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High power and high brightness laser lighting puts forward new requirements for phosphor converters such as high luminous efficiency, high thermal conductivity and high saturation threshold due to the severe thermal effect. The structure design of phosphor converters is proposed as what we believe to be a novel strategy for less heat production and more heat conduction. In this work, the rod-shaped YAG:Ce phosphor ceramics (PCs) and disc-shaped YAG:Ce PCs as control group were fabricated by the gel casting and vacuum sintering, to comparatively study the luminescence performance for LD lighting, on the premise that the total number of transverse Ce3+ ions and the volume of samples from two comparison groups were same. All rod YAG:Ce PCs with low Ce3+ concentration exhibited the high luminous efficiency and better thermal stability than YAG:Ce discs with high Ce3+ concentration. Under the laser power density of 47.8 W/mm2, the luminous saturation was never observed in all rod-shaped YAG:Ce PCs. The high luminous efficacy of 245â¼274 lm/W, CRI of 56.3â¼59.5 and CCT of 4509â¼4478â K were achieved. More importantly, due to the extremely low Ce3+ doping concentration (0.01 at%), rod-shaped ceramics based LDs devices showed the excellent thermal performance and their surface temperatures were even below 30.5 °C surprisingly under the laser power density of 20.3 W·mm-2 (2 W). These results indicate that the rod shape of phosphor converter is a promising structure engineering for high power laser lighting.
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Lu3Al5O12:Ce (LuAG:Ce) phosphor ceramics (PCs) with the excellent thermal stability and high saturation threshold are considered as the best green-fluorescent converters for high-power laser diodes (LDs) lighting. In this study, the effects of sintering additives and sintering processes on the transmittance and microstructure of LuAG:Ce PCs were systematically studied, and the luminescence performance of ceramics with different transmittance was compared. LuAG:Ce PCs with the transmittance of 80% (@800â nm, 1.5 mm) were obtained by using 0.1 wt.% MgO and 0.5 wt.% TEOS as sintering additives, combined with optimized vacuum pre-sintering and hot isostatic pressing. Compared to the non-HIP samples, the transmittance had increased by 11%. The microstructure of ceramics indicated that high transparency was closely related to the decrease in intergranular pores. Notably, the luminous efficiency of 253 lm/W and its saturation thresholds of > 46 W/mm2 were obtained simultaneously in green-emitting LDs devices. Moreover, under 3W laser irradiation, highly transparent ceramics had the low surface temperature of 66.4 °C, indicating the good heat dissipation performance. The observed high luminous efficiency and high saturation threshold of LuAG:Ce PCs were attributed to fewer pores and oxygen vacancies. Therefore, this work proves that highly transparent LuAG:Ce PCs are promising green-fluorescent converters for high-power LDs lighting.
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Developing a high quality ceramic laser gain medium for solar directly pumped solid state lasers is essential, and yet the light conversion efficiency of the gain media for solar pumping remains a challenge. In this study, Ce and Nd ions, co-doped YAG transparent ceramics with theoretical transmittance and stable Ce3+ valent state were developed, and revealed that the absorbed visible light and light conversion efficiency in Ce,Nd:YAG ceramics were 3.98 times and 1.34 times higher than those in widely reported Cr,Nd:YAG ceramics, respectively. A concentration matching principle between Ce3+ and Nd3+ ions in YAG was established, and a higher Nd3+ ion doping concentration with a relatively low Ce3+ concentration was favorable to improve both the light conversion efficiency and emission intensity at 1064â nm of Ce,Nd:YAG ceramics. Energy transfer efficiency from Ce3+ to Nd3+ of the 0.3 at.%Ce,1.5at.%Nd:YAG ceramic reached as high as 61.71% at room temperature. Surprisingly, it was further promoted to 64.31% at a higher temperature of 473â K. More excited electrons at the upper energy level of Ce3+ ion under the high temperature accounted for this novel phenomenon. This study proposes a new design strategy of gain materials for solar directly pumped solid state lasers.
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Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell-related biomarkers.
