Penetration Model Research Articles

P906 Prevalence and CARD9 IBD risk variant rs4077515 in a Chilean IBD Cohort

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of polymorphisms associated with an increased risk of developing IBD. Among risk genes identified by GWAS, CARD9, a gene encoding an adapter molecule involved in the innate immune response to fungi and bacteria, has been related to IBD risk. CARD9 alleles in IBD patients may have either a protective function or a high genetic risk factor such as rs4077515. Interestingly, the CARD9S12N (rs4077515) variant has a higher frequency in the Latin South American population than the Caucasian population. The relevance of rs4077515 in the risk of IBD in the Latino population is unknown. Aims (1) To estimate allele and genotype frequencies for rs4077515 in IBD patients and Chilean controls and compare with Ensembl genome database (public data available). (2) To compare the allele and genotype distributions in IBD patients and controls, including association tests and estimation of ORs according to additive, dominant and recessive penetrance models. Methods 260 IBD patients were genotyped using the TaqMan SNP genotyping technology based on qPCR. Aggregated genotype information for 3147 population-based Chilean controls was retrieved from a published study on gallstones in Chileans (Lorenzo et al., Hepatology 2021). We calculated the allele and genotype frequencies for rs4077515 and then compared these frequencies with controls. A Chi-square test of association was used under the null hypothesis of no association between genotypes and disease. Univariate and multiple logistic regression were performed (additive, dominant, and recessive penetrance models). Results Table 1 compares rs4077515 allele and genotype frequencies in Chileans and other populations (Ensembl data set). Table 2. exhibits the estimated odds ratio for IBD, CD, and UC in Chilean population. Table 3. reveals the association results for rs4077151 models in the Chilean population. Conclusion In this study, the A risk allele for rs4077515 is significantly more frequent in the Chilean population than reported in other populations such as European, but similar to Amerindian. In this Chilean cohort, the variant rs4077515 is not associated with higher IBD risk. However, this could be an effect of sample size, or patients carrying rs4077515 requires an additional factor to IBD development.

Systematic study of the effect of individual rotational energy levels on the fusion cross-section of 16 O-based reactions of range 480 ≤ Z P Z T ≤ 592

In heavy-ion fusion reactions, the enhancement in the sub-barrier fusion cross-section has been observed as compared to the 1-Dimensional barrier penetration model due to the coupling of many degrees of freedom to the relative motion. This enhancement can be explained theoretically by including nuclear structure effects like deformation and the coupling of relative motion among two colliding nuclei. The present work aims to investigate the effect of individual rotational energy levels on the fusion cross-sections for 16O-based reaction systems, namely, 16O + 182,184,186W, 16O + 176,180Hf, 16O + 174,176Yb, 16O + 166Er, 16O + 148,152,154Sm, 16O + 150Nd at energies below the fusion barrier. Using the CCFULL code, the effect of low-lying rotational energy levels on the fusion cross-section for 16O induced reactions has been investigated at energies below and around the Coulomb barrier. The calculations are performed by assuming the fixed value of diffuseness parameter a 0 = 0.65 fm in the Woods-Saxon nuclear potential and the other two parameters are optimised by fitting the experimental data at the above barrier. Here we have determined the V 0 and r 0 as a function of Z P Z T , where experimental cross-sections are available. From our calculations, it is observed that the hexadecapole deformation (β 4) with different magnitudes has a significant influence on the fusion cross sections. For the case of the +ve value of β 4, beyond 10+, the rotational levels cease to contribute significantly and also there is a significant difference between the contribution of sequential channels. On the other hand, in the case of -ve β 4, up to 6+ levels contribute significantly. Furthermore, we have established an algebraic systematic of fitting, which one can use to determine the parameters V 0, r 0 of Woods-Saxon nuclear potential within the range of Z P Z T lie in between 480 ≤ Z P Z T ≤ 592.

