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BACKGROUND: Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM. METHODS: We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells. RESULTS: We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN. CONCLUSION: These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.
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Antígenos HLA-G , Interleucina-6 , Mieloma Múltiplo , Neovascularização Patológica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Humanos , Animais , Neovascularização Patológica/metabolismo , Antígenos HLA-G/sangue , Antígenos HLA-G/metabolismo , Camundongos , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Feminino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Idoso , Modelos Animais de Doenças , AngiogêneseRESUMO
There are limited data on the optimal choice of anticoagulation in multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs). We conducted a propensity score-matched cohort study using the TriNetX database to compare the efficacy and safety of factor Xa inhibitors and warfarin in this patient population. Compared to warfarin, factor Xa inhibitors had a similar risk of deep vein thrombosis (hazard ratio [HR]: 1.11 [95% CI: 0.50-2.46]) or pulmonary embolism (HR: 1.08 [95% CI: 0.59-2.00]). There were no differences in the risk of gastrointestinal or intracranial bleeding. Factor Xa inhibitor-treated patients had lower all-cause mortality (HR: 0.56 [95% CI: 0.36-0.86]) compared with warfarin. These data suggest that factor Xa inhibitors had similar safety and efficacy compared with warfarin for MM patients on IMiDs.
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Anticoagulantes , Inibidores do Fator Xa , Mieloma Múltiplo , Varfarina , Humanos , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Trombose Venosa/prevenção & controle , Trombose Venosa/etiologia , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/efeitos adversos , Idoso de 80 Anos ou mais , Embolia Pulmonar/prevenção & controle , Embolia Pulmonar/etiologiaRESUMO
INTRODUCTION: Breast cancer is the most common cancer in women with a 5-year survival over 90%. However, anthracycline-based chemotherapy causes significant cardiotoxicity often requiring discontinuation of chemotherapeutic regimen among breast cancer survivors. We conducted a systematic review and meta-analysis to evaluate the efficacy of exercise training in mitigating anthracycline-related cardiotoxicity among women with breast cancer. METHODS: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases. The outcomes of interest were left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), early to atrial filling velocity (E/A) ratio, maximal oxygen consumption (VO2 max), and cardiac output (CO). We used the Cochrane risk-of-bias tool for randomized trials (RoB 2) to assess the risk of bias in individual studies. RESULTS: We identified a total of 596 articles with 5 trials included in the final analysis. Exercise training was associated with an increase in VO2 max compared with no exercise training (mean difference, 3.95 [95% CI, 0.63-7.26]; I2 = 99.68%). Other cardiovascular outcomes such as LVEF (mean difference, 1.76 [95% CI, -1.95 to 5.46]; I2 = 99.44%), GLS (mean difference, 0.30 [95% CI, -0.49 to 1.10]; I2 = 96.63%), E/A ratio (mean difference, 0.05 [95% CI, -0.05 to 0.15]; I2 = 94.16%), and CO (mean difference, 0.38 [95% CI, -0.91 to 1.66]; I2 = 99.73%) are similar between patients who underwent exercise training and those who did not. CONCLUSIONS: Exercise was associated with an improvement in maximal oxygen uptake among women with breast cancer receiving anthracycline-based chemotherapy.
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Antraciclinas , Neoplasias da Mama , Cardiotoxicidade , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Antraciclinas/efeitos adversos , Exercício Físico , Consumo de Oxigênio/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Terapia por Exercício/métodosRESUMO
The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.
