeatedly. We aim to improve efficacy by substituting PUMA with a more potent toxin, the bacterial MazF-MazE toxin-antitoxin system, under a very tight regulation., Results: A massive cell death, in a dose-dependent manner, reaching 73% at MOI 10 was seen in KRAS cells as compared to 22% in WT cells. Increase expression of MazE (the anti-toxin) protected normal cells from any possible internal or external leakage of the system and confirmed the selectivity, specificity and safety of the targeting system. Considerable tumor shrinkage (61%) was demonstrated in vivo following MazEF-encoding adenovirus treatment without any side effects., Design: Efficient vectors for cancer-directed gene delivery were constructed; "pAdEasy-Py4-SV40mP-mCherry-MazF""pAdEasy-Py4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP","pAdEasy-ΔPy4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP "and "pAdEasy-mCherry". Virus particles were produced and their potency was tested. Cell death was measured qualitatively by using the fluorescent microscopy and colony formation assay, and was quantified by MTT. FACS analysis using annexin V and RedDot2 dyes was performed for measuring apoptotic and dead cells, respectively. In vivo tumor formation was measured in a xenograft model., Conclusions: A proof of concept for a novel cancer safe and effective gene therapy exploiting an aberrant hyperactive pathway is achievable.

Many patients are reluctant to undergo optical colonoscopy for colorectal cancer screening. The Check-Cap colon imaging system is a non-invasive test that comprises an ingestible imaging capsule that emits and detects ultra-low-dose radiation. The capsule generates a 3D reconstruction of the colonic lumen for detection of polyps and cancer. Preliminary preclinical and clinical testing has demonstrated safety and feasibility. Mean radiation dose is estimated at 0.04 mSv. In conclusion, we describe a novel capsule-based, patient-friendly colorectal test that holds potential for non-invasive screening.

Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls., Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins., Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated., Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers., (© 2016 The Authors Liver International Published by John Wiley & Sons Ltd.)

Aim: To determine the prevalence of colorectal neoplasia in average risk persons 40-59 years of age in Israel and to compare the results with other populations., Methods: We reviewed the results of asymptomatic average-risk subjects, aged 40 to 59 years, undergoing their first screening colonoscopy between April 1994 and January 2014. The detection rates of adenoma, advanced adenoma (AA) and colorectal cancer (CRC) were determined in the 40's and 50's age groups by gender. The prevalence of lesions was compared between age groups. After meticulous review of the literature, these results were compared to published studies addressing the prevalence of colorectal neoplasia in similar patient groups, in a variety of geographical locations., Results: We included first screening colonoscopy results of 1750 individuals. The prevalence of adenomas, AA and CRC was 8.3%, 1.0% and 0.2% in the 40-49 age group and 13.7%, 2.4% and 0.2% in the 50-59 age group, respectively. Age-dependent differences in adenoma and AA rates were significant only among men (P < 0.005). Literature review disclosed 17 relevant studies. As expected, in both Asian and Western populations, the risks for overall adenoma and advanced adenoma was significantly higher in the 50's age group as compared to the 40's age group in a similar fashion. The result of the current study were similar to previous studies on Western populations. A substantially higher rate of adenoma, was observed in studies conducted among Asian populations in both age groups., Conclusion: The higher rate of colorectal neoplasia in Asian populations requires further investigation and reconsideration as to the starting age of screening in that population.

