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1.
J Pineal Res ; 76(1): e12925, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37986632

RESUMO

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.


Assuntos
Isquemia Encefálica , Indenos , AVC Isquêmico , Melatonina , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Camundongos , AVC Isquêmico/tratamento farmacológico , Receptor MT1 de Melatonina/agonistas , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais , Melatonina/farmacologia , Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Camundongos Knockout , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo
2.
Cancer Immunol Immunother ; 72(11): 3717-3726, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37787790

RESUMO

BACKGROUND: In clinical practice, some patients with advanced intrahepatic cholangiocarcinoma (ICC) cannot tolerate or refuse chemotherapy due to the toxicity, necessitating alternative treatments. PD-1 blockade combined with lenvatinib showed promising results in phase II studies with small sample size, but there is a lack of data on the routine use with this regimen. This study aimed to evaluate the effectiveness and safety of the regimen in patients with advanced ICC, and to identify predictors for treatment response and prognosis. METHODS: We conducted a retrospective cohort study of patients treated with PD-1 inhibitors plus lenvatinib for advanced ICC between July 2017 and August 2022. The study endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Biomarker analysis for CA19-9 and PD-L1 expression was performed. Exploratory analysis for genetic alternation was conducted. RESULTS: The study included 103 patients. It demonstrated a median PFS of 5.9 months and a median OS of 11.4 months. ORR was 18.4% and DCR was 80.6%. The incidence of grade 3 or 4 adverse events was 50.5%. Positive PD-L1 expression (TPS ≥ 1%) was associated with higher ORR (P = 0.013) and prolonged PFS (P = 0.023). Elevated CA19-9 (> 37 U/ml) was associated with decreased ORR (P = 0.019), poorer PFS (P = 0.005) and OS (P = 0.034). Patients with IDH1 mutations exhibited a favorable response to the treatment (P = 0.011), and patients with TP53 mutations tended to have worse OS (P = 0.031). CONCLUSIONS: PD-1 blockade plus lenvatinib is effective and safe in routine practice. PD-L1 expression and CA19-9 level appear to predict the treatment efficacy. IDH1 mutations might indicate a better treatment response. CLINICAL TRIAL REGISTRATION: NCT03892577.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Antígeno B7-H1 , Antígeno CA-19-9 , Estudos de Coortes , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos
3.
Molecules ; 28(14)2023 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-37513319

RESUMO

To prevent local tumor recurrence caused by possible residual cancer cells after surgery, avoid toxicity of systemic chemotherapy and protect the fragile immune system of postsurgical patients, an increasing amount of attention has been paid to local anti-cancer drug delivery systems. In this paper, golden buckwheat was first applied to prevent post-operative tumor recurrence, which is a Chinese herb and possesses anti-tumor activity. Golden buckwheat extract-loaded gellan gum injectable hydrogels were fabricated via Ca2+ crosslinking for localized chemotherapy. Blank and/or drug-loaded hydrogels were characterized via FT-IR, TG, SEM, density functional theory, drug release and rheology studies to explore the interaction among gellan gum, Ca2+ and golden buckwheat extract (GBE). Blank hydrogels were non-toxic to NIH3T3 cells. Of significance, GBE and GBE-loaded hydrogel inhibited the proliferation of tumor cells (up to 90% inhibition rate in HepG2 cells). In vitro hemolysis assay showed that blank hydrogel and GBE-loaded hydrogel had good blood compatibility. When GBE-loaded hydrogel was applied to the incompletely resected tumor of mice bearing B16 tumor xenografts, it showed inhibition of tumor growth in vivo and induced the apoptosis of tumor cells. Taken together, gellan gum injectable hydrogel containing GBE is a potential local anticancer drug delivery system for the prevention of postsurgical tumor recurrence.


