We numerically investigate and experimentally demonstrate an in situ topological band transition in a highly tunable mechanical system made of cylindrical granular particles. This system allows us to ...tune its interparticle stiffness in a controllable way, simply by changing the contact angles between the cylinders. The spatial variation of particles' stiffness results in an in situ transition of the system's topology. This manifests as the emergence of a boundary mode in the finite system, which we observe experimentally via laser Doppler vibrometry. When two topologically different systems are placed adjacently, we analytically predict and computationally and experimentally demonstrate the existence of a finite-frequency topologically protected mode at their interface.
Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack ...estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy.
Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic ...systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer.
We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19).
Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19.
Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future.
•Patients with cancer who develop breakthrough COVID-19 following full vaccination remain susceptible to severe outcomes.•Hematologic malignancies are over-represented among vaccinated patients with cancer who develop breakthrough COVID-19.•Vaccination of close contacts, masking, boosters, and social distancing are needed to protect patients with cancer.
•Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases and both are recognized as major causes of liver disease worldwide.•A SIRS model of transmission of the ...hepatitis C virus (HCV) under effect of liquoring in six compartments: Susceptible, Low liquoring, High liquoring, Acute, Chronic and Recovered Individuals. Disease-free equilibrium point is both locally and globally asymptotically stable.•Sensitivity analysis with respect to key parameters of R0 indicates that control strategies should target reduction of the amount of alcohol use amongst people to prevent disease progression. The control in model is in terms of rehabilitation center which helps people to divert from high liquoring to low liquoring.•This research shows the positive impact of rehabilitation on liquoring habits and subsequently on HCV transmission.
Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases and both are recognized as major causes of liver disease worldwide. Each poses a major public and economic burden to society, and when the two co-exist they appear to have a synergistic effect in the progression of chronic liver disease. In this research, we developed a SIRS model of transmission of the hepatitis C virus (HCV) under effect of liquoring in six compartments: Susceptible, Low liquoring, High liquoring, Acute, Chronic and Recovered Individuals. The system of non-linear ordinary differential equations is formulated. Basic reproduction number R0 is computed using the next generation matrix approach. The stability of the model is worked out at the equilibrium point. Model analysis shows that the disease-free equilibrium point is both locally and globally asymptotically stable. Sensitivity analysis with respect to key parameters of R0 indicates that control strategies should target reduction of the amount of alcohol use amongst people with HCV as it prevents or delays HCV disease progression. The control in our model is in terms of rehabilitation center which helps people to divert from high liquoring to low liquoring. Numerical simulation has been carried out to show the impact of control on different compartment. This research shows the positive impact of rehabilitation on liquoring habits and subsequently on HCV transmission.
Background & AimCellular therapy products are required to have meaningful tests determining safety and quality. This is to be achieved by establishing sterility, identity, purity and potency of the ...final product. As required by FDA per 21 CFR 610, potency of the cell therapy product should be determined by appropriate tests that shows effector function of such products. The methods that are currently being used to test effector function of immune cells include use of tumor cells as target cells and various labelling methods. Target tumor cells add biological variabilities to these tests which already have variabilities introduced by donor sources, tedious set ups, plate conditions, person to person variability in assay set up and readout variabilities from different labelling methods. There is an obvious need of a simpler potency assay with less variability and more reliable results.Methods, Results & ConclusionWe are developing potency assays to address the issues of current available assays and to satisfy FDA requirements of potency assay for advanced phase clinical trials of therapeutic effector cells. FDA allows the use of surrogate method to determine potency of the cell therapy product given it correlates with the effector function of such product. Here, we have tested PHA and K562-derived exosomes as easily-standardized surrogate methods to activate NK cells, and have assessed induced cytokine production as correlates of their effector function. Avoiding the use of target cells simplifies set up, and use of these assays removes the variabilities of traditional potency assays. The PHA-based assay can be used to test potency of purified therapeutic effector cells, whereas the exosome-based assay can elicit NK cell potency in pure or complex mixtures and modifications may be developed for specificity to other immune cell products.NK cells expanded with feeder cells expressing membrane-bound IL-21 have shown high IL-2 and IFN-g in correlation with high cytotoxicity against tumor cells. We were able to replicate this effector function using PHA based potency assay. Preliminary experiment for exosome based assay also showed similar trend.This rapidly-advancing industry has need of more rapid and reliable potency assays to test function of therapeutic immune cells. We hope to address this issue with development of these potency assays as a replacement to traditional cytotoxicity tests.
