RESUMEN
To analyze and evaluate the clinical efficacy of Chinese and Western medical techniques in the treatment of severe diabetic foot ulcers complicated with necrotizing fasciitis of the lower leg and summarize the treatment experience of such patients to identify a new method of limb salvage treatment. A total of 46 patients with severe diabetic foot ulcers and necrotizing fasciitis of the lower leg were treated with such techniques as surgical debridement, bone drilling, open joint fusion, and microskin implantation. Wounds were treated with moisture-exposed burn therapy (a regenerative medical treatment for burns, wounds, and ulcers) and moisture-exposed burn ointment (a traditional Chinese medicine); underlying diseases were also treated effectively. The wound healing time, rate of high amputation, and mortality of these patients were summarized, and the clinical efficacy of such treatments was evaluated. Of the 46 patients enrolled, 38 patients were cured, with a cure rate of 82.61%. The average wound healing time was 130 ± 74.37 days. Two patients underwent high amputations, with an amputation rate of 4.35%, and 4 deaths occurred, with a mortality rate of 8.70%. The combination of Chinese and Western medical techniques in the treatment of severe diabetic foot ulcers complicated with necrotizing fasciitis of the lower leg not only effectively saved patients' lives and promoted wound healing but also greatly reduced the rates of high amputation and disability.
Asunto(s)
Diabetes Mellitus , Pie Diabético , Fascitis Necrotizante , Humanos , Pierna , Fascitis Necrotizante/complicaciones , Fascitis Necrotizante/diagnóstico , Fascitis Necrotizante/cirugía , Pie Diabético/complicaciones , Pie Diabético/diagnóstico , Pie Diabético/cirugía , Extremidad Inferior , Amputación QuirúrgicaRESUMEN
BACKGROUND: The prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown. METHODS: We discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples. RESULTS: High expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation. CONCLUSION: TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph- B-ALL patients with C-MYC overexpression and without BAX deletion. CpG 685 may also serve as an effective combinational therapy against Ph+ B-ALL.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptor Toll-Like 9 , Ratones , Animales , Proteína X Asociada a bcl-2/metabolismo , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Fosfatidilinositol 3-Quinasas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/uso terapéuticoRESUMEN
Natural killer (NK) cells perform immune surveillance functions in tumors. The antitumor effects of NK cells are closely related to tumor occurrence and development. However, the molecular factors that determine NK cell antitumor activity remain to be characterized. In the present study, we identified a novel long noncoding RNA (lncRNA), NK cell activity-associated lncRNA 1 (NCAL1), and investigated its function in NK cells. NCAL1 was primarily located in NK cell nuclei, where it functioned by activating Gab2, a scaffold protein with an essential role in immune cells. Gab2 positively regulated the killing activity of NK cells. Mechanistically, NCAL1 upregulated Gab2 epigenetically by binding to the Gab2 promoter, which decreased methylation, recruited the transcription factor Sp1, and increased H3K4me3 and H3K27ac levels in the Gab2 promoter. Furthermore, NCAL1 enhanced the cytotoxicity of NK cells toward tumor cells through the Gab2-PI3K-AKT pathway. Thus, NCAL1 potentiates NK cell cytotoxicity and is a promising therapeutic target to improve NK cell therapy.
