Simultaneous Combinations Research Articles

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

The AUREX cell: a versatile operando electrochemical cell for studying catalytic materials using X-ray diffraction, total scattering and X-ray absorption spectroscopy under working conditions.

Understanding the structure-property relationship in electrocatalysts under working conditions is crucial for the rational design of novel and improved catalytic materials. This paper presents the Aarhus University reactor for electrochemical studies using X-rays (AUREX) operando electrocatalytic flow cell, designed as an easy-to-use versatile setup with a minimal background contribution and a uniform flow field to limit concentration polarization and handle gas formation. The cell has been employed to measure operando total scattering, diffraction and absorption spectroscopy as well as simultaneous combinations thereof on a commercial silver electrocatalyst for proof of concept. This combination of operando techniques allows for monitoring of the short-, medium- and long-range structure under working conditions, including an applied potential, liquid electrolyte and local reaction environment. The structural transformations of the Ag electrocatalyst are monitored with non-negative matrix factorization, linear combination analysis, the Pearson correlation coefficient matrix, and refinements in both real and reciprocal space. Upon application of an oxidative potential in an Ar-saturated aqueous 0.1 M KHCO3/K2CO3 electrolyte, the face-centered cubic (f.c.c.) Ag gradually transforms first to a trigonal Ag2CO3 phase, followed by the formation of a monoclinic Ag2CO3 phase. A reducing potential immediately reverts the structure to the Ag (f.c.c.) phase. Following the electrochemical-reaction-induced phase transitions is of fundamental interest and necessary for understanding and improving the stability of electrocatalysts, and the operando cell proves a versatile setup for probing this. In addition, it is demonstrated that, when studying electrochemical reactions, a high energy or short exposure time is needed to circumvent beam-induced effects.

On Simultaneous Approximation and Combinations of Lupas Type Operators

The purpose of the present paper is to study a sequence of linear and positive operators which was introduced by A. Lupas. First, we obtain estimate of moments of the operators and then prove a basic convergence theorem for simultaneous approximation. Further, we find error in approximation in terms of modulus of continuity of function. Finally, we establish a Voronovskaja asymptotic formula for linear combination of the above operators.

A Nonpharmacologic Treatment for Anxiety in Older Adults Based on Cognitive-Motor Training With Response-Generated Feedback.

Simultaneous combinations of cognitive and physical exercises (cognitive-motor dual-task training [CMDT]) are more effective than physical and cognitive training alone in counteracting the decline of older adults and promoting physical and psychological well-being. The CMDT can be particularly effective in improving cognitive and functional abilities. Here, we validated an innovative nonpharmacologic intervention for anxiety and general well-being in older people by combining CMDT and response-generated feedback (RGF) principles. As outcomes, anxiety, cognitive functions, and functional mobility were evaluated. In addition, electroencephalographic methods were employed to investigate the neural basis of the possible intervention effects. Thirty older adults were divided into an experimental group trained using a CMDT + RGF protocol and a control group using the CMDT only. The CMDT + RGF consisted of the simultaneous execution of whole-body exercises, cognitive tasks that were realized using interactive devices, and continuous feedback on every response. Results showed decreased anxiety and increased response speed in the experimental group, and both groups improved their functional ability and response accuracy after the intervention. According to electroencephalographic results, both groups showed an increase in the bilateral prefrontal cortex anticipatory activity, but the experimental group also showed a further increase in the left prefrontal cortex and in the premotor areas anticipatory functions. This study confirms the effectiveness of the proposed intervention on anxiety by adopting a nonpharmacology treatment that could affect public and individual health costs by proposing an alternative approach to expensive medications and psychotherapy and could significantly improve older adults' quality of life.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Performance of clinical scoring and microscopic combinations for diagnosing pulmonary tuberculosis with the GenXpert criteria