Using a non-invasive multiple-method approach to characterize rock glaciers in the periglacial critical zone: An example from the San Juan Mountains, Colorado

Anthropogenic climate change threatens water storage and supply in the periglacial critical zone. Rock glaciers are widely distributed alpine aquifers with slower response to temperature increases, that provide the summer water flow of many alpine streams. Knowing the extent and makeup of rock glaciers is necessary to evaluate their potential for water supply. We used non-invasive methods, integrating geological, geomorphological, meteorological, and geophysical information to characterize the internal structure and hydrology of the Upper Camp Bird rock glacier (UCBRG) located on level 3 of Camp Bird Mine in Ouray, Colorado, and assessed the applicability of two electromagnetic induction systems in this highly heterogeneous landform with a history of anthropogenic activity. The time-domain (G-TEM™) system achieved deep subsurface penetration (~100 m) and realistic modeling of the internal structure of the UCBRG: a shell of volcanic rock fragments (<3 m thick; 1–100 Ohm-m), a meltwater component (102–103 Ohm-m), located between 50 and 100 m near the toe (subpermafrost flow), and 1–30 m in the soundings farthest from the toe (suprapermafrost flow within the active layer), and a frozen component (permafrost 50–80 m thick; 103–106 Ohm-m). The frequency-domain system, however, was highly susceptible to local environmental conditions, including anthropogenic objects (i.e., mine carts, lamp posts, tunnel tracks, etc.) and was unable to resolve UCBRG's internal makeup. The non-invasive methodology and general conceptual framework presented here can be used to characterize other alpine aquifers, contributing to the quantification of global water resources, and highlighting the importance of preserving rock glaciers as storage for critical water supply in the future.

A Computational Prediction Model of Blood-Brain Barrier Penetration Based on Machine Learning Approaches

A Computational Prediction Model of Blood-Brain Barrier Penetration Based on Machine Learning Approaches

Fiber inclination model for the anti-penetration performance of a new type three-dimensional angle-interlock woven composite

This study establishes a fiber inclination model suitable for a new three-dimensional angle interlocking woven UHMWPEF/epoxy composite, and evaluates its anti-penetration performance. Specifically, the microstructural characteristics of the composite material were analyzed by CT scan images, the mesostructure model of the material was established with the help of the software TexGen, and the calculation method of the fiber volume fraction of the material was designed. The meta-software ANSYS/LS-DYNA simulated and analyzed the failure mode and stress after ballistic penetration, before verifying it with the ballistic penetration test of the composite material as the target. The results show that the fiber volume fraction of the material is calculated to be 49.5% according to the derivation formula, which is consistent with that measured in the laboratory (50%±1%). By simplifying the numerical simulation model of composite ballistic penetration with the “fiber inclination model,” the residual velocity of the projectile calculated is in good agreement with the experimental value with an error of &lt;7%. In the target penetration test, the damage patterns of the target surface and the ejection surface are similar to the numerical simulation results. In the fiber inclination model, the failure shape of the projectile penetrating the horizontal one-way plate is almost circular, while the failure shape in the inclined one-way plate is irregular with a more severe damage along the inclined direction. In both unidirectional plates the damage area of the incoming surface is smaller than that of the ejected surface. Therefore, it is valid to use the fiber inclination model established to study the penetration performance of composite materials.

An Overview of the Current Energy Situation of Pakistan and the Way Forward towards Green Energy Implementation

