Cinobufotalin Capsule Combined with Zoledronic Acid in the Treatment of Pain Symptoms and Clinical Efficacy in Prostate Cancer Patients with Bone Metastases: A Retrospective Study.

OBJECTIVE: To retrospectively analyse the effects of cinobufotalin capsule combined with zoledronic acid on pain symptoms and clinical efficacy of prostate cancer patients with bone metastases. METHODS: Patients with prostate cancer with bone metastasis admitted to our hospital from January 2021 to December 2022 were selected as study subjects. They were divided into the control group (treated with zoledronic acid) and the combined group (cinobufotalin capsules were added on the control group basis) according to different recorded treatment methods. The efficacies of the two groups after matching, lumbar L1-4 bone mineral density (BMD), serum calcium, serum phosphorus, visual analogue scale (VAS) score and Karnofsky performance status (KPS) score before and after treatment were compared, and adverse reactions were statistically analysed. RESULTS: A total of 102 patients were included in the study, encompassing 52 patients in the combined group and 50 patients in the control group. After 1:1 preference score matching, 64 patients were included in the two groups. No significant difference in baseline data was found between the two groups (p > 0.05). The total effective rate of the combination group was higher than that of the control group (p < 0.05). No significant differences in L1-4 bone mineral density, serum calcium and phosphorus, VAS score and KPS score were observed between the two groups prior to treatment (p > 0.05). After treatment, the L1-4 bone mineral density (BMD) and KPS score of the combined group decreased to less than those of the control group, the VAS score was lower than that of the control group, and the serum calcium and phosphorus level increased but less than that of the control group (p < 0.05). No significant difference in adverse reactions was found between the two groups (p > 0.05). CONCLUSIONS: Cinobufotalin capsule combined with zoledronic acid had ideal efficacy in the treatment of prostate cancer in patients with bone metastasis. This approach could improve their bone density and quality of life, improve their calcium and phosphorus metabolism, reduce their pain symptoms and provide increased safety. It may have an important guiding role in formulating future clinical treatment plans for patients with prostate cancer and bone metastasis.

Lipid profiling reveals Leymus Chinensis root insensitivity to Ca limitation.

BACKGROUND: Leymus chinensis (L. chinensis) is a perennial native forage grass widely distributed in the steppe of Inner Mongolia as the dominant species. Calcium (Ca) is an essential mineral element important for plant adaptation to the growth environment. Ca limitation was previously shown to strongly inhibit Arabidopsis (Arabidopsis thaliana) seedling growth and disrupt plasma membrane stability and selectivity, increasing fluid-phase-based endocytosis and contents of all major membrane lipids. RESULTS: In this study, we investigated the significance of Ca for L. chinensis growth and membrane stability relative to Arabidopsis. Our results showed that Ca limitation did not affect L. chinensis seedling growth and endocytosis in roots. Moreover, the plasma membrane maintained high selectivity. The lipid phosphatidylcholine (PC): phosphatidylethanolamine (PE) ratio, an indicator of the membrane stability, was five times higher in L. chinensis than in Arabidopsis. Furthermore, in L. chinensis, Ca limitation did not affect the content of any major lipid types, decreased malondialdehyde (MDA) content, and increased superoxide dismutase (SOD) activity, showing an opposite pattern to that in Arabidopsis. L. chinensis roots accumulated higher contents of PC, phosphatidylinositol (PI), monogalactosyldiacylglycerol (MGDG), phosphatidylglycerol (PG), cardiolipin (CL), digalactosyldiacylglycerol (DGDG), and lysophosphatidylcholine (LPC) but less phosphatidylethanolamine (PE), diacylglycerol (DAG), triacylglycerolv (TAG), phosphatidylserine (PS), lysobisphosphatidic acids (LPAs), lysophosphatidylethanolamine (LPE), and lysophosphatidylserine (LPS) than Arabidopsis roots. Moreover, we detected 31 and 66 unique lipids in L. chinensis and Arabidopsis, respectively. CONCLUSIONS: This study revealed that L. chinensis roots have unique membrane lipid composition that was not sensitive to Ca limitation, which might contribute to the wider natural distribution of this species.

Enhanced systemic tumor suppression by in situ vaccine combining radiation and OX40 agonist with CpG therapy.