Pulmonary tuberculosis is a prominent health issue in Indonesia, which ranks second in the world regarding the number of patients. Rapid tuberculosis detection is crucial for early treatment, a better prognosis, and a reduction in disease transmission; however, the availability of molecular rapid tests is limited. Cross-sectional design and retrospective analyses of pre-pandemic data from 723 patients with suspected pulmonary tuberculosis from 2017 to 2019 were conducted in this study. The study aimed to assess the performance of clinical scoring and microscopic examination in tuberculosis diagnosis at RSUD Sayang Cianjur. The effectiveness of sequential (two-stage) and simultaneous combinations of clinical scoring and sputum smear microscopic were investigated. Performance assessments consisted of 2x2 tables, calculation according to Gordis, and Receiver Operator Characteristic (ROC) analysis, with GenXpert results as the gold standard. The results showed lower performance of the individually performed scoring system, with clinical scoring having a sensitivity of 34.44% and a specificity of 97.15%. Microscopic Acid Fast Bacteria (AFB) had a sensitivity of 70.20% and a specificity of 98.57%. The net sensitivity of the sequential combination was 28.48%, and the specificity was 99.05%. The net sensitivity of the simultaneous combination was 77.15%, and the specificity was 95.72%. The area under the curve from the sequential diagnostic method was 0.728, and the area under the curve of the simultaneous diagnostic was 0.884. The sequential and simultaneous combinations of clinical scoring and the AFB microscopy improved the test performance. The simultaneous combination performed slightly better than the sequential combination.

Optimized Single-Step Recovery of Lipophilic and Hydrophilic Compounds from Raspberry, Strawberry and Blackberry Pomaces Using a Simultaneous Ultrasound-Enzyme-Assisted Extraction (UEAE).

An ultrasound-enzyme-assisted extraction (UEAE) was optimized to extract, simultaneously, the hydrophilic and lipophilic compounds from three berry pomaces (raspberry, strawberry and blackberry). First, an enzyme screening designated a thermostable alkaline protease as the most suitable enzyme to recover, in an aqueous medium, the highest yields of polyphenols and oil in the most efficient way. Secondly, the selected enzyme was coupled to ultrasounds (US) in sequential and simultaneous combinations. The simultaneous US-alkaline enzyme combination was selected as a one-single-step process and was then optimized by definitive screening design (DSD). The optimized parameters were: US amplitude, 20% (raspberry pomace) or 70% (strawberry and blackberry pomaces); pH, 8; E/S ratio, 1% (w/w); S/L ratio, 6% (w/v); extraction time, 30 min; temperature, 60 °C. Compared to conventional extractions using organic solvents, the UEAE extracted all the polyphenols, with around 75% of the active polyphenols (measured by the DPPH● method) and up to 75% of the initial oil from the berry pomaces. Characterized lipophilic compounds were rich in polyunsaturated fatty acids (PUFAs), tocols and phytosterols. The polyphenolics were analyzed by UPLC-MS/MS; characteristic ellagitannins of the Rosaceae family (sanguiin H-6 or agrimoniin, sanguiin H-10, …) and ellagic acid conjugates were found as the major components.

Strategies for new word formation in NGT

Abstract How do new words arise in a sign language? We present an empirical study of newly formed words in Sign Language of the Netherlands (NGT). Five signers were asked to create new forms for known concepts for which word forms exist in NGT. Participants used sequential strategies for word formation, also found in spoken languages. More frequently, however, they used simultaneous strategies, some of which are unique for the visual-manual modality. We describe and discuss each strategy and focus on the most prominent of these, namely the simultaneous combination of meaningful form elements (Form-Meaning Units or FMUs). The abundance of simultaneous combinations of FMUs in our data cannot be explained in terms of concatenative morphology. We propose an account for word formation phenomena in NGT that uses the phonological segment as the template for simultaneous combinations of FMUs. This study shows that the FMUs function as basic building blocks for words and accordingly can be considered morphemes. Given the large set of FMUs in NGT and their frequent occurrence in the newly formed lexical words in our data, we argue for the acknowledgement of more morphological complexity within the lexicon of sign languages and for a re-evaluation of the relation between sign language phonology, morphology, and syntax.

