RESUMO
Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.
RESUMO
Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.
Assuntos
Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/genética , Mutação , Calgranulina A/genética , Sequência de Bases , Fenótipo , Calreticulina/genética , Janus Quinase 2/genéticaRESUMO
Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP) has been assumed to be one of secondary ITP and associated with antiplatelet antibodies. This study was to clarify the antibody profile in HCV-ITP compared with primary ITP. We enrolled 55 HCV-ITP, 30 primary ITP, 11 Helicobacter pylori-ITP, 21 HCV control, and 16 healthy volunteers. We reviewed their blood cell counts, autoimmune markers, and spleen size. We used enzyme-linked immunosorbent assay kit to detect the specific antibody to glycoproteins IIb/IIIa, Ia/IIa, Ib/IX, IV, and human leukocyte antigen (HLA) class I. Compared with primary ITP patients, HCV-ITP patients had an older age, lower white blood cell (WBC) count and fewer presented with severe thrombocytopenia. The rate of positive antibody detection was 63.6% for the HCV-ITP group higher than the rate of 40% for the primary ITP. In the HCV control, antiplatelet antibodies were detected in 38.1% patients and no one had more than two types of antibodies. The antiplatelet antibodies correlated to severer thrombocytopenia. An HLA class I antibody was associated with lower WBCs and larger spleen. In conclusion, HCV-ITP patients had a high rate of positive antiplatelet antibody. The antibodies were associated with not only lower platelets but also leukopenia and splenomegaly.
Assuntos
Plaquetas/metabolismo , Hepacivirus/imunologia , Púrpura Trombocitopênica Idiopática/sangue , Trombocitopenia/sangue , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/PURPOSE: Ropeginterferon alpha-2b (Ropeg) is a novel pegylated interferon-alpha recently approved for the treatment of polycythemia vera (PV) in Europe. However, other than data from clinical trials, little is known about this agent in real world practice. METHODS: A compassionate use program employing Ropeg for treating patients with unmet medical need was initiated in Taiwan in 2017. Herein, we collected clinical data and assessed the safety as well as efficacy of Ropeg in nine patients treated in this program. RESULTS: Collectively, among evaluable patients, both the molecular response and complete blood count remission rates were 62.5%. Most therapy-related side effects were mild, and there was no treatment discontinuation attributable to intolerable adverse events. The agent also showed efficacy in symptom amelioration and spleen size reduction. Although no specific patterns of cytokine level alteration could be identified, significantly attenuated plasma levels of inflammation markers were observed in one particular patient who happened to have normalized spleen size and most remarkable reduction in JAK2 mutant allele burden, indicating all-around improvement in every aspect of this case. Furthermore, plasma hepcidin levels increased in two-thirds of PV patients, illustrating the potential of Ropeg to restore normal regulation of erythropoiesis. Using RNA sequencing on pre- and post-treatment samples from one patient, we demonstrated altered expression of genes participating in IFN response, inflammation, apoptosis, and cellular differentiation. CONCLUSION: Conclusively, observed signs of efficacy and safety in our real-world experience prove Ropeg as a promising option for the treatment of MPN.