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Linfoma Extranodal de Células T-NK , Mutação , Humanos , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/terapia , Linfoma Extranodal de Células T-NK/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Prognóstico , Variações do Número de Cópias de DNARESUMO
BACKGROUND: Dendritic cell (DC) vaccine is an emerging immunotherapy that could potentially improve glioblastoma survival. The first phase III clinical trial of DC vaccine was recently published. This meta-analysis aims to update and reappraise existing evidence on the efficacy of DC vaccine in patients with glioblastoma. METHODS: We searched PubMed, Embase, and Cochrane Library for clinical trials of DC vaccine for glioblastoma. The quality of the studies was assessed using the RoB 2.0 and ROBINS-I tools. The results of overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Summary effects were evaluated using random effects models. Trial sequential analysis (TSA) was performed. RESULTS: Seven clinical trials involving 3,619 patients were included. DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - 0.98). In the subgroup of newly diagnosed glioblastoma, DC vaccine was associated with improved PFS (HR = 0.59; 95% CI, 0.39 - 0.90). TSA of OS showed that the cumulative z-score line for the DC vaccine crossed the benefit boundary and reached the required sample size. TSA of PFS and subgroup analysis of newly diagnosed glioblastoma showed that the required sample size was not reached. CONCLUSIONS: This updated meta-analysis, which included the first phase III trial of a DC vaccine for glioblastoma, demonstrated that the DC vaccine was associated with improved OS. Moreover, TSA showed that the required sample size was reached, indicating a true-positive result. Future studies are required for patient subgroups with newly diagnosed and recurrent glioblastoma.
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BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.
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Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Resultado do Tratamento , Taxa de Sobrevida , Estudos de CoortesRESUMO
Patients with COVID-19 develop an increased risk of thromboembolism. Thromboprophylaxis is recommended for hospitalized COVID-19 patients, but the role of thromboprophylaxis in outpatients with COVID-19 is less well defined. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of thromboprophylaxis among outpatients with COVID-19. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to August 2023. The outcomes of interest were venous thromboembolic events including deep venous thrombosis and pulmonary embolism, all-cause mortality, cardiovascular events, hospitalization, major bleeding events, and non-major bleeding events. We included 6 trials comprising 3352 patients. Patients who received thromboprophylaxis had an approximately 70% reduction in venous thromboembolism (RR, 0.28 [95% CI, 0.08 to 0.93]) compared to patients who did not receive thromboprophylaxis. The risk of mortality (RR, 0.79 [95% CI, 0.35 to 1.77]), cardiovascular events (RR, 0.91 [95% CI, 0.30 to 2.73]), and hospitalization (RR, 1.09 [95% CI, 0.81 to 1.47]) were similar between the two groups. Patients who received thromboprophylaxis had a higher risk of non-major bleeding (RR, 3.48 [95% CI, 1.72 to 7.05) compared to patients who did not receive thromboprophylaxis. Thromboprophylaxis reduced the risk of venous thromboembolism but not mortality, cardiovascular events, or hospitalization among outpatients with COVID-19.
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COVID-19 , Tromboembolia Venosa , Humanos , COVID-19/complicações , COVID-19/mortalidade , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologia , Hemorragia/induzido quimicamente , Pacientes Ambulatoriais , Hospitalização , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , SARS-CoV-2 , Embolia Pulmonar/prevenção & controle , Embolia Pulmonar/etiologia , Assistência AmbulatorialRESUMO