Pakistan has been facing energy crises for more than a decade as a result of its reliance on imported fossil fuels, circular debt, political instability, and absurd energy policies. However, the country has abundant renewable energy resources which, if harnessed, may help to effectively cope with ever-increasing energy demand. This review study investigates the country’s economic and energy situations, energy crises, and energy sector performance. A critical analysis of studies conducted on Pakistan’s energy planning since its independence in 1947 is, and policies announced to date are assessed. This review reveals that the economic situation of the country has remained severely stressed, and energy sector performance has been compromised over the years for various underlying reasons. The energy policy narrative in the early decades of the post-independence period focused on water resource management, whereas energy concerns were only realized in the late 1960s as demand grew. The first-ever energy and power planning study in Pakistan was conducted in 1967, and since then, various studies have been conducted to support the medium-term development plans of the government. These planning studies inspired further development, and in 1994, the first-ever electricity-focused power policy was announced by the government in response to industrial growth and subsequent electricity demand. However, this and subsequent policies were fossil-fuel-centric until 2006, when the government announced the first-ever renewable energy policy. This 2006 policy focused on increasing renewable energy penetration in the overall energy mix by setting specific targets. However, these targets have rarely been accomplished as a result of a lack of an effective planning paradigm, as most of studies have been conducted without sound demand forecasting and without considering renewable energy’s potential to meet growing demand. As such, planning efforts based on proven methodologies/modeling tools and the undertaking of demand forecasts and renewable energy assessments are inevitable for countries such as Pakistan. Therefore, we suggest that sectoral energy demand forecasting, estimation of renewable energy potential with end use, and modeling of optimal penetration of renewable energy using energy modeling tools will be helpful to develop sustainable energy policies in Pakistan to eradicate the energy crisis.

An improved calibration of Karagozian & Case concrete/cementitious model for strain-hardening fibre-reinforced cementitious composites under explosion and penetration loadings

The ultra-high tensile capacity of strain-hardening fibre-reinforced cementitious composites makes them promising for impact dynamics applications, however, there is a lack of reference for taking the parameters of the constitutive model of materials in numerical simulations. In this study, the Karagozian & Case concrete/cementitious model parameters for strain-hardening fibre-reinforced cementitious composites were comprehensively and systematically calibrated. Multiaxial behaviour, crack-bridging constitutive relations, strain-rate effects, regularization of damage evolution parameters, and parameters scaling method for wide-range strength of materials were all considered and carefully discussed. The calibrated parameters were validated using low-velocity drop-weight impact tests, near-field explosion tests, and high-speed penetration tests. In this study, the traditional element erosion method and meshless/particle methods of Smoothed Particle Galerkin (SPG) method were used for failure analysis in penetration and explosion models. The results show that the calibrated parameters accurately predict the cratering and scabbing diameters and failure modes of explosion tests with the element erosion method. Furthermore, the residual velocity of the projectile and crack patterns of targets were also predicted with good precision with both element erosion and SPG methods. However, in the simulations of low-velocity impact tests, the predictions of maximum deflection were acceptable, and the errors in residual deflection were significant due to the inherent weakness of the material constitutive model.

Fusion-fission analysis of C12+Cm248 and O16+Pu244 nuclear reactions across the Coulomb barrier

