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Background Methods Results Conclusion 5‐Fluorouracil (5‐FU) is essential in treating gastrointestinal cancers, but some patients show severe toxicity. The toxicity is exposure‐related, which is linked to the enzyme dihydropyrimidine dehydrogenase (DPD) decoded by the DPYD gene. This study aimed to evaluate the possible toxicity related to 5‐FU plasma levels, DPYD genotyping, and DPD phenotyping.Forty‐seven gastrointestinal cancer patients receiving 5‐FU were included in this study. 5‐FU plasma levels and DPD phenotyping were analyzed by UPLC‐MS/MS. DPYD genotyping was also assessed. The Common Terminology Criteria for Adverse Events (CTCAE) was used to classify the toxicity.For hematological toxicity, 27.65% showed neutropenia, 78.72% anemia, and 29.78% thrombocytopenia. The area under the curve (AUC) of 5‐FU calculated from the plasma was evaluated for three treatment cycles, and we observed that at the initial cycle, 48.93% were underexposed and 10.63% were overexposed, with a total of 59.56% of patients outside the therapeutic range. In the DPYD genotyping, 97.87% of patients had a wild‐type genotype, and 2.12% had c.1236G>A mutation (E412E, rs56038477). A total of 82.97% of patients showed a phenotype compatible with normal DPD activity.These findings suggest that the evaluation of DPYD genotyping and DPD phenotyping in the Brazilian population still requires further study. Moreover, the analysis of the plasma AUC of 5‐FU could contribute to clinical routine, being a very useful tool, especially for identifying patients outside the therapeutic range and thus guiding more individualized doses, or even in the intervention of possible toxicities related to overexposure. [ABSTRACT FROM AUTHOR]

Introduction: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. Methods: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019–April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. Results: In those treated 2020–2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25–86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. Discussion: Other Irish studies estimated prevalence at 11–12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. Conclusions: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients. [ABSTRACT FROM AUTHOR]

An automated pipeline for comprehensive calculation of intermolecular interaction energies based on molecular force-fields using the Tinker molecular modelling package is presented. Starting with non-optimized chemically intuitive monomer structures, the pipeline allows the approximation of global minimum energy monomers and dimers, configuration sampling for various monomer–monomer distances, estimation of coordination numbers by molecular dynamics simulations, and the evaluation of differential pair interaction energies. The latter are used to derive Flory–Huggins parameters and isotropic particle–particle repulsions for Dissipative Particle Dynamics (DPD). The computational results for force fields MM3, MMFF94, OPLS-AA and AMOEBA09 are analyzed with Density Functional Theory (DFT) calculations and DPD simulations for a mixture of the non-ionic polyoxyethylene alkyl ether surfactant C10E4 with water to demonstrate the usefulness of the approach. Scientific Contribution To our knowledge, there is currently no open computational pipeline for differential pair interaction energies at all. This work aims to contribute an (at least academically available, open) approach based on molecular force fields that provides a robust and efficient computational scheme for their automated calculation for small to medium-sized (organic) molecular dimers. The usefulness of the proposed new calculation scheme is demonstrated for the generation of mesoscopic particles with their mutual repulsive interactions. [ABSTRACT FROM AUTHOR]

Amyloid cardiomyopathy (CA) was previously considered a rare disease; however, rapid advancements in imaging modalities have led to an increased frequency of its diagnosis. The aim of this prospective study was to assess the prevalence and clinical phenotype of transthyretin amyloidosis (ATTR) cardiomyopathy in patients exhibiting unexplained increased left ventricular (LV) wall thickness. From 2020 to 2022, we enrolled 100 consecutive adults with unexplained increased LV wall thickness in the study. The analysis included clinical data, electrocardiography, transthoracic echocardiography, single-photon emission computed tomography/computed tomography with 3,3-disphono-1,2-propanodicarboxylic acid, genetic testing. Overall, 18% of patients were diagnosed with CA, comprising 5% with light-chain amyloidosis, and 12% with ATTR. To evaluate associations with the ATTR diagnosis, a LOGIT model and multivariate analysis were applied. Notably, age, polyneuropathy, gastropathy, carpal tunnel syndrome, lumbar spine stenosis, low voltage, ventricular arrhythmia, LV mass, LV ejection fraction, global longitudinal strain (GLS), E/A, E/E′, right ventricle (RV) thickness, right atrium area, RV VTI, TAPSE, apical sparing, ground glass appearance of myocardium, thickening of interatrial septum, thickening of valves, and the "5–5–5" sign were found to be significantly associated with ATTR (p < 0.05). The best predictive model for ATTR diagnoses exhibited an area under the curve of 0.99, including LV mass, GLS and RV thickness. This study, conducted at a cardiology referral center, revealed that a very considerable proportion of patients with unexplained increased LV wall thickness may suffer from underlying CA. Moreover, the presence of ATTR should be considered in patients with increased LV mass accompanied by reduced GLS and RV thickening. [ABSTRACT FROM AUTHOR]

This study recommends a novel structured packing (SP) PACK-860X with a specific surface area of 860 m2/m3, which is defined utilizing a numerical method. We attempt to investigate the main properties of PACK-860X for illustration, height equal to a theoretical plate (HETP), dry pressure drop (DPD) and wet pressure drop (WPD). In addition, the flow pattern is expressed for packing through computational simulation. To assess the amounts of HETP, WPD and DPD, the 3D CFD simulation with the Eulerian–Eulerian multi-phase technique is employed in this work. Based on the results of this work, WPD and DPD are improved. According to the data, numerical outcomes are in good agreement with the theoretical results, which shows the reliability of CFD methods for modeling the separation processes. [ABSTRACT FROM AUTHOR]