Background: Terpinen-4-ol, a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities., Aim: To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies, alone and in combination with chemotherapeutic and biological agents., Methods: Terpinen-4-ol was administrated alone or combined with standard chemotherapy (Oxaliplatin, Fluorouracil, Gemcitabine, Tarceva) and biological agent (Cetuximab). It was also combined with humanized anti-CD24 mAbs (was developed by us). Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis, following treatment of colorectal, pancreatic, gastric and prostate cancer cells. Terpinen-4-ol effect on tumor development was evaluated in xenograft model., Results: Terpinen-4-ol induces a significant growth inhibition of colorectal, pancreatic, prostate and gastric cancer cells in a dose-dependent manner (10-90% in 0.005-0.1%). Terpinen-4-ol and various anti-cancer agents (0.2μM oxaliplatin and 0.5μM fluorouracil) demonstrated a synergistic inhibitory effect (83% and 91%, respectively) on cancer cell proliferation. In KRAS mutated colorectal cancer cells, which are resistant to anti-EGFR therapy, combining of terpinen-4-ol with cetuximab (1 μM) resulted in impressive efficacy of 80-90% growth inhibition. Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb (150μg/ml)-induced growth inhibition (90%). Considerable reduction in tumor volume was seen following terpinen-4-ol (0.2%) treatment alone and with cetuximab (10mg/kg) (40% and 63%, respectively) as compare to the control group., Conclusion: Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. The possible molecular mechanism for its activity involves induction of cell-death rendering this compound as a potential anti-cancer drug alone and in combination in the treatment of numerous malignancies. Terpinen-4-ol restores the activity of cetuximab in cancers with mutated KRAS.

This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is ∼ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan., (© 2015 UICC.)

Background: Although screening colonoscopy is effective for early detection of colorectal cancer (CRC), screening rates remain low. Multiple factors are thought to be responsible for the low rates of screening colonoscopy, but bowel preparation appears to be a key deterrent. Tolerability issues with bowel preparations may lead to poor patient compliance, inadequate colon cleansing, and reduced detection of colonic polyps., Aim: The aim of this article is to evaluate the feasibility, safety, and outcomes of minimally prepared intra-procedural hydroflush technique as an alternative to traditional bowel preparation in screening colonoscopy., Design: We conducted a prospective feasibility study of intraprocedural hydroflush technique aided by water-jet pumps and a mechanical suction novel device following minimal bowel preparation for CRC screening., Patients and Methods: Nine procedures were performed in nine healthy individuals scheduled for routine screening colonoscopy. Preparation included mild diet restriction, laxative tablets two to three days prior to the procedure and two Fleet enemas one to two hours before the colonoscopy. The cleanliness of the colon was assessed by using the Boston bowel preparation scale. Insertion and withdrawal times were recorded., Results: Complete colonoscopy to the cecum was performed in all patients (100%). Mean time to the cecum was 5.78 ± 2.68 minutes, and mean withdrawal time was 15.33 ± 3.94 minutes. Endoscopic visualization of the entire mucosa was achieved in all cases with no colonoscopy repeated because of inadequate preparation. Four polyps have been detected and removed in three patients. Mild mucosal erosions were seen in some areas where the suction was used extensively, similar to those that can be seen during conventional colonoscopy. Mild stiffness of the shaft of the scope was noted., Limitations: This was an uncontrolled feasibility study of selected patients., Conclusions: Minimally prepared colonoscopy with the intra-procedural hydroflush technique for colorectal screening is feasible. The water exchange technology compensates for the mild stiffness of the scope. This technique might increase patients' compliance for CRC screening.

Background: Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates., Aim: To examine the role of CD24 in the wound healing process., Methods: An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice., Results: Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice., Conclusions: Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair.

Background: There are no validated biomarkers that correlate with the prognosis of pancreatic ductal adenocarcinoma (PDA). The CD24 and adenomatous polyposis coli (APC) genes are important in the malignant transformation of gastrointestinal cells. This study examined APC and CD24 genetic polymorphisms and their possible impact on survival of patients with PDA., Methods: Clinical and pathological data as well as blood samples for extracting DNA were obtained for 73 patients with PDA. Real-time PCR assessed genetic variants of APC (I1307K and E1317Q), and four different single nucleotide polymorphisms (SNPs) in the CD24 gene: C170T (rs52812045), TG1527del (rs3838646), A1626G (rs1058881) and A1056G (rs1058818)., Results: The median age at diagnosis was 64 (41-90) years. Thirty-one patients (42.5%) were operable, 16 (22%) had locally advanced disease and 26 (35.5%) had disseminated metastatic cancer. The malignancy-related mortality rate was 84%. Median survival was 14 months (11.25-16.74). Survival was similar for wild-type (WT), heterozygous and homozygous variants of the APC or CD24 genes. The three most frequent CD24 SNP combinations were: heterozygote for A1626G and WT for the rest of the alleles (14% of patients), heterozygote for C170T, A1626G, A1056G and WT for the rest (14% of patients), and heterozygote for C170T, A1056G and WT for the rest (10% of patients). All patients were APC WT. The first two groups were significantly younger at diagnosis than the third group., Conclusions: Specific polymorphisms in the APC and CD24 genes may play a role in pancreatic cancer development. Correlation with survival requires a larger cohort.