BACKGROUND: In situ tumor vaccine has been gradually becoming a hot research field for its advantage of achieving personalized tumor therapy without prior antigen identification. Various in situ tumor vaccine regimens have been reported to exert considerable antitumor efficacy in preclinical and clinical studies. However, the design of in situ tumor vaccines still needs further optimization and the underlying immune mechanism also waits for deeper investigation. METHODS: A novel triple in situ vaccine strategy that combining local radiation with intratumoral injection of TLR9 agonist CpG and OX40 agonist was established in this sturdy. Local and abscopal antitumor efficacy as well as survival benefit were evaluated in the bilateral tumors and pulmonary metastasis model of B16F10 melanoma. In situ vaccine-induced immune responses and immune-associated variation in tumor environment were further investigated using multiparameter flow cytometry and RNA sequencing. Base on the analysis, the RT + CpG + αOX40 triple in situ vaccine was combined with checkpoint blockade therapy to explore the potential synergistic antitumor efficacy. RESULTS: Enhanced tumor suppression was observed with minimal toxicity in both treated and untreated abscopal tumors after receiving RT + CpG + αOX40 triple vaccine. The introduction of local radiation and OX40 agonist benefit more to the inhibition of local and abscopal lesions respectively, which might be partially attributed to the increase of effector memory T cells in the tumor microenvironment. Further analysis implied that the triple in situ vaccine did not only activate the microenvironment of treated tumors, with the upregulation of multiple immune-associated pathways, but also enhanced systemic antitumor responses, thus achieved superior systemic tumor control and survival benefit. Moreover, the triple in situ vaccine synergized with checkpoint blockade therapy, and significantly improved the therapeutic effect of anti-programmed cell death protein (PD)-1 antibody. CONCLUSION: This triple combining in situ vaccine induced intensive antitumor responses, mediated effective systemic tumor control and survival benefit, and displayed impressive synergistic antitumor effect with checkpoint blockade therapy. These data preliminary confirmed the efficacy, feasibility and safety of the triple combining in situ vaccine, suggesting its great application potential as both monotherapy and a part of combined immunotherapeutic regimens in clinical scenario.

iRGD-modified memory-like NK cells exhibit potent responses to hepatocellular carcinoma.

BACKGROUND: Cytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues. METHODS: After being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models. RESULTS: Treating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model. CONCLUSION: Our findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.

The Potential Predictive Biomarkers for Advanced Hepatocellular Carcinoma Treated With Anti-Angiogenic Drugs in Combination With PD-1 Antibody.

Background: Based on molecular biomarkers, anti-angiogenic drugs in combination with programmed cell death protein 1 (PD-1) antibodies can screen the potentially beneficial populations with hepatocellular carcinoma (HCC) and predict the efficacy after treatment. Therefore, we aimed to study predictive molecular biomarkers to improve the effectiveness of immuno-targeted combination therapy for HCC. Patients and Methods: Baseline clinical data, blood samples, and imaging data of the first evaluation after two cycles of treatment were collected for 40 patients with advanced HCC who underwent combination therapy, and then these data were compared according to the efficacy. Since 15 patients had complete hematology samples, we additionally tested the T lymphocyte subpopulations of these 15 patients and also compared them according to the efficacy. In addition, we also selected five patients who benefited the most from the combination therapy and five patients with the worst curative effect for gene detection based on survival time and efficacy evaluation. Finally, the relationship between certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, gene mutations and the response of immuno-targeted combination therapy for HCC was evaluated. Results: The high levels of CD3+CD4+CD279+, CD3+CD8+CD45RO+CD62L+T lymphocytes and tumor mutational burden (TMB) were associated with good efficacy of the combination therapy (P=0.03, P<0.01 and P=0.03). The high levels of CD3+CD4+CD28+ T lymphocytes were associated with poor efficacy of the combination therapy (P=0.02). The high mutation frequency of TP53 and ARID1A appeared in the non-response cohort. In addition, amplification mutation of 11q13-CCND1, FGF3, FGF4, and FGF19 was found in a patient with hyperprogression (HP). Conclusions: The certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, and gene mutations established in this paper were potential predictive biomarkers for HCC patients treated with combination therapy.

Whole-genome resequencing reveals domestication and signatures of selection in Ujimqin, Sunit, and Wu Ranke Mongolian sheep breeds.

