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Like the ovaries and prostate, the thyroid exhibits characteristic hormone secretion and regulation. Thyroid cancer (TC), especially differentiated thyroid carcinoma, has typical sex-specific and age-specific hormone-driven clinical features. Previous research has primarily focused on the effects of thyroid stimulating hormone, thyroid hormones, and estrogens on the onset and progression of TC, while the roles of growth hormone (GH), androgens, and glucocorticoids have largely been overlooked. Similarly, few studies have investigated the interactions between hormones and hormone systems. In fact, numerous studies of patients with acromegaly have shown that serum levels of GH and insulin-like growth factor-1 (IGF-1) may be associated with the onset and progression of TC, although the influences of age, sex, and other risk factors, such as obesity and stress, remain unclear. Sex hormones, the GH/IGF axis, and glucocorticoids are likely involved in the onset and progression of TC by regulating the tumor microenvironment and metabolism. The aim of this review was to clarify the roles of hormones and hormone systems in TC, especially papillary thyroid carcinoma, as references for further investigations.
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Sistema Hipotálamo-Hipofisário , Glândula Tireoide , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Fator de Crescimento Insulin-Like I/metabolismoRESUMO
Background/Objectives: Uvulopalatopharyngoplasty (UPPP) is a prevalent surgical procedure for treating obstructive sleep apnea. Effective postoperative pain management is crucial for patient comfort and recovery. This study aimed to compare the analgesic efficacies of parecoxib and ketorolac in patients undergoing UPPP. Methods: A prospective, randomized, double-blind study was conducted on 83 patients who received either parecoxib (40 mg intravenously every 12 h) or ketorolac (30 mg intravenously every 8 h) for 2 days following UPPP. Postoperative pain and swallowing discomfort were assessed using visual analog scales (VASs) at 4, 24, 48, and 72 h. The time to resume eating and adverse reactions were also recorded. Results: At 24 and 48 h postoperatively, the mean VAS score was significantly higher in the ketorolac group compared to the parecoxib group (5.0 ± 2.3 vs. 3.6 ± 2.2, p = 0.005 and 3.9 ± 2.2 vs. 2.5 ± 1.7, p < 0.001, respectively). However, no significant difference in the mean VAS scores was observed between the two groups at 72 h postoperatively. With regards to postoperative swallowing pain, the ketorolac group exhibited significantly higher mean VAS scores than the parecoxib group at 4, 24, 48, and 72 h postoperatively. Conclusions: Intravenous parecoxib may offer superior analgesic benefits in the early postoperative period, particularly in alleviating swallowing pain, compared to ketorolac in UPPP procedures.
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Ocular involvement is not uncommon in patients with COVID-19. However, the incidence of COVID-19 ophthalmopathy in COVID-19 patients is still not clear. In this prospective case series study, we recruited 2445 consecutive cases presenting at Neuro-ophthalmology clinic of our Eye Center during the last resurgence of SARS-CoV-2 infection from 8 December 2022 to 15 March 2023 in China, 149 cases were diagnosed as COVID-19 ophthalmopathy, 87 cases were female, with a mean age of 43.2 years, and the mean follow-up time was 15.4 weeks. One hundred and twenty of 149 cases suffered from systemic symptoms mostly manifesting as fever, cough and muscle pain prior to or soon after ocular involvement. The most common COVID-19 ophthalmopathy was optic neuritis (51/149), followed by acute zonal occult outer retinopathy complex disease (31/149), uveitis (17/149), ocular mobility disorder-related (third, fourth, or sixth) cranial nerve neuritis (15/149), anterior ischaemic optic neuropathy (9/149), retinal artery occlusion (8/149), retinal microangiopathy including retinal haemorrhage and cotton wool spot (8/149), viral conjunctivitis (7/149), retinal vein occlusion (3/149), viral keratitis (2/149), ptosis (2/149), and other rare ocular diseases. Except 5 cases with central retinal artery occlusion, other 144 COVID-19 ophthalmopathy cases showed good response to steroid therapy. Our study revealed an incidence of 6.09% for COVID-19 ophthalmopathy in outpatients at our Neuro-ophthalmology clinic during last resurgence of COVID-19 in China, and demonstrated that SARS-CoV-2 infection could induce an initial onset or a relapse of ophthalmic diseases, and that ocular involvement might manifest as the initial or even the only presentation of COVID-19.