Celosia spp. is a widely cultivated ornamental plant in gardens or parks in Taiwan. In September 2021, withering leaves and grayish-brown lesions were observed on the lower stem of plumed cockscombs (C. argentea var. plumosa) in Taichung City, with an incidence of about 22% in 136 plants after continuous precipitation, impacting the aesthetic value of the landscape. Symptomatic plants were collected, surface disinfected with 70% EtOH for ~20 sec., blotted dried, and excised diseased tissues (~ 3×3 mm2) were placed on 2% water agar. Four representative isolates were obtained after purification and the colonies were white with aerial and non-septated hyphae on V8 agar for 7 days. Sporangia were ovoid, ellipsoid or obpyriform, papillate, (26.3-55.9) 38.0 × 29.0 (20.1-40.6) µm (n = 200) (Ahonsi et al. 2007). Chlamydospores were spherical, terminal or intercalary, 26.0 (15.1-40.4) µm (n = 200). All isolates belong to A2 mating type with amphigynous antheridia and plerotic oospores, 21.0 (17.7-25.7) µm (n = 200), resembling the descriptions of Phytophthora (Erwin & Ribeiro 1996). For molecular identification, sequences of the ITS, ß-tubulin (ß-tub), and EF-1α regions of all isolates were amplified using ITS1/ITS4, TUBUF2/TUBUR1, and ELONGF1/ELONGR1 primers, respectively (White et al. 1990; Kroon et al. 2004). BLAST analyses of isolates cap1-2 (ITS: OQ581785; ß-tub: OQ590022; EF-1α: OQ590026), cap1-3 (ITS: OQ581786; ß-tub: OQ590023; EF-1α: OQ590027), cap2-1 (ITS: OQ581787; ß-tub: OQ590024; EF-1α: OQ590028), and cap2-2 (ITS: OQ581788; ß-tub: OQ590025; EF-1α: OQ590029) showed 100% of ITS identity, 99.5 to 99.9% of ß-tub identity, and 99.4 to 99.6% of EF-1α identity with Phytophthora nicotianae (ITS: MG865551; ß-tub: MH493987; EF-1α: MH359043). Phylogenetic trees were constructed using concatenated ITS, ß-tub, and EF-1α sequences based on maximum likelihood with a GTR+G model in MEGA X and Bayesian inference method in Geneious Prime 2022.2. All isolates were clustered in P. nicotianae with similar topology, thereby were identified as P. nicotianae. To confirm pathogenicity, 7 to 10-day-old seedlings and 6-week-old plumed cockscomb plants were inoculated in separate trials and each experiment was conducted twice. For each seedling, the lower stem was inoculated with 50 µl of zoospore suspension (104 zoospores/ml), 3 plants per isolate, and then incubated at 30±2â with 12 h light. For adult plants, each was inoculated with mycelial plugs from one V8 plate of 10-day-old P. nicotianae, 5 plants per isolate, and incubated at 25±2â in a greenhouse. Control plants were inoculated with sterile water and V8 agar plugs, respectively. Stem and root rot were observed on seedlings 4 days after inoculation while wilting and lower stem browning were observed on adult plants 2 months after inoculation. All control plants remained healthy at the end of repeated trials and identical pathogens were re-isolated only from symptomatic plants, thus fulfilling Koch's rules. P. nicotianae has been reported causing root rot and stem necrosis not only on cockscomb (C. plumosa Hort. ex Burvenich) in Argentina (Frezzi 1950), but also infecting several ornamental plants recently in Taiwan (Ann et al. 2018). To our knowledge, this is the first report of stem blight caused by P. nicotianae on plumed cockscombs in Taiwan. This finding suggests limited options for landscaping and the host preference of the isolates obtained in this study should warrant further studies.
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The rhizobacterial strain BJ3 showed 16S rDNA sequence similarity to species within the Burkholderia genus. Its complete genome sequence revealed a 97% match with Burkholderia contaminans and uncovered gene clusters essential for plant-growth-promoting traits (PGPTs). These clusters include genes responsible for producing indole acetic acid (IAA), osmolytes, non-ribosomal peptides (NRPS), volatile organic compounds (VOCs), siderophores, lipopolysaccharides, hydrolytic enzymes, and spermidine. Additionally, the genome contains genes for nitrogen fixation and phosphate solubilization, as well as a gene encoding 1-aminocyclopropane-1-carboxylate (ACC) deaminase. The treatment with BJ3 enhanced root architecture, boosted vegetative growth, and accelerated early flowering in Arabidopsis. Treated seedlings also showed increased lignin production and antioxidant capabilities, as well as notably increased tolerance to water deficit and high salinity. An RNA-seq transcriptome analysis indicated that BJ3 treatment significantly activated genes related to immunity induction, hormone signaling, and vegetative growth. It specifically activated genes involved in the production of auxin, ethylene, and salicylic acid (SA), as well as genes involved in the synthesis of defense compounds like glucosinolates, camalexin, and terpenoids. The expression of AP2/ERF transcription factors was markedly increased. These findings highlight BJ3's potential to produce various bioactive metabolites and its ability to activate auxin, ethylene, and SA signaling in Arabidopsis, positioning it as a new Burkholderia strain that could significantly improve plant growth, stress resilience, and immune function.
