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Background: Transmembrane E3 ubiquitin ligase (RNF43) mutations are present in approximately 6-18% of colorectal cancers (CRC) and could enhance Wnt/ß-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43-mutant CRC. Methods: A total of 78 patients with RNF43-mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43-mutated tumors harbored a hotspot variant (RNF43 R117fs), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.
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The proportion of correctly predicted prognoses and factors associated with prediction accuracy are unknown. The objective of this study was to explore the accuracy of physician and nurse predictions of 28-day mortality in the ICU. This was a prospective observational single-center study. All medical staff in the ICU have access to patient data, can communicate with patients or clients, and can independently predict the prognosis of patients within 24 h of patient admission. The only question of the questionnaire survey was: What is the patient's outcome on day 28 (alive or death)? There were 2155 questionnaires completed by 18 physicians and 1916 submitted by 15 nurses. In the 312 patients included, the 28-day mortality rates were predicted by physicians and nurses. The overall proportion of correct prognosis prediction was 90.1% for physicians and 64.4% for nurses (P = 0.000). There was no significant difference in the overall correct proportion and average correct proportion among physicians with different seniority levels. The overall correct proportion and average correct proportion increased among nurses with seniority. Physicians in the ICU can moderately predict 28-day mortality in critically ill patients. Nurses with a seniority of less than 10 years in ICU cannot accurately predict 28-day mortality in critically ill patients. However, the accuracy of nurses' prediction of patients' 28-day prognosis increased with their seniority in the ICU.
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Unidades de Terapia Intensiva , Médicos , Humanos , Estudos Prospectivos , Estado Terminal , PrognósticoRESUMO
Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.
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Febre Grave com Síndrome de Trombocitopenia , Neoplasias de Tecidos Moles , Tumores Fibrosos Solitários , Humanos , Tumores Fibrosos Solitários/genética , Tumores Fibrosos Solitários/terapia , Tumores Fibrosos Solitários/metabolismo , Fatores de Risco , Neoplasias de Tecidos Moles/patologia , Medição de RiscoRESUMO
Wave-absorbing materials are developing in the direction of "light weight, wide frequency band, thin layer and high strength", and it is difficult to achieve the synergy between wave-absorbing performance and mechanical properties when graphene absorbent is compounded with a single resin matrix. In this paper, based on the preparation of a new composite absorbing wire with a graphene (GR)/spherical graphite (SG) double absorbent and polylactic acid (PLA)/thermoplastic polyurethane (TPU) double matrix, we proposed a new method to prepare samples for testing the electromagnetic parameters and tensile strength by fused deposition modeling (FDM). Furthermore, the effect of SG/GR ratio on the microwave absorbing properties and mechanical properties of PLA/TPU composites was specifically studied. It was found that when the ratio of SG/GR was small (0:5, 1:4), the dielectric loss (interfacial polarization loss, dipole polarization loss, conductivity loss) and attenuation ability of the composites were stronger, and the impedance matching was better. When the SG/GR ratio was large (5:0, 4:1), the composites had high strength and toughness. When the ratio of SG/GR was moderate (2:3, 3:2), it could retain the absorbing and mechanical properties of the absorbing materials. On the one hand, the SG and PLA/TPU matrix formed an "island structure", which improves the dispersion of GR; on the other hand, the GR and PLA/TPU matrix formed a "core-shell structure", which promotes polarization and multiple scattering.
