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Perovskite semiconductor materials have attracted significant attention in the fields of photovoltaics and luminescence due to their excellent photoelectric properties, such as high carrier mobility, high absorption coefficient, and high fluorescence quantum yield. In particular, low-dimensional metal-halide perovskite microcrystalline materials have been reported to exhibit low-dimensional lasing phenomena and laser devices due to their high gain and widely tunable bandgap. In this Letter, one-dimensional (1-D) ZnO microwires with their ultraviolet lasing emissions are utilized as an excitation source to pump CsPbBr3 microwire on hybrid ZnO-CsPbBr3 microscale structures. At higher excitation, the amplified spontaneous emission (ASE) behaviors from CsPbBr3 microwire are realized with ultralow threshold by indirect pumping from the ZnO lasing emission for the first time, to the best of our knowledge. In comparison, the ASE behaviors from the CsPbBr3 microwire directly pumped by Nd:YAG Q-switched laser and continuous wave laser are also performed at room temperature. There are also no multimode lasing behaviors observed. The paper provides a new method to achieve a low threshold on-chip microlaser by a high-quality perovskite micro-nano structure.
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Conventional techniques for the closure of wounds, such as sutures and staples, have significant drawbacks that can negatively impact wound healing. Tissue adhesives have emerged as promising alternatives, but poor adhesion, low mechanical properties, and toxicity have hindered their widespread clinical adoption. In this work, a dual modified, aldehyde and methacrylate hyaluronic acid (HA) biopolymer (HA-MA-CHO) has been synthesized through a simplified route for use as a double cross-linked network (DCN) hydrogel (HA-MA-CHO-DCN) adhesive for the effective closure and sealing of wounds. HA-MA-CHO-DCN cross-links in two stages: initial cross-linking of the aldehyde functionality (CHO) of HA-MA-CHO using a disulfide-containing cross-linker, 3,3'-dithiobis (propionic hydrazide) (DTPH), leading to the formation of a self-healing injectable gel, followed by further cross-linking via ultraviolet (UV) initiated polymerization of the methacrylate (MA) functionality. This hydrogel adhesive shows a stable swelling behavior and remarkable versatility as the storage modulus (G') has shown to be highly tunable (103-105 Pa) for application to many different wound environments. The new HA-MA-CHO-DCN hydrogel showed excellent adhesive properties by surpassing the burst pressure and lap-shear strength for the widely used bovine serum albumin-glutaraldehyde (BSAG) glue while maintaining excellent cell viability.
Subject(s)
Hyaluronic Acid , Hydrogels , Hydrogels/chemistry , Hyaluronic Acid/chemistry , Adhesives , Glutaral , MethacrylatesABSTRACT
Single-stranded genomic DNA can fold into G-quadruplex (G4) structures or form DNA:RNA hybrids (R loops). Recent evidence suggests that such non-canonical DNA structures affect gene expression, DNA methylation, replication fork progression and genome stability. When and how G4 structures form and are resolved remains unclear. Here we report the use of Cleavage Under Targets and Tagmentation (CUT&Tag) for mapping native G4 in mammalian cell lines at high resolution and low background. Mild native conditions used for the procedure retain more G4 structures and provide a higher signal-to-noise ratio than ChIP-based methods. We determine the G4 landscape of mouse embryonic stem cells (ESC), observing widespread G4 formation at active promoters, active and poised enhancers. We discover that the presence of G4 motifs and G4 structures distinguishes active and primed enhancers in mouse ESCs. Upon differentiation to neural progenitor cells (NPC), enhancer G4s are lost. Further, performing R-loop CUT&Tag, we demonstrate the genome-wide co-occurrence of single-stranded DNA, G4s and R loops at promoters and enhancers. We confirm that G4 structures exist independent of ongoing transcription, suggesting an intricate relationship between transcription and non-canonical DNA structures.