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Anticorpos Monoclonais , Linfoma Extranodal de Células T-NK , Humanos , Anticorpos Monoclonais/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/imunologia , Masculino , Feminino , ADP-Ribosil Ciclase 1 , Pessoa de Meia-Idade , Idoso , Adulto , Glicoproteínas de MembranaRESUMO
Ceramic phosphors are widely considered the next-generation phosphor material for white LED/LD lighting, and a wide spectrum is a key factor in improving the CRI of lighting sources. In this paper, a novel, to our knowledge, barcode-structured YAG:Ce/YAG:Ce,Mn ceramic phosphor was designed and fabricated. The lighting sources with the CRI value of 73.5 and 68.9 were obtained under the excitation of blue LEDs and blue LDs, respectively. Simultaneously, thanks to the effective supplementary emission from a red LD, the CRI of the ceramic-based lighting source reached 81.8 under blue LD excitation. Specifically, the microstructure and luminescent property of ceramic phosphors with different thicknesses and ion doping concentrations were systematically studied. Besides, by changing the blue power from 0.52 W to 2.60 W, the CCT of the laser lighting source with the encapsulation of optimized YAG:Ce/YAG:Ce,Mn ceramic phosphors ranged from 3928â K to 5895â K, while the CRI always maintained above 80. The above results indicate that barcode-structured Ce:YAG/Ce,MnYAG ceramic phosphor is a candidate to achieve a high CRI and ican be applied to various lighting occasions.
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Realizing a high solar light conversion magnitude in Cr,Nd: YAG transparent ceramic is crucial to its applications in solar pumped solid state lasers. In this study, high quality Cr,Nd:YAG transparent laser ceramics with homogeneous microstructure and theoretical transmittance were fabricated, and an efficient laser oscillation of watt-level was realized by pumping ceramic at 808 nm. There were no any characteristic absorptions corresponding to Cr2+ or Cr4+ ions detected, even when the Cr3+ ion doping concentration reached 0.6 at.%. Increasing Cr3+ and Nd3+ doping concentrations significantly enhanced the emission intensity of ceramics at 1.06 µm, and energy transfer efficiency of the 0.3 at.% Cr,Nd: YAG ceramics was increased from 14.9% to 36.9% when increasing Nd3+ ion concentration from 0.3 at.% to 1.0 at.%, with an increasing magnitude of 247.6%. The results indicated that Cr,Nd: YAG transparent ceramic is a promising gain medium for solar pumped solid state lasers.
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The discovery of single structure Ce3+ doped garnet transparent ceramics (TCs) with a broad full width at half maximum (FWHM) is essential to realize a high CRI for high-power white light emitting diodes (LEDs) and laser diodes (LDs). In this work, by utilizing the ion substitution engineering strategy, pure phase Gd3Sc2Al3O12:Ce3+ (GSAG:Ce) TC with a broad FWHM of 132.4â nm and a high CRI value of 80.7 was fabricated through the vacuum sintering technique for the first time. The optimized in-line transmittance of TCs was 58.4% @ 800â nm. Notably, the GSAG:Ce TCs exhibited a remarkable red shift from 546â nm to 582â nm, with a high internal quantum efficiency (IQE) of 46.91%. The degraded thermal stability in Ce:GSAG TCs was observed compared with that of Ce:YAG TC, owing to the narrowed band gap of GSAG. Additionally, remote excitation white LEDs/LDs were constructed by combining GSAG:Ce TCs with blue LED chips or laser sources. A tunable color hue from yellow to shinning white was achieved in white LEDs, whereas the acquired CRI and CCT of the white LDs were 69.5 and 7766â K, respectively. This work provides a new perspective to develop TCs with high CRI for their real applications in high-power white LEDs/LDs.
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Silent information regulator 2 (SIR2) in histone deacetylase (HDAC) is particularly conserved and widely expressed in all eukaryotic cells. HDAC is a crucial post-translational modification protein regulating gene expression. In the present study, a Toxoplasma gondii (T. gondii) silent information regulator 2 (TgSIR2) gene in HDAC was cloned and the modulation effects of recombinant TgSIR2 (rTgSIR2) on murine Ana-1 macrophages were characterized in vitro. The results indicated that rTgSIR2 had a good capacity to eliminate T. gondii by promoting proliferation, apoptosis, and phagocytosis, and modulating the secretion of nitric oxide (NO), pro-inflammatory cytokines, and anti-inflammatory cytokines. In in vivo experiments, animals were immunized with recombinant TgSIR2, followed by a lethal dose of T. gondii RH strain challenge 14 days after the second immunization. As compared to the blank and control group, the animals immunized with rTgSIR2 could generate specific humoral responses, as demonstrated by the significantly high titers of total IgG and subclasses IgG1 and IgG2a. Significant increases of IFN-γ, IL-4, and IL-10 were seen, while no significant changes were detected in IL-17. The percentage of CD4+ and CD8+ T lymphocytes in animals immunized with rTgSIR2 significantly increased. A significantly long survival time was also observed in animals vaccinated with rTgSIR2 14 days after the last immunization. All these results clearly indicate that rTgSIR2 played an essential role in modulating host macrophages and offered the potential to develop a therapeutic strategy against T. gondii.