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BACKGROUND: Studies have shown that dexmedetomidine improves neurological function. Whether dexmedetomidine reduces mortality or improves quantitative electroencephalography (qEEG) among patients post-craniotomy remains unclear. METHODS: This single-center randomized study was conducted prospectively from 1 January 2019 to 31 December 2020. Patients who were transferred to the ICU after craniotomy within 24 h were included. The analgesic was titrated to a Critical care Pain Observation Tool (CPOT) score ≤2, and the sedative was titrated to a Richmond Agitation-Sedation Scale (RASS) score ≤-3 for at least 24 h. The qEEG signals were collected by four electrodes (F3, T3, F4, and T4 according to the international 10/20 EEG electrode practice). The primary outcome was 28-day mortality and qEEG results on day 1 and day 3 after sedation. RESULTS: One hundred and fifty-one patients were enrolled in this study, of whom 77 were in the dexmedetomidine group and 74 in the midazolam group. No significant difference was found between the two groups in mortality at 28 days (14.3% vs. 24.3%; p = 0.117) as well as in the theta/beta ratio (TBR), the delta/alpha ratio (DAR), and the (delta + theta)/(alpha + beta) ratio (DTABR) between the two groups on day 1 or day 3. However, both the TBR and the DTABR were significantly increased in the dexmedetomidine group. The DTABR in the midazolam group was significantly increased. The DAR was significantly increased on the right side in the dexmedetomidine group (20.4 (11.6-43.3) vs. 35.1 (16.7-65.0), p = 0.006) as well as on both sides in the midazolam group (Left: 19.5 (10.1-35.8) vs. 37.3 (19.3-75.7), p = 0.006; Right: 18.9 (10.1-52.3) vs. 39.8 (17.5-99.9), p = 0.002). CONCLUSION: Compared with midazolam, dexmedetomidine did not lead to a lower 28-day mortality or better qEEG results in brain injury patients after a craniotomy.
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BACKGROUND: Vancomycin treatment failure against vancomycin-susceptible gram-positive cocci is not rare in the intensive care unit (ICU). One of the reasons for this is the substandard drug trough concentration. We aimed to examine the hypothesis that the target serum concentration could be reached earlier with a loading dose of vancomycin. METHODS: This retrospective cohort study was conducted at our ICU between June 2018 and June 2020 and involved patients who were suspected of having, or confirmed to have, gram-positive cocci infection and treated with vancomycin. One group of the patients was administered a loading dose of vancomycin (loading group) and compared with the group that did not receive a loading dose (control group). The baseline characteristics, vancomycin serum concentrations, and clinical outcomes were collected and analyzed. RESULTS: Fifty-five patients were finally included, of which 29 received a loading dose of vancomycin. The serum concentration of vancomycin before the second dose was significantly higher for the loading group than for the control group (10.3â±â6.1âmg/L vs. 5.7â±â4.4âmg/L, Pâ=â0.002). The results for both groups were similar before the fifth dose (12.4â±â7.3âmg/L vs. 10.3â±â6.3âmg/L in the loading and the control groups, respectively; Pâ=â0.251). The 28-day mortality was lower for the loading group than for the control group (6.7% vs. 34.6% in the loading and control groups, respectively; Pâ=â0.026). No significant differences were observed in serum creatinine (Cr) concentrations of the two groups. CONCLUSION: With the loading dose of vancomycin, the target serum concentration of vancomycin may be reached earlier without increasing the risk of acute kidney injury. TRIAL REGISTRATION: https://www.chictr.org.cn; ChiCTR2000035369.
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Antibacterianos , Vancomicina , Antibacterianos/uso terapêutico , Creatinina , Humanos , Unidades de Terapia Intensiva , Estudos RetrospectivosRESUMO
BACKGROUND: This study was conducted to investigate the effect of alpha-fetoprotein (AFP) ratio on the prognosis of AFP-positive hepatocellular carcinoma (HCC) patients after hepatectomy. METHODS: We retrospectively included 879 HCC patients with AFP-positive who underwent hepatectomy from February 2012 to October 2017 and randomly divided into training cohort and validation cohort. AFP ratio was equal to the AFP level within one week before hepatectomy to AFP level within 20-40 days after surgery. The end point of follow-up was disease-free survival (DFS) and overall survival (OS). RESULTS: AFP ratio was not associated with clinical characteristics in training cohort and validation cohort. According to the X-tile software, the optimum cut-off point was 17.8 for AFP ratio. Significant differences between AFP ratio high and AFP ratio low were observed in DFS and OS in both cohort (p < 0.05). Kaplan-Meier curves and receiver-operating curves were showed that AFP ratio was better than AFP level preoperation in predicting the prognosis of AFP-positive HCC patients after hepatectomy. The multivariate analysis demonstrated that AFP ratio was a significant independent risk factor for both OS and DFS in HCC patients with AFP-positive. CONCLUSIONS: AFP ratio might be a prognosis predictor for HCC patients with AFP-positive after hepatectomy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , alfa-Fetoproteínas/análiseRESUMO
BACKGROUND: This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy. METHODS: We conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. RESULTS: We enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05). CONCLUSIONS: The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.
