RESUMEN
Objective: To evaluate the effectiveness of enhanced CT texture feature analysis in predicting pseudoprogression in patients with metastatic clear cell renal cell carcinoma (mccRCC) undergoing programmed cell death protein 1 (PD-1) inhibitor therapy. Methods: A cross-sectional study. Data from 32 patients with mccRCC were retrospectively collected who received monotherapy with PD-1 inhibitors after standard treatment failure at Henan Cancer Hospital, from June 2015 to January 2021. Clinical information and enhanced CT images were analyzed to assess target lesion response. The lesions were divided into pseudoprogression and non-pseudoprogression groups. Manual segmentation of target lesions was performed using ITK-Snap software on baseline enhanced CT, and texture analysis was conducted using A.K. software to extract feature parameters. Differences in texture features between the pseudoprogression and non-pseudoprogression groups were analyzed using univariate and multivariate logistic regression. A predictive model for pseudoprogression was constructed, and its performance was evaluated using ROC curve analysis. Results: A total of 32 patients with 89 lesions were included in the study. Statistical analysis revealed significant differences in seven texture features between the pseudoprogression and non-pseudoprogression groups. These features included"original_ngtdm_Strength"(0.49 vs. -0.61,P=0.006), "wavelet-HLH_glszm_ZonePercentage"(0.67 vs. -0.22,P=0.024),"wavelet-LHL_ngtdm_Strength"(1.20 vs. -0.51,P=0.002), "wavelet-HLL_gldm_LargeDependenceEmphasis"(-0.84 vs. 0.19,P=0.002), "wavelet-HLH_glcm_Id" (-0.30 vs. 0.43,P=0.037),"wavelet- HLH_glrlm_RunPercentage"(0.45 vs. -0.01,P=0.032),"wavelet-LHH_firstorder_Skewness"(0.25 vs. -0.27, P=0.011). Based on these features, a pseudoprogression prediction model was developed with a P-value of 0.000 2 and an odds ratio of 0.045 (95%CI 0.009-0.227). The model exhibited a high predictive performance with an AUC of 0.907 (95%CI 0.817-0.997) according to ROC curve analysis. Conclusions: Enhanced CT texture feature analysis shows promise in predicting lesion pseudoprogression in patients with metastatic ccRCC undergoing PD-1 inhibitor therapy. The developed predictive model based on texture features demonstrates good performance and may assist in evaluating treatment response in these patients.
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Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Estudios Transversales , Estudios Retrospectivos , Tomografía Computarizada por Rayos XAsunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 3 Asociado a Receptor de TNF/metabolismo , Proteínas Estructurales Virales/metabolismo , Células A549 , Células HEK293 , Humanos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Células THP-1 , UbiquitinaciónAsunto(s)
Quirópteros , Infecciones por Coronavirus , Animales , Betacoronavirus , Evolución Molecular , Genoma Viral , Humanos , FilogeniaRESUMEN
OBJECTIVE: To optimize the dose of lipid infusion in treatment of patients with acute dexmedetomidinepoisoning, in order to further guide the rational use of medication in clinical practice. METHODS: A total of 80 patients with acute dexmedetomidinepoisoning were admitted in this study from January 2012 to October 2014 at our hospital and divided into three groups based on the intensity of poisoning, including: slight poisoning (28 cases), moderate poisoning (32 cases) and severe poisoning (20 cases). Patients in each group were given 10% lipid infusion or 20% lipid infusion for treatment.Stable blood dexmedetomidineconcentrations of patients in pre-treatment and at different time points after treatment (pre-treatment and 0.5, 1, 2, 5, 10, 20 h after treatment) and the length of hospital stay, awake time in each group were investigated and compared.Ramsay sedation scores were recorded and compared in different time points (0.5 h before treatment and 2, 5, 20 h after treatment) in each group for different treatments.Side effects and complications were recorded, and follow-up was conducted during 1-3 d post discharge to record the recovery condition in patients. RESULTS: In each group, patients receiving 20% lipid infusion waked earlier than those receiving 10% lipid infusion.And the hospitalization duration for patients receiving 20% lipid infusion was significantly shorter than those receiving 10% lipid infusion [(4.6±1.6) h vs (6.7±2.0) h, (2.6±0.4) d vs (4.0±0.6) d, P<0.05]. The Ramsay sedation scores were significantly lower for patients receiving 20% lipid infusion than those receiving 10% lipid infusionat 2 h and 5 h after treatment in each group [(3.4±0.3) vs (4.7±0.4), (2.6±0.3) h vs (3.5±0.3) h, P<0.05]. The stable plasma concentrations of dexmedetomidine were gradually reduced after the treatment, and which were lower when compared with the theoretical metabolic concentration.What's more, the plasma concentrationsat 1 h, 2 h and 5 h after treatment were significantly lower for patientsreceiving 20% lipid infusion than those receiving 10% lipid infusion in each group (P>0.05). All patients in our study were cured and discharged without severe side effects and complications, and follow-ups showed that no patients showed evidence of rebound phenomenon. CONCLUSIONS: Different concentrations of lipid infusionare safe and effective in relieving the intensity of dexmedetomidinepoisoning, and promoting the clinical recovery.What's more, the therapeutic efficacy of 20% lipid infusion is greater than 10% lipid infusion.