By using the symmetric-asymmetric Gaussian barrier distribution (SAGBD) model, Wong formula, and coupled channel approach, heavy ion fusion dynamics is investigated for $^{12}\mathrm{C}+^{248}\mathrm{Cm}$ and $^{16}\mathrm{O}+^{244}\mathrm{Pu}$ reactions at energies lying below and near the Coulomb barrier. Coupling of various channels linked with the structure of participants to the relative motion of the collision partners is done by considering a Gaussian type of weight function in the SAGBD model and cross sections are found to be enhanced relative to the calculations obtained by the simple barrier penetration model. In the SAGBD model, the channel coupling effects are calculated in terms of channel coupling parameter ($\ensuremath{\lambda}$) and percentage reduction in the height of apparent fusion barrier with respect to the Coulomb barrier (${V}_{\mathrm{CBRED}}$). The channel coupling parameter estimates the cumulative influence of dominant intrinsic channels, which are responsible for the sub-barrier fusion enhancement. The SAGBD calculations appropriately explain the dynamics of $^{12}\mathrm{C}+^{248}\mathrm{Cm}$ and $^{16}\mathrm{O}+^{244}\mathrm{Pu}$ reactions at energies lying around the Coulomb barrier. The coupled channel analysis of the present reactions is done by using the code ccfull and the coupled channel calculations unambiguously identify the dominant influences of the rotational states up to ${10}^{+}$ spin states of the ground state rotational band of target isotopes in both reactions. In addition, the couplings to higher order deformation, such as ${\ensuremath{\beta}}_{4}$ for target and low lying quantum states of the projectile, are necessarily required to reproduce the experimental data of $^{12}\mathrm{C}+^{248}\mathrm{Cm}$ and $^{16}\mathrm{O}+^{244}\mathrm{Pu}$ reactions. Apart from the fusion analysis, the dynamical cluster-decay model (DCM) is applied to understand the fission dynamics of the $^{260}\mathrm{No}^{*}$ nucleus formed via the above-mentioned reactions. The decay study is carried out at the center-of-mass energies spread, ${E}_{\mathrm{c}.\mathrm{m}.}$ ($\ensuremath{\approx}79$ to 109 MeV) by including the quadrupole deformations (${\ensuremath{\beta}}_{2}$) and optimum orientations (${\ensuremath{\theta}}_{i}^{\mathrm{opt}}$) of the decaying fragments. According to the experimental observation, the noncompound nucleus (nCN) fission component competes with the compound nucleus (CN) fission processes. Consequently, the possibility of nCN contribution is also explored in the decay of the $^{260}\mathrm{No}^{*}$ compound nucleus. With an aim to have a comprehensive analysis of CN and nCN fission mechanisms, the role of the center-of-mass energy (${E}_{\mathrm{c}.\mathrm{m}.}$) and angular momentum ($\ensuremath{\ell}$) is explored in terms of various parameters of DCM such as fragmentation potential, preformation probability, barrier modification, etc.

Examining the correlation between multi-neutron transfer and inelastic excitations in sub-barrier fusion enhancement

Background: Heavy-ion fusion cross-sections at sub barrier energies are found to be enhanced by orders of magnitude as compared to the predictions of one-dimensional barrier penetration model (1-D BPM). The coupling of various internal degrees of freedom has been employed to decrypt the mechanism responsible for the observed sub-barrier fusion enhancement. However, the unambiguous role of multi-neutron transfer channels in the sub-barrier domain is still elusive.Purpose: We aim to explore and disentangle the effects of multi-neutron transfer channels from the inelastic excitations in the vicinity of the Coulomb barrier.Method: The fusion excitation functions for $^{28}\mathrm{Si} + ^{116,120,124}\mathrm{Sn}$ systems were measured from $\ensuremath{\approx}14%\phantom{\rule{0.222222em}{0ex}}$ below to $\ensuremath{\approx}15%\phantom{\rule{0.222222em}{0ex}}$ above the Coulomb barrier by detecting the evaporation residues (ERs) at the focal plane of the Recoil Mass Separator (RMS), Heavy Ion Reaction Analyzer (HIRA) at the Inter-University Accelerator Centre (IUAC), New Delhi.Results: The extracted fusion cross sections for the investigated systems at sub-barrier energies are significantly enhanced as compared to the predictions of 1-D BPM calculations. To probe the underlying mechanism responsible for the observed sub-barrier fusion enhancement, the coupled-channels (CC) formalism was employed. Coupled reaction channels (CRC) calculations by incorporating the one-neutron transfer channel to elucidate the significance of the transfer channel on the fusion dynamics were performed. Further, the semiempirical coupled channels (ECC) approach was explored to decipher the possible cause of the observed fusion excitation function trend. A systematic analysis of the neighboring systems available in the literature was also performed.Conclusions: CC calculations were able to reproduce the measured fusion excitation functions for $^{28}\mathrm{Si} + ^{116,120}\mathrm{Sn}$ systems to a reasonable extent. However, observed sub-barrier fusion enhancement in $^{28}\mathrm{Si}+^{124}\mathrm{Sn}$ system could not be explained using CC calculations. The influence of multi-neutron transfer channels was highlighted in the coupled-channels calculations. The interplay of collective excitations and neutron transfer was observed.