Subject(s)
G-Quadruplexes , Animals , DNA/chemistry , DNA/genetics , Genomic Instability , Mammals , Mice , R-Loop Structures , RNAABSTRACT
Arithmetic fluency is considered considers highly rely on language processing, encompassing essential skills. However, the independent predictive power of phonetic, semantic, or orthographic skills in relation to arithmetic fluency remains an unresolved query. This study introduces the common component hypothesis to elucidate the inconsistent findings in previous research. The hypothesis posits that significant correlations between language and mathematics hinge on whether the language and mathematics utilized in a given task share a common component. According to this hypothesis, processing skills for each of the three fundamental language elements (i.e., phonetic, semantic, orthographic) should correlate with arithmetic fluency, as these elements are also integral to simple arithmetic processing. A cohort of one hundred and ninety-eight primary school students participated in the study, undertaking a battery of tests assessing general cognitive abilities, psycholinguistic elements, and arithmetic fluency. The results showed that orthographic, phonetic, and semantic abilities independently predicted arithmetic fluency, even after accounting for all other cognitive predictors. These findings substantiate the common component hypothesis, providing empirical support for explaining the association between language and mathematics. This evidence contributes to addressing the interplay between language and mathematics in educational contexts.
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Navy escorts are considered crucial in countering illegal piracy attacks. In this paper, a novel approach is developed to investigate the effect of navy escorts on piracy incidents by models based on two enhanced Tree-Augmented Naïve (TAN) Bayesian networks. This approach offers a systematic investigation into the various factors that influence pirate activities, and helps to identify changes in piracy attack behaviors when confronted by navy escorts and assess the effectiveness of anti-piracy measures. An empirical study is conducted utilizing a unique data set compiled from multiple sources from 2000 to 2019. The empirical evidence shows that there was a gradual reduction in the incidence of piracy attacks in East Africa following the implementation of navy escorts in 2009, but with a surge in 2010 and 2011. The data set is, thus, divided into two time periods at the point of 2009 to facilitate a robust and comprehensive analysis, resulting in the development of two TAN models. Meanwhile, the geographical distribution of pirate attacks has shifted from international waters to port areas and territorial waters. We argue that the surge and geographical shift could be attributed to the calculating behavior of pirates when they encounter external pressures. Finally, a Shapely approach is introduced to evaluate the potential effectiveness of the implemented risk management strategies from a Game Theory perspective. This study offers new insights into the promotion of navy escorts and contributes to the development of a framework for assessing piracy risks in uncertain and dynamic anti-piracy environments.
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BACKGROUND: Gallstone disease (GSD), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), and metabolic syndrome (MetS) are common medical disorders worldwide. This study aimed to ascertain how NAFLD, MAFLD, MetS, and other factors affect the development of GSD, and how the GSD-associated factors influence patient recovery after laparoscopic cholecystectomy (LC). METHODS: We included 200 patients who were diagnosed with GSD and underwent LC between January 2017 and February 2022. A total of 200 subjects without GSD and "non-calculous causes" during the same period were also included as controls. We compared the metabolic disorder differences between GSD patients and controls. Furthermore, we sub-grouped patients based on the comorbidities of preoperative NAFLD, MAFLD, and MetS, and compared the impacts of these comorbidities on short-term post-LC functional recovery of the patients. RESULTS: The prevalence of NAFLD and MetS were higher in GSD patients (P < 0.05). Based on multivariate logistic regression analysis, hyperglycemia [odds ratio (OR) = 2.2, 95% confidence interval (CI): 1.4-3.4, P = 0.001] and low high-density lipoprotein cholesterol (HDL-C) level (OR = 1.8, 95% CI: 1.1-3.1, P = 0.048) were linked to GSD. NAFLD and MetS linked to liver enzymes after LC (P < 0.05). MetS also linked to the levels of inflammatory indicators after LC (P < 0.05). The obesity, hyperlipidemia, low HDL-C level, and hyperglycemia linked to liver enzymes after LC (P < 0.05). Hyperlipidemia, low HDL-C level, and hypertension linked to inflammation after LC (P < 0.05). CONCLUSIONS: The prevalence of GSD may be linked to NAFLD and MetS. Hyperglycemia and low HDL-C level were independent risk factors of GSD.
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Ginseng Radix et Rhizoma Rubra (Panax ginseng C.A. Mey, Hongshen, in Chinese) and Ophiopogonis Radix (Ophiopogon japonicus (L.f) Ker-Gawl., Maidong, in Chinese) are traditional Chinese herbal pairs, which were clinically employed to enhance the immune system of cancer patients. This study employed the pharmacokinetic and pharmacodynamic (PK-PD) spectrum-effect association model to investigate the antitumor active substances of P. ginseng and O. japonicus (PG-OJ). The metabolic processes of 20 major bioactive components were analyzed using Ultra-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS) in the lung tissue of tumor-bearing mice treated with PG-OJ. The ELISA method was employed to detect the levels of TGF-ß1, TNF-α, and IFN-γ in the lung tissue of mice at various time points, and to analyze their changes after drug administration. The results showed that all components presented a multiple peaks absorption pattern within 0.083 to 24 h post-drug administration. The tumor inhibition rate of tumor and repair rate of IFN-γ, TNF-α, and TGF-ß1 all increased, indicating a positive therapeutic effect of PG-OJ on A549 tumor-bearing mice. Finally, a PK-PD model based on the GBDT algorithm was developed for the first time to speculate that Methylophiopogonanone A, Methylophiopogonanone B, Ginsenoside Rb1, and Notoginsenoside R1 are the main active components in PG-OJ for lung cancer treatment.
