Killing Rate Research Articles

Immune Effect of Co-Culture of Dendritic Cells and Cytokine-Induced Killer Cells on Prostate Cancer Cells.

It was to explore the immune outcome of co-culture of dendritic cells (DC) and cytokine-induced killer cells (CIK) on prostate cancer (PCa) cells. Peripheral blood mononuclear cells (PBMCs) were extracted from healthy blood donors. DC and CIK cells were induced and co-cultured. The proliferation and phenotypic changes of DC, CIK, and DC-CIK cells/groups were observed. Model rats were constructed by injecting PC3 PCa cells into the abdominal cavity. The successful 50 cases were divided into a negative control group, a chemotherapy group, a DC group, a CIK group, and a DC-CIK treatment group (each consisting of 10 rats) to observe tumor progression. The secreted concentrations of interleukin-12 (IL-12) ((103.67 ± 2.77) pg/mL) and interferon-γ (IFN-γ) ((730.09 ± 23.52) pg/mL) were higher in DC-CIK group as against DC and CIK groups; the proliferation of CIK was higher in DC-CIK group as against CIK within 12 to 20 days of culture. The positive rate (PR) of CD3+/ CD56+ and CD8+ was higher and that of CD45RA+ was lower in DC-CIK group as against CIK.The killing rate of the DC-CIK group was higher than that of the DC and CIK groups at a target effect ratio of 10:1/20:1/50:1 (P < 0.05). After the treatment, the body weight of rats in the chemotherapy group, DC group, and CIK group was significantly reduced (P < 0.05), while no significant changes were observed in the negative control group and DC-CIK group (P > 0.05). After 25 days of treatment, the tumor size in the DC-CIK group was significantly smaller compared to the negative control group, chemotherapy group, DC group, and CIK group; the necrotic area of the tumor tissue in the DC-CIK group was also significantly larger than that in the negative control group, chemotherapy group, DC group, and CIK group (P < 0.05). Co-culture of DC and CIK is excellent in enhancing the proliferation of CIK cells, increasing the secretion of IL-12 and IFN-γ, and enhancing the activity of immune cells and anti-tumor ability, showing its potential in anti-PCa tumor immunotherapy.

Effectiveness of Butterfly Pea ( Clitoria Ternatea ) Extract Against Streptococcus Mutans Bacterial Growth In Vitro

Dental caries is still a major problem in dentistry and is the most common infectious disease in children. Caries is a microbiological infectious disease that can damage the hard tissue of the teeth. This study aims to determine the effectiveness of butterfly pea flower extract ( Clitoria ternatea ) on the growth of Streptococcus mutans in vitro. This type of research is laboratory experimental research using a post test only control group design approach The samples used were butterfly pea flower extract ( Clitoria ternatea ) diluted with DMSO to a concentration of 100%, 50%, 25%, 12.5%, 3.125%, 6.125% and Streptococcus mutans ATCC 25175. This research was conducted using the MIC test dilution method and KBM to see the effectiveness of the antibacterial extract against the test bacteria. Analysis of research data using the one way ANOVA test (p &lt;0.05) to see significant differences between study groups with the number of test bacteria, followed by a double comparison test with the Post Hoc Least Significance Different (LSD) method to determine the average difference between treatment groups. Antibacterial effectiveness test results showed that butterfly pea flower extract ( Clitoria ternatea ) was effective in inhibiting Streptococcus mutans bacteria (p&lt;0.05), at a concentration of 25% was the minimum inhibitory level (MIC) and 50% concentration was the minimum killing rate (MBC). ). The conclusion of this study is that the extract of butterfly pea flower ( Clitoria ternatea ) is effective in inhibiting and killing Streptococcus mutans bacteria.