Background & AimThe field of cellular immunotherapy is growing rapidly. Natural killer (NK) cells are part of the innate immune system and have wide potential for therapeutic application. Although ...CAR-T cells are now commercially available, NK cells are still in pre-commercial development and testing. It is likely that much higher numbers of NK cells will be required to achieve therapeutic results compared to that of antigen-specific T cells. With the development of feeder cells expressing membrane-bound IL-21, it has become possible to achieve large-scale expansion of non-senescent NK cells. To date, most studies have expanded NK cells at clinical scale by sequential application of open systems (G-rex) or small-volume closed systems. Achieving large-scale expansion of GMP-grade NK cells requires multiple systems operating in parallel, which increase labor costs, material costs and potential for contamination.To develop a large-scale process for NK-cell expansion in compliance with regulatory requirements, we combined the CliniMACS Prodigy (Miltenyi Biotec) and Xuri W25 (GE Healthcare) into one closed-system process.Methods, Results & ConclusionIn collaboration with Miltenyi, we optimized a custom program for the Prodigy to perform Ficoll density-gradient selection of mononuclear cells, CD3-based magnetic depletion of T cells, periodic addition of and forced interaction with feeder cells, and on-demand addition of media for the first phase of NK-cell culture, culminating in transfer of the cells to a secondary culture bag. We then applied a semi-continuous perfusion program on the Xuri for the second phase. We identified optimal glucose and pH levels to support log-phase expansion, and refined the Prodigy program to optimize CD3-depletion and allow efficient volume reduction steps for media exchanges. On the Xuri, pH and dissolved oxygen (DO) monitoring was utilized to identify optimal rocking rates, rocking angles and perfusion parameters to allow sufficient NK cell-feeder cell contact and achieve high cell densities. Finally, NK cells produced by this approach demonstrated very high cytotoxicity (mean 65.2% at 1.25:1 E:T ratio). With these optimized protocols, we achieved high-purity (≥99%, n=3) and high-density (∼10 7 cells/mL) conditions to yield 5 × 10 10 high-activity NK cells in a 5L final culture volume from one donor buffy coat. We anticipate realizing both reduced cost and increased regulatory compliance of NK cell production by using the automated closed systems of Prodigy and Xuri in sequence.
School students with specific learning disabilities (SpLDs) experience chronic academic underachievement and resultant stress. The present study aimed to determine if school students with newly ...diagnosed SpLD were more likely to have anxiety than their regular peers.
The study cases (aged 8-15 years) were recruited from our institute's learning disability clinic. The matched controls were recruited from four schools in Mumbai, Maharashtra, India. Anxiety was measured using the Spence Children's Anxiety Scale (SCAS)-child self-report version questionnaire. Median SCAS scores and the proportion of students with an SCAS score in the "clinical anxiety" range were compared between the groups.
SCAS scores were significantly higher in 8-11-year-old learning-disabled male and female students (P < 0.0001 for both groups) and 12-15-year-old female students (P = 0.004), as compared with matched controls. A significantly higher number of learning-disabled students were found to have "clinical anxiety" 24.64% vs. 4.35%, crude odds ratio (OR) = 7.19, 95% confidence interval (CI) 2.91-17.78, P = 0.0001, as compared with the controls regardless of gender, age group, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), or associated medical conditions. A significantly higher proportion of 8-11-year-old learning-disabled students, especially males, were found to have "clinical anxiety" as compared with 12-15-year-old learning-disabled students (crude OR = 4.38, 95% CI 1.94-9.92, P = 0.0004). Gender, presence of comorbid ADHD or associated medical conditions, and type of school attended or curriculum did not impact the prevalence of "clinical anxiety" in learning-disabled students.