Subject(s)
Lung Neoplasms , Ophiopogon , Panax , Humans , Animals , Mice , Transforming Growth Factor beta1 , Chromatography, Liquid , Tumor Necrosis Factor-alpha , Tandem Mass Spectrometry , Lung Neoplasms/drug therapyABSTRACT
This study aims to explore the mechanism of Shoutai Pills in treating threatened abortion. According to the random number table method, ICR female mice were randomized into a normal group, a model group, a dydrogesterone group, and a Shoutai Pills group, with 15 mice in each group. Mice were administrated with normal saline(normal and model groups) or the suspension of Shoutai Pills or dydrogesterone by gavage at 9:00 am every day. At 16:00 every day, mice in the normal group were administrated with an equal volume of distilled water, while those in the model, Shoutai Pills, and dydrogesterone groups were administrated with hydrocortisone solution by gavage for 4 consecutive days. ICR female and male mice were caged in a ratio of 2â¶1 during the pre-estrous or estrous period. From the first day of pregnancy, drug administration was continued for 5 consecutive days. On day 6, mice were administrated with mifepristone by gavage to establish the model of kidney deficiency-induced abortion. On day 6 of pregnancy, 10 female ICR mice were randomly selected from each group, and the uterus was collected for observation of the pathological changes of trophoblasts at the maternal-fetal interface by hematoxylin-eosin(HE) staining. The protein levels of key enzymes of glycolysis, hexokinase 2(HK2), enolase 1(ENO1), pyruvate kinase M2(PKM2), and lactate dehydrogenase A(LDHA), were determined by Western blot and immunofluorescence. The expression of apoptosis-related proteins including B cell lymphoma-2(Bcl-2), Bcl-2-associated protein X(Bax), and cysteinyl aspartate-specific proteinase-3(caspase-3) was determined by Western blot and real-time PCR. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling was employed to examine apoptosis. The embryo loss rate of the remaining five female mice was calculated by trypan blue staining method on day 14 of pregnancy. On day 14 of pregnancy, the embryo loss rate of the normal group was 5.00%, which was lower than that(27.78%) in the model group(P<0.05). Dydrogesterone and Shoutai Pills groups showed reduced embryo loss rates(10.26% and 7.50%, respectively) compared with the model group. On day 6 of pregnancy, compared with the normal group, the model group showed down-regulated expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and up-regulated expression of Bax and caspase-3(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills up-regulated the expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and down-regulated the expression of Bax and caspase-3(P<0.05). Compared with that in the normal group, the apoptosis rate in the model group increased(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills reduced the apoptosis rate(P<0.05). In conclusion, Shoutai Pills can reduce the embryo loss rate and protect embryos by promoting aerobic glycolysis at the maternal-fetal interface and inhibiting the apoptosis of trophoblasts in mice.
Subject(s)
Apoptosis , Drugs, Chinese Herbal , Mice, Inbred ICR , Animals , Female , Mice , Apoptosis/drug effects , Drugs, Chinese Herbal/administration & dosage , Pregnancy , Abortion, Threatened/drug therapy , Abortion, Threatened/metabolism , Glycolysis/drug effects , Male , Disease Models, Animal , HumansABSTRACT
X-ray scintillators have gained significant attention in medical diagnostics and industrial applications. Despite their widespread utility, scintillator development faces a significant hurdle when exposed to elevated temperatures, as it usually results in reduced scintillation efficiency and diminished luminescence output. Here we report a molecular design strategy based on a hybrid perovskite (TpyBiCl5) that overcomes thermal quenching through multi-excited state switching. The structure of perovskite provides a platform to modulate the luminescence centers. The rigid framework constructed by this perovskite structure stabilized its triplet states, resulting in TpyBiCl5 exhibiting an approximately 12â times higher (45 % vs. 3.8 %) photoluminescence quantum yield of room temperature phosphorescence than that of its organic ligand (Tpy). Most importantly, the interactions between the components of this perovskite enable the mixing of different excited states, which has been revealed by experimental and theoretical investigations. The TpyBiCl5 scintillator exhibits a detection limit of 38.92â nGy s-1 at 213â K and a detection limit of 196.31â nGy s-1 at 353â K through scintillation mode switching between thermally activated delayed fluorescence and phosphorescence. This work opens up the possibility of solving the thermal quenching in X-ray scintillators by tuning different excited states.
