Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of physiologically based pharmacokinetic models for therapeutic proteins and other novel modalities

Abstract The past two decades have seen diversification of drug development pipelines and approvals from traditional small molecule therapies to alternative modalities including monoclonal antibodies, engineered proteins, antibody drug conjugates (ADCs), oligonucleotides and gene therapies. At the same time, physiologically based pharmacokinetic (PBPK) models for small molecules have seen increased industry and regulatory acceptance. This review focusses on the current status of the application of PBPK models to these newer modalities and give a perspective on the successes, challenges and future directions of this field. There is greatest experience in the development of PBPK models for therapeutic proteins, and PBPK models for ADCs benefit from prior experience for both therapeutic proteins and small molecules. For other modalities, the application of PBPK models is in its infancy. Challenges are discussed and a common theme is lack of availability of physiological and experimental data to characterise systems and drug parameters to enable a priori prediction of pharmacokinetics. Furthermore, sufficient clinical data are required to build confidence in developed models. The PBPK modelling approach provides a quantitative framework for integrating knowledge and data from multiple sources and can be built on as more data becomes available.
The protective mechanism of salidroside modulating miR-199a-5p/TNFAIP8L2 on lipopolysaccharide-induced MLE-12 cells

Objectives Salidroside is used for treating inflammation-based diseases; however, its molecular mechanism is unclear. In this study, we determined the protective role of salidroside on the endotoxin-induced damage caused to the mouse alveolar epithelial type II (MLE-12) cells and its underlying mechanism. Methods An in vitro model for acute lung injury was constructed by inducing the MLE-12 cells using lipopolysaccharide (lipopolysaccharides, 1 mg/L). Then, The MTT assay was conducted to assess the survival rate of the MLE-12 cells in the different groups. After the treatment, apoptosis of MLE-12 cells was determined, and the mRNA and protein expression of miR-199a-5p, HMGB1, NF-kB65, TNFAIP8L2, p-IkB-α, and TLR4 was estimated by Western Blotting and RT-PCR. ELISA was also used to measure the concentration of inflammatory cytokine molecules IL-1β, IL-6, TNF-α, and IL-18 in the cell-free supernatant. Lastly, cell morphology was examined using the AO/EB technique. Results We showed that salidroside reduced the protein and gene expression of HMGB1, NF-kB65, miR-199a-5p, p-IkB-α, and TLR4, whereas it increased the gene and protein expression of TNFAIP8L2. Furthermore, it decreased the concentrations of cytokine molecules like IL-1β, IL-6, TNF-α, and IL-18 in the cell-free supernatant. MLE-12 also showed a lower apoptosis rate, higher survival rate, and better cell morphology. Conclusion Salidroside significantly inhibited the LPS-induced MLE-12 cell damage. Our results suggest that this could be by reducing miR-199a-5p and enhancing TNFAIP8L2 expression.
Anticancer effect of a pyrrole‐imidazole polyamide‐triphenylphosphonium conjugate selectively targeting a common mitochondrial DNA cancer risk variant in cervical cancer cells

Cervical cancer remains a major threat to women's health, especially in countries with limited medical resources, and new drugs are needed to improve patient survival and minimize adverse effects. Here, we examine the effects of a triphenylphosphonium (TPP)‐conjugated pyrrole‐imidazole polyamide (CCC‐h1005) targeting the common homoplasmic mitochondrial DNA (mtDNA) cancer risk variant (ATP6 8860A>G) on the survival of cervical cancer cell lines, cisplatin‐resistant HeLa cells and patient‐derived cervical clear cell carcinoma cells as models of cervical cancer treatment. We found that CCC‐h1005 induced death in these cells and suppressed the growth of xenografted HeLa tumors with no severe adverse effects. These results suggest that PIP‐TPP designed to target mtDNA cancer risk variants can be used to treat many cervical cancers harboring high copies of the target variant, providing a foundation for clinical trials of this class of molecules for treating cervical cancer and other types of cancers.
Noninvasive predictors of clinically significant portal hypertension in NASH cirrhosis: Validation of ANTICIPATE models and development of a lab‐based model

Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg, identifies patients with compensated cirrhosis at a high risk of decompensation. However, HVPG is an invasive and nuanced method. The ANTICIPATE models, which include liver stiffness measurements by transient elastography (TE) and platelet count ± body mass index, are robust noninvasive surrogates of CSPH but required external validation in patients with nonalcoholic steatohepatitis (NASH) cirrhosis. Additionally, TE is not widely available worldwide. The aims of the study were: (1) to externally validate the ANTICIPATE models using baseline data from patients with compensated NASH cirrhosis screened/enrolled in a multicenter international randomized controlled trial; and (2) to develop and externally validate a model using only laboratory values. Regarding aim 1, both ANTICIPATE models showed good calibration and discrimination (area under the curve [AUC] > 0.8) in our cohort (n = 222). Regarding aim 2, a new lab‐based model using the Fibrosis‐4 index (FIB‐4 [age, aspartate aminotransferase, alanine aminotransferase, platelet count]) plus serum albumin was developed. The discrimination in the training cohort (n = 309) was good (AUC of 0.78 [95% confidence interval [CI]:0.72–0.83]). It was then externally validated in a separate cohort of 245 patients with compensated NASH cirrhosis (AUC of 0.8 [95% CI: 0.75–0.86]). Given the difference in the prevalence of CSPH between training (74%) and validation (39%) cohorts, the model required an update of the baseline risk to achieve a good calibration. The updated model was named FIB4+. In conclusion, both ANTICIPATE models performed well in predicting the presence of CSPH in NASH cirrhosis. A model using FIB‐4 plus albumin (FIB4+) can be used to predict CSPH where TE is not available.
A comprehensive computational approach for the identification of structure-based potential pharmacological candidates as selective AKR1B1 and AKR1B10 inhibitors: repurposing of purine alkaloids for the treatment of cancer

Abstract Significant metabolic pathways have been linked to AKR1B1 and AKR1B10. These enzymes are crucial biological targets in the therapy of colon cancer. In the past several decades, drug repurposing has gained appeal as a time and cost-efficient strategy for providing new indications for existing drugs. The structural properties of the plant-based alkaloidal drugs theobromine and theophylline were examined using density functional theory (DFT) computations, where the B3LYP/SVP method was used to quantify the dipole moment, polarizability, and optimization energy. Optimized structures obtained through DFT studies were docked inside the active pocket of target proteins to evaluate their inhibitory potential. Moreover, molecular dynamic simulation provides significant insight into a dynamic view of molecular interactions. The findings of current revealed theobromine and theophylline as strong AKR1B1 and AKR1B10 inhibitors, respectively. In addition, the anti-cancer potential of theophylline and theobromine was validated by targeting various tumor proteins, i.e. NF-κB, cellular tumor antigen P53 and caspase-3 using a molecular docking approach. Theobromine was found to be strongly interacted with NF-κB and caspase-3, whereas theophylline potentially inhibited cellular tumor antigen P53. In addition, the ADMET characteristics of theobromine and theophylline were identified, confirming their drug-like capabilities. These results should open the way for further experimental validation and structure-based drug design/repurposing of AKR1B1/AKR1B10 inhibitors for the treatment of colon cancer and associated malignancies. Communicated by Ramaswamy H. Sarma
Body condition and energy content of the shore crab Carcinus maenas L. in a temperate coastal system: the cost of barnacle epibiosis

Abstract The impact of barnacle epibionts on the condition of the shore crab Carcinus maenas was studied for the western Wadden Sea population. Approximately 39% of the crabs were fouled with the barnacle Balanus crenatus. Although the morphological Fulton’s K condition decreased by 5.8% in fouled crabs, Linear Mixed-Effects Models (LMM) showed that only the energetic condition of the crabs was significantly affected by fouling. The energy density of fouled crabs was consistently poorer (4.1% in AFDW; 8.7% in dry weight) than that of non-fouled crabs, especially in females and green forms in dry weight (12.8% and 11.4% reduction, respectively). Cumulative infection with Sacculina carcini, detected in 4.5% of the fouled crabs, additionally reduced by 14.3% the energy density in dry weight and almost to half of the total energy of the fouled crabs. Impacts of energy density reduction on crabs’ growth and reproduction are discussed.
Hα imaging of the Herschel Reference Survey The star formation properties of a volume-limited, K-band-selected sample of nearby late-type galaxies ,