Cell models play a crucial role in analyzing the mechanical response of cells and quantifying cellular damage incurred during micromanipulation. While traditional models can capture the overall mechanical behavior of cells, they often lack the ability to discern among distinct cellular components. Consequently, by employing dissipative particle dynamics, this study constructed a triangular network-like representation of the cell membrane along with cross-linked cytoskeletal chains. The mechanical properties of both the membrane and cytoskeleton were then analyzed through a series of simulated mechanical tests, validated against real-world experiments. The investigation utilized particle-tracking rheology to monitor changes in the mean square displacements of membrane particles over time, facilitating the analysis of the membrane's storage and loss moduli. Additionally, the cytoskeletal network's storage and loss moduli were examined via a double-plate oscillatory shear experiment. The simulation results revealed that both the membrane and cytoskeleton exhibit viscoelastic behavior, as evidenced by the power-law dependency of their storage and loss moduli on frequency. Furthermore, indentation and microinjection simulations were conducted to examine the overall mechanical properties of cells. In the indentation experiments, an increase in the shear modulus of the membrane's WLCs correlated with a higher Young's modulus for the entire cell. Regarding the microinjection experiment, augmenting the microinjection speed resulted in reduced deformation of the cell at the point of membrane rupture and a lower percentage of high strain. [ABSTRACT FROM AUTHOR]

Power Amplifiers (PAs) play a vital role in mobile communication. However, their inherent nonlinearity can lead to issues such as unwanted radiation, interference with neighboring channels, and distortion within the desired frequency range. To address these problems, PAs are typically operated at a lower power level than their saturation point, sacrificing power efficiency to improve Error Vector Magnitude (EVM) performance. Consequently, more than 70-80% of the DC power is wasted as heat. This inefficiency necessitates the exploration of techniques to enhance PA efficiency while maintaining acceptable linearity and performance. Digital Pre-Distortion (DPD) is a useful technique to linearize PAs. DPD allows affordable nonlinear PAs to function with minimal distortion in their nonlinear operating regions. This results in amplified signals with increased power output and improved power efficiency. Using nonlinear functions, the output signal of the PA can be linearized, mitigate distortions, and be effectively optimized. When using various operating channels and varying time, temperature, and PA nonlinearity, the DPD must adjust. In order to increase the power efficiency of 5G systems, DPD-enabled systems are inculcating with adaptive DFT-s-OFDM employed 5G physical layer along with the Crest Factor Reduction (CFR) algorithm. [ABSTRACT FROM AUTHOR]

Gender quota policies for women in parliament or politics worldwide have developed since the 1990s. Indonesia applies this policy to the House of Representatives (DPR) as a political representation with a 30 (thirty) percent quota. As a fellow national parliamentary institution that is part of the People's Consultative Assembly (MPR), it turns out that there is a policy vacuum for DPD institutions. The vacuum, in addition to illustrating discriminatory practices, can potentially result in a very minimal representation of women in the institution. This study aims to assess the probability of implementing a similar policy for DPD institutions or provide other recommendations that are more appropriate. This research used normative legal research that uses the statute approach, conceptual approach, and comparative approach. Our data is obtained from a literature study and will be analyzed qualitatively. The results of this study, based on the consideration of nomination inequality and patriarchal culture, comparison of other countries, DPD as part of the MPR, Indonesia's bicameral system, and the correlation of Regional Representation and Women's Issues in Indonesia; DPD has several important and relevant arguments for implementing affirmative gender quota policy. However, against these considerations, there are also arguments that are not important and irrelevant, have no significant impact, or are impossible to apply, which is a challenge to implement affirmative policies such as DPR. Therefore, the most appropriate recommendation for DPD is simply through more massive socialization of candidacy by the General Election Commission (KPU) so that the legal culture in the form of awareness of the existence of female DPD members will grow and concerns about the lack of female DPD members can be prevented.

Simple Summary: We have been studying different combinations of medications to treat relapsed or refractory multiple myeloma. Among these combinations, one includes daratumumab with pomalidomide and dexamethasone (DPd), and another includes daratumumab with bortezomib and dexamethasone (DVd). So far, there have not been any direct comparisons performed through a clinical trial. In our analysis, we found that the DPd group had more patients with high-risk disease characteristics. Interestingly, the DPd group showed a better response to treatment. However, when we looked at the time until the disease progressed and overall survival, we found that these were similar between the two groups. It is important to note that we should be cautious in drawing conclusions from these findings because there were differences in the characteristics of the patients and lengths and durations of treatment, and the number of patients in both treatment groups was relatively small. Our study highlights the importance of considering factors like the type of patients, the side effects of the medications, and the characteristics of the disease when deciding which treatments to use. It is crucial to personalize the treatment approach for each individual based on these factors. Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] Dissolution processes of surfactants, especially when in the lamellar phase, into water are important for product formulation. Understanding this process at a molecular level will help to enhance product design and control surfactant processes. The main goal of this study is to examine the effect of different lengths of surfactants and the hydrophobic to hydrophilic ratio on the dissolution process of surfactants. To achieve this goal dissipative particle dynamic (DPD) simulations were used. Lamellar equilibrium simulations were carried out for different surfactant chain lengths at 80 vol% with water. The surfactant chains were each run in a simulation box of dimensions 20 × 20 × 20 until equilibrium was reached. The lamellar phase formed for all different surfactant chain lengths and, after the initial equilibrium the surfactant systems were then simulated with a water box for dissolution. The dissolution process was tracked by visual analysis, local concentration analysis, micelle size, and a zonal model to calculate the diffusion parameter. Results show that as the surfactant chain length increased by adding more of the hydrophobic beads, the dissolution process slowed down. Increasing the hydrophilic part of the surfactant speeds up the dissolution process, but the effect of adding more of the hydrophobic part is greater than the effect of adding more of the hydrophilic part on the dissolution process. [ABSTRACT FROM AUTHOR]