Students with newly diagnosed SpLD have greater odds of being "clinically anxious" relative to their regular peers. We recommend screening for anxiety in children with SpLD immediately after diagnosis so that their optimum rehabilitation can be facilitated.
Thirty isolates of bacteria and six isolates of Trichoderma were isolated from fertile agricultural soil and evaluated for their antagonistic activity against phytopathogens like Macrophomina ...phaseolina and Sclerotinia sclerotiorum, under in vitro conditions. Different isolates showed varying degrees of antagonism. The three most antagonistic bacteria Pseudomonas aeruginosa (MBAA1), Bacillus cereus (MBAA2) and Bacillus amyloliquefaciens (MBAA3) and one fungi Trichoderma citrinoviride (MBAAT) were selected as the most effective isolates as biocontrol agents. The present study was undertaken to develop a plant growth promoting microbial consortium to reduce the disease incidence in Glycine max both under in vitro and in vivo conditions. Biocontrol attributes such as ammonia, siderophore, enzymes like β -1,3 glucanase, chitinase and cellulase were more potential in consortia in comparison to single isolates. Plants treated with consortia + pathogen showed lower disease incidence in comparison to single antagonist + pathogen and pathogen infested control (p ≤ 0.05). Maximum disease control was observed in potted plants treated with S. sclerotiorum + MBAA1 + MBAAT showing only 15.8% disease incidence in comparison to Sclerotinia infested control, in which disease incidence was 97%. Seed bacterised with MBAA1 + MBAAT exhibited enhanced seed germination of G. max up to 68% along with subsequent increase in other plant growth parameters. Considerable increase in seedling vigour index (1863.2) and chlorophyll content (13.518 mg/g) was observed in seeds treated with MBAA1 + MBAAT in plants infected with M. phaseolina.
Bioremediation potential of
Phanerochaete chrysosporium strains NCIM 1073, NCIM 1106 and NCIM 1197 to decolourise molasses in solid and liquid molasses media was studied. Strains varied in the ...pattern of molasses decolourisation on solid medium by Giant colony method. Under submerged cultivation conditions, strain NCIM 1073 did not decolourise molasses while, strains NCIM 1106 and NCIM 1197 could decolourise molasses up to 82% and 76%, respectively. Under stationary cultivation conditions, none of the strains could decolourise molasses. This was overcome by increasing the surface area of the culture in flat bottom glass bottles under stationary cultivation conditions. Under submerged cultivation conditions, growth was more or less same in all strains. However, the lignin peroxidase and manganese peroxidase activities were significantly less in the strain NCIM 1073. Under stationary cultivation conditions, none of the strains could produce enzymes lignin peroxidase, manganese peroxidase and laccase. However, all of them could produce lignin peroxidase and manganese peroxidase when cultivated in flat bottom glass bottles under stationary cultivation conditions.
This paper presents a laboratory study on the Acoustic Emission (AE) generated during railway wheel–rail track interaction, with a view to developing methods of
in situ rail–wheel interaction ...monitoring using rail-mounted sensors. It is known that the physical processes of impact and wear generate AE and it was therefore expected that axle loads, speed and traction would influence the AE generated by an interaction and that the characteristics of “normal” interaction would be affected by wheel and/or track defects and/or any misalignment between rail and track.
A set of laboratory experiments were carried out on a scaled test rig to characterise the continuous AE generated by a wheel rolling on a rail and, secondarily, to assess the effect on the AE characteristic of the natural defects present on the contact profile of the rail. The natural defects were of a relatively minor nature and their assessment serves as part of the calibration of background AE for experiments with more significant simulated defects.
A simplified analytical model, devised for AE waves propagating from a moving source, based on “vehicle” speed and wave damping coefficients, has been developed for the test track and fitted to the measured results. As a wheel rolls towards a sensor and then away from the sensor the measured AE generally rises and falls in a predictable way. The effects of wheel and rail surface features were found to introduce deviations from this “background”, and a method to identify the location of surface defects, based on identifying peaks above the background is also demonstrated.
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