Photo-responsive Cu-tannic acid nanoparticle-mediated antibacterial film for efficient preservation of strawberries

The existing films used for fruit preservation suffer from insufficient preservation abilities. This study introduces Cu-tannic acid (Cu-TA) nanoparticles, synthesized from tannic acid (TA) and Cu2+, to enhance food packaging properties. Integrated into a chitosan-gelatin (CG) matrix, the resultant Cu-TA nanocomposite films exhibit superior antibacterial efficacy and killing rates of Escherichia coli and Staphylococcus aureus more than 99 %, and double the shelf life of strawberries, underscoring the exceptional freshness preservation capabilities of film. Additionally, the tensile strength of the Cu-TA nanocomposite films increased by 1.75 times, the DPPH radical scavenging percentage increased from 29.4 % to 68.4 %, and the water vapor permeability (WVP) decreased by about 60 % compared to the pure CG films. Comprehensive cytotoxicity and migration assessments confirm the safety of film, paving the way for their application in food packaging. The excellent performance of the Cu-TA nanocomposite films positions them as a formidable solution for protecting perishable food items.

Research on Intelligent Disinfection Robot Based on STC89C52 Microcontroller Control System

An intelligent disinfection robot based on STC89C52 microcontroller as the control system is proposed to address the current problems of high cost, scene limitations, and complex control factors. With the assistance of software development, the peripheral circuit of the chip is designed, and the robot can dynamically adjust its path according to its own and surrounding companions' position and motion status. The research results indicate that the various modules of the system can work in coordination, with high accuracy in tracking routes, precise image recognition, timely obstacle avoidance, fast response speed, and safe and reliable system operation. The disinfection robot carried out disinfection and sterilization test on the most common staphylococcus aureus and mold, and the test results showed that the pathogenic bacteria decreased significantly after 2 min, and all bacteria were removed after 3 min, and the killing rate of bacteria was up to&gt;96.0%. This method improves the obstacle avoidance ability and collaborative efficiency of robot systems in complex environments, and can effectively respond to various unexpected situations.

Robust Natural Light-Absorbable and -Degradable AIE Photosensitizers for Fluorescence Labeling and Efficient Photodynamic Eradication of Algal Pollutants.

Current water pollution caused by the excessive proliferation of harmful algae urges green methods that can efficiently utilize natural light to treat algal pollution. Herein, a series of aggregation-induced emission (AIE) photosensitizers that can efficiently harness sunshine were synthesized for the environmentally friendly and biocompatible treatment of algal pollution. By tuning the number of thiophene units and the electron conjugation degree, the photosensitizers' absorptions were broadened to cover the whole visible light range. The positive charges guided photosensitizers to aggregate on algal cell surfaces, resulting in a turn-on fluorescence signal and robust reactive oxygen species generation under sunshine, thereby achieving fluorescence labeling and photodynamic eradication of algae. The eradication outcomes demonstrated that the AIE photosensitizers significantly outperformed the commercial algaecide ALG. At 20 ppm photosensitizers, 90.4% and 94.2% killing rates were achieved for C. reinhardtii and C. vulgaris, respectively, 2.8- and 3.6-fold higher than those from the same concentration of ALG. Excellent performances in inhibiting algae growth were also verified with efficiency superior to that of ALG. Importantly, the photosensitizers can self-degrade into biocompatible fragments under irradiation to avoid secondary pollution. The developed photosensitizers that possess sunshine convertibility and degradability provide an efficient tool for algal treatment, showing broad research and application prospects.

α-Amylase and polydopamine@polypyrrole-based hydrogel microneedles promote wound healing by eliminating bacterial infection