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Arabidopsis , Burkholderia , Estresse Fisiológico , Burkholderia/genética , Burkholderia/metabolismo , Burkholderia/crescimento & desenvolvimento , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/microbiologia , Estresse Fisiológico/genética , Desenvolvimento Vegetal/genética , Ácidos Indolacéticos/metabolismo , Regulação da Expressão Gênica de Plantas , Genômica/métodos , Reguladores de Crescimento de Plantas/metabolismo , Raízes de Plantas/microbiologia , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Etilenos/metabolismoRESUMO
The binary heterostructured semiconducting visible light photocatalyst of the iron-doped graphitic carbon nitride/bismuth molybdate (Fe-g-C3N4/Bi2MoO6) composite was prepared by coupling with Fe-doped g-C3N4 and Bi2MoO6 particles. In the present study, a comparison of structural characteristics, optical properties, and photocatalytic degradation efficiency and activity between Fe-doped g-C3N4 particles, Bi2MoO6 particles, and Fe-g-C3N4/Bi2MoO6 composite was investigated. The results of X-ray diffraction (XRD) examination indicate that the hydrothermal Bi2MoO6 particles have a single orthorhombic phase and Fourier transform infrared (FTIR) spectroscopy analysis confirms the formation of Fe-doped g-C3N4. The optical bandgaps of the Fe-doped g-C3N4 and Bi2MoO6 particles are 2.74 and 2.73 eV, respectively, as estimated from the Taut plots obtained from UV-Vis diffuse reflectance spectroscopy (DRS) spectra. This characteristic indicates that the two semiconductor materials are suitable for absorbing visible light. The transmission electron microscopy (TEM) micrograph reveals the formation of the heterojunction Fe-g-C3N4/Bi2MoO6 composite. The results of photocatalytic degradation revealed that the developed Fe-g-C3N4/Bi2MoO6 composite photocatalyst exhibited significantly better photodegradation performance than the other two single semiconductor photocatalysts. This property can be attributed to the heterostructured nanostructure, which could effectively prevent the recombination of photogenerated carriers (electron-hole pairs) and enhance photocatalytic activity. Furthermore, cycling test showed that the Fe-g-C3N4/Bi2MoO6 heterostructured photocatalyst exhibited good reproducibility and stability for organic dye photodegradation.
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BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape of cancer treatment, but only a fraction of patients responds to treatment, leading to an increasing effort to repurpose clinically approved medications to augment ICI therapy. Metformin has been associated with improved survival outcomes in patients undergoing conventional chemotherapy. However, whether metformin provides survival benefits in patients receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: We performed a retrospective cohort study at two tertiary referral centers in Taiwan. All adult diabetes mellitus patients who were treated with ICIs between January 2015 and December 2021 were included. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: In total, 878 patients were enrolled in our study, of which 86 patients used metformin and 78 patients used non-metformin diabetes medications. Compared with non-users, metformin users had a longer median OS (15.4 [IQR 5.6-not reached] vs. 6.1 [IQR, 0.8-21.0] months, P = 0.003) and PFS (5.1 [IQR 2.0-14.3] vs. 1.9 [IQR 0.7-8.6] months, P = 0.041). In a univariate Cox proportional hazard analysis, the use of metformin was associated with a reduction in the risk of mortality (HR: 0.53 [95% confidence interval: 0.35-0.81], P = 0.004) and disease progression (HR: 0.69 [95% CI 0.49-0.99], P = 0.042). The use of metformin remained associated with a lower risk of mortality after adjusting for baseline variables such as age, cancer stage, and underlying comorbidities (OS, HR: 0.55 [95% CI 0.34-0.87], P = 0.011). Similarly, the use of metformin was associated with a lower risk of disease progression. Importantly, the use of metformin before ICI initiation was not associated with a reduction in mortality (HR: 0.61 [95% CI 0.27-1.42], P = 0.25) or disease progression (HR: 0.69 [95% CI 0.33-1.43], P = 0.32). CONCLUSION: The use of metformin is associated with survival benefits in patients undergoing immunotherapy. Prospective clinical trials are warranted to define the role of metformin in augmenting immunotherapy.