Assuntos
Antineoplásicos , Fagopyrum , Humanos , Animais , Camundongos , Hidrogéis , Neoplasia Residual , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Células NIH 3T3 , Espectroscopia de Infravermelho com Transformada de Fourier , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico
4.
Angew Chem Int Ed Engl ; 60(7): 3390-3396, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33259120

RESUMO

Herein, we report near-infrared (NIR) light-driven shape-morphing of programmable MXene-containing anisotropic hydrogel actuators that are fabricated through in situ free-radical copolymerization of a judiciously designed MXene nanomonomer with thermosensitive hydrogel network. A low electric field (few V mm-1 ) was found to enable a spatial distribution of MXene nanosheets and hence introduce anisotropy into the hydrogel network. Programmable anisotropic hydrogel actuators were developed by controlling ITO electrode pattern, direct-current (DC) electric field direction and mask-assisted photopolymerization. As a proof-of-concept, we demonstrate NIR light-driven shape morphing of the MXene-containing anisotropic hydrogel into various shapes and devise a four-arm soft gripper that can perform distinct photomechanical functions such as grasping, lifting/lowering down and releasing an object upon sequential NIR light exposure.

5.
Cereb Cortex ; 29(8): 3482-3495, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-30192926

RESUMO

Intraventricular hemorrhage (IVH) is a common complication of prematurity in infants born at 23-28 weeks of gestation. Survivors exhibit impaired growth of the cerebral cortex and neurodevelopmental sequeale, but the underlying mechanism(s) are obscure. Previously, we have shown that neocortical neurogenesis continues until at least 28 gestational weeks. This renders the prematurely born infants vulnerable to impaired neurogenesis. Here, we hypothesized that neurogenesis is impaired by IVH, and that signaling through GSK3ß, a critical intracellular kinase regulated by Wnt and other pathways, mediates this effect. These hypotheses were tested observationally in autopsy specimens from premature infants, and experimentally in a premature rabbit IVH model. Significantly, in premature infants with IVH, the number of neurogenic cortical progenitor cells was reduced compared with infants without IVH, indicating acutely decreased neurogenesis. This finding was corroborated in the rabbit IVH model, which further demonstrated reduction of upper layer cortical neurons after longer survival. Both the acute reduction of neurogenic progenitors, and the subsequent decrease of upper layer neurons, were rescued by treatment with AR-A014418, a specific inhibitor of GSK3ß. Together, these results indicate that IVH impairs late stages of cortical neurogenesis, and suggest that treatment with GSK3ß inhibitors may enhance neurodevelopment in premature infants with IVH.


Assuntos
Apoptose/efeitos dos fármacos , Hemorragia Cerebral Intraventricular/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Tiazóis/farmacologia , Ureia/análogos & derivados , Animais , Western Blotting , Estudos de Casos e Controles , Contagem de Células , Proliferação de Células , Córtex Cerebral , Hemorragia Cerebral Intraventricular/patologia , Modelos Animais de Doenças , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Humanos , Imuno-Histoquímica , Lactente Extremamente Prematuro , Recém-Nascido , Antígeno Ki-67/metabolismo , Ventrículos Laterais , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fator de Transcrição PAX6/metabolismo , Fosforilação , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Proteínas com Domínio T/metabolismo , Ureia/farmacologia , Substância Branca
7.
J Pineal Res ; 64(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28796402

RESUMO

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Melatonina/uso terapêutico , Receptor MT1 de Melatonina/metabolismo , Animais , Astrócitos/citologia , Western Blotting , Células Cultivadas , Feminino , Genótipo , Hipocampo/citologia , Imuno-Histoquímica , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Teóricos , Receptor MT1 de Melatonina/genética
8.
Opt Express ; 25(15): 18107-18121, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28789300

RESUMO

Vertex radius of curvature (VROC) is an important shape parameter used to determine the properties of an optical aspheric surface. Precise measurement of VROC error is critical for manufacturing and aligning optical aspheric surfaces. This paper introduces VROC error measurement of aspheric surface by using slope asphericity with partial compensation interferometry. VROC error and the decoupled surface figure error (SFE) can be simultaneously measured. Experimental results indicate that the method exhibits relative measurement accuracy of 0.01% when the nominal VROC is 889 mm, and the decoupled SFE error is λ/10 of the peak-to-valley value.