In this paper, we designed a novel “Freeze-thaw” type hydrogel microneedle (PP-CDLut-AMY MN). The “Freeze-thaw” cycle endows the MN excellent water absorption, with a dissolution rate of up to 486 %. The addition of polydopamine@polypyrrole (PP) enabled the MN to have a stable temperature increase to approximately 50 °C under near-infrared light irradiation, which exhibited killing rates of 99 % and 98 % against free S. aureus and E. coli, respectively. Natural macromolecule α-Amylase (AMY) was used as a bacterial biofilm disintegrator, and the destruction rate of S. aureus biofilm reached 83.2 %. Meanwhile, the incorporation of Hydroxypropyl-β-cyclodextrin @Luteolin (CDLut) provided the MN with good antioxidant properties, which could scavenge 73.35 % of DPPH free radicals. In vivo experiments have shown that the MN can effectively promote the healing of wounds infected by S. aureus biofilm and that the stable and gentle photothermal effect did not cause unnecessary damage to the surrounding tissues. We believe that this novel hydrogel MN has great potential to combat bacterial biofilms associated with wound infections.

Pd nanocubes supported on the porous V2CTx nanosheets with enhanced nanozyme activity and photothermal property for antibacterial application

Rational design and controllable construction of supported nanostructures with excellent antibacterial property remain a great challenge. Recently, transition metal carbides/nitrides/carbonitrides (MXenes) have attracted much interest in many fields due to their large specific surface areas and good photothermal property. Herein, a simple yet effective surface engineering strategy based on the tuning of MXene surface chemistry is presented, which allows in-situ controlled growth of the Pd nanocubes on the V2CTx nanosheets. Briefly, the exfoliated V2CTx nanosheets by HF are annealed, which changes the composition of surface terminations while creating the mesoporous structures. The annealing largely affects the exposure and oxidation states of the adjacent V atoms and allows the controllable growth of Pd nanocubes. Interestingly, the obtained Pd@V2CTx nanocomposites show enhanced peroxidase-/oxidase-like activities and intrinsic photothermal effect in the near infra-red (NIR) region due to the strong metal-support interaction. Furthermore, the combined nanocatalytic-photothermal treatment by their versatilities remarkably improves the antibacterial efficacy, giving a high killing rate (above 98 % for both Escherichia coli and Staphylococcus aureus). This work provides a new avenue to develop the supported metal nanostructures based on MXenes for antibacterial application.

Effectiveness of laser radiance on Morganella morganaii secluded from malignant tumors (cancer)

Objective: The aim of this research to affect study radiation emitted from Nd: YAG laser on Morganella morgana isolated from malignant tumors. Study design: Case –Control study design in Analytical study design by 15 isolates from malignant tumors compared with 15 isolates from normal person. Cross-Sectional study design in descriptive study design for 30 isolates. Backrgound: Morganella morganii is a fermissive anaerobic rod Gram-negative enteric bacterium that was headmost isolated in 1906 via Morgan et al. of a pediatric fecal culture. Cancer evolution is the result of a spectrum of genetic modifications that change the normal control of cell expansion and survival. These genetic modifications can be enhanced by a wide diversity of external factors inclusive smoking, alcohol and sunlight. Methodology: Morganella morganii implanted in Nutrient broth at 37° C for 24 h and rapprochement with MacCfrland 0.5, subsequently exposing 1 ml of suspension to Nd:YAG laser with comparison of control group (without exposure to radiance), each run was done in triplicate and inoculated in Trypton soy agar. Results: Results the collection from sample are 15 isolates of Morganella morganii from patient malignant tumors and 15 isolates from healthy human. The results in this research proved a high rate of killing of bacteria Morganella morganii isolated from malignant tumors after exposure to Nd:YAG laser during 500 pulses per second and the number of live cells was few after exposure to the laser at different times and the more time the higher the killing rate compared to the control of samples not exposed to the laser as well as with repeaters and that. The use of Nd:YAG laser is secure, as it is utilized in cosmetics and there are no side impacts, so the competence of killing Morganella morganii secluded of cancer utilizing secure laser with high competence is very significant and it is an substantial application for treatment. Conclusion: The use of laser is safe as it is used in cosmetics and there are no side effects, and thus the efficiency of killing bacteria isolated from cancer using a safe laser with high efficiency is very important and it is an important application for treatment.