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Toxoplasma , Toxoplasmose Animal , Vacinas de DNA , Animais , Anticorpos Antiprotozoários , Citocinas , Histona Desacetilases/genética , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/genética , Sirtuína 2 , Toxoplasmose Animal/prevenção & controleRESUMO
BACKGROUND: Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. RESULTS: ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo. To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo, transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and ß, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. CONCLUSIONS: These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.
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Infecções por HTLV-I/metabolismo , Fatores Reguladores de Interferon/metabolismo , Leucemia-Linfoma de Células T do Adulto/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Produtos do Gene tax/metabolismo , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/patologia , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Fatores Reguladores de Interferon/genética , Lenalidomida/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/patologia , Camundongos , Oligonucleotídeos Antissenso/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tionucleotídeos/farmacologiaRESUMO
Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved by the targeted delivery of ASOs to selected tissues. One example is the targeted delivery of ASOs to hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO, which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The activity of GalNAc-conjugated ASOs was superior to that of the unconjugated parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (-) cells. Both human- and mouse-derived HCC displayed reduced levels of ASGR, however, despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both enhanced antisense activity and antitumor activity in the diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced ASO activity in human circulating tumor cells from HCC patients, demonstrating the potential of this approach in primary human HCC tumor cells. Taken together, these results provide a strong rationale for a potential therapeutic use of GalNAc-conjugated ASOs for the treatment of HCC.
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Acetilgalactosamina/química , Técnicas de Transferência de Genes , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/química , Animais , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Células Cultivadas , Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , CamundongosRESUMO
We presented a Ho:LuAG ceramic laser in-band pumped by a narrow emission line-width Tm fiber laser at 1907 nm. All of potential transitions between 5I7 and 5I8 manifold were discussed to form the Ho's in-band-pump energy level systems, which were not described in details earlier. For the emission band centered at ~2095 nm, both laser absorption and emission transition separately consisted of two groups were first analyzed and observed. Using output couplers (OCs) with different transmittances (T = 6, 10 and 20%), the similar ~0.5 W continuous-wave (CW) output power under an incident pump power of ~4.9 W was obtained, with twin (or triplet) emission bands respectively. The blue shift of center emission wavelengths was observed with the increase of transmittances.
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Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins.
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Linfócitos B/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ácidos Nucleicos/metabolismo , Oligonucleotídeos/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Ácidos Siálicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Ácidos Siálicos/síntese química , Ácidos Siálicos/química , Relação Estrutura-AtividadeRESUMO
The separation of specific cell populations is instrumental in gaining insights into cellular processes, elucidating disease mechanisms, and advancing applications in tissue engineering, regenerative medicine, diagnostics, and cell therapies. Microfluidic methods for cell separation have propelled the field forward, benefitting from miniaturization, advanced fabrication technologies, a profound understanding of fluid dynamics governing particle separation mechanisms, and a surge in interdisciplinary investigations focused on diverse applications. Cell separation methodologies can be categorized according to their underlying separation mechanisms. Passive microfluidic separation systems rely on channel structures and fluidic rheology, obviating the necessity for external force fields to facilitate label-free cell separation. These passive approaches offer a compelling combination of cost-effectiveness and scalability when compared to active methods that depend on external fields to manipulate cells. This review delves into the extensive utilization of passive microfluidic techniques for cell separation, encompassing various strategies such as filtration, sedimentation, adhesion-based techniques, pinched flow fractionation (PFF), deterministic lateral displacement (DLD), inertial microfluidics, hydrophoresis, viscoelastic microfluidics, and hybrid microfluidics. Besides, the review provides an in-depth discussion concerning cell types, separation markers, and the commercialization of these technologies. Subsequently, it outlines the current challenges faced in the field and presents a forward-looking perspective on potential future developments. This work hopes to aid in facilitating the dissemination of knowledge in cell separation, guiding future research, and informing practical applications across diverse scientific disciplines.
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Terapia Baseada em Transplante de Células e Tecidos , Filtração , Separação Celular , Dispositivos Lab-On-A-Chip , MicrofluídicaRESUMO
Fibrotic skin diseases, such as keloids, are pathological results of aberrant tissue healing and are characterized by overgrowth of dermal fibroblasts. Remdesivir (RD), an antiviral drug, has been reported to have pharmacological activities in a wide range of fibrotic diseases. However, whether RD function on skin fibrosis remains unclear. Therefore, in our study, we explored the potential effect and mechanisms of RD on skin fibrosis both in vivo and in vitro. As expected, the results demonstrated that RD alleviated BLM-induced skin fibrosis and attenuates the gross weight of keloid tissues in vivo. Further studies suggested that RD suppressed fibroblast activation and autophagy both in vivo and in vitro. In addition, mechanistic research showed that RD attenuated fibroblasts activation by the TGF-ß1/Smad signaling pathway and inhibited fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. In summary, our results demonstrate therapeutic potential of RD for skin fibrosis in the future.