Nanoparticles for Topical Application in the Treatment of Skin Dysfunctions-An Overview of Dermo-Cosmetic and Dermatological Products.

Nanomaterials (NM) arouse interest in various fields of science and industry due to their composition-tunable properties and the ease of modification. They appear currently as components of many consumer products such as sunscreen, dressings, sports clothes, surface-cleaning agents, computer devices, paints, as well as pharmaceutical and cosmetics formulations. The use of NPs in products for topical applications improves the permeation/penetration of the bioactive compounds into deeper layers of the skin, providing a depot effect with sustained drug release and specific cellular and subcellular targeting. Nanocarriers provide advances in dermatology and systemic treatments. Examples are a non-invasive method of vaccination, advanced diagnostic techniques, and transdermal drug delivery. The mechanism of action of NPs, efficiency of skin penetration, and potential threat to human health are still open and not fully explained. This review gives a brief outline of the latest nanotechnology achievements in products used in topical applications to prevent and treat skin diseases. We highlighted aspects such as the penetration of NPs through the skin (influence of physical-chemical properties of NPs, the experimental models for skin penetration, methods applied to improve the penetration of NPs through the skin, and methods applied to investigate the skin penetration by NPs). The review summarizes various therapies using NPs to diagnose and treat skin diseases (melanoma, acne, alopecia, vitiligo, psoriasis) and anti-aging and UV-protectant nano-cosmetics.

Design and verification of flexible penetrometer for planetary subsurface exploration

In-situ extraction of geological information from planetary subsurfaces is of great importance. To achieve this goal with low power consumption and deep penetration, a novel subsurface sounding system for planetary regolith exploration is proposed based on the operating principle of tape measures. Penetration model analysis and validation were conducted. The penetration mechanics of the penetrator head and body were modeled separately, and static penetration tests were performed to verify the feasibility of the penetrator and modify the penetration load model. As the structural design of the penetrator was completed, a cam-based impact clamping scheme was proposed. The impact system dynamics model was established to analyze the effect of pene-tration resistance and kinetic parameters on the penetration capability of the penetrator. The principle prototype of the penetrator was developed, and a load-free simulated planetary regolith penetration test system was built to verify the correctness of the design. This study may provide technical support for the future application of flexible detectors in planetary exploration.

Welding Quality Detection for Variable Groove Weldments Based on Infrared Sensor and Artificial Neural Network

Connecting a variable groove weldment is always challenging, and it is necessary to monitor the course of the work and optimize the welding process parameters in real time to ensure the final welding forming quality. Welding penetration is an important index to appraise the welding forming quality; the visual sensing method for molten pool is the main method for detecting the weld penetration, but its detection accuracy is affected by the arc light. In this paper, a welding penetration sensing method for variable groove weldments based on the welding temperature field distribution is proposed. Firstly, a set of temperature field measurement system for a weldment is developed by means of an infrared sensor. Secondly, in the direction perpendicular to the welding direction, a linear temperature distribution feature extraction algorithm based on Gaussian fitting is studied; in the direction parallel to the welding direction, the linear temperature distribution feature extraction algorithm based on the thermal cycle parameters is studied, and the feasibility of using the extracted linear temperature distribution features to identify the weld penetration of a variable groove weldment is analyzed. Finally, taking the extracted linear temperature distribution features as input, using an artificial neural network, the prediction model for the welding penetration of a variable groove weldment is established. The experimental results showed that the weld penetration sensing method put forward in this paper can realize high-precision weld penetration sensing and has high reliability, which solves the problem that weld penetration sensing is affected by arc light to a great extent.

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies

PurposeThe congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon. MethodsWe generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure. ResultsBayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among “hot spot” regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain. ConclusionsBayesian penetrance estimates provide a continuous framework for variant interpretation.