We present new Hα+[NII] imaging data of late-type galaxies in the Herschel Reference Survey aimed at studying the star formation properties of a K-band-selected, volume-limited sample of nearby galaxies. The Hα+[NII] data are corrected for [NII] contamination and dust attenuation using different recipes based on the Balmer decrement and the 24 μm luminosities. We show that the Hα luminosities derived with different corrections give consistent results only whenever the uncertainty on the estimate of the Balmer decrement is σ[C(Hβ)] ≤ 0.1. We used these data to derive the star formation rate of the late-type galaxies of the sample and compare these estimates to those determined using independent monochromatic tracers (far-UV, radio continuum) or the output of spectral energy distribution (SED) fitting codes. This comparison suggests that the 24 μm based dust extinction correction for the Hα data might not be universal and that it should be used with caution in all objects with a low star formation activity, where dust heating can be dominated by the old stellar population. Furthermore, because of the sudden truncation of the star formation activity of cluster galaxies occurring after their interaction with the surrounding environment, the stationarity conditions required to transform monochromatic fluxes into star formation rates might not always be satisfied in tracers other than the Hα luminosity. In a similar way, the parametrisation of the star formation history generally used in SED fitting codes might not be adequate for these recently interacting systems. We then use the derived star formation rates to study the star formation rate luminosity distribution and the typical scaling relations of the late-type galaxies of the HRS. We observe a systematic decrease of the specific star formation rate with increasing stellar mass, stellar mass surface density, and metallicity. We also observe an increase of the asymmetry and smoothness parameters measured in the Hα-band with increasing specific star formation rate, probably induced by an increase of the contribution of giant HII regions to the Hα luminosity function in star-forming low-luminosity galaxies.
The positive effect of physical constraints on consumer evaluations of service providers

Consumers tend to have negative perceptions of service providers that limit their freedom. People might therefore be expected to respond particularly negatively to service providers that physically limit their freedom of movement. Yet, we suggest that physical constraints that a service provider unapologetically imposes with no obvious logical justification (e.g., closing a door and restricting consumers to stay inside a room) may, in fact, boost consumers’ evaluations of the service provider. We propose that this effect occurs because consumers perceive such constraints as creating a structured environment, which they inherently value. Six studies lend converging support to these propositions, while ruling out alternative accounts (cognitive dissonance, self-attribution theory). We further show that the positive effect of physical constraints on evaluations is reversed when consumers perceive the constraints as excessively restrictive (rather than mild). These findings suggest that service providers may benefit from creating consumption conditions that mildly restrict consumers’ freedom of movement.
Efficient learning representation of noise-reduced foam effects with convolutional denoising networks

This study proposes a neural network framework for modeling the foam effects found in liquid simulation without noise. The position and advection of the foam particles are calculated using the existing screen projection method, and the noise problem that occurs in this process is prevented by using the neural network. A significant problem in the screen projection approach is the noise generated in the projection map during the projecting of momentum onto the discretized screen space. We efficiently solve this problem by utilizing a denoising neural network. Following the selection of the foam generation area using a projection map, the foam particles are generated through the inverse transformation of the 2D space into 3D space. This solves the problem of small-sized foam dissipation that occurs in conventional denoising networks. Furthermore, by integrating the proposed algorithm with the screen-space projection framework, it is able to maintain all the advantages of this approach. In conclusion, the denoising process and clean foam effects enable the proposed network to model the foam effects stably.
Stein's Method and Minimum Parsimony Distance after Shuffles

Motivated by Bourque and Pevzner's simulation study of the parsimony method for studying genome rearrangement, Berestycki and Durrett used techniques from random graph theory to prove that the minimum parsimony distance after iterating the random transposition shuffle undergoes a transition from Poisson to normal behavior. This paper establishes an analogous result for minimum parsimony distance after iterates of riffle shuffles or iterates of riffle shuffles and cuts. The analysis is elegant and uses different tools: Stein's method and generating functions. A useful technique which emerges is that of making a problem more tractable by adding extra symmetry, then using Stein's method to exploit the symmetry in the modified problem, and from this deducing information about the original problem.
Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL.
Deep high spectral resolution spectroscopy and chemical composition of ionized nebulae

High spectral resolution spectroscopy has proved to be very useful for the advancement of chemical abundances studies in photoionized nebulae, such as H II regions and planetary nebulae (PNe). Classical analyses make use of the intensity of bright collisionally excited lines (CELs), which have a strong dependence on the electron temperature and density. By using high resolution spectrophotometric data, our group has led the determination of chemical abundances of some heavy element ions, mainly O++, O+ and C++ from faint recombination lines (RLs), allowing us to deblend them from other nearby emission lines or sky features. The importance of these lines is that their emissivity depends weakly on the temperature and density structure of the gas. The unresolved issue in this field is that recombination lines of heavy element ions give abundances that are about 2-3 times higher than those derived from CELs -in H II regions- for the same ion, and can even be a factor of 70 times higher in some PNe. This uncertainty puts into doubt the validity of face values of metallicity that we use as representative not only for ionized nebulae in the Local Universe, but also for star-forming dwarf and spiral galaxies at different redshifts. Additionally, high-resolution data can allow us to detect and deblend faint lines of neutron capture element ions in PNe. This information would introduce further restrictions to evolution models of AGBs and would help to quantify the chemical enrichment in s-elements produced by low and intermediate mass stars. The availability of an echelle spectrograph at the E-ELT will be of paramount interest to: (a) extend the studies of heavy element recombination lines to low metallicity objects, (b) to extend abundance determinations of s-elements to planetary nebulae in the extragalactic domain and to bright Galactic and extragalactic H II regions.
The efficacy and tolerability of combining pemetrexed-based chemotherapy with gefitinib in the first-line treatment of non-small cell lung cancer with mutated EGFR: A pooled analysis of randomized clinical trials