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Metformina , Adulto , Humanos , Metformina/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Estudos Prospectivos , Progressão da DoençaRESUMO
BACKGROUND: Statins are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the impact of lipophilic and hydrophilic statin properties on patient outcomes is unknown. OBJECTIVES: We aim to investigate if statins with lipophilic properties are associated with clinical outcomes in patients receiving ICIs. METHOD: We conducted a retrospective cohort study at two tertiary referral centers in Taiwan comprising patients receiving ICIs between January 2015 and December 2021. We compared the comparative effect of lipophilic and hydrophilic statins on patient outcomes. The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). RESULTS: Among 734 patients receiving ICIs, there were 51 lipophilic statin users, 25 hydrophilic statin users, and 658 nonusers. Lipophilic statin users had a longer median OS (38.0 [IQR, 16.7-not reached] vs. 15.2 [IQR, 8.2-not reached] months vs. 18.9 [IQR, 5.4 51.6] months) and PFS (13.0 [IQR, 4.7-41.5] vs. 8.2 [IQR, 2.2-14.7] months vs. 5.6 [2.3-18.7] months) than hydrophilic statin users and non-statin users. In Cox proportional hazard analyses, the use of lipophilic statins was associated with a 40-50% lower risk of mortality and disease progression compared with hydrophilic statin or non-statin users. CONCLUSIONS: The use of lipophilic statins seems to be associated with survival benefits in patients undergoing immunotherapy.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Inibidores de Checkpoint Imunológico , Humanos , Estudos Retrospectivos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Progressão da DoençaRESUMO
New Guinea impatiens (Impatiens hawkeri) is a common ornamental crop usually planted in pots and planters, flower beds, home gardens, or parks in Taiwan. In June 2021, leaf spots on 87.1% (27/31) of potted I. hawkeri plants on National Chung Hsing University (NCHU) campus were observed. Initially, tiny chlorotic leaf spots were found, which aged into brown to grayish white necrotic spots with reddish-purple margins. The necrotic spots enlarged, coalesced, and formed concentric rings. To isolate the pathogen, diseased leaves were surface-disinfected with 70% ethanol for 15 seconds and blotted dry with a paper towel. Small pieces (~2×6 mm2) of tissues were excised from the junction of the lesions and healthy areas, placed onto 2% water agar, and incubated at 25°C with 12-h photoperiod for three days. Individual hyphal tips growing out of diseased tissues were transferred onto potato dextrose agar (PDA). Three isolates, OM10, OM43, and OM45, were obtained and grown on half-strength PDA at 28°C in the dark for at least two weeks. Conidia of each isolate produced on the half-strength PDA were washed off in sterile water with 0.01% of Tween 20. Pathogenicity tests were performed by spraying leaves of 2- to 3-month-old potted healthy I. hawkeri plants with 5 ml of conidial suspension (1 × 105 conidia/ml) of the three isolates, respectively. Control plants were sprayed with sterile water. There were four plants per treatment and the experiments were conducted twice. Inoculated plants were covered with plastic bags for two days and incubated in a greenhouse with a temperature range of 19 to 31°C. Leaf spots similar to those observed in the field were observed at 7 to 14 days after inoculation in both trials. The same fungus was isolated from inoculated plants, whereas control plants showed no symptoms. Thereafter, the three isolates were subjected to morphological and molecular identification. Colonies were brown to gray in the center and white in the border with abundant aerial mycelia. Conidia were brown, obclavate to ovoid, produced in single or branched chains, one