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Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Fumar/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Diquat is a widely used herbicide that is substituted for paraquat. With paraquat off the market, cases of diquat poisoning have been gradually increasing. The kidney is the most frequently impaired organ in diquat poisoning. Few cases of multiple organ failure caused by diquat have been reported.We herein describe a 30-year-old man who orally ingested about 160 mL of enriched diquat. Despite aggressive treatment, the patient's condition progressed to multiple organ failure and death. The pulmonary lesions in this patient were different from those previously reported. This patient did not die of renal failure but of severe respiratory failure. He exhibited three different stages of pulmonary disease.The lung lesions in this case were unique. We hope that doctors will pay more attention to the lung lesions in patients with diquat poisoning in future and find new treatment methods to save the lives of such patients.
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Herbicidas , Insuficiência Respiratória , Adulto , Diquat , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/induzido quimicamente , ParaquatRESUMO
A core-removed D-shaped structure with different residual thickness (RT) was manufactured on a single mode silica fiber (SMF) to enhance the sensitivity by using of ultra-precise polishing technology. With six different RTs ranging from â¼55 µm to â¼28 µm, the RT enhancement effect in a D-shaped SMF was researched in detail. The influence of the RT on its transmission spectra was investigated both theoretically and experimentally. Considering a compromise between the multimode interference efficiency and optical power loss, an optimum RT value of 34.09 µm was achieved. The obtained refractive index (RI) sensitivity was 10243 nm/RIU in the RI range of 1.430-1.444, corresponding to a RI resolution of 1.9×10-6 RIU. A high-performance all-fiber sensor was developed to monitor the evaporation process volatile organic compounds (VOCs) based on the RT-enhanced D-shaped SMF. As proof of concept, a 2-hour continuous monitoring was carried to monitor the chloroform and alcohol mixture. As a result, the evaporation of alcohol and chloroform were clearly identified and monitored. The developed RT-enhanced D-shaped fiber sensor provides an alternative way for chemical process monitoring and industrial applications.
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The steroidal saponin RCE4 (1ß, 3ß, 5ß, 25S)spirostan1, 3diol 1[αLrhamnopyranosyl(1â2)ßDxylopyranoside], isolated from Reineckia carnea, exerts significant anticervical cancer activity by inducing apoptosis. The potential effect of RCE4 on proliferation inhibition and autophagy induction has rarely been studied. Therefore, the focus of the present study was to investigate the effects of RCE4 on proliferation, and to elucidate the detailed mechanisms involved in autophagy induction in cervical cancer cells. CaSki cells were treated with RCE4 or/and autophagy inhibitors, and the effect of RCE4 on cellular proliferation was assessed by MTT assay. The proautophagic properties of RCE4 were subsequently confirmed using monomeric red fluorescent proteingreen fluorescent proteinmicrotubuleassociated proteins 1A/1B light chain 3B (LC3) adenoviruses and CYTOID autophagy assays, and by assessing the accumulation of lipidmodified LC3 (LC3II). The mechanisms of RCE4induced autophagy were investigated by western blot analysis. The results demonstrated that inhibiting autophagy significantly promoted RCE4induced cell death, indicating that autophagy served a protective role following RCE4 treatment. In addition, RCE4induced autophagy was reflected by increased expression levels of the serine/threonineprotein kinase ULK1, phosphorylated (p)ULK1, pBeclin1 and LC3II, the formation of autophagosomes and autolysosomes, and sequestosome 1 (p62) degradation. Subsequent analysis indicated that RCE4 activated the AMPactivated protein kinase (AMPK) pathway by upregulating AMPK and pAMPK, and also inhibited the PI3K and extracellular signalregulated kinase (ERK) signaling pathways by downregulating pPI3K, pAkt, pmTOR, Ras, cRaf, pcRaf, dual specificity mitogenactivated protein kinase kinase (MEK)1/2, pMEK1/2 and pErk1/2. Additionally, with increased treatment times RCE4 may impair lysosomal cathepsin activity and inhibit autophagy flux by suppressing the expression of AMPK, pAMPK, ULK1, pULK1 and pBeclin1, and upregulating that of p62. These results indicated that the dual RCE4induced inhibition of the PI3K and ERK pathways may result in a more significant antitumor effect and prevent chemoresistance, compared with the inhibition of either single pathway; furthermore, dual blockade of PI3K and ERK, and the AMPK pathway may be involved in the regulation of autophagy caused by RCE4. Taken together, RCE4 induced autophagy to protect cancer cells against apoptosis, but AMPKmediated autophagy was inhibited in the later stages of RCE4 treatment. In addition, autophagy inhibition improved the therapeutic effect of RCE4. These data highlight RCE4 as a potential candidate for cervical cancer treatment.