Content of luteolin and luteolin-7-О-glucoside from the leaves of Vernonia amygdalina Del., and synergistic inhibitory effect with cisplatin on nasopharyngeal carcinoma cells

This study describes the quantification of luteolin and luteolin-7-О-glucoside in methanol leaf extract of Vernonia amygdalina by HPLC method. Dried powdered leaves were extracted with methanol at 40 °C for 6 h and freeze-dried. The freeze-dried sample was then analyzed by HPLC. The content of luteolin was lesser than luteolin-7-O-glucoside in the extract. The extract and the bioactive compounds were screened for inhibitory effects on nasopharyngeal carcinoma cells. Flow-cytometry and high content analysis were performed to detect luteolin-induced apoptosis. The effects of combining luteolin and cisplatin on cultured cells were explored. Luteolin produced a dose-dependent inhibition of all cell lines tested. Flow cytometry analysis revealed that luteolin did not induce apoptosis. Simultaneous combinations of luteolin and cisplatin produced synergistic effects, suggesting that the dosage of cisplatin required to treat NPC could be reduced with the addition of luteolin; sequentially lessening the risk of cisplatin-associated toxicity.

Combinatorial drug screening on 3D Ewing sarcoma spheroids using droplet-based microfluidics

Culturing and screening cells in microfluidics, particularly in three-dimensional formats, has the potential to impact diverse areas from fundamental biology to cancer precision medicine. Here, we use a platform based on anchored droplets for drug screening. The response of spheroids of Ewing sarcoma (EwS) A673 cells to simultaneous or sequential combinations of etoposide and cisplatin was evaluated. This was done by culturing spheroids of EwS cells inside 500nL droplets then merging them with secondary droplets containing fluorescent-barcoded drugs at different concentrations. Differences in EwS spheroid growth and viability were measured by microscopy. After drug exposure such measurements enabled estimation of their IC50 values, which were in agreement with values obtained in standard multiwell plates. Then, synergistic drug combination was evaluated. Sequential combination treatment of EwS with etoposide applied 24h before cisplatin resulted in amplified synergistic effect. As such, droplet-based microfluidics offers the modularity required for evaluation of drug combinations.

Thermally stable multi-directional magnetoelectric based embedded magnetic sensor

Owing to the multifunctional behavior possessed by magnetoelectric (ME) composites, they are sought-after materials for various magnetic field sensing applications. This article proposes a three-directional ME-based embedded magnetic sensor that has been fabricated using the press-fit technique. The employed fabrication method negates the use of epoxy in the ME sensor, thus enabling its use at elevated temperatures in excess of 100 ∘C. The fabricated sensor is tested using an experimental setup capable of producing ac and dc bias magnetic fields in three coordinate directions. Experiments are performed for various dc magnetic field conditions, including x, y, z directions, their simultaneous combinations, and magnetic field aligned at an angle with the sensor. Under all testing conditions, the embedded sensor shows a significantly high output voltage response. Additionally, the effect of the magnetic field generated by the double magnet system and single magnet system on the sensor performance has also been demonstrated, wherein the embedded sensor is observed to be marginally affected by magnetic field due to the presence of only one magnet. Finally, quasi-static ME measurements are performed at elevated temperatures up to 100 ∘C, and it is observed that the novel embedded sensor has reliable sensing capabilities in aggravated thermal environments even in excess of 100 ∘C. Thus, the proposed three-directional embedded magnetic sensor offers reliable response under all conditions of magnetic field and temperature and can thus be a reliable alternative for the traditionally used layered-based counterparts.

Recent research accomplishments on early detection of Xylella fastidiosa outbreaks in the Mediterranean Basin

Xylella fastidiosa is a major transboundary plant pest, causing severe socioeconomic impacts. Development of preventive strategies and methods for surveillance, early detection, monitoring, and accurate diagnosis of X. fastidiosa and its vectors, are keys to preventing the effects of this plant pathogen, and assist timely eradication or optimisation of containment measures. This review focuses on approaches for early detection of X. fastidiosa in the Mediterranean Basin, including development of climatic suitability risk maps to determine areas of potential establishment, and epidemiological models to assist in outbreak management through optimized surveillance and targeted responses. The usefulness of airborne hyperspectral and thermal images from remote sensing to discriminate X. fastidiosa infections from other biotic- and abiotic-induced spectral signatures is also discussed. The most commonly used methods for identifying X. fastidiosa in infected plants and vectors, and the molecular approaches available to genetically characterize X. fastidiosa strains, are described. Each of these approaches has trade-offs, but stepwise or simultaneous combinations of these methods may help to contain X. fastidiosa epidemics in the Mediterranean Basin.