9.
Opt Express ; 24(22): 25026-25042, 2016 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-27828443

RESUMO

The integrated model of echo laser pulse profile (ELPP) of a target with arbitrary shape is studied under the condition of the ELPP affected by target and atmospheric turbulence simultaneously. The ELPPs of four typical targets (a plane, a cone, a sphere and an aspherical surface) are employed to test the validity of the model by analytical and numerical approaches. Based on simulations of the ELPP under different targets and atmospheric turbulence intensity, the results show a good agreement between two methods, and the ELPP of a target with discontinuous surface is more easily affected by atmospheric turbulence than that with a continuous surface. Besides that, we study the relationship between the number of grids and the relative error of analytical and numerical approaches, which are of interest to obtain the optimal number of grids used in the simulations.

10.
J Neurosci ; 34(8): 2967-78, 2014 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-24553937

RESUMO

N-acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro, and organotypic hippocampal slice cultures ex vivo and reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo. We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochrome c, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.


Assuntos
Autofagia/efeitos dos fármacos , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores , Serotonina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Hipocampo/citologia , Hipocampo/patologia , Peróxido de Hidrogênio/toxicidade , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Serotonina/metabolismo , Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos
11.
Stroke ; 46(12): 3514-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26542693

RESUMO

BACKGROUND AND PURPOSE: The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the nonvascular and dynamic vascular responses and their genetic basis are not well understood. METHODS: We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive single-nucleotide polymorphisms from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke. RESULTS: We identified 4 genome-wide significant and suggestive single-nucleotide polymorphisms to be associated with infarct volume in mice (rs3694965, P=2.17×10(-7); rs31924033, P=5.61×10(-6); rs32249495, P=2.08×10(-7); and rs3677406, P=9.56×10(-6)). rs32249495, which corresponds to angiopoietin-1 (ANGPT1), was also significant in the recessive model in humans, whereas rs1944577, which corresponds to ZBTB7C, was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia. CONCLUSIONS: Genetic variations of ANGPT1 and ZBTB7C are associated with increased infarct size in both mice and humans. ZBTB7C may modulate the ischemic response via neuronal apoptosis and dynamic collateralization and, in addition to ANGPT1, may serve as potential novel targets for treatments of cerebral ischemia.


Assuntos
Angiopoietina-1/genética , Isquemia Encefálica/genética , Estudo de Associação Genômica Ampla , Proteínas/genética , Animais , Isquemia Encefálica/diagnóstico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Polimorfismo de Nucleotídeo Único/genética , Especificidade da Espécie
12.
J Neurochem ; 134(5): 956-68, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26031348

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss. Evidence suggests that mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, glutamate excitotoxicity, and proteasomal dysfunction are all responsible for ALS pathogenesis. N-acetyl-tryptophan has been identified as an inhibitor of mitochondrial cytochrome c release and therefore is a potential neuroprotective agent. By quantifying cell death, we demonstrate that N-acetyl-l-tryptophan (L-NAT) and N-acetyl-DL-tryptophan are neuroprotective in NSC-34 motor neuron-like cells and/or primary motor neurons, while their isomer N-acetyl-d-tryptophan has no protective effect. These findings are consistent with energy minimization and molecular modeling analysis, confirming that L-NAT generates the most stable complex with the neurokinin-1 receptor (NK-1R). L-NAT inhibits the secretion of Substance P and IL-1ß (Enzyme-Linked Immunosorbent Assay and/or dot blots) and mitochondrial dysfunction by effectively inhibiting the release of cytochrome c/Smac/AIF from mitochondria into the cytoplasm and activation of apoptotic pathways, including the activation of caspase-1, -9, and -3, as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity. These data provide insight into the molecular mechanisms by which L-NAT offers neuroprotection in models of ALS and suggest its potential as a novel therapeutic strategy for ALS. We demonstrate that L-NAT (N-acetyl-l-tryptophan), but not D-NAT, rescues NSC-34 cells and primary motor neurons from cell death. L-NAT inhibits the secretion of Substance P and IL-1ß, and caspase-1 activation, the release of cytochrome c/Smac/AIF, and the activation of caspase -9, and -3, as well as proteasomal dysfunction. The data suggest the potential of L-NAT as a novel therapeutic strategy for amyotrophic lateral sclerosis (ALS). AIF, apoptosis-inducing factor.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Neurônios Motores/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Fármacos Neuroprotetores/farmacologia , Triptofano/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Avaliação Pré-Clínica de Medicamentos , Células Híbridas , Interleucina-1beta/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Neurônios Motores/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores da Neurocinina-1 , Estereoisomerismo , Substância P/metabolismo , Triptofano/farmacologia
13.
J Pharmacol Exp Ther ; 352(1): 166-74, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25378375