Abstract The influence of molecular fragmentation and parameter settings on a mesoscopic dissipative particle dynamics (DPD) simulation of lamellar bilayer formation for a C10E4/water mixture is studied. A “bottom-up” decomposition of C10E4 into the smallest fragment molecules (particles) that satisfy chemical intuition leads to convincing simulation results which agree with experimental findings for bilayer formation and thickness. For integration of the equations of motion Shardlow’s S1 scheme proves to be a favorable choice with best overall performance. Increasing the integration time steps above the common setting of 0.04 DPD units leads to increasingly unphysical temperature drifts, but also to increasingly rapid formation of bilayer superstructures without significantly distorted particle distributions up to an integration time step of 0.12. A scaling of the mutual particle–particle repulsions that guide the dynamics has negligible influence within a considerable range of values but exhibits apparent lower thresholds beyond which a simulation fails. Repulsion parameter scaling and molecular particle decomposition show a mutual dependence. For mapping of concentrations to molecule numbers in the simulation box particle volume scaling should be taken into account. A repulsion parameter morphing investigation suggests to not overstretch repulsion parameter accuracy considerations.

Cell models play a crucial role in analyzing the mechanical response of cells and quantifying cellular damage incurred during micromanipulation. While traditional models can capture the overall mechanical behavior of cells, they often lack the ability to discern among distinct cellular components. Consequently, by employing dissipative particle dynamics, this study constructed a triangular network-like representation of the cell membrane along with cross-linked cytoskeletal chains. The mechanical properties of both the membrane and cytoskeleton were then analyzed through a series of simulated mechanical tests, validated against real-world experiments. The investigation utilized particle-tracking rheology to monitor changes in the mean square displacements of membrane particles over time, facilitating the analysis of the membrane’s storage and loss moduli. Additionally, the cytoskeletal network’s storage and loss moduli were examined via a double-plate oscillatory shear experiment. The simulation results revealed that both the membrane and cytoskeleton exhibit viscoelastic behavior, as evidenced by the power-law dependency of their storage and loss moduli on frequency. Furthermore, indentation and microinjection simulations were conducted to examine the overall mechanical properties of cells. In the indentation experiments, an increase in the shear modulus of the membrane’s WLCs correlated with a higher Young’s modulus for the entire cell. Regarding the microinjection experiment, augmenting the microinjection speed resulted in reduced deformation of the cell at the point of membrane rupture and a lower percentage of high strain.

Quorum sensing (QS) is enabled by the production of signalling molecules called autoinducers, whose presence in the environment modulates the behavior of bacterial populations. Autoinducer‐2 (AI‐2) is unique as it is recognized by different species of bacteria and fosters signalling across different species. To further understand QS mechanisms and to discover potential novel therapeutics based on the modulation of bacterial behavior many analogs have been synthesized. This review aims to provide a critical analysis of the state‐of‐the‐art of the synthesis of AI‐2 and its analogs. It serves as a non‐exhaustive consolidation of previous studies of analogs, focusing on the synthetic approaches and the structure‐activity relationship conclusions drawn after the analysis of the chemical libraries of the research groups involved in the field. This article is intended to be a strong foundation for the rational planning of synthetic strategies of analogs with specific bioactivities. [ABSTRACT FROM AUTHOR]

The effect of polyoxyethylene chain length on the formation and temperature stability of W/O microemulsion emulsified by polyoxyethylene ether surfactant is investigated by dissipative particle dynamics simulation (DPD) on the mesoscopic level. The results show that W/O microemulsions can be formed by three polyoxyethylene chain length ether nonionic surfactants with decreasing the water-oil ratio equal to increasing the oil phase content. However, W/O microemulsion is most easily formed by diethylene glycol monododecyl ether (H1T2) with the smallest oxyethylene base. The results of temperature stability show that W/O microemulsion emulsified by H1T2 has better stability resistant to high or low temperature. In addition, the interfacial tension of the W/O microemulsion system is the lowest, the end-to-end distance of the surfactant molecule is smallest, and the molecular chain is the most curved at the water-oil interface. The theoretical simulation results can guide the formation of the W/O microemulsion induced by polyoxyethylene ether nonionic surfactant, and provide the guidance for its practical application. The effect of polyoxyethylene chain length on the formation and temperature stability of W/O microemulsion emulsified by polyoxyethylene ether surfactant is investigated by Dissipative particle dynamics (DPD) simulation which can provide information on the mesoscopic level by a larger time and space scale. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this study was to determine if dihydropyrimidine dehydrogenase (DPD) activity measured in peripheral blood mononuclear cells (PBMCs) is related to adverse events during fluoropyrimidine therapy. Methods: A retrospective cohort study was conducted. The study population included 481 patients who received fluoropyrimidine treatment and for whom relevant patient characteristics were known and adverse events were noted in the electronic health records. Factors besides DPD phenotype that could affect the incidence of adverse events were corrected for using log regression. These log regression models were used to identify an association between the DPD phenotype measured in PBMCs and adverse events. Results: Patients with a decreased DPD activity measured in PBMCs suffered more adverse events. Results from log regression data show that this effect remains significant after correcting for dosage, chemotherapy regimen and relevant patient characteristics. Conclusion: A significant correlation was found between reduced DPD enzyme activity in PBMCs and adverse events. The findings in this paper support further exploring DPD phenotyping as a method for preventing fluoropyrimidine-related adverse events. Further assessment of DPD phenotyping will require clinical validation in a prospective study. [ABSTRACT FROM AUTHOR]

Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed. • EMA recommends DPD testing (DPYD variants or uracilemia) before FP-based chemotherapy. • Genotyping relevance of the 4 consensual DPYD variants is restricted to Caucasians. • DPYD genotype-guided FP dose reduction is clinically validated, contrary to uracilemia. • Impact of DPD -guided FP dose reduction on efficacy needs further investigation. • 5FU therapeutic drug monitoring is recommended in partial DPD-deficient patients. [ABSTRACT FROM AUTHOR]

The influence of molecular fragmentation and parameter settings on a mesoscopic dissipative particle dynamics (DPD) simulation of lamellar bilayer formation for a C10E4/water mixture is studied. A "bottom-up" decomposition of C10E4 into the smallest fragment molecules (particles) that satisfy chemical intuition leads to convincing simulation results which agree with experimental findings for bilayer formation and thickness. For integration of the equations of motion Shardlow's S1 scheme proves to be a favorable choice with best overall performance. Increasing the integration time steps above the common setting of 0.04 DPD units leads to increasingly unphysical temperature drifts, but also to increasingly rapid formation of bilayer superstructures without significantly distorted particle distributions up to an integration time step of 0.12. A scaling of the mutual particle–particle repulsions that guide the dynamics has negligible influence within a considerable range of values but exhibits apparent lower thresholds beyond which a simulation fails. Repulsion parameter scaling and molecular particle decomposition show a mutual dependence. For mapping of concentrations to molecule numbers in the simulation box particle volume scaling should be taken into account. A repulsion parameter morphing investigation suggests to not overstretch repulsion parameter accuracy considerations. [ABSTRACT FROM AUTHOR]

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective: To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods: Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results: Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions: Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort. [ABSTRACT FROM AUTHOR]

5-fluorouracil is an essential component of systemic chemotherapy for colon, breast, head, and neck cancer patients. However, tumoral overexpression of the dihydropyrimidine dehydrogenase has rendered 5-FU clinically ineffective by inactivating it to 5'-6'-dihydro fluorouracil. The responses to 5-FU in terms of efficacy and toxicity greatly differ depending upon the population group, because of variability in the DPD activity levels. In the current study, key active site amino acids involved in the 5-FU inactivation were investigated by modelling the 3D structure of human DPD in a complex with 5-FU. The identified amino acids were analyzed for their possible missense mutations available in dbSNP database. Out of 12 missense SNPs, four were validated either by sequencing in the 1000 Genomes project or frequency/genotype data. The recorded validated missense SNPs were further considered to analyze the effect of their respective alterations on 5-FU binding. Overall findings suggested that population bearing the Glu611Val DPD mutation (rs762523739) is highly vulnerable to 5-FU resistance. From the docking, electrostatic complementarity, dynamics, and energy decomposition analyses it was found that the above mutation showed superior scores than the wild DPD -5FU complex. Therefore, prescribing prodrug NUC-3373 or DPD inhibitors (Gimeracil/3-Cyano-2,6-Dihydroxypyridines) as adjuvant therapy may overcome the 5-FU resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Pseudo-gemini surfactants were synthesized from commercially available reagents. • Material-efficient and energy-efficient reaction pathway was selected. • Adsorption, micellization and antimicrobial properties were evaluated. • Molecular simulation was performed using Dissipative Particle Dynamics. • Theoretical CMC values were in good agreement with experimental values. In this work new pseudo-gemini type surfactants are constructed via a simple, energy and material efficient way, using piperazine, propylene oxide and seven different fatty acids: capric, lauric, myristic, stearic, oleic and linolenic. The compounds are characterized by 1H NMR, 13C NMR and FTIR studies. Micellization and adsorption properties of the novel pseudo-gemini surfactants are investigated via surface tension and conductivity measurements. Antimicrobial properties are evaluated using the simple disk diffusion test method. Dissipative Particle Dynamics (DPD) simulations are performed to model aggregation behavior of the new pseudo-gemini surfactants. Experimental studies revealed that Critical Micelle Concentration (CMC) of the obtained pseudo-gemini surfactants are lower than 1 mmol/L. Theoretically calculated CMC values are slightly higher than experimental CMC values. However, overall, very good agreement between theoretical and experimental CMC values is observed. Radial Distribution Function (RDF) and radius of gyration (R g) plots are analyzed to gain further insight into aggregation of the surfactant molecules in aqueous environment. The DPD model of the pseudo-gemini amphiphiles successfully predicts the most important traits of the aggregation process. [ABSTRACT FROM AUTHOR]

Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical practice for more than 20 years, being part of the therapeutic standard for digestive and breast cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the implementation of precision oncology. In particular for head and neck cancers, the identification of biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including "multi-omics" approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase (DPD) or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging and radiomics parameters in multi-omics models will help implement "precision chemotherapy" in HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio. [ABSTRACT FROM AUTHOR]

A method for measuring peracetic acid vapors in air using impinger sampling and field-portable colorimetric analysis is presented. The capture efficiency of aqueous media in glass and plastic impingers was evaluated when used for peracetic acid vapor sampling. Measurement of peracetic acid was done using an N,N-diethyl-p-phenylenediamine colorimetric method with a field-portable spectrometer. The linearity of the N,N-diethyl-p-phenylenediamine method was determined for peracetic acid both in solution and captured from vapor phase using glass or plastic impingers. The Limits of Detection for the glass and plastic impingers were 0.24 mg/m3 and 0.28 mg/m3, respectively, for a 15 L air sample. The Limits of Quantitation were 0.79 mg/m3 and 0.92 mg/m3 for the glass and plastic impingers, respectively. Both metrics were below the American Conference of Governmental Industrial Hygienists Threshold Limit Value Short-Term Exposure Limit of 1.24 mg/m3 (0.4 ppmv) during a 15-min period. The impinger sampling method presented herein allows for an easy-to-use and rapid in-field measurement that can be used for evaluating occupational exposure to peracetic acid. [ABSTRACT FROM AUTHOR]

Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments. [ABSTRACT FROM AUTHOR]

Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)., Methods: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm., Results: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332)., Conclusion: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Background: 5-Fluorouracil (5-FU) is essential in treating gastrointestinal cancers, but some patients show severe toxicity. The toxicity is exposure-related, which is linked to the enzyme dihydropyrimidine dehydrogenase (DPD) decoded by the DPYD gene. This study aimed to evaluate the possible toxicity related to 5-FU plasma levels, DPYD genotyping, and DPD phenotyping., Methods: Forty-seven gastrointestinal cancer patients receiving 5-FU were included in this study. 5-FU plasma levels and DPD phenotyping were analyzed by UPLC-MS/MS. DPYD genotyping was also assessed. The Common Terminology Criteria for Adverse Events (CTCAE) was used to classify the toxicity., Results: For hematological toxicity, 27.65% showed neutropenia, 78.72% anemia, and 29.78% thrombocytopenia. The area under the curve (AUC) of 5-FU calculated from the plasma was evaluated for three treatment cycles, and we observed that at the initial cycle, 48.93% were underexposed and 10.63% were overexposed, with a total of 59.56% of patients outside the therapeutic range. In the DPYD genotyping, 97.87% of patients had a wild-type genotype, and 2.12% had c.1236G>A mutation (E412E, rs56038477). A total of 82.97% of patients showed a phenotype compatible with normal DPD activity., Conclusion: These findings suggest that the evaluation of DPYD genotyping and DPD phenotyping in the Brazilian population still requires further study. Moreover, the analysis of the plasma AUC of 5-FU could contribute to clinical routine, being a very useful tool, especially for identifying patients outside the therapeutic range and thus guiding more individualized doses, or even in the intervention of possible toxicities related to overexposure., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background: Patients with relapsed or refractory multiple myeloma (RRMM) who have exhausted lenalidomide benefits require improved therapies. The 3-cohort phase 2 MM-014 trial (NCT01946477) explored pomalidomide in early lines of treatment for lenalidomide-exposed RRMM. In cohort B, pomalidomide plus daratumumab and dexamethasone (DPd) showed promising efficacy (median follow-up 28.4 months), as previously reported. Here, we report final overall survival (OS) in cohort B., Methods: Patients aged ≥ 18 years were treated in 28-day cycles: pomalidomide 4 mg orally daily from days 1 to 21; daratumumab 16 mg/kg intravenously on days 1, 8, 15, and 22 (cycles 1-2), days 1 and 15 (cycles 3-6), and day 1 (cycle ≥ 7); and dexamethasone 40 mg (age ≤ 75 years) or 20 mg (age > 75 years) orally on days 1, 8, 15, and 22. The primary endpoint was ORR. OS and safety were secondary endpoints., Results: Among 112 patients enrolled, 85 (75.9%) had lenalidomide-refractory disease and 27 (24.1%) had lenalidomide-relapsed disease. At a median follow-up of 41.9 months (range, 0.4-73.1), median OS was 56.7 months (95% confidence interval, 46.5-not reached). Treatment-emergent adverse events related to, and leading to discontinuation of, pomalidomide, dexamethasone, or daratumumab occurred in 7 (6.3%), 9 (8.0%), and 6 (5.4%) patients, respectively., Conclusion: With long-term follow-up, our results show favorable OS with DPd. The safety profile was consistent with previous reports, with no new safety signals identified. IMiD agent-based therapy can still be considered in patients with RRMM who experience progressive disease on or after lenalidomide., Competing Interests: Disclosure N.J.B. declares research funding from Bristol Myers Squibb (BMS); honoraria from AbbVie, Amgen, BMS/Celgene, Forus, Genentech, GlaxoSmithKline (GSK), Janssen, Karyopharm, Pfizer, Sanofi, and Takeda; and payment for expert testimony from BMS/Celgene, Karyopharm, and Pfizer. C.S. declares no competing financial interests. D.R. declares research funding from BMS; consulting fees from Amgen, BMS, and Janssen; honoraria from Amgen, BMS, GSK, Sanofi, and Takeda; payment for expert testimony from BMS and Janssen; and board membership with Canadian Myeloma Research Network (CMRG; Chief Medical Officer). M.S. declares payment for expert testimony from BMS, Gilead/Kite, Janssen, Novartis, Pfizer, and Sanofi; and participation on a data safety monitoring or advisory board with Janssen. J.M. declares consulting fees from BeiGene and Pharmacyclics; and participation on a data safety monitoring or advisory board with BeiGene. J.G.B. declares research funding from 2seventy bio, AbbVie, Acetylon, Amgen, BMS/Celgene, bluebird bio, C4 Therapeutics, CARsgen, Cartesian, Celularity, CRISPR, EMD Serono, Fate, Genentech, GSK, Ichnos, Incyte, Janssen, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Takeda, and Teva; and consulting fees from bluebird bio, BMS/Celgene, CRISPR, Janssen, Kite, Legend, Roche, Secura, and Takeda. J.S. declares honoraria from BMS, Janssen, Pfizer, and Sanofi. G.J.S. declares research funding from AbbVie, Actinium, Actuate, Agios, AltruBio, Amgen, Aptevo, Arog, Astellas, AVM Bio, BioMea, Biopath, Biosight, BMS/Celgene, Celator, Cellectis, Celularity, Cogent, Constellation, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech/Roche, Geron, Gilead/Kite, Glycomimetics, Immunogene, Incyte, Janssen, Jazz, Karyopharm, Kiadis, Kronos Bio, Kura, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consulting fees from BMS/Celgene, Curios, and Daiichi Sankyo; honoraria from AbbVie, Agios, Amgen, Astellas, AstraZeneca, AVM Biotech, BMS, Celgene, Gamida, Gilead, GSK, Incyte, Karyopharm, Novartis, Ono, and Stemline; participation on a data safety monitoring or advisory board with Agios, Amgen, AstraZeneca, AVM Biotech, BMS, Gamida, Gilead, GSK, Incyte, Novartis, and Ono; and stock or stock options with Amgen, BMS, and Janssen/Johnson & Johnson. S.G. declares consulting fees from AstraZeneca, BMS, Kite, and Sanofi; and honoraria from Kite and Seagen. K.S. declares research funding from BMS; and honoraria from Amgen, BMS, and Sanofi. C.S.S. declares no competing financial interests. M.A-R. declares honoraria from BMS, Eisai, and Merck Sharp Dohme. M.B. declares no competing financial interests. D.Q. declares no competing financial interests. G.F. declares honoraria from Amgen, BMS, and Sanofi. H.L. declares employment and stock/stock options with BMS. C.G. declares employment and equity ownership with BMS. P.S. declares employment with BMS. D.S. declares research funding from BMS; consulting fees from BMS, Janssen, and Karyopharm; honoraria from BMS and Janssen; participation on a data safety monitoring or advisory board with BMS; and stock or stock options with COTA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Compensation of nonlinear distortion in hybrid beamforming MIMO transmitters is an open and challenging field of research. The goal of the study is to find an efficient method for linearization of power amplifiers in fully connected hybrid beamforming MIMO transmitters, which would not additionally increase the complexity of the system too much. In this paper, the polynomial-based compensation method of nonlinear distortion in hybrid beamforming MIMO transmitters is presented. The method is verified through comprehensive Matlab simulations. A 64x64 fully connected hybrid beamforming MIMO system with 2 RF branches on the transmitting side and 2 RF branches on the receiving side was considered. The proposed memory polynomial digital predistortion model is based on direct transmit-end feedback. Simulations were performed for different parameters of the memory polynomial model and analyzed. The obtained results are presented in graphical form, using Power Spectrum Density, and in numerical form, using metrics in time and frequency domain, such as Normalized Mean-Squared Error and Error Vector Magnitude. It is shown that the proposed memory polynomial digital predistortion model can very well compensate nonlinear distortion in fully connected hybrid beamforming MIMO transmitter. It has been also demonstrated that with increasing model complexity, ie with increasing memory depth and nonlinearity order of memory polynomial model, better compensation of nonlinear distortion in hybrid beamforming MIMO transmitters can be achieved. [ABSTRACT FROM AUTHOR]

Algorithmic decision-making based on profiling may significantly affect people's destinies. As a rule, however, explanations for such decisions are lacking. What are the chances for a "right to explanation" to be realized soon? After an exploration of the regulatory efforts that are currently pushing for such a right it is concluded that, at the moment, the GDPR stands out as the main force to be reckoned with. In cases of profiling, data subjects are granted the right to receive meaningful information about the functionality of the system in use; for fully automated profiling decisions even an explanation has to be given. However, the trade secrets and intellectual property rights (IPRs) involved must be respected as well. These conflicting rights must be balanced against each other; what will be the outcome? Looking back to 1995, when a similar kind of balancing had been decreed in Europe concerning the right of access (DPD), Wachter et al. (2017) find that according to judicial opinion only generalities of the algorithm had to be disclosed, not specific details. This hardly augurs well for a future right of access let alone to explanation. Thereupon the landscape of IPRs for machine learning (ML) is analysed. Spurred by new USPTO guidelines that clarify when inventions are eligible to be patented, the number of patent applications in the US related to ML in general, and to "predictive analytics" in particular, has soared since 2010—and Europe has followed. I conjecture that in such a climate of intensified protection of intellectual property, companies may legitimately claim that the more their application combines several ML assets that, in addition, are useful in multiple sectors, the more value is at stake when confronted with a call for explanation by data subjects. Consequently, the right to explanation may be severely crippled. [ABSTRACT FROM AUTHOR]

