Exploring Pyroelectricity, Thermal and Photochemical Switching in a Hybrid Organic-Inorganic Crystal by In Situ X-Ray Diffraction.

The switching behavior of the novel hybrid material (FA)Na[Fe(CN)5(NO)].H2O (1) in response to temperature (T), light irradiation and electric field (E) is studied using in situ X-ray diffraction (XRD). Crystals of 1 display piezoelectricity, pyroelectricity, second and third harmonic generation. XRD shows that the FA+ are disordered at room-temperature, but stepwise cooling from 273-100 K induces gradual ordering, while cooling under an applied field (E=+40 kVcm-1) induces a sudden phase change at 140 K. Structural-dynamics calculations suggest the field pushes the system into a region of the structural potential-energy surface that is otherwise inaccessible, demonstrating that application of T and E offers an effective route to manipulating the crystal chemistry of these materials. Photocrystallography also reveals photoinduced linkage isomerism, which coexists with but is not correlated to other switching behaviors. These experiments highlight a new approach to in situ studies of hybrid materials, providing insight into the structure-property relationships that underpin their functionality.

Room-temperature sub-100 nm Néel-type skyrmions in non-stoichiometric van der Waals ferromagnet Fe3-xGaTe2 with ultrafast laser writability.

Realizing room-temperature magnetic skyrmions in two-dimensional van der Waals ferromagnets offers unparalleled prospects for future spintronic applications. However, due to the intrinsic spin fluctuations that suppress atomic long-range magnetic order and the inherent inversion crystal symmetry that excludes the presence of the Dzyaloshinskii-Moriya interaction, achieving room-temperature skyrmions in 2D magnets remains a formidable challenge. In this study, we target room-temperature 2D magnet Fe3GaTe2 and unveil that the introduction of iron-deficient into this compound enables spatial inversion symmetry breaking, thus inducing a significant Dzyaloshinskii-Moriya interaction that brings about room-temperature Néel-type skyrmions with unprecedentedly small size. To further enhance the practical applications of this finding, we employ a homemade in-situ optical Lorentz transmission electron microscopy to demonstrate ultrafast writing of skyrmions in Fe3-xGaTe2 using a single femtosecond laser pulse. Our results manifest the Fe3-xGaTe2 as a promising building block for realizing skyrmion-based magneto-optical functionalities.

Foliar spraying of Zn/Si affects Cd accumulation in paddy grains by regulating the remobilization and transport of Cd in vegetative organs.

The reduction of cadmium (Cd) accumulation in rice grains through biofortification of essential nutrients like zinc (Zn) and silicon (Si) is an area of study that has gained significant attention. However, there is limited understanding of the mechanism of Zn/Si interaction on Cd accumulation and remobilization in rice plants. This work used a pot experiment to examine the effects of Zn and Si applied singly or in combination on the physiological metabolism of Cd in different rice organs under Cd stress. The results revealed that: Zn/Si application led to a significant decrease in root Cd concentration and reduce the value of Tf Soil-Root in filling stage. The content of phytochelatin (PCs, particularly PC2) and glutathione (GSH) in roots, top and basal nodes were increased with Zn/Si treatment application. Furthermore, Zn/Si treatment promoted the distribution of Cd in cell wall during Cd stress. These findings suggest that Zn/Si application facilitates the compartmentalization of Cd within subcellular structures and enhances PCs production in vegetative organs, thereby reducing Cd remobilization. Zn/Si treatment upregulated the metabolism of amino acid components involved in osmotic regulation, secondary metabolite synthesis, and plant chelating peptide synthesis in vegetative organs. Additionally, it significantly decreased the accumulation of Cd in globulin, albumin, and glutelin, resulting in an average reduction of 50.87% in Cd concentration in milled rice. These results indicate that Zn/Si nutrition plays a crucial role in mitigating heavy metal stress and improving the nutritional quality of rice by regulating protein composition and coordinating amino acid metabolism balance.

Highly Flexible, High-Performance, and Stretchable Piezoelectric Sensor Based on a Hierarchical Droplet-Shaped Ceramics with Enhanced Damage Tolerance.

