3. The computer system already allows us to make a library publications search. Why had it not included a feature where we can select those publications we wish to place a reservation on and just ...enter our name and library card number to confirm the reservation? Likewise the computer can be programmed to telephone us automatically when the publications are in, again enabling a savings in postage and paperwork costs.
We describe the development of an indexed atlas of digital mammograms to facilitate content-based retrieval and comparative analysis of mammograms for computer-aided diagnosis (CAD) of breast cancer. ...Specifically, the requirements and the design of the components of the indexed archival and retrieval system are examined. In order to facilitate search by categories, the mammograms in the atlas are indexed by case number, year of acquisition, category (normal, benign disease, and malignant disease that could be screen-detected or interval cancer), and the presence of signs of disease such as masses, calcifications, bilateral asymmetry, and architectural distortion. In the initial phase of the project, mammograms with masses have been indexed with objective diagnostic features related to their shape, edge definition, and texture. Interfaces to the atlas provide tools for selection and retrieval of cases by text-based or content-based indices. The system should assist radiologists and clinical specialists in CAD of breast cancer.
Summary Objectives Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and ...Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed. Methods We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. Results Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1–3 times. Conclusions Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Abstract
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant, designated as a variant of concern by the World Health Organization, carries numerous spike ...mutations that are known to evade neutralizing antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines. A deeper understanding of the susceptibility of omicron variant to vaccine-induced neutralizing antibodies is urgently needed for risk assessment.
Methods
Omicron variant strains HKU691 and HKU344-R346K were isolated from patients using TMPRSS2-overexpressing VeroE6 cells. Whole genome sequence was determined using nanopore sequencing. Neutralization susceptibility of ancestral lineage A virus and the omicron, delta and beta variants to sera from 25 BNT162b2 and 25 CoronaVac vaccine recipients was determined using a live virus microneutralization assay.
Results
The omicron variant strain HKU344-R346K has an additional spike R346K mutation, which is present in 8.5% of strains deposited in the GISAID database. Only 20% and 24% of BNT162b2 recipients had detectable neutralizing antibody against the omicron variant HKU691 and HKU344-R346K, respectively, whereas none of the CoronaVac recipients had detectable neutralizing antibody titer against either omicron isolate. For BNT162b2 recipients, the geometric mean neutralization antibody titers (GMTs) of the omicron variant isolates (5.43 and 6.42) were 35.7–39.9-fold lower than that of the ancestral virus (229.4), and the GMTs of both omicron variant isolates were significantly lower than those of the beta and delta variants. There was no significant difference in the GMTs between HKU691 and HKU344-R346K.
Conclusions
Omicron variant escapes neutralizing antibodies elicited by BNT162b2 or CoronaVac. The additional R346K mutation did not affect the neutralization susceptibility. Our data suggest that the omicron variant may be associated with lower COVID-19 vaccine effectiveness.
Immune sera from BNT162b2 and Coronavac recipients had substantially reduced neutralizing antibody titers against the omicron variant. There was no statistically significant difference between the geometric mean neutralization titers against omicron variant strains with or without spike R346K mutation.
Background
: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the ...under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
Methods
: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
Results
: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
Conclusions
: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010.
The emergence of SARS-CoV-2 has led to the current global coronavirus pandemic and more than one million infections since December 2019. The exact origin of SARS-CoV-2 remains elusive, but the ...presence of a distinct motif in the S1/S2 junction region suggests the possible acquisition of cleavage site(s) in the spike protein that promoted cross-species transmission. Through plaque purification of Vero-E6 cultured SARS-CoV-2, we found a series of variants which contain 15-30-bp deletions (Del-mut) or point mutations respectively at the S1/S2 junction. Examination of the original clinical specimen from which the isolate was derived, and 26 additional SARS-CoV-2 positive clinical specimens, failed to detect these variants. Infection of hamsters shows that one of the variants (Del-mut-1) which carries deletion of 10 amino acids (30bp) does not cause the body weight loss or more severe pathological changes in the lungs that is associated with wild type virus infection. We suggest that the unique cleavage motif promoting SARS-CoV-2 infection in humans may be under strong selective pressure, given that replication in permissive Vero-E6 cells leads to the loss of this adaptive function. It would be important to screen the prevalence of these variants in asymptomatic infected cases. The potential of the Del-mut variants as an attenuated vaccine or laboratory tool should be evaluated.
Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common ...comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8
T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.
The in vivo pathogenicity, transmissibility, and fitness of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant are not well understood. We compared these ...virological attributes of this new variant of concern (VOC) with those of the Delta (B.1.617.2) variant in a Syrian hamster model of COVID-19. Omicron-infected hamsters lost significantly less body weight and exhibited reduced clinical scores, respiratory tract viral burdens, cytokine and chemokine dysregulation, and lung damage than Delta-infected hamsters. Both variants were highly transmissible through contact transmission. In noncontact transmission studies Omicron demonstrated similar or higher transmissibility than Delta. Delta outcompeted Omicron without selection pressure, but this scenario changed once immune selection pressure with neutralizing antibodies—active against Delta but poorly active against Omicron—was introduced. Next-generation vaccines and antivirals effective against this new VOC are therefore urgently needed.
Delta and Omicron go toe to toe
There is growing evidence that the Omicron variant of concern (VOC) is more transmissible and infectious than previous iterations of severe acute respiratory syndrome coronavirus 2. Yuan
et al
. compared Syrian hamsters exposed to either Omicron or Delta VOCs. Animals infected with Omicron showed lower respiratory tract viral burdens and reduced clinical severity. Nevertheless, Omicron was at least as transmissible as Delta, if not more so. When animals were challenged with a mixture of both variants, Delta outcompeted Omicron in naïve hamsters. This competitive advantage disappeared, however, in vaccinated animals. Moreover, vaccinated hamsters were better than unvaccinated animals at transmitting Omicron to co-housed companions. This work helps to clarify how Omicron might have gone on to become the predominant strain in populations with high rates of previous infection and vaccination. —STS
Less pathogenic but highly transmissible, SARS-CoV-2 Omicron can outcompete Delta under immune selection pressure.
SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of ...attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.
A digital cognitive test can be a useful and quick tool for the screening of cognitive impairment. Previous studies have shown that the diagnostic performance of digital cognitive tests is comparable ...with that of conventional paper-and-pencil tests. However, the use of commercially available digital cognitive tests is not common in Hong Kong, which may be due to the high cost of the tests and the language barrier. Thus, we developed a brief and user-friendly digital cognitive test called the Electronic Cognitive Screen (EC-Screen) for the detection of mild cognitive impairment (MCI) and dementia of older adults.
The aim of this study was to evaluate the performance of the EC-Screen for the detection of MCI and dementia in older adults.
The EC-Screen is a brief digital cognitive test that has been adapted from the Rapid Cognitive Screen test. The EC-Screen uses a cloud-based platform and runs on a tablet. Participants with MCI, dementia, and cognitively healthy controls were recruited from research clinics and the community. The outcomes were the performance of the EC-Screen in distinguishing participants with MCI and dementia from controls, and in distinguishing participants with dementia from those with MCI and controls. The cohort was randomly split into derivation and validation cohorts based on the participants' disease group. In the derivation cohort, the regression-derived score of the EC-Screen was calculated using binomial logistic regression. Two predictive models were produced. The first model was used to distinguish participants with MCI and dementia from controls, and the second model was used to distinguish participants with dementia from those with MCI and controls. Receiver operating characteristic curves were constructed and the areas under the curves (AUCs) were calculated. The performances of the two predictive models were tested using the validation cohorts. The relationship between the EC-Screen and paper-and-pencil Montreal Cognitive Assessment-Hong Kong version (HK-MoCA) was evaluated by the Pearson correlation coefficient.
A total of 126 controls, 54 participants with MCI, and 63 participants with dementia were included in the study. In differentiating participants with MCI and dementia from controls, the AUC of the EC-Screen in the derivation and validation cohorts was 0.87 and 0.84, respectively. The optimal sensitivity and specificity in the derivation cohorts were 0.81 and 0.80, respectively. In differentiating participants with dementia from those with MCI and controls, the AUC of the derivation and validation cohorts was 0.90 and 0.88, respectively. The optimal sensitivity and specificity in the derivation cohort were 0.83 and 0.83, respectively. There was a significant correlation between the EC-Screen and HK-MoCA (r=-0.67, P<.001).
The EC-Screen is suggested to be a promising tool for the detection of MCI and dementia. This test can be self-administered or assisted by a nonprofessional staff or family member. Therefore, the EC-Screen can be a useful tool for case finding in primary health care and community settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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