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Dexmedetomidina/envenenamiento , Lípidos/administración & dosificación , Humanos , Tiempo de Internación , Lípidos/uso terapéuticoRESUMEN
BACKGROUND: Although electroacupuncture (EA) is effective in the relief of neuropathic pain, the underlying mechanisms remain unclear. Previous studies have reported immunomodulatory effects of EA in rats. Since excessive release of interferon-γ (IFN-γ) after nerve injury transforms quiescent spinal microglia into an activated state with more neuropathic pain, associated with purinergic receptor P2X4 expression, it is possible that EA may mediate its analgesic effect by attenuating IFN-γ release and subsequent generation of P2X4R(+) microglia. METHODS: Male rats underwent chronic constriction injury (CCI) or IFN-γ intrathecal injection and von Frey tests were performed to evaluate the effect of EA on pain thresholds. Spinal IFN-γ and P2X4R expression levels were measured by immunohistochemistry, real-time PCR, enzyme immunoassay, and/or western blots. In vitro primary cultures of microglia were used to examine IFN-γ activation of P2X4R(+) cells. RESULTS: In CCI rats, EA treatment significantly increased paw withdrawal threshold relative to control. IFN-γ facilitated P2X4R(+) microglia activation both in vitro and in vivo. EA also down-regulated both P2X4R and IFN-γ expression in the spinal cord after CCI. However, EA did not exert the same analgesic effect after intrathecal IFN-γ injection. CONCLUSIONS: EA ameliorated tactile allodynia after peripheral nerve injury by down-regulating excessive expression of IFN-γ in the spinal cord and subsequently reducing expression of P2X4R.
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Electroacupuntura/métodos , Interferón gamma/metabolismo , Microglía/metabolismo , Neuralgia/terapia , Receptores Purinérgicos P2X4/metabolismo , Regulación hacia Arriba/fisiología , Animales , Western Blotting/métodos , Modelos Animales de Enfermedad , Hiperalgesia , Técnicas para Inmunoenzimas/métodos , Masculino , Neuralgia/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Médula Espinal/metabolismoRESUMEN
We investigated a possible person-to-person transmission within a family cluster of two confirmed influenza A(H7N9) patients in Guangzhou, China. The index case, a man in his late twenties, worked in a wet market that was confirmed to be contaminated by the influenza A(H7N9) virus. He developed a consistent fever and severe pneumonia after 4 January 2014. In contrast, the second case, his five-year-old child, who only developed a mild disease 10 days after disease onset of the index case, did not have any contact with poultry and birds but had unprotected and very close contact with the index case. The sequences of the haemagglutinin (HA) genes of the virus stains isolated from the two cases were 100% identical. These findings strongly suggest that the second case might have acquired the infection via transmission of the virus from the sick father. Fortunately, all 40 close contacts, including the other four family members who also had unprotected and very close contact with the cases, did not acquire influenza A(H7N9) virus infection, indicating that the person-to-person transmissibility of the virus remained limited. Our finding underlines the importance of carefully, thoroughly and punctually following-up close contacts of influenza A(H7N9) cases to allow detection of any secondary cases, as these may constitute an early warning signal of the virus's increasing ability to transmit from person-to-person.