OBJECTIVE: The current study aimed to perform whole-genome resequencing of Chinese indigenous Mongolian sheep breeds including Ujimqin, Sunit, and Wu Ranke sheep breeds (UJMQ, SNT, WRK) and deeply analyze genetic variation, population structure, domestication, and selection for domestication traits among these Mongolian sheep breeds. METHODS: Blood samples were collected from a total of 60 individuals comprising 20 WRK, 20 UJMQ, and 20 SNT. For genome sequencing, about 1.5 µg of genomic DNA was used for library construction with an insert size of about 350 bp. Pair-end sequencing were performed on Illumina NovaSeq platform, with the read length of 150 bp at each end. We then investigated the domestication and signatures of selection in these sheep breeds. RESULTS: According to the population and demographic analyses, WRK and SNT populations were very similar, which were different from UJMQ populations. Genome wide association study identified 468 and 779 significant loci from SNT vs UJMQ, and UJMQ vs WRK, respectively. However, only 3 loci were identified from SNT vs WRK. Genomic comparison and selective sweep analysis among these sheep breeds suggested that genes associated with regulation of secretion, metabolic pathways including estrogen metabolism and amino acid metabolism, and neuron development have undergone strong selection during domestication. CONCLUSION: Our findings will facilitate the understanding of Chinese indigenous Mongolian sheep breeds domestication and selection for complex traits and provide a valuable genomic resource for future studies of sheep and other domestic animal breeding.

A comparative analysis of carcass and meat traits, and rumen bacteria between Chinese Mongolian sheep and Dorper × Chinese Mongolian crossbred sheep.

Mutton is one of the most widely consumed meats globally. The Chinese Mongolian sheep (MS) breed is an indigenous breed of sheep characterised by high-quality meat and strong adaptability. Dorper × Chinese Mongolian crossbred sheep (DS) is an improved breed with a rapid growth rate and high mutton yield found in parts of China. The rumen microbiota is known to play a key role in shaping host nutrition and health. However, the carcass traits and meat nutritional qualities of DS and MS remain poorly defined, as does how rumen microbes affect these characteristics. The objective of this study was to compare carcass profiles, rumen bacterial communities, and meat nutritional qualities between MS and DS and clarify the associations between rumen microbiota and meat nutritional composition. We found that DS had a faster growth rate and better carcass traits than MS, including BW, carcass weight, meat weight, and loin-eye area. We further found that metabolite and rumen bacterial community composition differed between the two sheep breeds. First, compared with MS, DS had lower contents of some sweet amino acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, and beneficial metabolites. Secondly, MS and DS had distinct rumen bacterial compositions, and these differential bacteria were related to carcass traits as well as to contents of meat amino acids, free fatty acids, and other metabolites. Taken together, our data showed that DS had better carcass characteristics but lower meat nutritional quality, parameters that were associated with differences in rumen bacterial community composition. These findings may benefit future breeding strategies aimed at improving sheep carcass performance and meat quality worldwide.

Advanced HCC Patient Benefit From Neoantigen Reactive T Cells Based Immunotherapy: A Case Report.

Advanced hepatocellular carcinoma (HCC) is a highly lethal disease, mainly due to the late stage at diagnosis and its rapid progression. Although patients with advanced HCC can choose targeted therapy or chemotherapy, overall, the treatment response rate is extremely low and the average survival time is one year more or less. But the application of immunotherapy have led to a paradigm shift in the treatment of HCC,such as TILs (tumor infiltrating lymphocytes),Checkpoint blockade (immune Checkpoint blockade), CAR-T(chimeric antigen receptor T cells) and TCR-T (engineered t-cell receptor T cells). And recent data indicate neoantigens generated when tumors mutate are the main target of tumor-specific TILs, and they are also the main antigens mediating tumor regression in TILs treatment. Moreover, numerous evidences have revealed that radiotherapy lead to massive release of tumor antigens, which may increase the effectiveness of immunotherapy. Based on the above theory, we used neoantigen reactive T cells combined with tomotherapy to treat a patient with advanced HCC (Clinical Trial Study Registration Number: NCT03199807), who reached a long time progress free survival.

A Retrospective Study of Lenvatinib Monotherapy or Combined With Programmed Cell Death Protein 1 Antibody in the Treatment of Patients With Hepatocellular Carcinoma or Intrahepatic Cholangiocarcinoma in China.

Lenvatinib has been ratified as a first-line medication for advanced liver tumors by the American Food and Drug Administration. To assess the effectiveness and security of Lenvatinib in the Chinese population in a real-world setting, we enrolled 48 patients with unresectable liver cancer, managed from December 2018 to March 2021. Among them, 9 and 39 (83.30% men) patients had intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), respectively. Twenty-one (43.75%) patients had progressive disease after first-line treatment, and others (56.25%) had not receiving systemic treatment. Lenvatinib was administered alone or in combination with a programmed cell death protein 1 antibody (anti-PD-1). Treatment duration, median progression-free survival (mPFS), and median overall survival (mOS) were examined. The mOS and mPFS were 22.43 and 8.93 months, respectively. Of HCC patients treated with Lenvatinib only, the mOS and mPFS were 22.43 and 11.60 months, respectively. The corresponding values for HCC cases managed with anti-PD-1 combined with Lenvatinib were 21.77 and 7.10 months, respectively. ICC patients did not reach the mOS and their mPFS was 8.63 months. The present findings support the efficacy and security of Lenvatinib in the real-world therapy of Chinese patients with unresectable liver cancer.