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Antineoplásicos Fitogênicos/farmacologia , Asparagaceae/química , Autofagia/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Espirostanos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Feminino , Humanos , Saponinas/química , Espirostanos/química , Serina-Treonina Quinases TOR/metabolismo , Neoplasias do Colo do ÚteroRESUMO
Porous biochar (PBC) derived from Cr-containing waste collagen fibers was prepared by two-step pyrolysis to 800 °C (PBC-800) and alkali activation. Brunauer-Emmet-Teller (BET) analysis, scanning electron microscopy (SEM), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence (XRF), thermogravimetric analysis (TGA) and zeta potential analysis were used to characterize PBC-800. Batch experiments showed that PBC-800 had an excellent removal effect on tetracycline (TC), and the maximum adsorption capacity was 593.84 mg g-1. Meanwhile, PBC-800 was found to be suitable for a wide pH range. The isothermal adsorption and kinetic model fitting proved that the TC adsorption by PBC-800 occurred via 5 types of chemical adsorption. The main rate-limiting step was closely related to the initial concentration of TC. The total release of Cr was less than 0.05 mg L-1, which indicated that PBC-800 was stable and did not cause serious secondary pollution. Compared to the conventional metal-free biomass, Cr in a waste collagen fiber (WCF) played an important role in carbon formation and adsorption. The excellent adsorption properties of PBC-800 indicated that it could enrich low concentrations of TC in water. Thus, WCF can be used to prepare cost-effective PBC, which supplies a new process to reuse Cr-containing waste.
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BACKGROUND As a serious clinical problem, severe burn injury disturbs the immune system, resulting in progressive suppression of immune response. TLRs are associated with immune system activation, but the effect of TLRs levels on circulating cDCs of severe burn injury patients has not been fully assessed. MATERIAL AND METHODS Ten patients with total body surface area (TBSA) burned >90% admitted to our institution were enrolled in this study. We analyzed TLR2, TLR4, and TLR9 expression on the circulating cDCs by using multicolor flow cytometric analysis in patients at 14 days to 28 days after burn injury according to mortality, and We also assessed Demographics, clinical outcomes, organ function, and inflammatory and acute-phase responses. RESULTS No difference in TBSA, sex, age, or number of operations before the first 14 days after injury were observed between surviving and non-surviving burn patients. The levels of TLR2, TLR4, and TLR9 in circulating cDCs were significantly and consistently elevated in all patients compared to age-matched healthy volunteers, and survivors exhibited higher TLR2 and TLR4 values than non-survivors. Of the survivors, TLR2 and TLR4 levels were higher at 28 days than at 14 days after injury, while the difference in TLR9 levels was not significant. TLR2 levels of non-survivors at 28 days after injury decreased, and the TLR4 and TLR9 levels showed no significant difference. CONCLUSIONS TLRs levels in circulating cDCs are highly activated in severe burn injury patients up to 28 days after injury. The low expression of TLR2 in cDCs may be useful as a potential marker predicting the poor prognosis of severe burn patients.