Stretchable self-powered sensors are of significant interest in next-generation wearable electronics. However, current strategies for creating stretchable piezoelectric sensors based on piezoelectric polymers or 0-3 piezoelectric composites face several challenges such as low piezoelectric activity, low sensitivity, and poor durability. In this paper, a biomimetic soft-rigid hybrid strategy is used to construct a new form of highly flexible, high-performance, and stretchable piezoelectric sensor. Inspired by the hinged bivalve Cristaria plicata, hierarchical droplet-shaped ceramics are manufactured and used as rigid components, where computational models indicate that the unique arched curved surface and rounded corners of this bionic structure can alleviate stress concentrations. To ensure electrical connectivity of the piezoelectric phase during stretching, a patterned liquid metal acts as a soft circuit and a silicone polymer with optimized wettability and stretchability serves as a soft component that forms a strong mechanical interlock with the hierarchical ceramics. The novel sensor design exhibits excellent sensitivity and durability, where the open circuit voltage remains stable after 5000 stretching cycles at 60% strain and 5000 twisting cycles at 180°. To demonstrate its potential in heathcare applications, this new stretchable sensor is successfully used for wireless gesture recognition and assessing the progression of knee osteoarthritis.

Preparation and Photocatalytic Degradation Performance of Amine-Rich Carbon Nitride with Structural Modulation of the Precursor.

The photocatalytic performance of graphitic phase carbon nitride (g-C3N4) is strongly influenced by its own microstructure as well as the precursor structure that causes the microstructure changes. In this paper, a composite precursor of sodium chloride and cyanamide (NaCl/CA-2) was obtained by freeze-drying, which possess an aggregated state different from that of the non-freeze-drying method. This new aggregation state with the introduction of sodium ions into the cyanamide lattice results in a higher activation energy of NaCl/CA-2 in the thermal polycondensation process of the molten salt-assisted preparation of g-C3N4, which prevented the condensation of two cyanamides to one dicyandiamide, ultimately obtaining FD-CN with an amino-rich structure. The nitrogen atoms on the amino group can provide the photocatalyst with more unpaired electrons that can participate in the photoexcitation process, further improving its electron-hole separation ability and charge transfer efficiency, thus effectively enhancing its photocatalytic activity. Compared to the original g-C3N4, the photocatalytic activity of FD-CN for the degradation of methylene blue increased 2.19 times.

Controllable Skyrmionic Phase Transition between Néel Skyrmions and Bloch Skyrmionic Bubbles in van der Waals Ferromagnet Fe3-δ GeTe2.

The van der Waals (vdW) ferromagnet Fe3-δ GeTe2 has garnered significant research interest as a platform for skyrmionic spin configurations, that is, skyrmions and skyrmionic bubbles. However, despite extensive efforts, the origin of the Dzyaloshinskii-Moriya interaction (DMI) in Fe3-δ GeTe2 remains elusive, making it challenging to acquire these skyrmionic phases in a controlled manner. In this study, it is demonstrated that the Fe content in Fe3-δ GeTe2 has a profound effect on the crystal structure, DMI, and skyrmionic phase. For the first time, a marked increase in Fe atom displacement with decreasing Fe content is observed, transforming the original centrosymmetric crystal structure into a non-centrosymmetric symmetry, leading to a considerable DMI. Additionally, by varying the Fe content and sample thickness, a controllable transition between Néel-type skyrmions and Bloch-type skyrmionic bubbles is achieved, governed by a delicate interplay between dipole-dipole interaction and the DMI. The findings offer novel insights into the variable skyrmionic phases in Fe3-δ GeTe2 and provide the impetus for developing vdW ferromagnet-based spintronic devices.

Effect of aeration/micro-aeration on lignocellulosic decomposition, maturity and seedling phytotoxicity during full-scale biogas residues composting.