Whole-exome sequencing (WES) arises as a new approach in diagnosing individuals affected by multigenic and complex phenotypes. Herein, we aim to examine whether WES is useful in screening asymptomatic individuals for actionable interventions, which has not yet been established. Twenty-five healthy adults underwent WES, bioinformatics, and manual curation of their exomes. Six participants (24%) harbored significant, management-changing variants in cancer predisposition genes, American College of Medical Genetics, and genomics reportable cardiac diseases and pharmacogenomic biomarkers that have led to clinical recommendations and interventions. Furthermore, more than 80% of the participants (21) carried 1-3 genetic variants with an associated clinical guideline for an altered drug dosing or administration based on the FDA's table of pharmacogenomics. These results support WES potential not only to answer specific diagnostic questions presented by the relevant personal and/or family history but also to uncover clinically important genetic findings unrelated to the primary indication for sequencing.

Objective: CD24 and the adenomatous polyposis coli (APC) gene polymorphisms are known to predispose to malignant disease. We aimed to investigate their association with risk and susceptibility of oral lichen planus (OLP) in an Israeli Jewish population., Study Design: The study included 54 patients, of which 41 were females (75.9%) and 13 males (24.1%); of the 533 controls, 224 were females (42.0%) and 309 males (57.9%). Genotyping was performed. Two APC (I1307 K, E1317 Q) and four CD24 variants--C170 T (rs52812045), TG1527 del (rs3838646), A1626 G (rs1058881), and A1056 G (rs1058818)--were assessed. Frequencies were analyzed using the Chi-square test. Two-sided P < .05 values were considered significant. Odds ratios and 95% confidence intervals were obtained by logistic regression analyses., Results: CD24 A1056 G carriers have a significantly lower risk of OLP compared with individuals with the wild-type variant (P = .001). A significantly lower risk was found for heterozygote (P = .008) and homozygote carriers (P = .002). Homozygote CD24 A1626 G carriers had a significant higher risk for OLP compared with nonhomozygote carriers (P = .040). CD24 C170 T, TG1527 del, and APC polymorphisms did not show significant associations with OLP risk., Conclusions: CD24 A1626 G is more frequent in OLP patients, contributes to disease risk, and could play a role in OLP susceptibility. A significant association between CD24 A1056 G and a lower OLP incidence was found, suggesting that it may confer protection against OLP risk and progression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aspirin has been extensively investigated in the context of the prevention of cardiovascular disease. It has one of the strongest cumulative evidence supporting its use in colorectal cancer (CRC) chemoprevention. Epidemiological, clinical, and observational studies have demonstrated that aspirin and non-steroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, can protect against CRC and significantly reduce its incidence. Moreover, prospective randomized controlled trials of colorectal polyp recurrence and in patients with hereditary CRC syndromes have shown that aspirin can produce regression of existing colorectal adenomas and prevent the formation of new polyps. However, the lowest effective doses, treatment duration, target populations, and the effects on survival are not entirely clear. Although not common serious side effects and in particular gastrointestinal and intracerebral hemorrhage do occur, better selection of individuals who might benefit the most from aspirin use must be carefully performed in order to maximize their risk/benefit ratio. In the era of precision medicine, genetic information, blood and/or urinary biomarkers, could potentially help in tailoring chemopreventive therapeutic strategies, based on aspirin use, while limiting adverse toxic effects. The current review will cover the use of aspirin for the prevention of colorectal adenomas and CRC, potential markers for chemoprevention, and patient stratification.