Physics-informed machine learning model for prediction of long-rod penetration depth in a semi-infinite target

Traditional data-driven approaches to long-rod penetration modeling incorporate significant expert bias through handcrafted analytical formulas. In this work, we investigate machine learning as an alternative to build a more flexible, less biased model. Published data from approximately 900 experiments were used to train an artificial neural network to predict the depth of penetration into a semi-infinite target. On the basis of empirical parameter studies, we optimized the neural network architecture and regularization technique for this task. To aid the learning process, we incorporated into the machine learning model general physical principles, such as formalized in the Buckingham Pi theorem. The resulting physics-informed machine learning model shows good performance in generalization to new combinations of penetrator and target materials. As exemplary model application, we accurately postdict experimental results on the influence of target hardness fluctuations on penetration depth.

Investigation of the process of pipeline penetration at a shallow embedment in clay with large-deformation analysis

Pipe-soil interaction is an essential aspect of a deep-water pipeline system. It may significantly influence both the structural behavior and integrity of the pipeline during installation and operation. The pipe embedment is an important factor influencing the pipe-soil interaction for an exposed pipeline. The embedment will determine the boundary conditions around the pipe for the subsequent loading scenarios. In this paper, based on the assumption of plane strain, the “Remeshing and Interpolation Technique with Small Strain” (RITSS) method was used to establish the large deformation finite-element model of vertical penetration of pipelines in clay. Compared with the previous literature, the robustness of the model was verified. Based on this model, the development mechanism of the soil shear band has been discussed during pipeline penetration; the effect of pipeline roughness on the undrained shear strength degradation mechanism and enhancement mechanism has been further explored. Finally, the effects of soil buoyancy, soil strength gradient, strain softening, and strain rate on the penetration resistance were discussed through parametric analysis. According to the influence sensitivity of each parameter, the evaluation framework of the penetration resistance has been developed. Compared with the previous literature, the validity of the framework was verified. The framework could provide guidance and reference for designing vertical penetration of pipelines in deep-water engineering.

Low velocity impact penetration response of foam core sandwich panels with face sheets

Foam aluminum sandwich panels have potential applications in many fields because of their excellent performance. This study aims to explore the low velocity penetration dynamic response of foam sandwich panels. Based on the experimental results, a three-stage penetration model is established. Based on the principle of energy conservation, minimum potential energy and accumulating damage theory, the load and displacement time history, energy absorption and initial failure mode of the sandwich panel during penetration are predicted theoretically. The theoretical prediction results are compared with the experimental results, showing that the predicted failure load and deformation are within 10% of the experimental data. This paper provides an analytical method for studying the deformation failure mode and energy absorption mechanism of metal foam sandwich panels, which is helpful to improve the efficiency of metal foam sandwich panels in design.

Orthogonal optimization design and experiments on explosively formed projectiles with fins

In this study, a polygonal shell is used to produce an explosively formed projectile (EFP) with fins for good flight stability. The forming characteristics of an EFP with fins produced by a polygonal shell are studied numerically using the LS-DYNA 3D finite element code. Orthogonal design method combined with range analysis is applied to optimize the EFP with fins. The orthogonal test schemes are established with 5 levels under plane initiation of 0.2 times the charge diameter and point initiation, respectively. The influence rankings of the EFP length-to-head diameter ratio, compactness, velocity, kinetic energy and length of fin-to-tail radius ratio are determined. Furthermore, the EFPs of the optimized design are tested for forming and recycling. Subsequently, the EFPs recovered from the tests are reconstructed. Finally, an EFP penetration performance test is conducted. When ignoring the influence of EFP initial state on target penetration, Steinberg and Johnson-Cook (J-C) constitutive models are used for the formation and penetration processes, respectively. The results show that the forming effects of EFPs with fins are coupled by the structure of liner, charge arrangement and shell structure. The ranges of the various structural parameters of the EFPs are obtained. The numerical simulation results of EFP with fins designed by orthogonal optimization method are in good agreement with the experimental results. The effectiveness of Steinberg algorithm and J-C algorithm in EFP forming and penetration process is verified.