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Genoma Viral/genética , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Gripe Aviar/transmisión , Gripe Humana/transmisión , Adulto , Animales , Preescolar , China , Trazado de Contacto , Exposición a Riesgos Ambientales , Familia , Femenino , Humanos , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Aviar/virología , Gripe Humana/virología , Masculino , Filogenia , Vigilancia de la Población , Aves de Corral , Análisis de Secuencia de ADNRESUMEN
1. There is no effective anti-H5N1 avian influenza agent. 2. A chemical compound BFDBSCcan inhibit H5N1 virus infection in cell cultures, and such inhibition might be attributable to its halogenated benzoyl residues. 3. This pilot study assessed anti- H5N1 activity and toxicity of four chemical compounds with halogenated benzoyl residues in cell culture system. 4. Two compoundsFPBFDBSC and BFB-gallate showed higher antiviral effectsthan BFDBSC, whearas the other twoBFB-borneol and BFB-mentholshowed lower antiviral effects. These compounds did not show toxicity. 5. The halogenated benzoyl residues may play a key role in anti-H5N1 effects. However, all these compounds showed poor solubility, which may limit their utility
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Antivirales/farmacología , Diseño de Fármacos , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/tratamiento farmacológico , Animales , Antivirales/química , Antivirales/toxicidad , Perros , Humanos , Gripe Humana/virología , Células de Riñón Canino Madin Darby , Proyectos Piloto , SolubilidadAsunto(s)
Antivirales/farmacología , Bacterias/metabolismo , Proteínas Bacterianas/farmacología , Gripe Humana/prevención & control , Animales , Bacterias/genética , Proteínas Bacterianas/metabolismo , Ingeniería Genética , Humanos , Virus de la Influenza A/aislamiento & purificación , Gripe Humana/virología , Ratones , Ratones Endogámicos BALB C , Péptidos/metabolismo , Péptidos/farmacologíaAsunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Piranocumarinas/farmacología , Fármacos Anti-VIH/química , Productos Biológicos/química , Productos Biológicos/farmacología , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Humanos , Mutación , Piranocumarinas/químicaRESUMEN
The type I interferon (IFN-alpha/beta) receptor 1 (IFNAR1) mediates the potent antiviral and immuno-regulatory effects of IFN-alpha/beta that are believed to be pivotal to eradicate hepatitis B virus (HBV) infection. IFNAR1 promoter polymorphisms (at -568/-77) have been shown to be associated with susceptibility to chronic HBV infection; however, whether these markers are genetic determinants of HBV infection remains unknown. The functional significance of promoter -568/-77 polymorphisms was assessed by mutagenesis and luciferase assays. Sequencing and restriction fragment length polymorphisms in 328 chronic HBV patients, 130 spontaneous resolvers and 148 healthy blood donors identified other polymorphism at IFNAR1 open reading frame. IFNAR1 expression levels in peripheral blood cells were detected by flow cytometry. We found that the -568/-77 promoter variants were unlikely to affect transcription levels. A C/G single nucleotide polymorphism, in strong linkage disequilibrium with the promoter polymorphisms, was found in the coding sequence of IFNAR1 (nt19158). This resulted in a nonsynonymous substitution in the extracellular region of IFNAR1 protein and correlated with susceptibility to chronic HBV infection. Bioinformatic analysis suggested decreased stability of the IFNAR1 protein. Chronic HBV patients with the 19158C/C genotype (Leu141) exhibited higher IFNAR1 protein expression levels in peripheral blood monocytes than those with the 19158G/G genotype (Val141). In conclusion, IFNAR1 19158C/G polymorphism is primarily associated with susceptibility to chronic HBV infection.
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Susceptibilidad a Enfermedades , Hepatitis B Crónica/genética , Polimorfismo de Nucleótido Simple , Receptor de Interferón alfa y beta/genética , Sustitución de Aminoácidos/genética , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Masculino , Mutación Missense , Mutación Puntual , Polimorfismo de Longitud del Fragmento de Restricción , Receptor de Interferón alfa y beta/biosíntesis , Análisis de Secuencia de ADNRESUMEN
1. Infection with SARS coronavirus (SARS-CoV) induces a cellular stress condition known as the unfolded protein response (UPR). UPR induction is mediated primarily by viral spike (S) protein. The modulation of UPR by S protein involves activation of PERK protein kinase. Other branches of the UPR pathways controlled by IRE1 and ATF6 proteins, respectively, are not involved. 2. The protease inhibitor Ben-HCl effectively suppresses SARS-CoV infection by blocking virus entry. Viral infectivity is associated with the cleavage of S protein by the cellular protease factor Xa. 3. Two new aspects of the interaction between SARS-CoV S protein and the cell have been defined. These have important implications in the pathogenesis of SARS, providing opportunities for developing vaccines and antivirals against SARS-CoV. 4. Counteracting the UPR and targeting the cleavage of S protein with small molecule pharmaceutical agents represent two new anti-SARS-CoV strategies. 5. The receptor-binding domain of S protein delivered via adeno-associated virus can efficiently induce mucosal immunity and provide long-term protection against SARS-CoV infection.