Article 38 Paragraph (1) of Law No. 23 of 2014 concerning Local Government as amended by Law No. 9 of 2015 concerning the second Amendment to Law No. 23 of 2014 concerning Local Government is contrary to Article 20A Paragraph (1), Article 21 and Article 22D paragraph (1) of the 1945 Constitution. Where the proposal for regional expansion proposed by Governor is takeover of authority. In the 1945 Constitution has been regulated in a limitative manner the authority given to the DPR and DPD institutionally the power to form the law and give authority to the President to submit a draft law. Author examines legal analysis of the authority of the DPR and DPD in the process of regional expansion. Type of research is normative research and qualitative descriptive form. The authority of the DPR and DPD in the process of regional expansion as regulated has been constitutionally harmed, namely the right to submit a draft law related to regional expansion and participate together to discuss the draft law which results in the process of regional expansion cannot be submitted by the DPR and DPD which has a legislative function.

Background: The purpose of the present study was to investigate the role of the 5-Fluorouracil (5-FU) resistance-related factor dihydropyrimidine dehydrogenase (DPD) in tumor immunity and prognosis and to study the relationship between drug resistance and the immune microenvironment of colon cancer. Methods: Bioinformatics methods were used to analyze the expression of DPD associated with prognosis, immunity, microsatellite instability, and tumor mutational burden in colon cancer. Immunohistochemistry (IHC) was used to detect DPD, MLH1, MSH2, MSH6, and PMS2 in 219 colon cancer tissue samples. Additional IHC analyses were conducted to detect CD4, CD8, CD20, and CD163 in 30 colon cancer tissue samples with the most extensive immune infiltration. The significance of the correlations and clinical significance of DPD with immune infiltration, immune-related markers, microsatellite instability-related indicators, and prognosis were evaluated. Results: The major findings of the present study are as follows: (1) DPD was expressed in tumor and immune cells and associated with certain immune cell-related markers, particularly M2 macrophages that expressed CD163. (2) DPD expression significantly and positively correlated with immune cell markers and immune checkpoints PD-1 and PD-L1. High expression of DPD in immune cells, but not tumor cells, led to increased immune infiltration. (3) High expression of DPD in immune and tumor cells induced 5-FU resistance and was associated with unfavorable prognosis. (4) DPD expression closely correlated with microsatellite instability and tumor mutational burden and led to resistance to 5-FU in patients with microsatellite instability. (5) Bioinformatics analyses revealed that DPD was enriched in immune-related functions and pathways such as activation of T cells and macrophages. Conclusions: DPD plays an important role in the immune microenvironment and drug resistance of colon cancers and their functional association.

Cardiac transthyretin amyloidosis is a usually fatal form of restrictive cardiomyopathy for which clinical trials of treatments are ongoing. It is anticipated that quantitative nuclear medicine scintigraphy, which is experiencing growing interest, will soon be used to evaluate treatment efficacy. We investigated its utility for monitoring changes in disease load over a significant time period. Sixty-two treatment-naive patients underwent 99mTc-labelled 3,3-diphosphono-1,2propanodicarboxylic acid (99mTc-DPD) scintigraphy two to four times each over a five-year period. Quantitation of cardiac 99mTc-DPD retention was performed according to two established methods: measurement of heart-to-contralateral ratio (H/CL) in the anterior view (planar) and percentage of administered activity in the myocardium (SPECT). In total 170 datasets were analysed. Increased myocardial retention of 99mTc-DPD was demonstrable as early as 12 months from baseline. Year-on-year progression across the cohort was observed using SPECT-based quantitation, though on 30 occasions (27.8%) the change in our estimate was negative. The spread of our results was notably high compared to the year-on-year increases. If left unaccounted for, variance may draw fallacious conclusions about changes in disease load. We therefore urge caution in drawing conclusions solely from nuclear medicine scintigraphy on a patient-by-patient basis, particularly across a short time period. [ABSTRACT FROM AUTHOR]

Predistortion techniques can be categorized into digital predistortion (DPD) and analog predistortion (APD), which are always implemented separately in their own domains. The baseband-domain mean square error (MSE) is the design target of DPD, and the RF-domain inter-modulation distortions (IMDs) are applied for APD. In this letter, we propose a hybrid MSE-IMDs based DPD framework that optimizes the above two criteria simultaneously. Specifically, to make the joint optimization possible, we define a new IMDs metric which can capture the DPD model coefficients. The classic recursive least square (RLS)-based DPD scheme is improved to balance the MSE and IMDs metrics without increasing the complexity. [ABSTRACT FROM AUTHOR]