α-Cyclodextrin-based poly(pseudo)rotaxane for antifungal drug delivery to the vaginal mucosa

This work aimed to evaluate poly(pseudo)rotaxanes (PPRs) potential for vaginal antifungal delivery. For this, PPRs containing terbinafine (TB) 2 % were obtained using two small surfactants, Kolliphor® RH40 and Gelucire® 48/16, and different α-cyclodextrin (α-CD) concentrations (5 and 10 %). PPRs were characterized by their physicochemical characteristics, irritation, and mucoadhesion capabilities. Formulations' performance was assessed in a vertical penetration model, which uses ex vivo entire porcine vagina. Conventional penetration experiments with excised vaginal tissue were performed as a control. Results showed all formulations were non-irritant according to the HET-CAM test. Furthermore, PPRs with 10 % αCD showed superior mucoadhesion (p < 0.05). Conventional horizontal penetration studies could not differentiate formulations (p > 0.05). However, PPRs with 10 % αCD presented a better performance in vertical ex vivo studies, achieving higher drug penetration into the vaginal mucosa (p < 0.05), which is probably related to the formulation's prolonged residence time. In addition, the antifungal activity of the formulations was maintained against Candida albicans and C. glabrata cultures. More importantly, the formulation's viscosity and drug delivery control had no negative impact on the antifungal activity. In conclusion, the best performance in a more realistic model evidenced the remarkable potential of PPRs for vaginal drug delivery.

Leveraging Pre-Clinical Animal Model of CTCL to Explore Therapeutic Potential of a Novel STAT3 Degrader