Assuntos
Leucemia Mieloide Crônica Atípica BCR-ABL Negativa , Policitemia Vera , Alelos , Europa (Continente) , Humanos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Polietilenoglicóis , TaiwanRESUMO
In this study, liquid chromatography-mass spectrometry(LC-MS) and high performance liquid chromatography(HPLC) were employed for qualitative and quantitative analysis of the steroidal saponins in rhizomes of Paris polyphylla var. yunnanensis from three different habitats cultured in vitro, in an attempt to explore whether the rhizomes of the medicinal herb cultured in vitro can synthesize the steroidal saponins, including polyphyllinsâ , â ¡, and â ¦, the quality markers specified in Chinese Pharmacopoeia(2020 edition). A total of 20 steroidal saponins were identified in the rhizomes from Changxin, Yunlong(S1), Fengyi, Dali(S2), and Niujie, Eryuan(S3): parisyunnanoside A and parisyunnanoside D or E, proto-polyphyllin â ¡, polyphyllins G and H, polyphyllinsâ , â ¡, â ¤, â ¥, and â ¦, dioscin, gracillin, prosapogenin A, Tg, isomer of Th, saponin Th, reclinatoside, proto-pairs D, pseudoproto-dioscin, and 23-O-glc-(23S,25R)-spirost-5-en-3ß,23α,27-triol-3-O-rha-(1â2)-[ara(1â4)]-glc or 27-O-glc-(23S,25R)-spirost-5-en-3ß,27α-diol-3-O-rha-(1â2)-[ara(1â4)]-glc. Among them, polyphyllinsâ , â ¡, and â ¦ were detected in the rhizomes from S1, with the mass fraction of 0.109 1%, 0.165 2%, and 0.051 03%, respectively(total 0.325 3%). Polyphyllins â ¡ and â ¦ were identified in the rhizomes from S2 with the respective mass fraction of 0.192 2% and 0.074 23% and total content of 0.266 5%. Moreover, polyphyllins â ¡ and â ¦ were also found in the rhizomes from S3, which had the mass fraction of 0.207 7% and 0.186 9%, separately, with the total content of 0.394 6%. Thus, steroidal saponins, including the quality makers polyphyllins â , â ¡, and â ¦ recorded in Chinese Pharmacopoeia(2020 edition) can be synthesized in rhizomes of Paris polyphylla var. yunnanensis cultured in vitro, but their total content fails to meet the standard(0.60% in Chinese Pharmacopoeia). Therefore, in vitro culture of the Paris polyphylla var. yunnanensis is feasible, but the culture conditions need to be further improved.
Assuntos
Liliaceae , Melanthiaceae , Saponinas , Cromatografia Líquida de Alta Pressão , RizomaRESUMO
Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single-cell RNA sequencing (scRNA-Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple-negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra-individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA-Seq extended our knowledge of clonal diversity and inter-individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.
Assuntos
Calreticulina , Janus Quinase 2 , RNA-Seq , Análise de Célula Única , Trombocitemia Essencial , Transcriptoma , Adulto , Substituição de Aminoácidos , Calreticulina/genética , Calreticulina/metabolismo , Feminino , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Trombocitemia Essencial/sangue , Trombocitemia Essencial/genéticaRESUMO
BACKGROUND: Although C-reactive protein (CRP) and procalcitonin (PCT) are widely used inflammatory markers for infectious diseases, their role and potential application for rickettsioses were rarely studied. METHODS: A retrospective chart review and serological study were conducted in patients with rickettsioses. The clinical presentations, characteristics, laboratory data, and treatment responses were recorded and their associations with CRP and PCT values were analyzed. RESULTS: A total of 189 cases of rickettsioses, including 115 cases of acute Q fever (60.8%), 55 cases of scrub typhus (29.1%), and 19 cases of murine typhus (10.1%) were investigated. Both CRP and PCT values increased in the acute phase and declined in the convalescent phase. In the acute phase, mean CRP and PCT values were 78.2 ± 63.7 mg/L and 1.05 ± 1.40 ng/mL, respectively. Percentages of patients falling under different cut-off values of CRP and PCT were calculated systematically. Only 10.8% of CRP was > 150 mg/L and 14.2% of PCT was > 2.0 ng/mL. Patients with delayed responses to doxycycline treatment (> 3 days from treatment to defervescence) had significantly higher CRP values (102.7 ± 77.1 vs. 72.2 ± 58.2 mg/L, p = 0.041) and more PCT > 1.0 ng/ml (48.4% vs. 26.0%, p = 0.019) in the acute phase; higher CRP values (19.1 ± 37.4 vs. 3.6 ± 13.1 mg/L, p = 0.049) and more PCT > 0.5 ng/ml (19.2% vs. 1.4%, p = 0.005) in the convalescent phase. Correlation analysis was conducted for patients with acute Q fever. CRP and PCT values were positively correlated to each other, and both markers also had a positive correlation with serum aspartate transaminase values. Both CRP and PCT values and white blood cell counts were positively correlated to the days needed from doxycycline treatment to defervescence. CONCLUSION: CRP and PCT values might be useful in clinical investigations for patients with suspected rickettsioses and in predicting the response to doxycycline treatment for rickettsioses.