RESUMO

It has been reported that ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from Ophiopogon japonicas, promotes antioxidative protection of the cardiovascular system. However, it is unknown whether OP-D exerts protective effects against doxorubicin (DOX)-induced autophagic cardiomyocyte injury. Here, we demonstrate that DOX induced excessive autophagy through the generation of reactive oxygen species (ROS) in H9c2 cells and in mouse hearts, which was indicated by a significant increase in the number of autophagic vacuoles, LC3-II/LC3-I ratio, and upregulation of the expression of GFP-LC3. Pretreatment with OP-D partially attenuated the above phenomena, similar to the effects of treatment with 3-methyladenine. In addition, OP-D treatment significantly relieved the disruption of the mitochondrial membrane potential by antioxidative effects through downregulating the expression of both phosphorylated c-Jun N-terminal kinase and extracellular signal-regulated kinase. The ability of OP-D to reduce the generation of ROS due to mitochondrial damage and, consequently, to inhibit autophagic activity partially accounts for its protective effects in the hearts against DOX-induced toxicity.


Assuntos
Autofagia/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Animais , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
14.
Int J Radiat Oncol Biol Phys ; 118(5): 1461-1471, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37433375

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have limited efficacy in treating advanced hepatocellular carcinoma (HCC). The synergistic effect of systemic therapy and radiation therapy (RT) might resolve this problem. We aimed to investigate the effect of RT on the treatment outcomes of ICIs and antiangiogenic combination therapy in patients with advanced-stage HCC. METHODS AND MATERIALS: This retrospective observational study analyzed the medical records of 194 patients with Barcelona Clinic Liver Cancer stage C HCC who were admitted to our center from August 2018 to June 2022 and received ICIs combined with antiangiogenic therapy as the first-line treatment. Patients who were administered RT for tumor thrombus or symptomatic metastases within 8 weeks of the commencement of combination therapy were allocated to the RT group, whereas those who did not receive RT were assigned to the non-radiation therapy (NRT) group. Propensity score matching was used to mitigate selection bias. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included objective response rate, disease control rate (DCR), local PFS, out-of-field PFS, and treatment-related adverse events. RESULTS: A total of 76 patients diagnosed with advanced-stage HCC and treated with ICIs and antiangiogenic therapy were included in the study, with 33 patients in the RT group and 43 patients in the non-RT group. After propensity score matching, 29 matched patient pairs were generated. The median follow-up was 15.5 months, and the RT sites were mainly located on the tumor thrombus (55.2%) and extrahepatic metastatic lesions (48.3%). The median PFS was 8.3 months (95% CI, 5.4-11.3) in the RT group and 4.2 months (95% CI, 3.4-5.0) in the NRT group (P < .001). The median OS was not reached in the RT group and was 9.7 months (95% CI, 4.1-15.3) in the NRT group (P = .002). The objective response rate was 75.9% (95% CI, 56.5-89.7) in the RT group and 24.1% (95% CI, 10.3-43.5) in the NRT group (P < .001). The DCR was 100% in the RT group and 75.9% (95% CI, 56.5-89.7) in the NRT group (P = .005). The median local PFS and out-of-field PFS were 13.2 months (95% CI, 6.3-20.1) and 10.8 months (95% CI, 7.0-14.7), respectively. RT was an independent prognostic factor for PFS (hazard ratio = 0.33; 95% CI, 0.17-0.64; P < .001) and OS (hazard ratio = 0.28; 95% CI, 0.11-0.68; P = .005), respectively. The rates of any grade treatment-related adverse events were similar between the 2 groups. CONCLUSIONS: In comparison to the combination of ICIs and antiangiogenic therapy, the inclusion of RT has been observed to improve the DCR and survival outcomes in patients with advanced-stage HCC. The safety profile of this triple therapy was satisfactory.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose , Humanos , Carcinoma Hepatocelular/radioterapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Hepáticas/radioterapia , Terapia Combinada
15.
Biomark Res ; 12(1): 26, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355603

RESUMO

Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/ß-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.

