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1.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806084

RESUMO

Six parts of lotus (seeds, leaves, plumule, stamens, receptacles and rhizome nodes) are herbal medicines that are listed in the Chinese Pharmacopoeia. Their indications and functions have been confirmed by a long history of clinical practice. To fully understand the material basis of clinical applications, UPLC-QToF-MS combined with the UNIFI platform and multivariate statistical analysis was used in this study. As a result, a total of 171 compounds were detected and characterized from the six parts, and 23 robust biomarkers were discovered. The method can be used as a standard protocol for the direct identification and prediction of the six parts of lotus. Meanwhile, these discoveries are valuable for improving the quality control method of herbal medicines. Most importantly, this was the first time that alkaloids were detected in the stamen, and terpenoids were detected in the cored seed. The stamen is a noteworthy part because it contains the greatest diversity of flavonoids and terpenoids, but research on the stamen is rather limited.

2.
Nat Commun ; 12(1): 2008, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790295

RESUMO

Despite the tremendous progress of coupling organic electrooxidation with hydrogen generation in a hybrid electrolysis, electroreforming of raw biomass coupled to green hydrogen generation has not been reported yet due to the rigid polymeric structures of raw biomass. Herein, we electrooxidize the most abundant natural amino biopolymer chitin to acetate with over 90% yield in hybrid electrolysis. The overall energy consumption of electrolysis can be reduced by 15% due to the thermodynamically and kinetically more favorable chitin oxidation over water oxidation. In obvious contrast to small organics as the anodic reactant, the abundance of chitin endows the new oxidation reaction excellent scalability. A solar-driven electroreforming of chitin and chitin-containing shrimp shell waste is coupled to safe green hydrogen production thanks to the liquid anodic product and suppression of oxygen evolution. Our work thus demonstrates a scalable and safe process for resource upcycling and green hydrogen production for a sustainable energy future.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33793093

RESUMO

While there is increased interest in utilizing machine learning (ML) to support drug development, technical hurdles associated with complex algorithms have limited widespread adoption. In response, we have developed Pharm-AutoML, an open-source Python package that enables users to automate the construction of ML models and predict clinical outcomes, especially in the context of pharmacological interventions. In particular, our approach streamlines tedious steps within the ML workflow, including data preprocessing, model tuning, model selection, results analysis and model interpretation. Moreover, our open source package helps to identify the most predictive ML pipeline amongst defined search spaces by selecting the best data preprocessing strategy and tuning the ML model hyperparameters. The package currently supports multiclass classification tasks, and additional functions are being developed. Using a set of five publicly available biomedical datasets, we show that our Pharm-AutoML outperforms other ML frameworks, including H2O with default settings, by demonstrating improved predictive accuracy of classification. We further illustrate how model interpretation methods can be utilized to help explain the fine-tuned ML pipeline to end users. Pharm-AutoML provides both novice and expert users improved clinical predictions and scientific insights.

4.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(3): 259-264, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33691919

RESUMO

OBJECTIVE: To study the clinical features of pericardial effusion caused by central venous catheterization in preterm infants. METHODS: A retrospective analysis was performed on 11 preterm infants with pericardial effusion caused by central venous catheterization. Their catheterization features, manifestations, treatment, and prognosis were analyzed. RESULTS: A total of 11 preterm infants (11/2 599, 0.42%) developed pericardial effusion, with a mean gestational age of (30.1±2.6) weeks and a mean birth weight of (1 240±234) g. Pericardial effusion mostly occurred within 4 days after central venous catheterization (10 cases, 91%). The main manifestations included poor response (6/11, 55%), cyanosis (5/11, 45%), increased respiratory rate (6/11, 55%), increased heart rate (6/11, 55%), aggravated dyspnea (5/11, 45%), and muffled heart sound (5/11, 45%). At the time of disease progression, 7 preterm infants (64%) had a deep position of the end of the catheter, 3 preterm infants (27%) had a correct position, and 1 preterm infant (9%) had a shallow position. Five preterm infants (45%) experienced cardiac tamponade, among whom 4 underwent pericardiocentesis. Seven preterm infants were given conservative medical treatment. Among the 11 children, 2 (18%) died and 9 (82%) improved. CONCLUSIONS: Pericardial effusion caused by central venous catheterization mostly occurs in the early stage of catheterization and has critical clinical manifestations. Pericardiocentesis is required for cardiac tamponade, and early diagnosis and intervention can effectively improve prognosis.