Asunto(s)
Neoplasias , ARN Largo no Codificante , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , Células Asesinas Naturales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Natural killer (NK) cells are becoming valuable tools for cancer therapy because of their cytotoxicity against tumor cells without prior sensitization and their involvement in graft-versus-host disease; however, it is difficult to obtain highly cytotoxic NK cells without adding extra feeder cells. In this study, we developed a new method for obtaining highly cytotoxic NK cells from peripheral blood mononuclear cells (PBMCs) independently of extra feeder cell addition using rituximab not coated on a flask (non-coated rituximab). We found that rituximab could promote both the activation and expansion of NK cells from PBMCs, irrespective of being coated on a flask or not. However, NK cells activated by non-coated rituximab had much greater antitumor activity against cancer cells, and these effects were dependent on autologous living B cells. The antibody-dependent cellular cytotoxicity effect of NK cells activated by non-coated rituximab was also more substantial. Furthermore, these cells expressed higher levels of CD107a, perforin, granzyme B, and IFN-γ. However, there was no difference in the percentage, apoptosis, and cell-cycle progression of NK cells induced by coated and non-coated rituximab. Non-coated rituximab activated NK cells by increasing AKT phosphorylation, further enhancing the abundance of XBP1s. In conclusion, we developed a new method for amplifying NK cells with higher antitumor functions with non-coated rituximab via autologous B cells from PBMCs, and this method more efficiently stimulated NK cell activation than by using coated rituximab.
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Citotoxicidad Celular Dependiente de Anticuerpos , Antineoplásicos Inmunológicos/farmacología , Linfocitos B/inmunología , Factores Inmunológicos/farmacología , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/inmunología , Rituximab/farmacología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antineoplásicos Inmunológicos/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Biomarcadores , Línea Celular Tumoral , Citocinas/biosíntesis , Granzimas/metabolismo , Humanos , Factores Inmunológicos/inmunología , Inmunofenotipificación , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Perforina/metabolismo , Rituximab/inmunologíaRESUMEN
Antibodies targeting the immune checkpoint inhibitor, programmed cell death 1 (PD-1), have provided a breakthrough in the treatment of lung cancer. However, the function of PD-1 in natural killer (NK) cells of cancer patients remains unclear. Herein, we analyzed the expression of PD-1 on the NK cells in the peripheral blood of patients with lung cancer and found that the level of PD-1+ NK cells in patients was significantly higher than that in healthy individuals. Moreover, these PD-1+ NK cells demonstrated a weaker ability to secrete interferon-gamma (INF-γ), granzyme B, and perforin, and exhibited lower CD107a expression. Importantly, in patients with lung cancer, the percentage of PD-1+ NK cells was significantly positively correlated with the concentration of IL-2 in the plasma, which was also higher than that in healthy individuals. In addition, IL-2 could increase the expression of PD-1 on NK cells in vitro, indicating that high IL-2 level in the plasma is largely responsible for the abundance of PD-1+ NK cells in patients with lung cancer. These findings demonstrate intriguing mechanisms for understanding the expression of PD-1 on NK cells and the function of PD-1+ NK cells in lung cancer. This study confirms and extends previous studies demonstrating that PD-1 can negatively regulate the antitumor function of NK cells.
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Citotoxicidad Inmunológica/genética , Células Asesinas Naturales/metabolismo , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano , Citotoxicidad Inmunológica/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Granzimas/genética , Humanos , Interferón gamma/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteína 1 de la Membrana Asociada a los Lisosomas/genética , Masculino , Persona de Mediana Edad , Perforina/genéticaRESUMEN
The electrochemical performance of ZnS-based anode materials for Li-ion storage is far from satisfactory due to the incomplete protection of carbon against the volume change. To address this issue, we synthesized a pitaya-like carbon-coated ZnS/carbon nanosphere with rich mesopores (denoted as ZnS/C@C) that can be a promising anode material for Li-ion storage. ZnS/C@C were synthetized via a facile hydrothermal method followed by a chemical vapor deposition process. In this novel hierarchical architecture, the internal carbon framework with mesoporous structure acted as a cushion matrix, effectively preventing ZnS from fracturing and agglomerating during the repeatedly cycling. The outer carbon-coating layer with a thickness of â¼10â¯nm as a buffer cage accommodated the large strain caused by the volume change. Meanwhile, both the inner carbon framework and the outer carbon-coating layer provided ZnS/C@C with abundant electrical pathways that boosted the reaction kinetics efficiently. The porous structure allowed the infiltration of electrolyte and decreased the transport length of Li ions. Merited by the optimized structure, the ZnS/C@C anodes showed exceptional rate capability (751â¯mAhâ¯g-1 at 1000â¯mAâ¯g-1) and cycling stability (659â¯mAhâ¯g-1 at 1000â¯mAâ¯g-1 over 1200 cycles). An ultrahigh reversible capacity of 949.6â¯mAhâ¯g-1 at 100â¯mAâ¯g-1 was achieved.