Context Diabetes mellitus increases the risk of bone diseases including osteoporosis and osteoarthritis. We have previously demonstrated that Ficus deltoidea Jack (Moraceae) is capable of reducing hyperglycaemia. However, whether F. deltoidea could protect against diabetic osteoporosis remains to be determined. Objective The study examines the effect of F. deltoidea on bone histomorphometric parameters, oxidative stress, and turnover markers in diabetic rats. Materials and methods Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats (n = 6 animals per group) received one of the following treatments via gavage for 8 weeks: saline (diabetic control), metformin (1000 mg/kg bwt), and methanol leaves extract of F. deltoidea (1000 mg/kg bwt). A group of healthy rats served as normal control. The femoral bones were excised and scanned ex vivo using micro-computed tomography (micro-CT) for histomorphometric analysis. The serum levels of insulin, oxidative stress, and bone turnover markers were determined by ELISA assays. Results Treatment of diabetic rats with F. deltoidea could significantly increase bone mineral density (BMD) (from 526.98 ± 11.87 to 637.74 ± 3.90). Higher levels of insulin (2.41 ± 0.08 vs. 1.58 ± 0.16), osteocalcin (155.66 ± 4.11 vs. 14.35 ± 0.97), and total bone n-3 PUFA (2.34 ± 0.47 vs. 1.44 ± 0.18) in parallel with the presence of chondrocyte hypertrophy were also observed following F. deltoidea treatment compared to diabetic control. Conclusions F. deltoidea could prevent diabetic osteoporosis by enhancing osteogenesis and inhibiting bone oxidative stress. These findings support the potential use of F. deltoidea for osteoporosis therapy in diabetes.

Reliable and efficient High-speed Railways (HSR) is the key component to the concept of Green Smart Cities to combat the prevailing traffic congestion on roads and increasing greenhouse gases in the atmosphere. It is also a fast, safe, and economical transport medium. Long Term Evolution – Railways (LTE-R), though in the developing stage, is a new wireless communications standard for providing intelligent broadband communication services to passengers and train operators. Reliable HSR communication requires more base stations (BSs). The radio frequency power amplifier (RFPA), an integral part of the BS, dominates the overall energy consumption and is inherently nonlinear. Digital Predistortion (DPD), the ultimate Green communication technique, is used to linearize RFPAs and provide less power waste. Multiple-input-multiple-output (MIMO) schemes have been used to achieve enhanced data throughputs and superior transmission reliability. This paper analyzes the effect of DPD arrangement corresponding to these schemes for reliable HSR communication in infrastructure-to-train and inside-station scenarios. The authors consider downlink transmission for the LTE-R specifications at different train speeds. Furthermore, the paper proposes an analytical framework to evaluate the performance of the complete HSR MIMO communications system. This analytical framework characterizes the antenna effects on the Block Error Rate (BLER) and throughput by adopting various transmission modes, viz. SISO, MISO, SIMO and MIMO. Numerical analyses and simulations for the proposed system illustrate better reliability and high throughput performances with higher-order MIMO configurations. Moreover, significant energy savings can be realized by universally deploying DPD across the HSR network in Smart Cities.

The main problem of this research is that there is no firmness regarding the diction of individual words in the Constitution which is useful as a condition for nominating Regional Representative Council or Dewan Perwakilan Daerah (DPD) membership. This indecisiveness has led to the composition of DPD membership being dominated by members of political parties. This journal aims to explore the meaning of the diction of words contained in the 1945 NRI Constitution, namely "Individual" which is clearly written in Article 22E paragraph (4) of the 1945 Constitution of the Republic of Indonesia after the Constitutional Court Decision No30/PUU-XVI/2018. The meaning of the term “individual” in this article will determine the conditions for nominating members of the DPD so that they are more in line with the objectives of establishing the institution. This journal uses a statutory approach and a historical approach. The results of this discussion show that the original intense definition concluded by the author regarding the word "individual" in the 1945 Constitution of the Republic of Indonesia after the Constitutional Court Decision has the following meaning: an individual who does not have a political party background or political party management and really understands his / her region.

Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ABCC11/DPYD to improve systemic chemotherapy in CRC.

Diabetes mellitus increases the risk of bone diseases including osteoporosis and osteoarthritis. We have previously demonstrated that Ficus deltoidea Jack (Moraceae) is capable of reducing hyperglycaemia. However, whether F. deltoidea could protect against diabetic osteoporosis remains to be determined. The study examines the effect of F. deltoidea on bone histomorphometric parameters, oxidative stress, and turnover markers in diabetic rats. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats (n = 6 animals per group) received one of the following treatments via gavage for 8 weeks: saline (diabetic control), metformin (1000 mg/kg bwt), and methanol leaves extract of F. deltoidea (1000 mg/kg bwt). A group of healthy rats served as normal control. The femoral bones were excised and scanned ex vivo using micro-computed tomography (micro-CT) for histomorphometric analysis. The serum levels of insulin, oxidative stress, and bone turnover markers were determined by ELISA assays. Treatment of diabetic rats with F. deltoidea could significantly increase bone mineral density (BMD) (from 526.98 ± 11.87 to 637.74 ± 3.90). Higher levels of insulin (2.41 ± 0.08 vs. 1.58 ± 0.16), osteocalcin (155.66 ± 4.11 vs. 14.35 ± 0.97), and total bone n-3 PUFA (2.34 ± 0.47 vs. 1.44 ± 0.18) in parallel with the presence of chondrocyte hypertrophy were also observed following F. deltoidea treatment compared to diabetic control. F. deltoidea could prevent diabetic osteoporosis by enhancing osteogenesis and inhibiting bone oxidative stress. These findings support the potential use of F. deltoidea for osteoporosis therapy in diabetes. [ABSTRACT FROM AUTHOR]

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