Assuntos
Cateterismo Venoso Central , Derrame Pericárdico , Cateterismo Venoso Central/efeitos adversos , Criança , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Derrame Pericárdico/cirurgia , Derrame Pericárdico/terapia , Pericardiocentese , Estudos Retrospectivos
5.
J Vis Exp ; (169)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33779591

RESUMO

The major histocompatibility complex (MHC) plays a pivotal role in antigen peptide presentation and T cell immune responses against infectious disease and tumor development. The hybrid MHC I complexed with heterologous ß2-microglobulin (ß2m) substitution from different species can be stabilized in vitro. This is a feasible means to study MHC I of mammals, when the homologous ß2m is not available. Meanwhile, it is indicated that mammalian ß2m substitution does not significantly affect peptide presentation. However, there is limited summarization regarding the methodology and the technology for the hybrid MHC I complexed with heterologous ß2-microglobulin (ß2m). Herein, methods to evaluate the feasibility of heterologous ß2m substitution in MHC I study are presented. These methods include preparation of expression constructs; purification of inclusion bodies and refolding of the MHC complex; determination of protein thermostability; crystal screening and structure determination. This study provides a recommendation for understanding function and structure of MHC I, and is also significant for T cell response evaluation during infectious disease and tumor immunotherapy.

6.
Nat Chem Biol ; 17(4): 465-476, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33542532

RESUMO

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

7.
Sci Total Environ ; 775: 145786, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33621877

RESUMO

Thermal hydrolysis (TH) is an efficient technology for food waste (FW) management. This study investigated the nutrients released from FW under various TH temperature (140, 160, 180, 200 and 220 °C) and evaluated the feasibility of the hydrolyzed liquor (HL) as liquid organic fertilizer. The phytotoxicity and biotoxicity of HL was analyzed using wheat seed and Pseudomonas putida. Results revealed that TH could effectively solubilize FW and release nutrients (N, P and K) and organic substances. The highest content of total nitrogen (TN, 1685 mgN/L) and phosphorus (TP, 235 mgP/L) in the HL was obtained under 180 °C. The K+ was 278-293 mg/L regardless of treatment temperature. Secondary nutrients (Ca and Mg) and micro metals (Fe, Cu, Zn, Al, Co and Mn) were all detected at relatively high level, while heavy metals (As and Cd) were generally lower than 0.5 mg/L. Twenty types of free amino acid were identified and the maximum total concentration was 4965.13 mg/L. 2% HL displayed higher germination index (>80%) and enhanced root and shoot lengths. No biotoxicity was observed as confirmed by the bioassay. This study proposes a feasible method to solubilize food waste and produce liquid organic fertilizer.

8.
Mater Sci Eng C Mater Biol Appl ; 121: 111820, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33579463

RESUMO

The functionalization of tough and biodegradable hydrogels is an important way to broaden their applications in biomedical field. However, most of the hydrophobic functional drugs are difficult to incorporate with the hydrogels. In this work, curcumin (Cur), a hydrophobic functional drug, was chosen to composite with polyurethane (PU) to obtain PU-Cur hydrogels by a direct and simple in-situ copolymerization. The incorporation of curcumin in PU hydrogel increases the crosslink but reduces the hydrophilicity and degradation rate of PU-Cur hydrogels. Thus, it can increase the mechanical strength to a maximum of 6.4±0.8 MPa and initial modulus to a maximum of 3.0±0.4 MPa. More importantly, curcumin incorporated in PU networks is not deactivated. The degradation products of PU-Curs at relatively low concentrations (2.5 mg/mL) can scavenge free radicals very efficiently (maximum over 90%), which exhibits strong antioxidant properties to improve wound healing. Moreover, based on the photochemical activity of curcumin, notable inhibition effects of the degradation products of PU-Curs against bacteria (maximum over 80%) and cancer cells are demonstrated with blue light treatment as a photodynamic therapy (PDT). Therefore, the beneficial effects of curcumin are retained in PU-Cur hydrogels, suggesting potential use as wound dressings or tumor isolation membranes. This work proposes a promising strategy to combine hydrophobic functional drugs with hydrophilic hydrogels for applications in a wide range of biomaterials.