Gesture Vocalizer for Assisting Deaf and Dumb

Some individuals possess the innate ability to engage in communication with one another. However, regrettably, not everyone possesses the capacity for speech and hearing. Nonverbal communication, employed within the community of individuals with diverse abilities, serves as a method of interaction. To convey meaning, sign language combines simultaneous combinations of hand forms and movements with body, arm, and hand gestures as well as facial expressions. Those who are unable to speak use sign language to communicate with other people who are also speech-impaired as well as with average people who are familiar with the subtleties of sign language. Sometimes, an interpreter is necessary to translate the intentions behind the signs for those who can speak but may not fully understand sign language. However, consistent access to interpreters for sign language communication is not always feasible, and not everyone can master the intricacies of sign language. Hence, an alternative approach is the implementation of a device known as the Gesture Vocalizer. The Gesture Vocalizer functions as an intermediary. It translates the gestures produced by the person with speech impairment into audio output. The hardware iteration of this Gesture Vocalizer project is an array of microcontroller systems designed to enable inter-system communication between mute, deaf, and visually impaired communities and those who do not face such communication challenges. In this effort, we proposed a gesture vocalizer that is based on sensors and a microcontroller. The design of the gesture vocalizer primarily revolves around a hand glove integrated with a microcontroller system.

Phonological development in American Sign Language-signing children: Insights from pseudosign repetition tasks.

In this study, we conducted a pseudosign (nonce sign) repetition task with 22 children (mean age: 6;04) acquiring American Sign Language (ASL) as a first language (L1) from deaf parents. Thirty-nine pseudosigns with varying complexity were developed and organized into eight categories depending on number of hands, number of simultaneous movement types, and number of movement sequences. Pseudosigns also varied in handshape complexity. The children’s performance on the ASL pseudosign task improved with age, displaying relatively accurate (re)production of location and orientation, but much less accurate handshape and movement, a finding in line with real sign productions for both L1 and L2 signers. Handshapes with higher complexity were correlated with lower accuracy in the handshape parameter. We found main effects of sequential and simultaneous movement combinations on overall performance. Items with no movement sequence were produced with higher overall accuracy than those with a movement sequence. Items with two simultaneous movement types or a single movement type were produced with higher overall accuracy than those with three simultaneous movement types. Finally, number of hands did not affect the overall accuracy. Remarkably, movement sequences impose processing constraints on signing children whereas complex hands (two hands) and two simultaneous movement types do not significantly lower accuracy, indicating a capacity for processing multiple simultaneous components in signs. Spoken languages, in contrast, manifest greater complexity in temporal length. Hearing children’s pseudoword repetition still displays high levels of accuracy on disyllabic words, with complexity effects affecting only longer multisyllabic words. We conclude that the pseudosign repetition task is an informative tool for studies of signing children’s phonological development and that sheds light on potential modality effects for phonological development.

Simultaneous and alternate combinations of action-observation and motor imagery involve a common lower-level sensorimotor process

Combining the motor simulation techniques of action observation and motor imagery (AOMI) is known to enhance motor performance more than when these techniques are presented in isolation. The present study examined the involvement of lower-level sensorimotor processes for the improvement in a dart-throwing task using AOMI. Novice participants (n = 70) were assessed on their dart-throwing both before and after a six-week AOMI training intervention that was contingent upon the random allocation of groups. Participants were randomly allocated into groups involving AOMI, where they observed either a congruent action, incongruent action or fixation cross (control), while simultaneously or alternately imagining the dart-throwing task. Dart-throwing performance was significantly more improved for the simultaneous- and alternate-congruent groups compared to the simultaneous-fixation and control groups. There was no indication of improvement by any of the other groups. This improvement appeared to coincide with lower EMG activity at the agonist and antagonist muscles, which would indicate greater movement efficiency. The findings suggest that AOMI involves a common lower-level sensorimotor process, which can lead to motor facilitation or interference, dependent upon whether the simulation techniques are congruent or incongruent with each other, respectively. What's more, this feature does not appear to differ as a function of the structure of delivery (i.e., simultaneous vs. alternate).