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Monofosfato de Adenosina , Alanina , Fibroblastos , Fibrose , Transdução de Sinais , Pele , Fator de Crescimento Transformador beta1 , Animais , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fibrose/tratamento farmacológico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/metabolismo , Camundongos , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Humanos , Autofagia/efeitos dos fármacos , Queloide/tratamento farmacológico , Queloide/metabolismo , Queloide/patologia , Antivirais/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Bleomicina , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Smad/metabolismoRESUMO
A series of transcription factors critical for maintenance of the neural stem cell state have been identified, but the role of functionally important corepressors in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT (also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems; however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor-dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.
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Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Neurônios/citologia , Oxirredutases N-Desmetilantes/metabolismo , Proteínas Repressoras/metabolismo , Células-Tronco/citologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/enzimologia , Embrião de Mamíferos/metabolismo , Células-Tronco de Carcinoma Embrionário , Histonas/química , Humanos , Histona Desmetilases com o Domínio Jumonji , Lisina/metabolismo , Metilação , Camundongos , Neurônios/enzimologia , Neurônios/metabolismo , Correpressor 2 de Receptor Nuclear , Oxirredutases N-Desmetilantes/genética , Ratos , Proteínas Repressoras/genética , Células-Tronco/enzimologia , Células-Tronco/metabolismoRESUMO
INTRODUCTION: In the global phase 3 ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) improved outcomes versus VMP in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Here, we report the primary analysis of the phase 3 OCTANS trial of D-VMP versus VMP in transplant-ineligible Asian NDMM patients. PATIENTS AND METHODS: In total, 220 patients were randomized (2:1) to receive 9 cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously twice weekly in Cycle 1 and weekly in Cycles 2 to 9; melphalan 9 mg/m2 orally; and prednisone 60 mg/m2 orally on Days 1 to 4 of each cycle) ± daratumumab 16 mg/kg intravenously weekly in Cycle 1, every 3 weeks in Cycles 2 to 9, and every 4 weeks thereafter until disease progression. RESULTS: After a median follow-up of 12.3 months, very good partial response or better rates (primary endpoint) were 74.0% versus 43.2% with D-VMP versus VMP (odds ratio, 3.57; 95% confidence interval [CI], 1.99-6.43; P < .0001). Median progression-free survival (PFS) with D-VMP versus VMP was not reached versus 18.2 months (hazard ratio, .43; 95% CI, .24-.77; Pâ¯=â¯.0033); 12-month PFS rates were 84.2% versus 64.6%. The most frequent grade 3/4 treatment-emergent adverse events with D-VMP/VMP were thrombocytopenia (46.5%/45.1%), neutropenia (39.6%/50.7%), and leukopenia (31.3%/36.6%). CONCLUSION: D-VMP demonstrated a favorable benefit/risk profile in transplant-ineligible Asian NDMM patients. This trial was registered at www. CLINICALTRIALS: gov as #NCT03217812.
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Mieloma Múltiplo , Trombocitopenia , Humanos , Bortezomib/efeitos adversos , Melfalan/efeitos adversos , Prednisona/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.
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Mieloma Múltiplo , Preparações Farmacêuticas , Animais , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia , Oligonucleotídeos AntissensoRESUMO
MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.
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Antineoplásicos/farmacologia , Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. METHODS: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). RESULTS: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. CONCLUSIONS: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Supplementary immunization activities (SIAs) have been demonstrated being effective in reducing measles incidence within a short period of time in China, but the effects are short-lived if there is no follow-up SIA with high routine immunization coverage. OBJECTIVES: To assess the change in measles seroprevalence from 2009 to 2013 after the launch of 2 large-scale SIAs within the period. METHODS: Three population-based cross-sectional serologic surveys of measles antibodies were conducted in 2009, 2011 and 2013 in Zhejiang, a province in eastern China, with serologic samples collected from 1541, 896 and 1474 subjects, respectively. The serum levels of immunoglobulin G antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: We found that the seropositivity rate among infants 0-7 months of age, a group having no vaccination benefit, was below 80% throughout the study period. In addition, the seropositivity rate among adults 30-49 years of age decreased significantly from 96.0% (95% confidence interval: 93.7%-98.3%) in 2011 to 88.5% (95% confidence interval: 84.3%-92.8%) in 2013. CONCLUSION: We showed that large-scale SIAs were effective, but their effects were not long lasting. Given the drop in seropositivity among adults, their susceptibility should be carefully monitored. While older individuals could benefit from the immunization activities, children who were too young to be vaccinated still have a weak seropositivity profile and the optimal age for the administration of the first dose of vaccine should be reconsidered.