With the accelerated construction of biogas plants, the amount of biogas residues are expanding. Composting has been widely implemented to deal with biogas residues. Aeration regulation is the main factor affecting the post-composting treatment of biogas residues as high-quality fertilizer or soil amendment. Therefore, this study aimed to investigate the impact of different aeration regulations on full-scale biogas residues compost maturity by controlling oxygen concentration under micro-aeration and aeration conditions. Results showed that micro-aerobic extended the thermophilic stage of 17 days at above 55 ℃ and facilitated the mineralization process of organic nitrogen into nitrate nitrogen to retain higher N nutrition levels compared to aerobic treatment. For biogas residues with high moisture, aeration should be regulated at different full-scale composting stages. Total organic carbon (TOC), NH4+-N, NO3--N, total potassium (TK), total phosphorus (TP) and the germination index (GI) could be used to evaluate stabilization, fertilizer efficiency and phytotoxicity of compost with frequent monitoring times. However, seedling growth trials were still necessary in full-scale composting plants when changing of composting process or biogas residues feedstock.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Investigation on the Effect of Calcium on the Properties of Geopolymer Prepared from Uncalcined Coal Gangue.

In this paper, the influence of calcium on coal gangue and fly ash geopolymer is explored, and the problem of low utilization of unburned coal gangue is analyzed and solved. The experiment took uncalcined coal gangue and fly ash as raw materials, and a regression model was developed with the response surface methodology. The independent variables were the CG content, alkali activator concentration, and Ca(OH)2 to NaOH ratio (CH/SH). The response target value was the coal gangue and fly-ash geopolymer compressive strength. The compressive strength tests and the regression model obtained by the response surface methodology showed that the coal gangue and fly ash geopolymer prepared with the content of uncalcined coal gangue is 30%, alkali activator content of 15%, and the value of CH/SH is 1.727 had a dense structure and better performance. The microscopic results demonstrated that the uncalcined coal gangue structure is destroyed under an alkali activator's action, and a dense microstructure is formed based on C(N)-A-S-H and C-S-H gel, which provides a reasonable basis for the preparation of geopolymers from the uncalcined coal gangue.

Current-Induced Reversible Split of Elliptically Distorted Skyrmions in Geometrically Confined Fe3 Sn2 Nanotrack.

Skyrmions are swirling spin textures with topological characters promising for future spintronic applications. Skyrmionic devices typically rely on the electrical manipulation of skyrmions with a circular shape. However, manipulating elliptically distorted skyrmions can lead to numerous exotic magneto-electrical functions distinct from those of conventional circular skyrmions, significantly broadening the capability to design innovative spintronic devices. Despite the promising potential, its experimental realization so far remains elusive. In this study, the current-driven dynamics of the elliptically distorted skyrmions in geometrically confined magnet Fe3 Sn2 is experimentally explored. This study finds that the elliptical skyrmions can reversibly split into smaller-sized circular skyrmions at a current density of 3.8 × 1010 A m-2 with the current injected along their minor axis. Combined experiments with micromagnetic simulations reveal that this dynamic behavior originates from a delicate interplay of the spin-transfer torque, geometrical confinement, and pinning effect, and strongly depends on the ratio of the major axis to the minor axis of the elliptical skyrmions. The results indicate that the morphology is a new degree of freedom for manipulating the current-driven dynamics of skyrmions, providing a compelling route for the future development of spintronic devices.

The greenhouse gas emission potential and phytotoxicity of biogas slurry in static storage under different temperatures.

With the booming development of biogas industry to treat organic waste in China, the by-product of biogas slurry was accompanied with a huge amount. Static storage process of biogas slurry was normally operated under different seasons before application to land which would cause nutrition decomposition and greenhouse gas emission. Thus, the aim of this study was to investigate the nutrition decomposition, greenhouse gas emission (CH4 and N2O), and phytotoxicity of biogas slurry under different static temperatures, furthermore to illuminate the network among them and functional microorganism. According to the results, higher temperature at 30 °C contributed to fast and complete degradation of COD. In addition, more quantity of NH4+ conversion and NO3- formation appeared at 30 °C. These factors resulted in relatively less crop toxicity together. CH4 was the dominant greenhouse gas emission than N2O and was highest in 30 °C treatment with total emission of 273.7 L/(m3·d) and greenhouse gas emission of 20.01 kg CO2e (carbon dioxide equivalent). Lower temperature was conductive to N reservation and reduction of greenhouse gas emission, but making against with stabilization of organic matter and crop safety. At the same dilution times (≤3) of biogas slurry with deionized water, higher temperature at 30 °C could reduce 30 days of storage time, but 10 °C was still unsafe for crop. Structural equation model was further illustrated the positive effect of temperature on NO3-, CH4, GI, and N2O and negative on COD and NH4+. These results could help to monitor the environmental risk, evaluate the maturity, guide the irrigation scheme, and regulate the static storage condition of biogas slurry under different seasons.