to seven transverse and zero to three longitudinal septa. Conidial size of the three isolates ranged between 11.2 to 43.1 × 6.0 to 12.7 µm (n = 50 for each isolate). Conidiophores of the three isolates were dark-brown, septate, branched or unbranched, and measured 27.0 to 147.65 × 2.71 to 4.54 µm (n = 50 for each isolate). Based on the morphological characteristics, the three isolates were identified as Alternaria spp. (Simmons 2007). For molecular identification, the internal transcribed spacer (ITS) region, RNA polymerase II second largest subunit (RPB2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and major allergen Alt-a-1 gene (Alt-a-1) were amplified using primer pairs ITS1/ITS4 (White et al. 1990), RPB2-5F2/RPB2-7cR (Sung et al. 2007), gpd1/gpd2 (Berbee et al. 1999), and Alt-for/Alt-rev (Hong et al. 2005), respectively. Sequence analyses of isolates OM10 (ITS: GenBank Accession no. OP358436; RPB2: OP377483; GAPDH: OP377468; Alt-a-1: OP377471), OM43 (ITS: OP358437; RPB2: OP377484; GAPDH: OP377469; Alt-a-1: OP377472), and OM45 (ITS: OP358438; RPB2: OP377485; GAPDH: OP377470; Alt-a-1: OP377473) showed 100%, 99.61 to 100%, 99.65%, and 100% identities with a reference strain CBS 107.38 of A. burnsii for ITS (KP124420), RPB2 (KP124889), GAPDH (JQ646305), and Alt-a-1 (KP123967), respectively. They also showed 100%, 99.61 to 100%, 99.65%, and 99.58% identities with an A. tomato strain CBS 103.30 for ITS (KP124445), RPB2 (KP124915), GAPDH (KP124294), and Alt-a-1 (KP123991), respectively. Based on the morphological and sequence characteristics, the pathogen causing New Guinea impatiens leaf spot was identified as a member of the Alternaria burnsii - A. tomato species complex. The diseased plants on NCHU campus were destroyed. There have been no reports of the disease in other landscape areas or nurseries. To our knowledge, this is the first report of A. burnsii - A. tomato species complex causing New Guinea impatiens leaf spot in Taiwan. Since the pathogens in the species complex have been documented causing diseases on several important economic crops and the New Guinea impatiens is widely planted in nurseries and landscapes, the host range and the significance of the pathogen in agro-ecosystem may warrant further investigations.
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A multi-step procedure was effectively employed to synthesize innovative three-dimensional (3D) heterostructures encompassing sodium titanate (Na2Ti3O7) nanowire cores, an intermediate resorcinol-formaldehyde (RF) layer, and outer silver (Ag) nanoparticle sheaths, referred to as Na2Ti3O7@RF@Ag heterostructures. Initially, a one-step hydrothermal technique facilitated the direct growth of single-crystal Na2Ti3O7 nanowires onto a flexible Ti foil. Subsequently, a two-step wet chemical process facilitated the sequential deposition of an RF layer and Ag nanoparticles onto the Na2Ti3O7 nanowires at a low reaction temperature. Optimal concentrations of silver nitrate and L-ascorbic acid can lead to the cultivation of Na2Ti3O7@RF@Ag heterostructures exhibiting heightened surface-enhanced Raman scattering (SERS), which is particularly beneficial for the detection of rhodamine B (RhB) molecules. This phenomenon can be ascribed to the distinctive geometry of the Na2Ti3O7@RF@Ag heterostructures, which offer an increased number of hot spots and surface-active sites, thereby showcasing notable SERS enhancement, commendable reproducibility, and enduring stability over the long term. Furthermore, the Na2Ti3O7@RF@Ag heterostructures demonstrate remarkable follow-up as first-order chemical kinetic and recyclable photocatalysts for the photodecomposition of an RhB solution under UV light irradiation. This result can be attributed to the enhanced inhibition of electron-hole pair recombination and increased surface-active sites.