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Glicoproteínas de Membrana/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Proteínas del Envoltorio Viral/metabolismo , eIF-2 Quinasa/metabolismo , Animales , Células Cultivadas , Chlorocebus aethiops , Sistemas de Liberación de Medicamentos , Factor Xa/metabolismo , Inhibidores de Proteasas/farmacología , Pliegue de Proteína/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Síndrome Respiratorio Agudo Grave/prevención & control , Glicoproteína de la Espiga del Coronavirus , Células Vero , Internalización del Virus/efectos de los fármacosRESUMEN
1. We have demonstrated for the first time that the helicase of a ribonucleic acid virus, the SARS coronavirus (SARS-CoV), is a valid target for drug development. 2. Using high throughput screen and chemical synthesis, several lead compounds targeting the SARS-CoV helicase have been identified. We have shown that these compounds can inhibit SARS-CoV helicase activity and viral growth in cell culture systems. These compounds can potentially be used to target other viruses.
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ADN Helicasas/farmacología , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Antivirales/farmacología , Células Cultivadas , Chlorocebus aethiops , ADN Helicasas/genética , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Sensibilidad y Especificidad , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología , Células Vero/citología , Células Vero/efectos de los fármacos , Replicación Viral/genéticaRESUMEN
1. Intranasal vaccination using inactivated SARS coronavirus (SARS-CoV) vaccine with adjuvant can induce strong systemic (serum immunoglobulin [Ig] G) and respiratory tract local (tracheal-lung wash fluid IgA) antibody responses with neutralising activity. 2. RBD-Fc (protein-based vaccine) is able to induce effective neutralising antibodies able to provide protection from SARS-CoV infection in animal models. 3. A single dose of RBD-rAAV vaccination can induce adequate neutralising antibody against SARS-CoV infection. 4. Additional doses of vaccine increased the production of neutralising antibody 5-fold compared with a single dose. 5. RBD-rAAV vaccination provoked a prolonged antibody response with continually increasing levels of neutralising activity. 6. Intranasal vaccination with RBD-rAAV induced local IgA and systemic IgG neutralising antibodies and specific T-cell responses, able to protect against SARS-CoV infection in animal models. 7. When compared with the RBD-rAAV prime/boost vaccination, RBD-rAAV prime/RBD-peptide boost induced similar levels of Th1 and neutralising antibody responses that protected vaccinated mice from subsequent SARS-CoV challenges,but stronger Th2 and CTL responses. 8. Overall, our findings suggest that the inactivated vaccine, RBD-Fc and RBD-rAAV, can be further developed into effective and safe vaccines against SARS and that intranasal vaccination may be the preferred route of administration.
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Control de Enfermedades Transmisibles , Síndrome Respiratorio Agudo Grave/prevención & control , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Vacunación/estadística & datos numéricos , Vacunas Virales/administración & dosificación , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Brotes de Enfermedades/prevención & control , Femenino , Predicción , Hong Kong , Humanos , Inyecciones Intramusculares , Masculino , Ratones , Valor Predictivo de las Pruebas , Medición de Riesgo , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Vacunas Virales/inmunología , Vacunas Virales/farmacologíaRESUMEN
INTRODUCTION: The human immunodeficiency virus type 1 (HIV-1) genotyping resistance test (GRT) has been considered essential for HIV-1 drug resistance monitoring. However, it is not commonly used in some developing countries in Asia and Africa due to its high running cost. OBJECTIVE: This study aims to evaluate a new low-cost in-house GRT for both subtype B and non-B HIV-1. STUDY DESIGN: The in-house GRT sequenced the entire protease and 410 codons of reverse transcriptase (RT) in the pol gene. Its performance on drug resistance interpretation was evaluated against the FDA-approved ViroSeq HIV-1 Genotyping System. Particularly, a panel of 235 plasma samples from 205 HIV-1-infected patients in Hong Kong was investigated. The HIV-1 drug resistance-related mutations detected by the two systems were compared. The HIV-1 subtypes were analyzed through the REGA HIV-1 Genotyping Tool and env phylogenetic analysis. RESULTS: Among the 235 samples, 229 (97.4%) were successfully amplified by both in-house and ViroSeq systems. All PCR-negative samples harbored viral RNA at <400 copies/mL. The in-house and ViroSeq system showed identical drug resistance-related mutation patterns in 216 out of 229 samples (94.3%). The REGA pol genotyping results showed 93.9% (215/229) concordance with the env phylogenetic results including HIV-1 subtype A1, B, C, D, G, CRF01_AE, CRF02_AG, CRF06_cpx, CRF07_BC, CRF08_BC, CRF15_01B and other recombinant strains. The cost of running the in-house GRT is only 25% of that for the commercial system, thus making it suitable for the developing countries in Asia and Africa. CONCLUSIONS: Overall, our in-house GRT provided comparable results to those of the commercial ViroSeq genotyping system on diversified HIV-1 subtypes at a more affordable price which make it suitable for HIV-1 monitoring in developing countries.