Assuntos
Proteína C-Reativa/análise , Coxiella burnetii/imunologia , Orientia tsutsugamushi/imunologia , Pró-Calcitonina/sangue , Febre Q/sangue , Rickettsia typhi/imunologia , Tifo por Ácaros/sangue , Tifo Endêmico Transmitido por Pulgas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biomarcadores/sangue , Doxiciclina/uso terapêutico , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Febre Q/tratamento farmacológico , Febre Q/microbiologia , Estudos Retrospectivos , Tifo por Ácaros/tratamento farmacológico , Tifo por Ácaros/microbiologia , Tifo Endêmico Transmitido por Pulgas/tratamento farmacológico , Tifo Endêmico Transmitido por Pulgas/microbiologia , Adulto JovemRESUMO
In pathogenesis of Parkinson's disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP+- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP+. Further studies demonstrated that SC79 attenuated MPP+- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Acetatos/farmacologia , Benzopiranos/farmacologia , Neurônios Dopaminérgicos/patologia , Ativadores de Enzimas/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rotenona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
BH3 mimetics exert anticancer activity by inhibiting anti-apoptotic BCL2 proteins. However, accumulating evidence indicates that the off-target effects of these drugs tightly modulates their anticancer activities. In this study, we investigated whether the BCL2L1 inhibitor A-1331852 induced the death of U937 acute myeloid leukemia (AML) cells through a non-BCL2L1-targeted effect. A-1331852-induced apoptosis in U937 cells was characterized by increased ROS production, downregulation of MCL1, and loss of mitochondrial membrane potential. Ectopic expression of MCL1 alleviated A-1331852-induced mitochondrial depolarization and cytotoxicity in U937 cells. A-1331852-induced ROS production increased p38 MAPK phosphorylation and inhibited MCL1 transcription. Inhibition of p38 MAPK activation restored MCL1 expression in A-1331852-treated cells. A-1331852 triggered p38 MAPK-mediated Cullin 3 downregulation, which in turn increased PP2Acα expression, thereby reducing CREB phosphorylation. A-1331852 reduced the binding of CREB to the MCL1 promoter, leading to the inhibition of CREB-mediated MCL1 transcription. Furthermore, A-1331852 acted synergistically with the BCL2 inhibitor ABT-199 to induce U937 and ABT-199-resistant U937 cell death by inhibiting MCL1 expression. A similar phenomenon caused A-1331852-induced MCL1 downregulation and cytotoxicity in AML HL-60 cells. Collectively, our data suggest that A-1331852 shows an off-target effect of inhibiting MCL1 transcription, ultimately leading to U937 and HL-60 cell death.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Células U937 , Espécies Reativas de Oxigênio , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Proteínas Reguladoras de Apoptose , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
OBJECTIVE: Adequate brain swelling resolution prior to cranioplasty (CP) is an important yet loosely defined issue. Despite efforts to balance timely CP and patient safety, heterogeneous study methodologies have led to conflicting results. This study aims to standardize this issue through quantifying degree of brain swelling resolution using a proposed Visual CP Scale. METHODS: The proposed Visual CP Scale is validated through a 2-pronged approach. The first prong involves a national survey in Taiwan, where neurosurgeons were surveyed to determine what constitutes a patient's readiness for CP. The second prong involves a large retrospective cohort, where the correlations between timing, degree of brain swelling resolution, and post-CP complication rates, are evaluated. RESULTS: In the national Taiwan CP Survey, 124 out of 772 neurosurgeons (17.2%) completed the survey. Respondents who chose higher grades on the Visual CP Scale preferred later CP timings. In the retrospective data, 378 out of 770 (49.1%) patients had pre-CP brain images, allowing for the utilization of the Visual CP Scale. A Visual CP Scale score of greater than or equal to 4 was associated with fewer complications after CP. CONCLUSIONS: The timing of CP should be determined by the degree of brain swelling resolution, not vice versa. The proposed Visual CP Scale offers an objective method for assessing brain swelling resolution, making it an adjuvant tool for clinical decision-making and future research related to CP.