Sequential Immune Acquisition of Monoclonal Antibodies Enhances Phagocytosis of Acinetobacter baumannii by Recognizing ATP Synthase

Objectives: The aim of this study was to prepare monoclonal antibodies (mAbs) that broadly target Acinetobacter baumannii and protect against infection by multi-drug-resistant (MDR) A. baumannii from different sources. Methods: mAb 8E6 and mAb 1B5 were prepared by sequentially immunizing mice with a sublethal inoculation of three heterogeneous serotypes of pan-drug-resistant (PDR) A. baumannii, ST-208, ST-195, and ST-229. Results: The cross-recognition of heterogeneous bacteria (n = 13) by two mAbs and potential targets was verified, and the in vitro antibacterial efficacy of mAbs was assessed. The median killing rate of mAb 8E6 against A. baumannii in the presence of complement and dHL-60 cells was found to be 61.51%, while that of mAb 1B5 was 41.96%. When only dHL-60 cells were present, the killing rate of mAb 8E6 was 65.73%, while that of mAb 1B5 was 69.93%. We found that mAb 8E6 and mAb 1B5 broadly targeted MDR A. baumannii on the ATP synthase complex and were equipped with an antibacterial killing ability by enhancing the innate immune bacteriolytic effect of ST-208 and ST-195 strains. Both monoclonal antibodies were validated to protect against respiratory infection at 4 and 24 h via enhancing the release of innate immune substances and inflammatory cytokines, effectively shortening the disease period in mice. Conclusions: mAb 8E6 and mAb 1B5 significantly enhanced the opsonization process of phagocytosis against A. baumannii strains prevalent in southern China by targeting ATP synthase antigens thereof, resulting in protective effects in mice.

Exploration of Time-Fractional Cancer Tumor Models with Variable Cell Killing Rates via Hybrid Algorithm

Abstract Cancer is marked by abnormal cell growth that invades healthy tissues, potentially spreading throughout the body through the bloodstream or lymphatic system. It arises when body cells show irregularities in the genes that control cell growth. To treat and minimize the growth of these abnormal cells, different models have been proposed to predict and analyze cancer-tumor. The current study contains analysis of fractional cancer-tumor with different uncertain conditions. To include the uncertainties in the model, Pentagonal fuzzy numbers (PFNs) approach is utilized. A hybrid mechanism, combining homotopies with perturbation technique and a generalized integral transform, is proposed to efficiently handle fractional derivatives with fuzzified conditions. The validity of obtained solutions is checked by calculating residual errors. Graphical analysis assesses the impact of important parameters on the solution profiles, and confirms the reliability of the proposed methodology for complex fractional tumor models and other intricate physical phenomena.

Research on Drug Efficacy using a Terahertz Metasurface Microfluidic Biosensor Based on Fano Resonance Effect.

Advanced biosensors must exhibit high sensitivity, reliability, and convenience, making them suitable for detecting trace samples in biological or medical applications. Currently, biometric identification is the predominant method in clinical practice, but it is complex and time-consuming. In this study, we propose an optical metasurface utilizing the Fano resonance effect, which exhibits a sharp resonance with a transmittance of 32% at 0.65 THz. The resonance dip has a narrow bandwidth of 0.07 THz and a high Q-factor of 42. This resonance arises from the coupling of bright and dark modes, underpinned by the electromagnetic mechanism of Fano resonance. We integrated the metasurface into a microfluidic platform and fabricated low-temperature gallium arsenide photoconductive antennas (LT-GaAs-PCAs) on both sides of the microfluidics to efficiently generate and detect THz waves, significantly reducing the system's volume. The biosensor's detection limits for Escherichia coli (E. coli) and cefamandole nafate are 5 × 103 cells/mL and 5 μg/mL, respectively. Experimentally, when E. coli and cefamandole nafate solutions were sequentially injected into the microfluidic chip, a blue shift in the spectrum was observed. The sensor measured a 95.2% killing rate of E. coli by 40 μg/mL cefamandole nafate solution, with only a 3% deviation from biological experiments. Additionally, a timed killing experiment using 40 μg/mL cefamandole nafate on E. coli revealed a 93.7% killing rate within 3 min. This research presents a THz microfluidic biosensor with rapid detection, high sensitivity, and enhanced portability and integration, offering a promising approach for biomedical research, including antibiotic efficacy assessment and bacterial concentration monitoring.