16.
World J Gastroenterol ; 29(26): 4174-4185, 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37475845

RESUMO

Neuroendocrine neoplasms (NENs) are rare heterogeneous tumors that can develop in almost any organ, with the digestive organs, including the gastrointestinal tract and pancreas being the most commonly affected sites. Despite the fact that advances in initial therapies have progressed, there is presently no recognized effective treatment for advanced NEN. Immune checkpoint inhibitors (ICIs) have shown superior efficacy in treating several types of solid tumors. Despite their successful role in the treatment of partial NENs, such as small cell lung cancer, and Merkel cell carcinoma, the role of ICIs in most of the NENs remains limited. Nevertheless, due to their specific anti-tumor mechanisms and acceptable safety profile, ICIs are a promising avenue for further study in NENs therapy. Recent clinical trials have illustrated that combination therapy with ICI is more efficient than monotherapy, and multiple clinical trials are constantly ongoing to evaluate the efficacy and safety of these combination therapies. Therefore, the purpose of this review is to provide a comprehensive summary of the clinical progress of immunotherapy in NENs affecting the digestive system, with a specific emphasis on the application of programmed cell death protein 1/programmed death receptor ligand 1 inhibitor. Furthermore, this review has an exploration of the potential beneficiary population and the inherent value of utilizing immunotherapy in the management of NENs.


Assuntos
Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Resultado do Tratamento , Imunoterapia/efeitos adversos , Terapia Combinada , Pâncreas/patologia
17.
Am J Cancer Res ; 13(6): 2392-2409, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37424823

RESUMO

Ubiquitin specific peptidase 2a (USP2a) plays critical roles in protein degradation and other cellular activities. Currently, our understanding on USP2a dysregulation in subjects with hepatocellular carcinoma (HCC) and its roles in HCC pathogenesis is limited. In this study, we found that USP2a mRNA and protein levels were significantly upregulated in HCC tumors from both human and mice. USP2a overexpression in HepG2 and Huh 7 cells significantly increased cell proliferation while inhibition of USP2a activity by chemical inhibitor or stable knockout of USP2 by CRISPR markedly reduced cell proliferation. In addition, USP2a overexpression significantly augmented the resistance while knockout of USP2a markedly increased the susceptibility of HepG2 cells to bile acid-induced apoptosis and necrosis. Consistent with the oncogenic activities detected in vitro, overexpression of USP2a promoted de novo HCC development in mice with significantly increased tumor occurrence rates, tumor sizes and liver/body ratios. Further investigations with unbiased co-immunoprecipitation (Co-IP)-coupled proteomic analysis and Western blot identified novel USP2a target proteins involved in cell proliferation, apoptosis, and tumorigenesis. Analysis of those USP2a target proteins revealed that USP2a's oncogenic activities are mediated through multiple pathways, including modulating protein folding and assembling through regulating protein chaperones/co-chaperones HSPA1A, DNAJA1 and TCP1, promoting DNA replication and transcription through regulating RUVBL1, PCNA and TARDBP, and altering mitochondrial apoptotic pathway through regulating VDAC2. Indeed, those newly identified USP2a target proteins were markedly dysregulated in HCC tumors. In summary, USP2a was upregulated in HCC subjects and acted as an oncogene in the pathogenesis of HCC through multiple downstream pathways. The findings provided molecular and pathogenesis bases for developing interventions to treat HCC by targeting USP2a or its downstream pathways.