RESUMEN
Gamma delta (γδ) T cells, which possess potent cytotoxicity against a wide range of cancer cells, have become a potential avenue for adoptive immunotherapy. Decitabine (DAC) has been reported to enhance the immunogenicity of tumor cells, thereby reinstating endogenous immune recognition and tumor lysis. However, DAC has also been demonstrated to have direct effects on immune cells. In this study, we report that DAC inhibits γδ T cell proliferation. In addition, DAC increases the number of KIR2DL2/3-positive γδ T cells, which are less cytotoxic than the KIR2DL2/3-negative γδ T cells. We found that DAC upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances the binding of KIR2DL2/3 promoter to Sp-1 and activates KIR2DL2/3 gene expression. Our data demonstrated that DAC can inhibit the function of human γδ T cells at both cellular and molecular levels, which confirms and extrapolates the results of previous studies showing that DAC can negatively regulate the function of NK cells and αß T cells of the immune system.
Asunto(s)
Antineoplásicos/farmacología , Decitabina/farmacología , Inmunoterapia Adoptiva/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Receptores KIR2DL2/metabolismo , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citotoxicidad Inmunológica , Metilación de ADN , Decitabina/uso terapéutico , Regulación de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Quinasas/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores KIR2DL2/genética , Linfocitos T/efectos de los fármacos , Linfocitos T/trasplanteRESUMEN
PURPOSE: The purpose is to study the effect of Enhanced Extracorporeal Counterpulsation (EECP) in patients with non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: EECP is a noninvasive, mechanical, and circulatory support therapy. Sixteen patients with unilateral NAION were treated with EECP (twelve 1-h daily treatment sessions for each patient). Color Doppler imaging (CDI) was applied to measure the mean flow velocity (MFV), peak-systolic velocity (PSV), end-diastolic velocity (EDV) of the ophthalmic artery (OA) and central retinal artery (CRA). Intraocular pressure (IOP) was measured by Goldmann applanation tonometry. Measurements were collected before and immediately after the first and the last sessions of EECP in both eyes, and they were compared with the baseline measurement before EECP. The measurements were also compared between the NAION eyes and the normal fellow eyes. Visual acuity (VA) and visual field (VF) were assessed before EECP and after the last EECP. RESULTS: EECP progressively increased blood flow velocities of the OA and CRA and progressively decreased IOP in both eyes (P < 0.05). After the first session of EECP, there was a 16 ± 5.3% increase in EDV and a 13.9 ± 9.5% increase in MFV of the OA, and a 17.1 ± 2.5% increase in PSV, a 21.2 ± 9.3% increase, in EDV and a 16.5 ± 3.3% increase in MFV of the CRA in NAION eyes. After the last EECP treatment, there was a 16.8 ± 6.7% increase in EDV and a 14.0 ± 5.1% increase in MFV of the OA, and a 17.7 ± 12.3 % increase in PSV, a 23.1 ± 6.3% increase in DSV, and a 21.1 ± 8.4% increase in MFV of the CRA in NAION eyes (P < 0.05). The change of the PSV, EDV, and MFV in the CRA were more significant in NAION eyes than that of their fellow eyes (P < 0.05). VA was improved and VF mean deviation was decreased in NAION eyes after the last EECP treatment (P = 0.003 and 0.049, respectively), and VA improvement was correlated positively with the blood flow parameter. CONCLUSIONS: EECP could be a clinically effective and safe treatment for NAION.