9.
J Matern Fetal Neonatal Med ; : 1-7, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588678

RESUMO

OBJECTIVE: To compare cesarean delivery (CD) rates in referral and non-referral hospitals in Maternal Safety Collaboration in Jiangsu province, China. METHODS: Sixteen participants (4 referral hospitals, 12 non-referral hospitals) from Drum Tower Hospital Collaboration for Maternal Safety reported CD rates in 2019 using ten-group classification system and maternal/neonatal morbidity and mortality. RESULTS: A total of 22,676 CDs were performed among 52,499 deliveries and the average CD rate was 43.2% (range 34.8-69.6%). CD rate in non-referral hospitals (44.7%) was significantly higher than it was in referral hospitals (40.4%, p < .001). Term singleton cephalic nulliparous women with spontaneous labor (Group 1) or induced labor (Group 2a) had higher CD rates if they were cared in non-referral hospitals compared with those in referral hospitals (Group 1: 11.8% vs. 4.4%, p < .001; Group 2a: 29.1% vs. 21.3%, p < .001). In non-referral hospitals, CD rate in Group 5 and the proportion of Group 5 to the overall population were also significantly higher than those in referral hospitals (98.5% vs. 92.5%, p < .001; and 21.0% vs. 14.5%, p < .001). CONCLUSION: To decrease the CD rate, we need to take efforts in decreasing unnecessary operations for term singleton cephalic nulliparous women and increasing the rate of trial of labor after CD.

10.
J Neurol ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555418

RESUMO

OBJECTIVE: To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. METHODS: A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. RESULTS: The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). CONCLUSION: The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.

11.
Anal Chim Acta ; 1145: 79-86, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33453883

RESUMO

Currently, nano-titanium dioxide (nTiO2) is considered an emerging environmental contaminant. Bottlenecked by the traditional destructive and lethal sampling methods, nTiO2's effect in living plants is poorly investigated. Here, in vivo tracing of endogenous salicylic acids at regular intervals was performed by using solid phase microextraction (SPME) technique for evaluating the effects of nTiO2 on plants. By planting aloe in soil containing varying amounts of nTiO2, the titanium (Ti) element accumulated in the leaves to concentrations and then reached the maximum of 1.1 ± 0.4 µg/g after nTiO2 exceeding 0.1 g/kg. The levels of salicylic acid (SA) and acetylsalicylic acid (ASA) were up-regulated upon the exposure to nTiO2, while were positively correlated to the contents of Ti. Moreover, the increased malondialdehyde, decreased total superoxide dismutase and fluctuated glutathione along with the addition of nTiO2 demonstrated the oxidative stress caused by nTiO2. Meanwhile, apparent growth indicators including leaf elongation, plant fresh weight and root development were influenced, which further confirmed the toxicity of nTiO2 imparted on aloe. This study presents the possibility of using salicylic acids as biomarkers for revealing the toxicity of nTiO2 on plants in addition to the other biomarkers and biomass data, and the in vivo SPME technique is powerful for their monitoring.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33461476

RESUMO

BACKGROUND: With the increasing prevalence of diabetes in recent years, diabetic nephropathy (DN) has also become a dangerous disease that greatly endangers human health. The study was designed to determine the mechanism and effect of Electro-acupuncture (EA) in alleviating DN-induced inflammation. METHODS: Mice were intraperitoneally injected with STZ (streptozotocin, 50 mg/kg, S0130, Sigma, St. Louis, MO, USA) for five consecutive days. After 12 weeks after induction, blood glucose levels were measured (>300 mg/dL). RESULTS: The serum levels of IL-1ß and IL-6 were decreased in EA-treated DN mice, and EA protected renal injury. EA could suppress HMGB1/NLRP3/NF-κB pathway. HMGB1 inhibition increased the anti-inflammatory effects of EA on DN by suppressing NLRP3/NF-κB pathway. The activation of HMGB1 attenuated the anti-inflammatory effects of EA on DN by inducing NLRP3/NF-κB pathway. CONCLUSIONS: These results suggested that EA protected DN-induced inflammation through suppression of NLRP3 inflammasome.