RESUMO
Sarcopenia has been associated with conventional chemotherapy-related toxicity, postoperative complications and poor overall survival in patients with genotype-unselected metastatic colorectal cancer (mCRC). This study aimed to evaluate the prognostic implications of sarcopenia and its change after perioperative cetuximab plus doublet chemotherapy and hepatectomy in patients with RAS wild-type colorectal liver metastasis (CRLM). Patients with CRLM from 2007 to 2018 in Chang Gung Research Database were retrospectively analyzed. Baseline characteristics as well as skeletal muscle index (SMI) at baseline and dynamic changes after interventions were collected. A multivariate Cox proportional hazard model was used to evaluate the effect of each parameter on overall survival (OS), and the Kaplan-Meier method was used to establish survival curves. A two-sided p value < 0.05 was considered statistically significance. Of 214 RAS wild-type mCRC patients who received both cetuximab and doublet chemotherapy, 77 who received upfront or subsequent hepatectomy were included in this study. The median follow-up time was 2.3 years. The rate of sarcopenia was higher in the patients who received neoadjuvant cetuximab-containing regimens than in those who received upfront hepatectomy (95% versus 63%, p = 0.001). Increased SMI after perioperative systemic therapy remained independently associated with better OS in multivariate analysis [hazard ratio (HR) = 0.27/10% increase, p = 0.013). The patients with sarcopenia had a trend of worse OS than those without sarcopenia (median OS: 4.5 versus 3.6 years, log-rank p = 0.282). Improvement in sarcopenia ([SMI after intervention - initial SMI]/initial SMI × 100%) is an important prognostic factor for OS. Future research is warranted to investigate direct interventions for sarcopenia and the impact on OS.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Sarcopenia , Humanos , Sarcopenia/etiologia , Hepatectomia/efeitos adversos , Cetuximab/uso terapêutico , Estudos Retrospectivos , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
AIM: To provide quality care to older adults, healthcare professionals should be aware that osteoporotic vertebral compression fractures (OVCFs) might occur sequentially in the same patient, involving different vertebral bodies, each separated by short intervals. This situation is called chronologically clustered OVCFs (CCOVCF). METHODS: A total of 40 patients with CCOVCFs (index cohort) were retrospectively analyzed, and compared with 40 patients having only one OVCF (comparison cohort). All fractures were treated with percutaneous balloon kyphoplasty. RESULTS: In the index cohort, the number of patients having the second, third, fourth and fifth OVCF events within 3 months were 40, 15, five and two, respectively. Recurring pain or seemingly non-stop pain were the major reasons why new OCVFs were found. The average interval between pain relief provided by percutaneous balloon kyphoplasty and radiographic diagnosis of new OVCFs was significantly longer than that between pain relief and a new episode of disabling pain (26.7 ± 16.8 vs 16.4 ± 15.8 days, P < 0.0001), reflecting how shortly new OCVFs occurred after successful surgery, and how often they were neglected. The mean T-score of the index cohort was significantly lower than that of the comparison cohort (-3.66 ± 0.79 vs -3.17 ± 0.80, P = 0.01). CONCLUSIONS: CCOVCFs make a patient seem constantly in pain, despite repeated admissions and operations. Recurrent symptoms after an effective procedure should be taken as a warning that a new OCVF might have occurred, even if only a few days apart. Advanced osteoporosis is a significant risk factor for CCOVCFs. Geriatr Gerontol Int 2023; 23: 44-49.