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PURPOSE: Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone. METHODS: We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB. RESULTS: We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB. CONCLUSIONS: Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Compostos de Anilina/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
Immune thrombocytopenia (ITP) is a condition that is distinct from thrombosis with thrombocytopenia syndrome (TTS) that may also occur after coronavirus disease 2019 (COVID-19) vaccinations. Previous reports revealed an increased ITP incidence after ChAdOx1, a vaccine for COVID-19. Our study aimed to highlight the key features of ITP after COVID-19 vaccination. From April to October 2021, we collected data on 23 patients, including nine men and 14 women, with ITP from five hospitals across Taiwan who received either the ChAdOx1 or mRNA-1273 vaccine before development or exacerbation of ITP. Our findings revealed that both ChAdOx1 and mRNA-1273 vaccines were associated with ITP. Many patients responded well to steroids and immune suppressants, which may also suggest that the nature of thrombocytopenia is more like ITP rather than TTS. Lack of thrombosis, low D-dimer level, and negative anti-PF4 result could help to exclude TTS, which is also a rare but a far more lethal condition.
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COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Trombose , Vacinas , Vacina de mRNA-1273 contra 2019-nCoV , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/complicações , Síndrome , Taiwan/epidemiologia , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia , Trombose/complicações , Vacinação/efeitos adversosRESUMO
Vertical-aligned CuO nanowires have been directly fabricated on Cu foil through a facile thermal oxidation process by a hotplate at 550 °C for 6 h under ambient conditions. The intermediate layer of resorcinol-formaldehyde (RF) and silver (Ag) nanoparticles can be sequentially deposited on Cu nanowires to form CuO@RF@Ag core-shell nanowires by a two-step wet chemical approach. The appropriate resorcinol weight and silver nitrate concentration can be favorable to grow the CuO@RF@Ag nanowires with higher surface-enhanced Raman scattering (SERS) enhancement for detecting rhodamine 6G (R6G) molecules. Compared with CuO@Ag nanowires grown by ion sputtering, CuO@RF@Ag nanowires exhibited a higher SERS enhancement factor of 5.33 × 108 and a lower detection limit (10-12 M) for detecting R6G molecules. This result is ascribed to the CuO@RF@Ag nanowires with higher-density hot spots and surface-active sites for enhanced high SERS enhancement, good reproducibility, and uniformity. Furthermore, the CuO@RF@Ag nanowires can also reveal a high-sensitivity SERS-active substrate for detecting amoxicillin (10-10 M) and 5-fluorouracil (10-7 M). CuO@RF@Ag nanowires exhibit a simple fabrication process, high SERS sensitivity, high reproducibility, high uniformity, and low detection limit, which are helpful for the practical application of SERS in different fields.
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Nanopartículas Metálicas , Nanofios , Análise Espectral Raman/métodos , Nanopartículas Metálicas/química , Reprodutibilidade dos Testes , Prata , Nanofios/química , FormaldeídoRESUMO
Mucopolysaccharidosis Type VII (MPS7, also called ß-glucuronidase deficiency or Sly syndrome; MIM 253220) is an extremely rare autosomal recessive lysosomal storage disease, caused by mutations in the GUSB gene. ß-glucuronidase (GUSB) is a lysosomal hydrolase involved in the stepwise degradation of glucuronic acid-containing glycosaminoglycans (GAGs). Patients affected with MPS VII are not able to completely degrade glucuronic acid-containing GAGs, including chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and heparan sulfate. The accumulation of these GAGs in lysosomes of various tissues leads to cellular and organ dysfunctions. Characteristic features of MPS VII include short stature, macrocephaly, hirsutism, coarse facies, hearing loss, cloudy cornea, short neck, valvular cardiac defects, hepatosplenomegaly, and dysostosis multiplex. Oral manifestations in patients affected with MPS VII have never been reported. Oral manifestations observed in three patients consist of wide root canal spaces, taurodontism, hyperplastic dental follicles, malposition of unerupted permanent molars, and failure of tooth eruption with malformed roots. The unusual skeletal features of the patients include maxillary hypoplasia, hypoplastic midface, long mandibular length, mandibular prognathism, hypoplastic and aplastic mandibular condyles, absence of the dens of the second cervical vertebra, and erosion of the cortex of the lower border of mandibles. Dogs affected with MPS VII had anterior and posterior open bite, maxillary hypoplasia, premolar crowding, and mandibular prognathism. Unlike patients with MPS VII, the dogs had unremarkable mandibular condyles. This is the first report of oral manifestations in patients affected with MPS VII.