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Chrysanthemum (Chrysanthemum morifolium) is well known as a photoperiod-sensitive flowering plant. However, it has also evolved into a temperature-sensitive ecotype. Low temperature can promote the floral transition of the temperature-sensitive ecotype, but little is known about the underlying molecular mechanisms. Here, we identified MADS AFFECTING FLOWERING 2 (CmMAF2), a putative MADS-box gene, which induces floral transition in response to low temperatures independent of day length conditions in this ecotype. CmMAF2 was shown to bind to the promoter of the GA biosynthesis gene CmGA20ox1 and to directly regulate the biosynthesis of bioactive GA1 and GA4 . The elevated bioactive GA levels activated LEAFY (CmLFY) expression, ultimately initiating floral transition. In addition, CmMAF2 expression in response to low temperatures was directly activated by CmC3H1, a CCCH-type zinc-finger protein upstream. In summary, our results reveal that the CmC3H1-CmMAF2 module regulates flowering time in response to low temperatures by regulating GA biosynthesis in the temperature-sensitive chrysanthemum ecotype.
Subject(s)
Chrysanthemum , Chrysanthemum/physiology , Gibberellins/metabolism , Temperature , Flowers/metabolism , Gene Expression Regulation, Plant , Plant Proteins/genetics , Plant Proteins/metabolism , PhotoperiodABSTRACT
The topological structures of polymers play a critical role in determining their gene delivery efficiency. Exploring novel polymeric structures as gene delivery vectors is thus of great interest. In this work, a new generation of multi-cyclic poly(ß-amino ester)s (CPAEs) with unique topology structure was synthesized for the first time via step growth polymerization. Through controlling the occurrence stage of cyclization, three types of CPAEs with rings of different sizes and topologies were obtained. In vitro experiments demonstrated that the CPAEs with macro rings (MCPAEs) significantly boosted the transgene expression comparing to their branched counterparts. Moreover, the MCPAE vector with optimized terminal group efficiently delivered the CRISPR plasmid coding both Staphylococcus aureus Cas9 nuclease and dual guide sgRNAs for gene editing therapy.
Subject(s)
Gene Transfer Techniques , RNA, Guide, CRISPR-Cas Systems , Polymerization , Polymers/chemistry , CRISPR-Cas SystemsABSTRACT
BACKGROUND: Cosmetic adverse reactions (CARs) are becoming widespread in China. However, a comprehensive analysis of data is lacking. OBJECTIVE: To analyse the clinical characteristics of patients with reported adverse reactions to cosmetics in Chongqing, China. METHODS: Cases with CARs reported to the Chongqing Adverse Drug Reaction Monitoring Centre System from 2017 to 2021 were analysed. RESULTS: A total of 23 245 cases were identified, of which 94.5% were women. Contact dermatitis (84.3%) was the most common diagnosis of CARs, followed by acne (3.1%). The most frequently reported clinical signs were erythema (70.1%), followed by papules (35.5%). The majority of CARs were reported to be due to ordinary cosmetics (87.9%), of which 81.0% were skin care products and 7.1% were makeup products. Cosmetics with special functions constituted 12.2%, of these, skin whitening (54.0%) and sunscreen (28.0%) products were most frequently reported. CONCLUSION: Our results suggest that adverse reactions to cosmetics are of concern in China, and dermatologists should actively identify and diagnose CARs. In addition, we should establish a convenient and effective model for collecting, reporting, and evaluating CARs.