Assuntos
Fraturas por Compressão , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Idoso , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/etiologia , Fraturas por Compressão/cirurgia , Estudos Retrospectivos , Cifoplastia/métodos , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/cirurgia , Dor , Resultado do TratamentoRESUMO
Background And Objectives: Human platelet antigens (HPAs) are alloantigens associated with antiplatelet alloantibodies and the risk of immune thrombocytopenia (ITP). However, few studies have investigated associations among HPAs, antiplatelet autoantibodies, and cryoglobulins. Methods: We enrolled 43 patients with primary ITP, 47 with hepatitis C virus-associated ITP (HCV-ITP), 21 with hepatitis B virus-associated ITP (HBV-ITP), 25 controls with HCV, and 1013 normal controls. We analyzed HPA allele frequencies, including HPA1-6 and 15, antiplatelet antibodies binding to platelet glycoprotein (GP) IIb/IIIa, Ia/IIa, Ib/IX, IV, human leukocyte antigen class I, cryoglobulin IgG/A/M, and their associations with thrombocytopenia. Results: In the ITP cohort, HPA2ab, rather than HPA2aa, predicted a low platelet count. HPA2b was associated with the risk of developing ITP. HPA15b was correlated with multiple antiplatelet antibodies. In HCV-ITP patients, HPA3b was correlated with anti-GPIIb/IIIa antibodies. HCV-ITP patients with anti-GPIIb/IIIa antibodies had a higher positive rate of cryoglobulin IgG and IgA compared with those without anti-GPIIb/IIIa antibodies. Overlapping detection was also found among other antiplatelet antibodies and cryoglobulins. Like the antiplatelet antibodies, cryoglobulins were associated with clinical thrombocytopenia, implying their close relationship. Finally, we extracted cryoglobulins to confirm the exhibition of cryoglobulin-like antiplatelet antibodies. In contrast, in primary ITP patients, HPA3b was correlated with cryoglobulin IgG/A/M rather than anti-GPIIb/IIIa antibodies. Conclusion: HPA alleles were associated with antiplatelet autoantibodies and had different impacts in primary ITP and HCV-ITP patients. HCV-ITP was considered to be a symptom of mixed cryoglobulinemia in HCV patients. The pathophysiology may differ between these two groups.
RESUMO
Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
Assuntos
Neoplasias Ósseas , Condrossarcoma , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Anfirregulina/genética , Glutamina , Resistencia a Medicamentos Antineoplásicos/genética , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de AminoácidosRESUMO
Cranioplasty to reconstruct a skull defect after a decompressive craniectomy (DC) is a common neurosurgical procedure. However, cranioplasty is associated with relatively high complication rates, with optimal timing from craniectomy to cranioplasty remaining a controversial matter. Recent studies demonstrated early cranioplasty with appropriate risk mitigation to be a viable option with many clinical advantages, propelling the advocacy for cranioplasty as soon as brain swelling resolves. We report on a 33-year-old male with traumatic brain injury who received an early cranioplasty, 18 days post-DC. The extent of adequate brain swelling resolution was determined by superimposing selected pre-cranioplasty computed tomography (CT) images onto corresponding pre-craniectomy CT images. By ensuring all brain matter lies within the outer table of the skull in superimposed brain images, the extent of brain swelling resolution could be determined reliably and the feasibility of cranioplasty can be assessed objectively.
RESUMO
Introduction: Stroke remains a leading cause of death worldwide. Stroke in young adults is an important issue, gaining extra attention in recent years. This study aims to investigate the mortality after stroke in young adults in Taiwan. Patients and methods: This is a registry- and population-based study in Taiwan of patients aged 20-50 years with first-ever stroke between 1999 and 2012, with follow-up until January 1, 2022. Patients and mortalities were identified through Taiwan National Health Insurance database. Results: The study population included 65,097 patients with stroke (mean age, 42.6 ± 6.6 years; 30.5% woman). There were 23,481 (36.1%) intracranial hemorrhage, 37,522 (57.6%) ischemic stroke, and 4094 (6.3%) stroke not otherwise specified. At the end of follow-up, a total of 18,248 deaths (28.0%) occurred during a median follow-up of 9.8 years (interquartile range, 6.4-13.7 years). Conclusion: Taiwan young adults who were 30-day survivors of first-ever stroke have significantly higher long-term mortality rates when compared to other population-based studies.