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Doenças do Cão/diagnóstico , Anormalidades da Boca/diagnóstico , Mucopolissacaridose VII/diagnóstico , Fenótipo , Adolescente , Animais , Criança , Doenças do Cão/genética , Cães , Fácies , Feminino , Glucuronidase/química , Glucuronidase/genética , Glucuronidase/metabolismo , Humanos , Lactente , Modelos Moleculares , Mucopolissacaridose VII/genética , Conformação Proteica , Radiografia , Relação Estrutura-Atividade , Tomografia Computadorizada por Raios XRESUMO
The K+ channel pore-forming subunit Kv4.3 is expressed in a subset of nonpeptidergic nociceptors within the dorsal root ganglion (DRG), and knockdown of Kv4.3 selectively induces mechanical hypersensitivity, a major symptom of neuropathic pain. K+ channel modulatory subunits KChIP1, KChIP2, and DPP10 are coexpressed in Kv4.3+ DRG neurons, but whether they participate in Kv4.3-mediated pain control is unknown. Here, we show the existence of a Kv4.3/KChIP1/KChIP2/DPP10 complex (abbreviated as the Kv4 complex) in the endoplasmic reticulum and cell surface of DRG neurons. After intrathecal injection of a gene-specific antisense oligodeoxynucleotide to knock down the expression of each component in the Kv4 complex, mechanical hypersensitivity develops in the hindlimbs of rats in parallel with a reduction in all components in the lumbar DRGs. Electrophysiological data further indicate that the excitability of nonpeptidergic nociceptors is enhanced. The expression of all Kv4 complex components in DRG neurons is downregulated following spinal nerve ligation (SNL). To rescue Kv4 complex downregulation, cDNA constructs encoding Kv4.3, KChIP1, and DPP10 were transfected into the injured DRGs (defined as DRGs with injured spinal nerves) of living SNL rats. SNL-evoked mechanical hypersensitivity was attenuated, accompanied by a partial recovery of Kv4.3, KChIP1, and DPP10 surface levels in the injured DRGs. By showing an interdependent regulation among components in the Kv4 complex, this study demonstrates that K+ channel modulatory subunits KChIP1, KChIP2, and DPP10 participate in Kv4.3-mediated mechanical pain control. Thus, these modulatory subunits could be potential drug targets for neuropathic pain.SIGNIFICANCE STATEMENT Neuropathic pain, a type of moderate to severe chronic pain resulting from nerve injury or disorder, affects 6.9%-10% of the global population. However, less than half of patients report satisfactory pain relief from current treatments. K+ channels, which act to reduce nociceptor activity, have been suggested to be novel drug targets for neuropathic pain. This study is the first to show that K+ channel modulatory subunits KChIP1, KChIP2, and DPP10 are potential drug targets for neuropathic pain because they form a channel complex with the K+ channel pore-forming subunit Kv4.3 in a subset of nociceptors to selectively inhibit mechanical hypersensitivity, a major symptom of neuropathic pain.
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Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Proteínas Interatuantes com Canais de Kv/metabolismo , Dor Nociceptiva/metabolismo , Canais de Potássio Shal/metabolismo , Animais , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Proteínas Interatuantes com Canais de Kv/genética , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Dor Nociceptiva/fisiopatologia , Ratos , Ratos Sprague-Dawley , Canais de Potássio Shal/genética , TatoRESUMO
The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.