Subject(s)
Cosmetics , Dermatitis, Allergic Contact , Humans , Female , Male , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/epidemiology , Dermatitis, Allergic Contact/etiology , Cosmetics/adverse effects , Skin , Patch Tests , China/epidemiologyABSTRACT
Global south countries, including China, have faced a challenging dilemma of reducing carbon emissions while maintaining rapid economic growth. The low-carbon city pilots (LCCPs) policy in China is a demonstration of how state power intervenes and commands national low-carbon development through voluntary policy tools. Our study, based on panel data of 331 cities from 2005 to 2019, evaluates the policy effect of all three batches of LCCPs and presents an analysis of time-varying effects through batch decomposition and synthetic difference-in-difference models. The study found that implementing low-carbon policies can significantly reduce total carbon emissions and carbon emissions per capita. However, the reduction in carbon emissions per unit of GDP is insignificant, and the policy effect varies according to the batches and their characteristics. The reduction effects in the first and second batches, as well as the insignificance or even increasing effects of the third batch, may be due to carbon leakage between different batches of LCCPs. Overall, this research provides novel and quantitative evidence on low-carbon development in China, making theoretical and empirical contributions to the field, and expanding econometric assessment methods to evaluate the effectiveness of environmental and climate change policies.
Subject(s)
Carbon , Pilots , Humans , Cities , Carbon/analysis , Carbon Dioxide/analysis , China , Economic DevelopmentABSTRACT
Radical polymerization (RP) of multivinyl monomers (MVMs) provides a facile solution for manipulating polymer topology and has received increasing attention due to their industrial and academic significance. Continuous efforts have been made to understand their mechanism, which is the key to regulating materials structure. Modelling techniques have become a powerful tool that can provide detailed information on polymerization kinetics which is inaccessible by experiments. Many publications have reported the combination of experiments and modelling for free radical polymerization (FRP) and reversible-deactivation radical polymerizations (RDRP) of MVMs. Herein, a minireview is presented for the most important modelling techniques and their applications in FRP/RDRP of MVMs. This review hopes to illustrate that the combination of modelling and wet experiments can be a great asset to polymer researchers and inspire new thinking for the future MVMs experiment optimization and product design.
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In this article, we report a low-threshold random laser enhanced by TiN nanoparticles (NPs) suspended randomly in gain solutions. Results show that the random laser with TiN NPs has a lower threshold than the random laser with TiO2 NPs and the underlying mechanisms are discussed in detail. The localized surface plasmon resonance of individual TiN NPs increases the pump efficiency and strengthens the fluorescence amplification efficiency of the DCM. The multiple scattering of integral TiN NPs extends the dwelling time of light in random systems, which provides more possibilities for the light amplification in the gain medium. Then, the random laser threshold as a function of the number density of TiN NPs is studied. Results show that the optimum number density of TiN NPs for the lowest-threshold random lasers is about 1.468 × 1012ml-1. When we substitute the ethanol solution with the nematic liquid crystal (NLC), the random laser threshold can be further decreased to 5.11 µJ/pulse, which is about 7.7 times lower than that of DCM dye solution with TiN NPs under the same conditions. These findings provide a cost-effective strategy for the realization of low-threshold random lasers with high-quality.
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LESSONS LEARNED: The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. BACKGROUND: Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. METHODS: TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. CONCLUSION: The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Antibodies, Monoclonal , Axitinib , Carcinoma, Renal Cell/drug therapy , Humans , Kidney Neoplasms/drug therapy , Vascular Endothelial Growth Factor AABSTRACT
In the past several months, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated infection (coronavirus disease 2019 [COVID-19]) developed rapidly and has turned into a global pandemic. Although SARS-CoV-2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. A great concern was raised about whether COVID-19 may affect male reproductive functions. In this study, we collected semen specimens from 12 male COVID-19 patients for virus detection and semen characteristics analysis. No SARS-CoV-2 was found in semen specimens. Eight out of 12 patients had normal semen quality. We also compared the sex-related hormone levels between 119 reproductive-aged men with SARS-CoV-2 infection and 273 age-matched control men. A higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID-19 group. Multiple regression analysis indicated that serum T: LH ratio was negatively associated with white blood cell counts and C-reactive protein levels in COVID-19 patients. It's the first report about semen assessment and sex-hormone evaluation in reproductive-aged male COVID-19 patients. Although further study is needed to clarify the reasons and underlying mechanisms, our study presents an abnormal sex hormone secretion among COVID-19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow-up.