Background Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR. Methods We systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes. Results Eight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37–0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39–0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34–0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26–0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44–2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94–2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69–11.44, p = 0.1509). Conclusion Compared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.
Attenuation of diethylnitrosamine-induced hepatocellular carcinoma in a rat model by combination therapy of diacerein and gold nanoparticles: a histopathological and immunohistochemical study

ABSTRACT The purpose of this study was to investigate the effect of combined therapy of diacerein and gold nanoparticles (AuNP) on diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in a rat model. Normal healthy and DEN-induced (HCC) rats were divided into five groups. Group I healthy rats served as normal control, Group II untreated HCC rats, Group III HCC rats administered diacerein, Group IV HCC rats administered AuNP, and Group V HCC rats administered diacerein and AuNP. All treatments were given once daily for 4 weeks. Liver morphology and necroinflammation in all groups were evaluated using hematoxylin and eosin (H&E), Masson’s trichrome for fibrosis, and immunohistochemistry assays for expression of TNF-α, IL-6, β-catenin, and caspase-3. Liver sections from Group II HCC rats showed loss of lobular architecture, thick fibrous tissue deposition, leukocyte infiltration, degenerated hepatocytes and HCC neoplastic nodules surrounded by extensive fibrosis. Group II had high expression of TNF-α, IL-6, and β-catenin, and low caspase-3 expression as compared to Group I. HCC rats treated with the combined therapy of diacerein and AuNP (Group V) showed markedly decreased HCC lesions, significant necroinflammation reduction (p ˂ 0.05) and 90% reduction in fibrosis as compared to Group II HCC + diacerein. This combined therapy also reduced (p ˂ 0.05) TNF-α, IL-6, β-catenin expression and increased caspase-3 expression. In conclusion, diacerein combined with AuNP synergistically attenuated the severity of HCC lesions by reducing necroinflammation and fibrosis, decreased TNF-α, IL-6, β-catenin expression, and increased caspase-3 expression for apoptosis.
3D Hall MHD Modeling of Solar Wind Plasma Spectra

We present fully self consistent 3D simulations of compressible Hall MHD plasma that describe spectral features relevant to the solar wind plasma. We find that a k−7/3 spectrum sets in for the fluctuations that are smaller than ion gyro radius. We further investigate scale dependent anisotropy led by nonlinear processes relevant to the solar wind plasma. Our work is important particularly in understanding the role of wave and nonlinear cascades in the evolution of the solar wind, structure formation at the largest scales.We present fully self consistent 3D simulations of compressible Hall MHD plasma that describe spectral features relevant to the solar wind plasma. We find that a k−7/3 spectrum sets in for the fluctuations that are smaller than ion gyro radius. We further investigate scale dependent anisotropy led by nonlinear processes relevant to the solar wind plasma. Our work is important particularly in understanding the role of wave and nonlinear cascades in the evolution of the solar wind, structure formation at the largest scales.
Examining QI Knowledge Among Frontline Nurses and Nurse Leaders

Background: Frontline nurses deliver direct patient care and by participating in quality improvement (QI) can have an impact on health care quality and safety. Unfortunately, nurses are not participating in QI, which may be due to a lack of QI knowledge. Purpose: The purpose of this study was to evaluate nurses QI knowledge utilizing the revised Quality Improvement Knowledge Application Tool (QIKAT-R), with newly created nursing scenarios, among frontline nurses and nurse leaders. Methods: Using a cross-sectional design, this study evaluated nurses QI knowledge utilizing the QIKAT-R. Results: Overall, QI knowledge among nurses was low. The frontline nurses (n = 44) scored higher than nurse leaders (n = 11) on overall QI knowledge scores, although not significant. Frontline nurses scored higher in QI knowledge related to aim and measure, whereas nurse leaders scored higher in change. Conclusions: Understanding frontline nurses QI knowledge, such as with the QIKAT-R with newly created nursing scenarios, can assist with creating targeted strategies for improving overall engagement in QI.