The presence of clear cell glands around the ovarian endometrioid cyst has an association with clear cell carcinoma.

We found some clear cell glands appeared in the endometrioid cysts (ECs) of the ovary (EC-CCG). To explore the clinicopathological features, molecular biological changes, and prognosis in EC-CCG and analyze the association with ovarian clear cell borderline tumors (CCBT) and clear cell carcinoma (CCC). We retrospectively examined 35 cases of EC-CCG, compared them to 13 cases of clear cell cystadenomas, 14 cases of CCBT, and 49 cases of CCC. We analyzed the differences in clinicopathological features and prognosis between the four groups. Data on clinicopathology and survival were gathered. Immunohistochemistry (IHC) was performed in all cases, and we analyzed the molecular changes of 2 cases of EC-CCG and 1 case of CCC by whole-exome sequencing (WES). EC-CCG shared some common clinicopathological features with CCBT: they occurred before menopause, had an elevated serum CA125 level in some cases, had an ovarian cystic mass on B-ultrasound, and had a risk of recurrence. Microscopically, both diseases were based on typical EC, and clear cell glands in the EC cyst wall were seen in varying numbers. Some cases of EC-CCG had IHC results similar to those of CCBT and CCC, with positive expression of HNF1ß and NapsinA; decreased expression of ER, PR, and ARID1A; and increased expression of Ki67 (> 5%). WES results revealed that EC-CCG had mutations in TP53BP1, ZNF462, FN1, and FTL (which was also mutated in CCC). In summary, we found that clear cell glands appearing around EC in the ovary have an association with CCC.

Chronic inflammatory demyelinating polyneuropathy and psoriasis comorbidity with significantly alleviated in symptoms after secukinumab: case report.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that involves damage to the peripheral nervous system. The course of the disease can progress for more than 8 weeks, with frequent incidences of relapse-remission courses. This article reported a rare combination of CIDP with fluctuating symptoms, recurrence-remission, and comorbidity with psoriasis. CASE PRESENTATION: A 29-year-old male patient with repeated limb weakness and numbness was admitted to the hospital several times in the past six months. He had a history of psoriasis for 6 years, and the medications (clobetasol propionate ointment and calcipotriol ointment) treated for psoriasis were discontinued 1 year ago. During the hospitalization, repeated intravenous injections of human immunoglobulin G (IVIg), immunoadsorption, and secukinumab were performed. Nerve electrophysiology tests, ganglioside autoantibody spectrum tests, and clinical MRC muscle strength scores were performed on a regular basis to confirm the diagnosis of CIDP. The patient was regularly followed up. RESULTS: After repeated rounds of human IVIg and immunoadsorption, the patient's MRC score was increased by ≥ 6 points. The first ganglioside autoantibody spectrum test showed anti-GQ1b IgG ( +) and anti-GM1 IgM ( +) antibodies, and all were negative after re-examination. Finally, the patient was treated with the IL-17A inhibitor secukinumab for psoriasis. During 7 months of follow-up, the CIDP and psoriasis symptoms are relatively stable. CONCLUSION: Combination of IVIg and immunoadsorption was highly effective in treating CIDP complicated with psoriasis. The clinical manifestations of CIDP are diverse. When relapse-remission occurs in the course of the disease, it is necessary to clarify whether it is combined with other autoimmune diseases and should control the autoimmune diseases as soon as possible.

Flexible PVDF-TrFE Nanocomposites with Ag-decorated BCZT Heterostructures for Piezoelectric Nanogenerator Applications.

Flexible piezoelectric nanogenerators are playing an important role in delivering power to next-generation wearable electronic devices due to their high-power density and potential to create self-powered sensors for the Internet of Things. Among the range of available piezoelectric materials, poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE)-based piezoelectric composites exhibit significant potential for flexible piezoelectric nanogenerator applications. However, the high electric fields that are required for poling cannot be readily applied to polymer composites containing piezoelectric fillers due to the high permittivity contrast between the filler and matrix, which reduces the dielectric strength. In this paper, novel Ag-decorated BCZT heterostructures were synthesized via a photoreduction method, which were introduced at a low level (3 wt %) into the matrix of PVDF-TrFE to fabricate piezoelectric composite films. The effect of Ag nanoparticle loading content on the dielectric, ferroelectric, and piezoelectric properties was investigated in detail, where a maximum piezoelectric energy-harvesting figure of merit of 5.68 × 10-12 m2/N was obtained in a 0.04Ag-BCZT NWs/PVDF-TrFE composite film, where 0.04 represents the concentration of the AgNO3 solution. Modeling showed that an optimum performance was achieved by tailoring the fraction and distribution of the conductive silver nanoparticles to achieve a careful balance between generating electric field concentrations to increase the level of polarization, while not degrading the dielectric strength. This work therefore provides a strategy for the design and manufacture of highly polarized piezoelectric composite films for piezoelectric nanogenerator applications.

Structure and Piezoelectricity Due to B Site Cation Variation in ABn+Cln+2 Hybrid Histammonium Chlorometallate Materials.

To provide new insights for understanding the influence of B site cations on the structure in chlorometallate materials of the form ABn+Cln+2, we report novel organic-inorganic hybrid metallates (OIHMs) incorporating histammonium (HistNH3) dications and various transition-metal and main group B site cations. Single crystals of OIHMs with the basic formula (HistNH3Mn+Cln+2, M = Fe, Co, Ni, Cu, Zn, Cd, Hg, Sb, Sn, Pb, Bi) were grown and their structures characterized by single-crystal X-ray crystallography. HistNH3CoCl4, HistNH3ZnCl4, and HistNH3SbCl5 were crystallized in a non-centrosymmetric space group and were subsequently studied with piezoresponse force microscopy (PFM). While bulk measurements of crystals and poly(vinylidene difluoride) (PVDF)/metallate composite films exhibited low bulk response values, the surface-measured local response values using PFM were 5.17 pm/V for HistNH3CoCl4, 22.6 pm/V for HistNH3ZnCl4, and 2.9 pm/V for HistNH3SbCl5 compared with 2.50 pm/V for PVDF reference samples. The magnitudes of the d33 coefficient, net dipole, and cation-Cl bond dipole obtained from the density functional theory calculations confirm the higher response in HistNH3ZnCl4 compared to HistNH3CoCl4. Density of states and crystal orbital Hamilton population analysis indicate that the higher net dipole in HistNH3ZnCl4 compared to HistNH3CoCl4 is due to the lower hybridization of the M-Cl bond.

Effect of cardiac output - guided hemodynamic management on acute lung injury in pediatric living donor liver transplantation.

BACKGROUND: Acute lung injury (ALI) after liver transplantation (LT) may lead to acute respiratory distress syndrome, which is associated with adverse postoperative outcomes, such as prolonged hospital stay, high morbidity, and mortality. Therefore, it is vital to maintain hemodynamic stability and optimize fluid management. However, few studies have reported cardiac output-guided (CO-G) management in pediatric LT. AIM: To investigate the effect of CO-G hemodynamic management on early postoperative ALI and hemodynamic stability during pediatric living donor LT. METHODS: A total of 130 pediatric patients scheduled for elective living donor LT were enrolled as study participants and were assigned to the control group (65 cases) and CO-G group (65 cases). In the CO-G group, CO was considered the target for hemodynamic management. In the control group, hemodynamic management was based on usual perioperative care guided by central venous pressure, continuous invasive arterial pressure, urinary volume, etc. The primary outcome was early postoperative ALI. Secondary outcomes included other early postoperative pulmonary complications, readmission to the intense care unit (ICU) for pulmonary complications, ICU stay, hospital stay, and in-hospital mortality. RESULTS: The incidence of early postoperative ALI was 27.7% in the CO-G group, which was significantly lower than that in the control group (44.6%) (P < 0.05). During the surgery, the incidence of postreperfusion syndrome was lower in the CO-G group (P < 0.05). The level of intraoperative positive fluid transfusions was lower and the rate of dobutamine use before portal vein opening was higher, while the usage and dosage of epinephrine during portal vein opening and vasoactive inotropic score after portal vein opening were lower in the CO-G group (P < 0.05). Compared to the control group, serum inflammatory factors (interleukin-6 and tumor necrosis factor-α), cardiac troponin I, and N-terminal pro-brain natriuretic peptide were lower in the CO-G group after the operation (P < 0.05). CONCLUSION: CO-G hemodynamic management in pediatric living-donor LT decreases the incidence of early postoperative ALI due to hemodynamic stability through optimized fluid management and appropriate administration of vasopressors and inotropes.