Subject(s)
COVID-19/complications , Gonadal Steroid Hormones/analysis , Gonadal Steroid Hormones/blood , Semen Analysis , Semen/chemistry , Adult , Humans , Male , Middle Aged , Testosterone/blood , Young AdultABSTRACT
Targeting the androgen receptor (AR) signalling pathway remains the main therapeutic option for advanced prostate cancer. However, resistance to AR-targeting inhibitors represents a great challenge, highlighting the need for new therapies. Activation of the PI3K/AKT pathway and increased expression of histone deacetylases (HDACs) are common aberrations in prostate cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy for this patient population. Previous reports demonstrated that combination of PI3K inhibitors (PI3KIs) with histone deacetylase inhibitors (HDACIs) resulted in synergistic antitumour activities against preclinical models of prostate cancer. In this study, we demonstrate that the novel dual PI3K and HDAC inhibitor CUDC-907 has promising antitumour activity against prostate cancer cell lines in vitro and castration-resistant LuCaP 35CR patient-derived xenograft (PDX) mouse model in vivo. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bcl-xL, Bim and c-Myc. Further, down-regulation of Wee1, CHK1, RRM1 and RRM2 contributed to CUDC-907-induced DNA damage and apoptosis. In the LuCaP 35CR PDX model, treatment with CUDC-907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC-907 for the treatment of prostate cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Morpholines/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Prostatic Neoplasms/drug therapy , Pyrimidines/therapeutic use , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , DNA Damage , Down-Regulation/drug effects , Down-Regulation/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Humans , Male , Morpholines/pharmacology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Pyrimidines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Regorafenib is an oral multikinase inhibitor targeting angiogenesis, oncogenesis, and cancer proliferation/metastasis. This study evaluated the efficacy of regorafenib in refractory biliary tract cancer (BTC) in a multi-institutional phase 2 study. METHODS: Patients with BTC who progressed on at least 1 line of systemic therapy received regorafenib at 160 mg daily for 21 days on and 7 days off. The primary endpoint was 6-month overall survival (OS), and the secondary endpoints were median OS, progression-free survival (PFS), and objective response rates. Pretreatment plasma was collected for cytokine evaluation. RESULTS: A total of 39 patients were enrolled, and 33 were evaluable for efficacy. The median PFS and OS were 3.7 and 5.4 months, respectively, with survival rates of 46.2% at 6 months, 35.9% at 12 months, and 25.6% at 18 months for the intention-to-treat population. For the 33 evaluable patients who received regorafenib for at least 3 weeks, the median PFS and OS were 3.9 and 6.7 months, respectively, with survival rates of 51.5% at 6 months, 39.4% at 12 months, and 27.3% at 18 months. The objective response rate was 9.1%, and the disease control rate was 63.6%. Twenty-eight patients (71.8%) experienced grade 3/4 adverse events. Among the 23 cytokines analyzed, elevated baseline vascular endothelial growth factor D (VEGF-D) was associated with shorter PFS, whereas elevated baseline interleukin 6 (IL-6) and glycoprotein 130 (GP130) were associated with shorter OS. CONCLUSIONS: Regorafenib demonstrated modest clinical efficacy in heavily pretreated patients with BTC. Further exploration of biomarkers is warranted to identify a group of patients with BTC who may benefit from regorafenib.
Subject(s)
Biliary Tract Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Phenylurea Compounds/administration & dosage , Pyridines/administration & dosage , Vascular Endothelial Growth Factor D/genetics , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Biliary Tract Neoplasms/epidemiology , Biliary Tract Neoplasms/genetics , Biliary Tract Neoplasms/pathology , Cholangiocarcinoma/epidemiology , Cholangiocarcinoma/pathology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Middle Aged , Phenylurea Compounds/adverse effects , Progression-Free Survival , Pyridines/adverse effectsABSTRACT
In this study, the morphology and morphogenesis of Bakuella granulifera Foissner, Agatha, and Berger, 2002, isolated from soil in the Chanba National Wetland Park, Xi'an, China, were studied based on in vivo observations and protargol staining. The Chinese population is distinctly smaller than the type population from Namibia. Details of the ontogenetic process are provided for the first time and are summarized as follows: (1) the parental adoral zone is partly retained; (2) the left of the endoral forms a rather wide anlage and the proximal adoral membranelles are renewed; (3) the parental midventral complex contributes to the formation of the FVT cirral anlagen; (4) the marginal rows anlagen and dorsal kineties anlagen develop intrakinetally; (5) no caudal cirri are produced; and (6) the macronuclear nodules fuse to a single mass. In combination with previous studies, these findings suggest that the genus Bakuella is ontogenetically diverse.