18.
Hepatobiliary Surg Nutr ; 12(6): 882-897, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38115944

RESUMO

Background: The development of immunotherapy resistance is associated with a poor prognosis in patients diagnosed with hepatocellular carcinoma (HCC) who are undergoing treatment with immune checkpoint inhibitors (ICI). This study aimed to evaluate the efficacy and safety of subsequent radiotherapy (RT) for patients with advanced-stage HCC who had lesion enlargement or new lesions (NLs) during ICI therapy. Methods: This retrospective observational study enrolled 36 patients with advanced-stage HCC who underwent subsequent RT for lesion enlargement or NLs during ICI therapy from two centers. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), 1- and 2-year local control (LC) rates, in-field PFS (IFPFS), out-field PFS (OFPFS), and safety. Results: The median follow-up time was 15.3 months. The median PFS was 7.4 months [95% confidence interval (CI): 3.1-11.7 months], and the median OS was 18.8 months (95% CI: 17.1-20.5 months). ORR and DCR were 38.9% and 72.2%, respectively. In addition, the median IFPFS was 17.8 months (95% CI: 11.5-24.2 months), median OFPFS was 7.9 months (95% CI: 3.4-12.5 months), and estimated 1- and 2-year LC rates were 67.1% and 31.9%, respectively. The most common treatment-related adverse events (all grades) were diarrhea (33.3%), rash (30.6%), and malaise (27.8%); a total of 14 (38.9%) patients developed grade 3-4 AEs. Conclusions: Subsequent RT showed reliable antitumor effects and an acceptable safety profile in patients with advanced-stage HCC who had unsatisfactory response to ICI therapy; therefore, it could serve as an optional salvage strategy.

19.
Am J Cancer Res ; 13(8): 3582-3590, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37693157

RESUMO

As is well understood that malignant tumour progression requires additional blood vessels to provide the nutrients necessary for growth. Many patients with advanced hepatocellular carcinoma (aHCC) experience disease progression after treatment with lenvatinib (Lenva) and immune checkpoint inhibitors (ICIs). Therefore, we designed a double-arm retrospective study to evaluate the antitumour activity of additional bevacizumab (Beva, an anti-vascular endothelial growth factor-targeting drug) as a means to reduce the blood vessels needed for tumour growth. Compared with the control group, the group that received Beva had prolonged progression-free survival (PFS) and a trend toward a benefit for overall survival duration. This study aimed to evaluate the anticancer effect of Beva in patients with aHCC who experienced tumour progression after treatment with Lenva+ICIs. From April 2021 to March 2023, we retrospectively included 20 patients as the experimental group and 21 patients as the control group. The patients in the experimental group experienced disease progression after receiving targeted therapy and ICIs, after which we added Beva to the treatment. The patients in the control group only received targeted therapy and ICIs. The efficacy endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), which were evaluated according to RECIST v1.1. Adverse events were assessed using NCI-CTCAE v5.0. Ultimately, 20 patients with aHCC in the experimental group of received Beva after disease progression, compared with 21 patients in the control group. The median OS was 12.6 mo (95% CI: 6.8-18.7) vs. 9.3 mo (95% CI: 4.3-14.4), and the median PFS was 6.9 mo (95% CI: 6.4-7.4) vs. 4.1 mo (95% CI: 2.4-5.8). The ORR for all patients was 5%, and the DCR for all patients was 70.0%. The median follow-up time for all patients was 7.5 mo (95% CI: 5.0-10.0). All patients had adverse events, but no fatal adverse events were observed. In conclusion, Bevacizumab is a drug resistant treatment option for patients with advanced hepatocellular carcinoma after Lenva+PD-1/PD-L1 treatment.

20.
ACS Appl Mater Interfaces ; 14(9): 11834-11841, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35192332

RESUMO

Shape-programmable hydrogel-based soft actuators that can adaptively respond to external stimuli are of paramount significance for the development of bioinspired aquatic smart soft robots. Herein, we report the design and synthesis of near-infrared (NIR) light-driven hydrogel actuators through in situ photopolymerization of poly(N-isopropylacrylamide) (PNIPAM) hydrogels loaded with metal-organic frameworks (MOFs) onto the surface of the poly(dimethylsiloxane) (PDMS) thin film. The MOFs can not only function as an excellent photothermal nanotransducer but also accelerate the adsorption/desorption of water due to their porous nanostructure, which speeds up the response rate of the actuators. Shape-programmable hydrogel actuators are fabricated by tailoring the patterning of PDMS thin film, and thus different shape-morphing modes such as directional bending and chiral twisting are observed under the NIR light irradiations. As the proof-of-concept demonstrations, an artificial hand, biomimetic mimosa, and flower are conceptualized with light-driven MOF-containing hydrogel actuators. Interestingly, we are able to achieve an octopus-inspired light-driven soft swimmer upon cyclic NIR illumination due to the fast photoresponsiveness of as-prepared hydrogel actuators. This work can offer insights for fabricating programmable and reconfigurable smart aquatic soft actuators, thus shining a light into their potential applications in emerging fields including soft robots, biomedical devices, and beyond.

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