STAT3 enhances pro-survival signaling essential for T cell expansion, but when this pathway is not appropriately regulated, aberrant STAT3 signaling contributes to T cell lymphomagenesis. Cutaneous T cell lymphoma (CTCL) is a type of mature T cell lymphoma characterized by the accumulation of malignant T cells in the skin. Our analysis, along with other recently published sequencing studies, identified upregulation of the STAT3 cytokine signaling pathway as a key driver of CTCL pathogenesis. In normal processes, STAT3 activity is transient, but dysregulation of this pathway is observed in several human malignancies, including CTCL. Aberrant STAT3 activity in malignant cells promotes transcription of target genes that promote proliferation and survival of transformed T cells. Translocations resulting in STAT3 duplications, activating mutations in the SH2 domain of STAT3 and activating mutations in kinases upstream of STAT3 all contribute to hyperactivation of this JAK/STAT signaling pathway in CTCL. STAT3 signaling in bystander cells within the tumor microenvironment may further contribute to tumor progression, although the precise role of this signaling pathway in malignant disease is context dependent. We have used conditional gene targeting to develop a fully penetrant STAT3-dependent small animal model of CTCL that recapitulates many key features of human disease. In this model, a constitutively active form of STAT3 is expressed exclusively in T lymphocytes. The autochthonous mouse model is characterized by progressive accumulation of malignant T cells in the skin and secondary lymphoid organs. Our molecular analysis of T cells from this mouse model revealed a transcriptional signature that largely mirrored the one found in malignant cells from patients. We have now taken advantage of this tractable animal model of CTCL to evaluate the therapeutic potential of a potent and selective E3 ubiquitin ligase-based novel STAT3 heterobifunctional degrader for targeting this difficult-to-treat hematologic malignancy. Weekly intravenous administration of the degrader was well tolerated and led to significant reduction of STAT3 levels in circulating and skin-resident T lymphocytes. Progression of disease in our preclinical model was notably blunted upon administration of the STAT3 degrader with dramatic reduction in T cell accumulation in the skin and lymph nodes. We will report on pre-clinical evaluation of the degrader and the impact on disease progression, T cell accumulation, activation and proliferation in vivo following weekly drug administration. Targeted protein degradation represents a novel therapeutic modality enabling direct targeting of previously undruggable oncoproteins such as STAT3. These data provide a rationale for selective STAT3 degradation as a therapeutic strategy for malignancies such as CTCL that are associated with constitutive activation of STAT3 signaling. Fig Legend:Treatment of mice exhibiting CTCL phenotypes starting at ~3mo of age. Phenotype score reflects presentation of fur loss, scaling/flaking of the skin, appearance of lesions and death. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Iron Chelation Improves Ineffective Erythropoiesis and Iron Overload in a Mouse Model of Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Patients are treated with periodic red cell (RBC) transfusions, resulting in iron overload. Iron overload in MDS patients correlates with decreased survival, yet despite the availability of effective, safe, and orally administered iron chelation therapy, the treatment of iron overload in MDS remains controversial. The TELESTO trial, using deferasirox in low risk MDS patients, revealed an increase in event-free survival without impacting overall survival, hemoglobin, or RBC transfusion requirements [Angelucci Ann Int Med 2020]. However, iron chelators have different affinities for iron relative to transferrin; deferiprone has the lowest affinity of available iron chelators [Sohn Blood 2008], consistent with its ability to increase hepcidin expression in mice [Schmidt Am J Hematol 2015; Casu haematol 2016]. We hypothesize that deferiprone (DFP) impacts systemic and cellular iron distribution to enhance erythropoiesis in MDS. To test this hypothesis, we employed a highly penetrant well-established mouse model of MDS, NUP98:HOXD13 fusion transgenic mice. These MDS mice exhibit hypercellular marrow, increased apoptosis in the bone marrow compartment, and impaired survival relative to control; a proportion of mice progress to acute leukemic transformation after 7 months of age [Lin Blood 2005]. Using MDS mice, we further characterize parameters of iron trafficking in erythroblasts, evaluate the effects of DFP on erythropoiesis and iron distribution, and provide correlatory evidence in stem and progenitor cells from MDS patients. MDS mice were treated at 5 months of age with 1.25 mg/mL DFP in the drinking water for 4 weeks and compared with untreated MDS mice. Our results characterize an iron overload phenotype with aberrant erythropoiesis in MDS mice, reversed in DFP-treated MDS mice (Figure 1). Specifically, DFP leads to a redistribution of iron from liver and spleen to increase serum iron concentration and transferrin saturation, increased hemoglobin and RBC concentration in circulation, and normalized hepcidin responsiveness to iron. While MDS mice exhibit relatively decreased WBC count, no changes in WBC count are observed in DFP-treated MDS mice. Importantly, serum erythropoietin (Epo) concentration, splenomegaly, expanded erythropoiesis and erythroblast differentiation in the bone marrow are normalized in DFP-treated MDS mice. As expected when erythropoiesis is reversed, erythroblast expression of Fam132b (erythroferrone) is suppressed but no changes in STAT5 or AKT signaling, pathways downstream of Epo, are evident in DFP-treated MDS mice. These findings suggest that the expected changes in signaling downstream of Epo are unaffected by DFP administration, implicating possible changes in erythroblast Epor expression in DFP-treated MDS mice. We used sorted bone marrow to evaluate Epor expression in progressive stages of terminal erythropoiesis and demonstrate decreased Epor expression in later stage bone marrow erythroblasts from MDS mice, normalized in DFP-treated MDS mice. These findings provide evidence that increased Epor expression is a potential mechanism by which DFP leads to enhanced Epo-responsiveness and enhanced erythroblast differentiation despite decreased serum Epo concentration in MDS mice. In addition, we demonstrate for the first time increased ferritin concentration and normalized Tfr1, Pcbp1 and Ncoa4 expression in late stage erythroblasts from DFP-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts and their normalization with DFP treatment (Figure 2). Importantly, this effect is not observed in DFP-treated WT mice. Our data also provides evidence that reversal of ineffective erythropoiesis in DFP-treated MDS mice occurs independently of effects on erythroblast apoptosis. Finally, we confirm increased expression of genes involved in Epo-mediation as well as iron uptake and trafficking-Epor, Fam132b, Tfr1, Pcbp1 and Ncoa4-in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS and provide a rationale for exploring the effect of DFP in patients with low risk MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal