Abstract As medicine progresses into a new era of personalised therapy, the use of monoclonal antibodies to treat a wide range of diseases lies at the heart of this new forefront. Since the licencing ...of the first monoclonal antibody for clinical use 30 years ago, the monoclonal antibody industry has expanded exponentially and is now valued at billions of dollars. With major advances in genetic sequencing and biomedical research, much research into monoclonal antibodies now focuses on identifying new targets for development and maximising their efficacy for use in clinical practice. However, a balance has to be struck with regards to reducing numbers of side-effects and overall economic cost, which arguably somewhat blighted their early clinical and commercial successes. Nowadays, there are approximately 30 monoclonal antibodies that have been approved for use in clinical practice with many more currently being tested in clinical trials. Some of the current major limitations include: the use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness. Some of the current research focuses on ways to improve the efficacy of existing monoclonal antibodies through optimising their effects and the addition of beneficial modifications. This review will focus on the history of monoclonal antibody development – how it has increasingly moved away from using laborious animal models to a more effective phage display system, some of the major drawbacks from a clinical and economical point of view and future innovations that are currently being researched to maximise their effectiveness for future clinical use.
AbstractBuilding façade inspection and maintenance needs to be carried out periodically, and the detection of cracks is a core component of the inspection process. The current inspection procedure is ...labor-intensive and time-consuming and poses significant safety issues like falling from height. Unmanned aerial vehicles (UAVs) with computer vision techniques represent a promising approach for visual crack inspection on high-rise building façades. One research challenge to achieving automated visual crack inspection is image degradation in the form of motion blur caused by UAVs during image acquisition. Motion blur arises due to excessive vibrations of the UAV platform, and this may adversely affect crack detection. In this paper, a deep learning–based deblurring model based on a generative adversarial network (GAN) is proposed to address this challenge. Further, by recognizing a strong correlation between blurred and sharpened crack images, the idea of using a localized skip connection is introduced. Experimental validation of the proposed deblurring model is carried out by investigating the impact of skip connections on deblurring. The proposed model is also compared against the state-of-the-art deblurring model, and results indicate that the proposed model is able to achieve significant improvements in deblurring performance in terms of both global structure and feature details in crack images.
Immunotherapies for hepatocellular carcinoma Liu, Justin K. H.; Irvine, Andrew F.; Jones, Rebecca L. ...
Cancer medicine (Malden, MA),
February 2022, Letnik:
11, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to ...lifestyle‐associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first‐line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T‐cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
Cancer immunotherapies are emerging as one of the main faces in the new era of cancer treatment and personalised medicine. The cancer immunotherapy pharmaceutical industry is now worth billions of dollars and much research is now focused on harnessing their huge potential in treating a wide range of diseases. In this review, we discuss the different types of cancer immunotherapies currently licensed and in development for the treatment of hepatocellular carcinoma, their drawbacks and limitations, and future innovations that are currently being researched in order to maximise their effectiveness for use in clinical practice.
Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype ...evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission.
People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against ...breakthrough SARS-CoV-2 infections in patients with cancer at a population level.
In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3–6 months after the second dose in the cancer cohort and control population.
The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8–69·9) in the control population and 65·5% (65·1–65·9) in the cancer cohort. Vaccine effectiveness at 3–6 months was lower in the cancer cohort (47·0%, 46·3–47·6) than in the control population (61·4%, 61·4–61·5).
COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer.
University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.
Magnetic resonance (MR) imaging (MRI) provides compelling features for the guidance of interventional procedures, including high-contrast soft tissue imaging, detailed visualization of physiological ...changes, and thermometry. Laser-based tumor ablation stands to benefit greatly from MRI guidance because 3D resection margins alongside thermal distributions can be evaluated in real time to protect critical structures while ensuring adequate resection margins. However, few studies have investigated the use of projection-based lasers like those for transoral laser microsurgery, potentially because dexterous laser steering is required at the ablation site, raising substantial challenges in the confined MRI bore and its strong magnetic field. Here, we propose an MR-safe soft robotic system for MRI-guided transoral laser microsurgery. Owing to its miniature size (Ø12 × 100 mm), inherent compliance, and five degrees of freedom, the soft robot ensures zero electromagnetic interference with MRI and enables safe and dexterous operation within the confined oral and pharyngeal cavities. The laser manipulator is rapidly fabricated with hybrid soft and hard structures and is powered by microvolume (<0.004 milliter) fluid flow to enable laser steering with enhanced stiffness and lowered hysteresis. A learning-based controller accommodates the inherent nonlinear robot actuation, which was validated with laser path-following tests. Submillimeter laser steering accuracy was demonstrated with a mean error < 0.20 mm. MRI compatibility testing demonstrated zero observable image artifacts during robot operation. Ex vivo tissue ablation and a cadaveric head-and-neck trial were carried out under MRI, where we employed MR thermometry to monitor the tissue ablation margin and thermal diffusion intraoperatively.
Accurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable ...populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer.
To evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer.
This was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK's third-dose vaccination booster program.
Anti-SARS-CoV-2 COV-S antibody test (Elecsys; Roche).
Odds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization.
The evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results 4.68% vs 376 of 294 230 0.13%; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio OR, 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2-related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response.
The findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.
People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third ...dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated.
This study is a population-scale real-world evaluation of the United Kingdom’s third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England’s national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population.
The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both).
Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.
•Largest population evaluation of third dose SARS-CoV-2 disease (COVID-19) vaccination in patients with cancer.•Vaccine effectiveness against COVID-19 infections, hospitalisation and death assessed.•Lower vaccine effectiveness associated with recent systemic anti-cancer therapy.•Patients with lymphoma had low levels of vaccine protection from symptomatic COVID-19.•Patients with cancer remain at a higher risk of severe COVID-19 hospitalisation and death.
The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are activated by collagen. DDR activation does not appear to occur by the common mechanism of ligand-induced receptor ...dimerization: the DDRs form stable noncovalent dimers in the absence of ligand, and ligand-induced autophosphorylation of cytoplasmic tyrosines is unusually slow and sustained. Here we sought to identify functionally important dimer contacts within the extracellular region of DDR1 by using cysteine-scanning mutagenesis. Cysteine substitutions close to the transmembrane domain resulted in receptors that formed covalent dimers with high efficiency, both in the absence and presence of collagen. Enforced covalent dimerization did not result in constitutive activation and did not affect the ability of collagen to induce receptor autophosphorylation. Cysteines farther away from the transmembrane domain were also cross-linked with high efficiency, but some of these mutants could no longer be activated. Furthermore, the extracellular juxtamembrane region of DDR1 tolerated large deletions as well as insertions of flexible segments, with no adverse effect on activation. These findings indicate that the extracellular juxtamembrane region of DDR1 is exceptionally flexible and does not constrain the basal or ligand-activated state of the receptor. DDR1 transmembrane signaling thus appears to occur without conformational coupling through the juxtamembrane region, but requires specific receptor interactions farther away from the cell membrane. A plausible mechanism to explain these findings is signaling by DDR1 clusters.
We report new molecular evidence of locally acquired dengue virus infections in Ghana. We detected dengue viral RNA among children with suspected malaria by using a multipathogen real-time PCR. ...Subsequent sequence analysis revealed a close relationship with dengue virus serotype 2, which was implicated in a 2016 outbreak in Burkina Faso.
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