Anharmonic phonon frequency and ultralow lattice thermal conductivity in ß-Cu2Se liquid-like thermoelectrics.

The prototype phonon-liquid electron-crystal ß-Cu2Se has been ranked among the best thermoelectric material with its ultralow lattice thermal conductivity (κL). The atomic fluidity, harmonic approximation failure, and the existence of a large number of imaginary phonon modes hinder the atomistic analysis of phonon transport in ß-Cu2Se. Thus, the atomistic origins of its ultralow κL remain elusive. In this study, we present a self-consistent phonon (SCPH) calculation of the lattice dynamical properties of ß-Cu2Se by including quartic anharmonicity and stiffening imaginary phonon modes in the anharmonic phonon dispersion, aiming to unravel the atomistic origins of ultralow κL. Upon renormalizing harmonic phonon dispersion with quartic anharmonicity, those imaginary phonon modes arising from copper fluidity diminish as temperature increases and anharmonic phonon dispersions are obtained. By solving the Boltzmann transport equation within the relaxation time approximation (BTE-RTA), we predicted ultralow κL which demonstrated an overall agreement with previous experiments. After analyzing the harmonic as well as anharmonic phonon density of states, it was found that the inclusion of quartic anharmonicity induces the suppression of low-lying phonon modes, which coincides with the experimental observation of the selective breakdown of long-wave transverse acoustic phonons. However, for the propagative heat-carriers, the anharmonic scattering enhances and phonon relaxation lifetime decreases as temperature increases, leading to a further reduction of κL. This study provides an extra insight into the atomistic origins of ultralow κL in ß-Cu2Se from first-principles anharmonic force constants and helps engineer the lattice dynamical properties for better thermoelectric performance.

Influence Analysis of Target Surface Emissivity on Infrared Radiation Polarization Characteristics.

Polarization imaging contains rich target parameters including spectrum, radiant intensity, polarization state, space geometry, etc. Polarization imaging can improve the target detection and recognition ability. The infrared polarization imaging is a new infrared detect technology in recent years. Infrared polarization imaging mainly aims to detect and identify the target with the difference of infrared radiation polarization characteristic between target and scene. But the state of polarization is affected by transmission medium in the transmission process of infrared radiation polarization information while the common method is to analyze the infrared radiation polarization characteristics of target that is not able to describe effects of all interrelated parameters and is difficult to estimate influence factors in the process of transmission. The equation of infrared polarized radiation is established through bidirectional reflectance distribution function based on micro-facet theory. And the mathematical model of the relationship between infrared radiation polarization degree and emissivity is derived in this paper. Result shows that the influence of target surface emissivity on the infrared degree can be ignored. On the basis of theoretical analysis, the infrared spectrum polarization imaging tests are unfolded, and the analysis of test data is consistent with the theoretical analysis. It is concluded that the correlation between the polarization degree of infrared and the emissivity of target surface can be neglected. The research production of this paper is conductive to increase of target detect efficiency, and it will provide new ways and means for camouflage target detect and identify. Therefore, the research production can be applied to detect and identify the camouflage target that is accomplished camouflage through change emissivity of camouflage target surface.

Epoxyeicosatrienoic acids--novel mechanism and pharmacological therapy of chronic renocardiac syndrome.

Cardiorenal syndromes were defined and classified recently, but the mechanism of chronic renocardiac syndrome remains disputed. Theories about chronic renocardiac syndrome cannot offer a convincing explanation for it. As a result, the current therapies of chronic renocardiac syndrome do not contribute to a satisfied prognosis. Epoxyeicosatrienoic acids, the products of arachidonic acid metabolized by cytochrome P450 enzymes, play an important role in the maintenance of renal hemodynamics, and regulation of renal, cardiac, and vascular function with antihypertensive and anti-inflammatory properties. It is well documented that down-regulation of epoxyeicosatrienoic acids might be involved in alterations in various pathophysiological states, including hypertension, uremia and hepatorenal syndrome. Likewise, epoxyeicosatrienoic acids were reduced in heart failure and renal dysfunction. This leads to the proposed hypothesis that epoxyeicosatrienoic acids down-regulation may be the novel mechanism of chronic renocardiac syndrome. These findings suggest that manipulation of epoxyeicosatrienoic acid levels could be a novel pharmacological therapy strategy for chronic renocardiac syndrome.