CDK4/6 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a poor prognosis and limited treatment options. Considering that alterations of the CDK4/6-cyclin D-Rb pathway occur frequently in HCC, we tested the efficacy of two CDK4/6 inhibitors, abemaciclib and ribociclib, in combination with lenvatinib, a multi-kinase inhibitor approved as first-line therapy for advanced HCC, in a panel of HCC Rb-expressing cell lines. The simultaneous drug combinations showed a superior anti-proliferative activity as compared with single agents or sequential schedules of treatment, either in short or in long-term experiments. In addition, the simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration. Mechanistically, these growth-inhibitory effects were associated with a stronger down-regulation of c-myc protein expression. Depending on the HCC cell model, reduced activation of MAPK, mTORC1/p70S6K or src/FAK signaling was also observed. Abemaciclib combined with lenvatinib arrested the cells in the G1 cell cycle phase, induced p21 accumulation, and promoted a stronger increase of cellular senescence, associated with elevation of β-galactosidase activity and accumulation of ROS, as compared with single treatments. After drug withdrawal, the capacity of forming colonies was significantly impaired, suggesting that the anti-tumor efficacy of abemaciclib and lenvatinib combination was persistent.Our pre-clinical results demonstrate the effectiveness of the simultaneous combination of CDK4/6 inhibitors with lenvatinib in HCC cell models, suggesting that this combination may be worthy of further investigation as a therapeutic approach for the treatment of advanced HCC.

Development and characterisation of an irradiation device for biomedical studies covering the solar spectrum with individual regulated spectral bands

To understand the importance of terrestrial solar exposure on human skin, not only individual spectral components need to be considered in biomedical studies, but also the relevance of the combined action profile of the complete solar spectrum (cSS) must be established. We therefore developed a novel irradiation device that combines the emission of four individual lamps (UVB, UVA, VIS and nIR) to achieve exposure from 280 to 1400 nm with individual controllable lamps. The integrated irradiance of each spectral band is similar to the solar spectrum. The lamps can be utilised individually or in any desired combination. Here we present the design, realisation, and validation of this irradiation device as well as biological results on cellular metabolism (MTT assay), cell cycle alterations, and clonogenic growth in HaCaT cells after exposures to the individual spectral bands as well as their simultaneous combinations. Thereby, we demonstrate that UVB combined with UVA is the main determinant for the metabolic activity within cSS. Also, UVB-dependent effects dominate cell cycle regulation in cSS, whilst UVA and nIR have little influence. Lastly, also clonogenic growth is dominated by the UVB action profile in cSS, despite nIR showing modulatory activity when applied in combination with UVB. Together, this highlights the regulatory influence of the different spectral bands on the three biological endpoints and demonstrates their modulation when being part of the complete solar spectrum.Graphical abstract

Abstract P078: Synergistic immunotherapy effects of anti-COVID-19 and anti-cancer vaccines in preventing tumors and infections