RESUMO
BACKGROUND: Thrombocytopenia is a common extrahepatic manifestation in chronic liver disease. However, there have been rare studies of impacts of risk for hepatitis C virus-associated thrombocytopenia (HCV-TP) and hepatitis B virus-associated thrombocytopenia (HBV-TP). The aim of this study is to evaluate different impacts of risk factors for HCV-TP and HBV-TP. METHODS: We retrospectively collected 1803 HCV patients and 1652 HBV patients to examine the risk factors for time to moderate and severe thrombocytopenia (platelet counts <100 × 109/L and <50 × 109/L, respectively) by Cox proportional hazards models. Moreover, we prospectively enrolled 63 HCV-TP patients, 11 HBV-TP patients, and 27 HCV controls to detect specific antiplatelet antibodies by enzyme-linked immunosorbent assay and analyze their effects. RESULTS: Prevalence of platelet <100 × 109/L was 11.86% and 6.35% in HCV and HBV patients without cancer history, respectively. HCV-to-HBV incidence rate ratio for thrombocytopenia was 6.95. Initial thrombocytopenia was the most significant risk factor for HCV-TP and HBV-TP regardless of thrombocytopenia severity. Splenomegaly and cirrhosis were significant risk factors for moderate, but not severe HCV-TP. Hyperbilirubinemia was an important moderate and severe HBV-TP risk factor. Antiplatelet antibodies were correlated with HCV-TP severity, of which anti-glycoprotein IIb/IIIa antibody being associated with smaller spleen size. The antiplatelet autoantibody might contribute to thrombocytopenia either independently or with splenomegaly as the important risk in HCV-TP patients without advanced cirrhosis. CONCLUSION: HCV was associated with higher thrombocytopenia incidence than HBV. Thrombocytopenia risk factors varied with virus type and severity. Different management for HCV-TP and HBV-TP was suggested.
Assuntos
Hepatite B , Hepatite C , Trombocitopenia , Humanos , Vírus da Hepatite B , Hepacivirus , Hepatite B/complicações , Hepatite B/epidemiologia , Esplenomegalia/complicações , Estudos Retrospectivos , Hepatite C/complicações , Hepatite C/epidemiologia , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Fatores de Risco , PrevalênciaRESUMO
Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN−SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN−SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-ß and IL-23. Noteworthily, variants of KRT6A, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN−SC patients. Analysis through OncodriveCLUST disclosed that KRT6A replaces JAK2V617F as the more prominent disease driver in MPN−SC, whereas a major mutation in this gene (KRT6A c.745T>C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN−SC pathogenesis.
RESUMO
Ethanol organosolv pretreatment is a green and effective deconstruction process for main components in lignocellulose biomass. Herein, balsa wood was firstly subjected to a modified ethanol/water solution (EWS) pretreatment with different Lewis acids catalysts (AlCl3, CuCl2, FeCl3) at 140-180 °C. The delignification ratios and structural characteristics of the dissociated lignin, enzymatic hydrolysis of cellulose in the pretreated substrates as well as the degradation products from hemicellulose during the pretreatment process were comprehensively investigated. Results showed that dissociation and depolymerization of lignin fragments was robust in AlCl3-catalyzed pretreatment than those by CuCl2 and FeCl3-catalyzed pretreatment. In detail, the results showed that the optimal delignification ratio and removal of the hemicelluloses occurred in AlCl3-catalyzed pretreatment. Moreover, the structural characterizations of lignin fractions by 2D-HSQC, 31P NMR and GPC also revealed that the obtained lignin has the advantages of small and homogeneous molecules as well as abundant functional groups. As a result of adequate removal of hemicellulose and lignin, the enzymatic digestibility of cellulose in the pretreated residue was significantly elevated. In short, the above findings are also in line with the concept of maximizing the utilization of bioresources, which will be beneficial for value-added applications of balsa wood in the biorefinery.