A global assessment of large terrestrial carnivore kill rates.

Through killing and instilling fear in their prey, large terrestrial carnivores shape the structure and function of ecosystems globally. Most large carnivore species have experienced severe range and population declines due to human activities, and many are now threatened with extinction. Consequently, the impacts of these predators on food webs have been diminished or lost completely from many ecosystems. Kill rates provide a fundamental metric for understanding large carnivore ecology and assessing and comparing predation within and across ecological communities. Our systematic review of large terrestrial mammalian carnivore kill rates reveals significant positive geographic (North America, Europe, and Africa) and taxonomic (grey wolf Canis lupus, puma Puma concolor, lion Panthera leo, and Eurasian lynx Lynx lynx) bias, with most studies apparently motivated by human-carnivore conflict over access to ungulate prey and wildlife management objectives. Our current understanding of the behaviour and functional roles of many large carnivore species and populations thus remains limited. By synthesising and comparing kill rates, we show that solitary carnivores (e.g. brown bears Ursus arctos and most felids) exhibit higher per capita kill rates than social carnivores. However, ungulate predation by bears is typically limited to predation of neonates during a short period. Lower per capita kill rates by social carnivores suggests group living significantly reduces energetic demands, or, alternatively, that group-living carnivores defend and consume a greater proportion of large prey carcasses, or may acquire more food through other means (e.g. scavenging, kleptoparasitism) than solitary hunters. Kill and consumption rates for Canidae - measured as kilograms of prey per kilogram of carnivore per day - are positively correlated with body mass, consistent with increasing energy costs associated with a cursorial hunting strategy. By contrast, ambush predators such as felids show an opposite trend, and thus the potential energetic advantage of an ambush hunting strategy for carnivores as body mass increases. Additionally, ungulate kill rates remain relatively constant across solitary felid body sizes, indicative of energetic constraints and optimal foraging. Kill rate estimates also reveal potential insights into trophic structuring within carnivore guilds, with subordinate carnivores often killing more than their larger counterparts, which may be indicative of having to cope with food losses to scavengers and dominant competitors. Subordinate carnivores may thus serve an important role in provisioning food to other trophic levels within their respective ecosystems. Importantly, kill rates also clarify misconceptions around the predatory behaviour of carnivores (e.g. spotted hyaenas Crocuta crocuta and wolverines Gulo gulo are often considered scavengers rather than the capable hunters that they are) and thus the potential impacts of various carnivore species on their ecological communities. Despite the importance of kill rates in understanding predator-prey interactions, their utility is not widely recognised, and insufficient research limits our ability to fully appreciate and predict the consequences of modified predation regimes, justify current management actions affecting carnivores, or inform effective conservation measures. Together with other important research on predator-prey interactions, robust kill rate studies that address the research deficiencies we highlight will provide a deeper understanding of the foraging behaviours and potential ecosystem impacts of many of the world's carnivores, thus aiding effective conservation and management actions.