Abstract To assure efficacy, safety and security of medicines and products including those of cancer and infection prevention ones, the concepts of immunology and immunotherapy, treatments, therapeutics, research, reviews, approvals and according agency, nation and world-wide managements are highly important. Often rationally planned combinations of U.S. Food and Drug Administration (USFDA) approved medicines in preventing or treating the same or similar or multiple diseases are realized to be pharmacologically and biologically effective in mechanisms and toxicologically safe in applications. Because, multiple mechanisms are simultaneously combined in enhancing systemic immunities within the permissible limits of the doses. In this work, the immunology and immunotherapy aspects of both anti-cancer vaccines and anti-COVID-19 vaccines are taken into account to prevent current and future occurrences of cancer and infectious diseases. Though the intended mechanisms of actions are only disease specific and are primarily different between anti-cancer and anti-COVID-19 vaccines, their combinations are worthwhile in providing synergistic effects against carcinogenesis, metastasis and infections. Based on the chemical, biological and pharmacological input and output information for both kinetics and dynamics of vaccines including mRNA-1273, BNT162b2, and JNJ-78436735 to prevent covid-19 are explored in combinations with anti-cancer vaccines including Human Papillomavirus (HPV) Vaccine and Hepatitis B Vaccine (HBV). In addition to safety and efficacy, mRNA, viral-vector, protein and antigen mechanisms, pH, vaccine-vaccine interactions, independent and combined dose regimens, toxicities, solubilities, intrinsic and extrinsic covariates were taken into account for careful planning of combinations. Simultaneous dual combinations from both groups were improved to three to five levels of combinations. It was realized that these combinations qualify for pre-clinical followed by clinical-investigations further. Also, these conclusions promised us to explore additional new and approved vaccines of these indications. Citation Format: Narayana Garimella. Synergistic immunotherapy effects of anti-COVID-19 and anti-cancer vaccines in preventing tumors and infections [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P078.

Network-Based Systems Analysis Explains Sequence-Dependent Synergism of Bortezomib and Vorinostat in Multiple Myeloma

Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular determinants of the interaction using a systems pharmacology approach. A Boolean network model consisting of 79 proteins and 225 connections was developed using literature information characterizing mechanisms of drug action and intracellular signal transduction. Network visualization and structural analysis were conducted, and model simulations were compared with experimental data. Critical biomarkers, such as pNFκB, p53, cellular stress, and p21, were identified using measures of network centrality and model reduction. U266 cells were then exposed to bortezomib (3 nM) and vorinostat (2 μM) as single agents or in simultaneous and sequential (bortezomib for first 24 h, followed by addition of vorinostat for another 24 h) combinations. Temporal changes for nine of the critical proteins in the reduced Boolean model were measured over 48 h, and cellular proliferation was measured over 96 h. A mechanism-based systems model was developed that captured the biological basis of a bortezomib and vorinostat sequence-dependent pharmacodynamic interaction. The model was further extended in vivo by linking in vitro parameter values and dynamics of p21, caspase-3, and pAKT biomarkers to tumor growth in xenograft mice reported in the literature. Network-based methodologies and pharmacodynamic principles were integrated successfully to evaluate bortezomib and vorinostat interactions in a mechanistic and quantitative manner. The model can be potentially applied to evaluate their combination regimens and explore in vivo dosing regimens.

Signal Competition in Dynamic Visual Environments: Relative Conspicuousness of Social Displays in the Jacky Dragon (Amphibolurus muricatus)

Selection for conspicuousness has been an important force on visual signal design. Although signal efficacy has been extensively studied in acoustic systems, few studies have examined this attribute in dynamic visual signals. Here, I simulated signal competition between Jacky lizards (Amphibolurus muricatus) by presenting the motor patterns (tail-flick, push-up body rock, and slow arm wave) in isolation that are typically used in social communication. Phase 1 used four digital video playback systems to present simultaneous animated display combinations on opposing monitors to a subject that was situated in the middle, and measured orientation towards the monitors and latency to respond. Phase 2 maintained the same set-up and simultaneous display combinations, but tested signal conspicuousness across three levels of visual noise (calm, typical, and windy) simulated by the movement of windblown vegetation in the background. The results suggest that the most conspicuous visual display is the tail-flick, followed by the push-up body rock, and the slow arm wave is the least conspicuous. Moreover, this relationship is robust across the full range of environmental wind conditions. No significant side biases in orientation to displays were detected, which suggested no lateralization in perceptual processes. Jacky lizard display motor patterns which address distinct functional requirements: the tail flick is an ideal alerting component, with high efficacy over a range of signaling conditions. The push-up body rock, which is used only in aggressive displays, has a more restricted range, and the submissive slow arm wave is likely designed to appease nearby dominant males.