13.
EMBO Rep ; 22(2): e51162, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393230

RESUMO

Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.

14.
J Exp Bot ; 72(7): 2434-2449, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33337484

RESUMO

Floral patterning is regulated by intricate networks of floral identity genes. The peculiar MADS32 subfamily genes, absent in eudicots but prevalent in monocots, control floral organ identity. However, how the MADS32 family genes interact with other floral homeotic genes during flower development is mostly unknown. We show here that the rice homeotic transcription factor OsMADS32 regulates floral patterning by interacting synergistically with E class protein OsMADS6 in a dosage-dependent manner. Furthermore, our results indicate important roles for OsMADS32 in defining stamen, pistil, and ovule development through physical and genetic interactions with OsMADS1, OsMADS58, and OsMADS13, and in specifying floral meristem identity with OsMADS6, OsMADS3, and OsMADS58, respectively. Our findings suggest that OsMADS32 is an important factor for floral meristem identity maintenance and that it integrates the action of other MADS-box homeotic proteins to sustain floral organ specification and development in rice. Given that OsMADS32 is an orphan gene and absent in eudicots, our data substantially expand our understanding of flower development in plants.

15.
J Hazard Mater ; 403: 123650, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32810713

RESUMO

This study proposes a new path to utilize thermal hydrolyzed sludge (TH sludge) as fertilizer given high value chemical compounds that can promote plant growth were identified in the liquid fraction of TH sludge (TH liquor). Together with micro- and macro-nutrients released/synthesized during thermal hydrolysis, the feasibility of using TH liquor as organic fertilizer was evaluated. Besides high contents of N, P and K, total free amino acids (FAAs) and plant-growth-promoting FAAs (including glutamic acid, leucine and cystine) also presented in high concentration (4.98-6.48 and 1.12-2.73 g/100 g) in the TH liquor. For the first time, phytohormone compound, indole-3-acetic acid, was observed and the content was the highest in TH liquor with 165 °C treatment (165 °C TH liquor). Meantime, 165 °C TH liquor did not have negative impact on the growth of soil microbes, and this product, instead, demonstrated stimulating effect on the plant growth. These results suggest that 165 °C TH liquor has a great potential to be an organic fertilizer. The remaining solids of TH sludge could be converted to valuable biochar. The holistic approach of using TH liquor as organic fertilizer and producing biochar could realize nearly zero-waste discharge in sludge management.

16.
Sci Adv ; 6(50)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33298433

RESUMO

DNA methylation plays critical roles in vascular pathology of pulmonary hypertension (PH). The underlying mechanism, however, remains undetermined. Here, we demonstrate that global DNA methylation was elevated in the lungs of PH rat models after monocrotaline administration or hypobaric hypoxia exposure. We showed that DNA methyltransferase 3B (DNMT3B) was up-regulated in both PH patients and rodent models. Furthermore, Dnmt3b -/- rats exhibited more severe pulmonary vascular remodeling. Consistently, inhibition of DNMT3B promoted proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, overexpressing DNMT3B in PASMCs attenuated PDGF-BB-induced proliferation/migration and ameliorated hypoxia-mediated PH and right ventricular hypertrophy in mice. We also showed that DNMT3B transcriptionally regulated inflammatory pathways. Our results reveal that DNMT3B is a previously undefined mediator in the pathogenesis of PH, which couples epigenetic regulations with vascular remodeling and represents a therapeutic target to tackle PH.