Logistic regression models of cytokines in differentiating vitreoretinal lymphoma from uveitis.

BACKGROUND: Vitreoretinal lymphoma (VRL) can commonly masquerade as chronic idiopathic uveitis due to its nonspecific clinical presentation. Thus, its early diagnosis is difficult. In this study, new logistic regression models were used to classify VRL and uveitis. Additionally, the diagnostic performance of interleukin (IL)-10, the IL-10/IL-6, and the Interleukin Score for IntraOcular Lymphoma Diagnosis (ISOLD) are evaluated. METHODS: Sixty-nine aqueous humors (AH) (46 VRL, 23 uveitis) and 65 vitreous humors (VH) (49 VRL, 16 uveitis) were collected from a single-center retrospective cohort. Logistic regression models were conducted based on IL-6 and IL-10. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of IL-10, the IL-10/IL-6, the ISOLD, and the models were calculated from the ROC. Furthermore, Spearman's rank correlation analysis was performed to determine cytokine levels in VH and AH. RESULTS: We redefined the cut-off values of IL-10, the IL-10/IL-6, the ISOLD, and the logistic regression models. In AH, the AUC values of IL-10, ISOLD, IL10/IL6, and the model were 0.91, 0.953, 0.952, and 0.967. In VH, they were 0.93, 0.95, 0.954, and 0.954, respectively. IL-6 (r = 0.7844) and IL-10 (r = 0.8506) in AH and VH showed a strong correlation. CONCLUSIONS: IL-6 and IL-10 levels were introduced into new logistic regression models. The diagnostic efficacy of the models improved compared to the indicators mentioned above among Chinese patients. Additionally, the models could predict the probability of VRL more accurately. A strong correlation of cytokine levels showed the great potential of AH as prioritized auxiliary diagnostic for VRL.

Effect of long noncoding RNA CCAT2 on drug sensitivity to 5-fluorouracil of breast cancer cells through microRNA-145 meditated by p53.

The current study was set out to investigate the mechanism by which silenced long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) modulates the cell growth, migration, invasion, and drug sensitivity of breast cancer (BC) cells to 5-fluorouracil (5-Fu) with the involvement of miR-145 and p53. First, high CCAT2 expression was presented in BC cells and tissues. Subsequently, the links between CCAT2 expression and BC clinicopathological features were analyzed. Highly-expressed CCAT2 was linked to lymph node metastasis, positive progesterone receptor, estrogen receptor, and Ki-67 of BC cells. Then, the gain- and loss-of-function approaches were performed to measure the regulatory role of CCAT2 in the biological processes of BC cells. Silencing of CCAT2 suppressed in vitro cell growth, proliferation, invasion, migration abilities, and epithelial-mesenchymal transformation, increased cell apoptosis, and enhanced drug sensitivity of BC cells. Silencing of CCAT2 upregulated miR-145, which was poorly expressed in drug-resistant BC cells. p53 can bind to the miR-145 promoter region and increase miR-145 expression. Upregulation of miR-145 induced by silencing of CCAT2 can be invalidated by p53-siRNA. To conclude, p53-induced activation of miR-145 could be inhibited by CCAT2, while overexpression of CCAT2 could improve the drug resistance of BC cells to 5-Fu.

A multi-model approach to predict efficacious clinical dose for an anti-TGF-ß antibody (GC2008) in the treatment of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multidisciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-ß) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of patients with OI. In this work, we have developed a multitiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-ß antibody drug candidate (GC2008). This method aims to translate GC2008 pharmacokinetic/pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in patients with OI. Furthermore, a physiologically-based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the TGF-ß level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection of GC2008 in humans. The different modeling efforts predicted a similar range of pharmacologically relevant doses in patients with OI providing an informed approach for an early clinical dose setting.