Characterization of increased mortality of Drosophila melanogaster exposed to sucrose-fermenting yeast

Adult fruit flies are strongly attracted to odors emitted by the microbial fermentation of sugars in fruits. Such microbes, particularly yeasts, also serve as an essential nutritional source for fruit flies and influence their reproduction and fecundity. Despite being known as natural symbionts, it was previously observed that sucrose-fermenting Saccharomyces cerevisiae can be lethal to Drosophila melanogaster. This study characterizes the conditions that affect the lethality of S. cerevisiae in fruit flies. We showed that the insecticidal activity of yeast was equal in five tested S. cerevisiae strains. Another yeast, Pichia anomala, killed fruit flies, although to a lesser degree than S. cerevisiae. Higher concentrations of yeast resulted in faster killing of fruit flies, although the killing rate was capped at two days of continuous exposure. Both sexes were similarly sensitive to yeast at 30, whereas males were less sensitive to yeast at 25 degrees Celsius. Higher sucrose amounts in food slightly decreased the sensitivity of male but not female flies to yeast. This study characterizes a relatively uncharted side of the intricate interaction between fruit flies and yeast and highlights the possibility for manipulation aimed at mitigating the agricultural impact of these pests.

Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection: Learning in vivo dynamics using ex vivo data.

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of previously published data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control. For each macaque, we considered, in addition to the canonical in vivo plasma viral load and SIV DNA data, longitudinal ex vivo measurements of the virus suppressive capacity of CD8 T-cells. Available mathematical models do not allow analysis of such combined in vivo-ex vivo datasets. We explicitly modeled the ex vivo assay, derived analytical approximations that link the ex vivo measurements with the in vivo effector function of CD8-T cells, and integrated them with an in vivo model of virus dynamics, thus developing a new learning framework that enabled the analysis. Our model fit the data well and estimated the recruitment rate and/or maximal killing rate of CD8 T-cells to be up to 2-fold higher in controllers than non-controllers (p = 0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with virus control (Spearman's ρ = -0.51; p = 0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T-cells as a predictor of natural control. Furthermore, simulating a large virtual population, our model quantified the minimum capacity of this early CD8 T-cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T-cells in the natural control of HIV infection and has implications for remission strategies.

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Oncolytic Newcastle Disease Virus and Photodynamic Therapy as Dual Approach for Breast Cancer Treatment.

We hypothesized that attacking cancer cells by combining various modes of action can hinder them from taking the chance to evolve resistance to treatment. Incorporation of photodynamic therapy (PDT) with oncolytic virotherapy might be a promising dual approach to cancer treatment. NDV AMHA1 strain as virotherapy in integration with aminolaevulinic acid (ALA) using low power He-Ne laser as PDT in the existing work was examined against breast cancer cells derived from Iraqi cancer patients named (AMJ13). This combination was evaluated using Chou-Talalay analysis. The results showed an increased killing rate when using both 0.01 and 0.1 Multiplicity of infection (MOI) of the virus when combined with a dose of 6172.8 photons/gm (ph/gm) of PDT focused on cancer cells. integration of the attenuated NDV-AMHA1 strain with photodynamic therapy has a synergistic killing effect on breast cancer cells in vitro, suggesting that this strategy could have clinical application to overcome breast cancer.

Accounting for cellular-level variation in lysis: implications for virus-host dynamics.

Viral impacts on microbial populations depend on interaction phenotypes-including viral traits spanning the adsorption rate, latent period, and burst size. The latent period is a key viral trait in lytic infections. Defined as the time from viral adsorption to viral progeny release, the latent period of bacteriophage is conventionally inferred via one-step growth curves in which the accumulation of free virus is measured over time in a population of infected cells. Developed more than 80 years ago, one-step growth curves do not account for cellular-level variability in the timing of lysis, potentially biasing inference of viral traits. Here, we use nonlinear dynamical models to understand how individual-level variation of the latent period impacts virus-host dynamics. Our modeling approach shows that inference of the latent period via one-step growth curves is systematically biased-generating estimates of shorter latent periods than the underlying population-level mean. The bias arises because variability in lysis timing at the cellular level leads to a fraction of early burst events, which are interpreted, artefactually, as an earlier mean time of viral release. We develop a computational framework to estimate latent period variability from joint measurements of host and free virus populations. Our computational framework recovers both the mean and variance of the latent period within simulated infections including realistic measurement noise. This work suggests that reframing the latent period as a distribution to account for variability in the population will improve the study of viral traits and their role in shaping microbial populations.IMPORTANCEQuantifying viral traits-including the adsorption rate, burst size, and latent period-is critical to characterize viral infection dynamics and develop predictive models of viral impacts across scales from cells to ecosystems. Here, we revisit the gold standard of viral trait estimation-the one-step growth curve-to assess the extent to which assumptions at the core of viral infection dynamics lead to ongoing and systematic biases in inferences of viral traits. We show that latent period estimates obtained via one-step growth curves systematically underestimate the mean latent period and, in turn, overestimate the rate of viral killing at population scales. By explicitly incorporating trait variability into a dynamical inference framework that leverages both virus and host time series, we provide a practical route to improve estimates of the mean and variance of viral traits across diverse virus-microbe systems.

Discovery and engineering of a novel peptide, Temporin-WY2, with enhanced in vitro and in vivo efficacy against multi-drug resistant bacteria

Infections by drug-resistant microorganisms are a threat to global health and antimicrobial peptides are considered to be a new hope for their treatment. Temporin-WY2 was identified from the cutaneous secretion of the Ranidae frog, Amolops wuyiensis. It presented with a potent anti-Gram-positive bacterial efficacy, but its activity against Gram-negative bacteria and cancer cell lines was unremarkable. Also, it produced a relatively high lytic effect on horse erythrocytes. For further improvement of its functions, a perfect amphipathic analogue, QUB-1426, and two lysine-clustered analogues, 6K-WY2 and 6K-1426, were synthesised and investigated. The modified peptides were found to be between 8- and 64-fold more potent against Gram-negative bacteria than the original peptide. Additionally, the 6K analogues showed a rapid killing rate. Also, their antiproliferation activities were more than 100-fold more potent than the parent peptide. All of the peptides that were examined demonstrated considerable biofilm inhibition activity. Moreover, QUB-1426, 6K-WY2 and 6K-1426, demonstrated in vivo antimicrobial activity against MRSA and E. coli in an insect larvae model. Despite observing a slight increase in the hemolytic activity and cytotoxicity of the modified peptides, they still demonstrated a improved therapeutic index. Overall, QUB-1426, 6K-WY2 and 6K-1426, with dual antimicrobial and anticancer functions, are proposed as putative drug candidates for the future.

A fast-acting inhibitor of blood-stage P. falciparum with mechanism distinct from artemisinin and chloroquine.

Artemisinins are first-line treatment for malaria, prized for their extremely fast reduction of parasite load in patients. New fast-acting antimalarial compounds are urgently needed to counter artemisinin resistance, but the fast parasite reduction observed with artemisinins is rare among antimalarial compounds. Here we show that MMV1580853 has a very fast in vitro killing rate, comparable to that of dihydroartemisinin. Near-complete parasite growth inhibition was observed within 1 hour of treatment with MMV1580853 and dihydroartemisinin, while chloroquine, another fast-acting antimalarial, showed partial growth inhibition after 1h. MMV1580853 was reported to inhibit prenyltransferases, but its fast killing rate is inconsistent with this mechanism-of-action and we were unable to validate any of 3 annotated P. falciparum prenyltransferases as MMV1580853 targets. MMV1580853 also did not phenocopy the inhibition phenotype of either chloroquine or dihydroartemisinin. These results indicate that MMV1580853 has a distinct mechanism-of-action leading to a very fast killing rate. MMV1580853 compound development and investigation of its mechanism-of-action will be critical avenues in the search for drugs matching the remarkable clinical efficacy of artemisinin.

Model-informed Evidence for Clinical Non-inferiority of Every-2-Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer.

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every-2-weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non-inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I-III clinical trials in 852 patients with KRAS wild-type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure-tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi-mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration-time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model-based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non-inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non-inferiority in 94% of cases. Taken together, these analyses provide model-based evidence for clinical non-inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.