17.
ACS Chem Neurosci ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300334

RESUMO

Receptor for advanced glycation end products (RAGEs), a multiligand receptor belonging to the cell-surface immunoglobulin superfamily, has been reported to play a crucial role in neuroinflammation and neurodegenerative diseases. Here, we tested our hypothesis that the RAGE-specific antagonist FPS-ZM1 is neuroprotective against ischemic brain injury. Distal middle cerebral artery occlusion (MCAO) or sham operation was performed on anesthetized Sprague-Dawley male rats (n = 60), which were then treated with FPS-ZM1 or vehicle (four groups in total = Vehicle + MCAO, FPS-ZM1 + MCAO, Vehicle + sham, and FPS-ZM1 + sham). After 1 week, neurological function was evaluated, and then, brain tissues were collected for 2,3,5-triphenyltetrazolium chloride staining, Nissl staining, TUNEL staining, Western blotting, and immunohistochemical analyses. FPS-ZM1 treatment after MCAO markedly attenuated neurological deficits and reduced the infarct area. More interestingly, FPS-ZM1 inhibited ischemia-induced astrocytic activation and microgliosis and decreased the elevated levels of proinflammatory cytokines. Furthermore, FPS-ZM1 blocked the increase in the level of RAGE and, notably, of DIAPH1, the key cytoplasmic hub for RAGE-ligand-mediated activation of cellular signaling. Accordingly, FPS-ZM1 also reversed the MCAO-induced increase in phosphorylation of NF-κB targets that are potentially downstream from RAGE/DIAPH1. Our findings reveal that FPS-ZM1 treatment reduces neuroinflammation in rats with focal cerebral ischemia and further suggest that the ligand/RAGE/DIAPH1 pathway contributes to this FPS-ZM1-mediated alleviation of neuroinflammation.

18.
Blood Adv ; 4(23): 5958-5965, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33275768

RESUMO

The prevalence and distribution of congenital thrombophilia is still unclear in patients with pulmonary embolism (PE). We aimed to determine the prevalence and clinical characteristics of congenital thrombophilia in PE patients and their subsequent outcomes. A prospective observational study was conducted from May 2013 to June 2018. A total of 436 consecutive patients with PE were enrolled. All patients were tested for protein C, protein S, antithrombin III (ATIII), factor V Leiden, and prothrombin G20210A mutations. The median follow-up duration was ∼800 days (range, 11-1872 days). Congenital thrombophilia was diagnosed in 31 of 436 (7.1%) patients; 12 patients had protein C deficiency (2.8%), 13 had protein S deficiency (3.0%), 5 had ATIII deficiency (1.1%), and 1 had (0.2%) factor V Leiden. Age ≤50 years at the first episode (odds ratio [OR], 5.43; 95% confidence interval [CI], 2.35-13.52; P < .001) and male sex (OR, 2.67; 95% CI, 1.15-6.78; P = .03) were 2 independent predictors of congenital thrombophilia in PE patients. There was no statistically significant difference in the prevalence of congenital thrombophilia between PE patients with and without risk factors (P = .58). We also found no significant difference in the risk of having a composite outcome of death or recurrent venous thromboembolism between patients with and without congenital thrombophilia (hazard ratio, 0.18; 95% CI, 0.02-5.69; P = .08). These results suggest that age and male sex are independently associated with the occurrence of congenital thrombophilia in PE patients but that congenital thrombophilia is not associated with the risk of recurrence or death with anticoagulation therapy.

19.
Pharm Res ; 37(12): 252, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33258982

RESUMO

PURPOSE: The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. METHODS: Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. RESULTS: No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100-146 kg versus 38-<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. CONCLUSIONS: In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100-146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.

20.
Mol Cancer Ther ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293344

RESUMO

Immunocytokines hold great potential as anti-cancer agents as they utilize a specific anti-tumor antibody to deliver an immune activating cytokine directly to the immunosuppressive tumor-microenvironment (TME). We have developed a novel immunocytokine (KD033) comprised of a fully human, high affinity anti-programmed death-ligand 1 (PD-L1) linked to the sushi domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a non-targeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models. Efficacy analyses showed a robust anti-tumor effect of single-dose srKD033 in several diverse syngeneic murine tumor models. In a CT26 murine colon tumor model, single dose srKD033 produced durable anti-tumor immunity as evidenced by resistance to subsequent tumor re-challenges. Mice responding to srKD033 treatment showed increased retention of PD-L1/IL-15 in the TME which likely facilitated prolonged IL-15-induced expansion of cytotoxic cells. Importantly, target-based PD-L1/IL-15 delivery via srKD033 was well-tolerated and induced significant anti-tumor activity in murine carcinoma models that are non- or minimally responsive to IL-15 or anti-PD-L1/PD-1 monotherapy.

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