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INTRODUCTION: This study endeavors to decipher the association between Activin A and PRISm, thereby addressing the potential of Activin A as a serum biomarker for early detection and long-term clinical outcome prediction of PRISm and subsequent all-cause mortality. METHODS: The study sample comprised middle-aged and older adults from the I-Lan Longitudinal Aging Study. Pulmonary function including forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured. Demographic data and laboratory data (including serum Activin A levels) were also collected. Multivariate logistic regression and Cox proportional hazards models were used to identify independent predictors of PRISm and all-cause mortality, respectively. RESULTS: Among 711 eligible participants, 34 % had PRISm. The risk of PRISm elevated with Activin A levels in group quartiles (adjusted odds ratio (aOR), Q2: 1.606 [95 % CI 0.972-2.652], p = 0.064, Q3: 2.666 [1.635-4.348], p < 0.001, Q4: 3.225 [1.965-5.293], p < 0.001). On the other hand, lower hemoglobin (aOR: 1.122, p = 0.041) and higher blood urea nitrogen (BUN) levels (aOR: 1.033, p = 0.048) were associated with increased risk of PRISm. In addition, the PRISm group had a higher all-cause mortality rate (non-PRISm 4.5% vs. PRISm 8.3 %, p = 0.038). Multivariate Cox models also identify a higher level of Activin A as a risk factor of all-cause mortality (aHR: 1.001 [1.000-1.003], p = 0.042). CONCLUSIONS: Higher Activin A quartiles were linked to increased risk of PRISm, along with lower hemoglobin and higher BUN levels. Additonally, elevated Activin A was a significant risk factor of all-cause mortality.
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PURPOSE: To investigate the value of metagenomic next-generation sequencing (mNGS) for virus detection in patients with suspected viral infectious uveitis. METHODS: In this retrospective, multicenter case series study, 70 patients with suspected viral infectious uveitis were recruited. All patients underwent mNGS test using intraocular fluid samples and serological screening tests for pathogens. Twelve cases also underwent a PCR panel test for herpetic viruses using intraocular fluid samples; 7 cases also underwent aqueous anti-herpetic viral IgG level tests. RESULTS: Among 70 patients with suspected viral infectious uveitis, 34 cases were female, mean age was 45.3 years with a range from 6 to 78 years; 53 cases (75.7%) were diagnosed as infectious uveitis, 17 cases (24.3%) diagnosed as non-infectious uveitis. Among 53 cases with infectious uveitis, herpetic viruses, Bartonella henselae, Toxoplasma gondii, and Treponema pallidum were detected in 43, 6, 4, and 1 case, respectively. Among 43 cases with viral infectious uveitis, herpetic virus was detected in 39 cases by mNGS, the other 4 cases showed negative results in mNGS test, but positive results in 2 cases in serological screening tests, in 1 case in PCR, and in 1 case in aqueous anti-herpetic viral IgG level test, respectively. The sensitivity, specificity, positive predictive value, negative predictive value of mNGS in detecting viruses were 90.7%, 100%, 100%, and 81.0%, respectively. CONCLUSIONS: mNGS is a sensitive and valuable method to detect viruses in intraocular fluid samples, and an alternative for pathogen detection in cases with suspected viral infectious uveitis but negative test results in PCR.
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This study pioneered the use of WIRA whole-body infrared hyperthermia combined with ICI therapy to treat GIT and verified the feasibility and safety of HIT. The final results showed a DCR of 55.6%, with a median PFS of 53.5 days, median OS of 134 days, and an irAE incidence of 22.2%. Therefore, we believe that HIT can exert multiple synergistic sensitisation effects, thereby providing clinical benefits to patients with advanced GITs, increasing overall safety, and improving patients' QOL.
INTRODUCTION: This study aimed to validate the effectiveness, safety and feasibility of waterfiltered infrared A radiation (WIRA) wholebody hyperthermia combined with immune checkpoint inhibitor (ICI) therapy (HIT) and evaluate the realworld clinical application prospects. METHODS: This openlabel singlearm phase 2 clinical trial (NCT06022692) aimed to enrol advanced gastrointestinal tumour (GIT) patients with the MSS/pMMR phenotype. The patients were treated with wholebody hyperthermia on Days 1 and 8 of each HIT cycle along with administration of tislelizumab on Day 2. RESULTS: Between 1 June 2020 and 31 May 2022, 18 patients were enrolled in the study, including those with gastric cancer (n = 6), colon cancer (n = 7), rectal cancer (n = 3) and appendiceal cancer (n = 2). As of 19 May 2023, 17 of the 18 patients had died, including 14 deaths caused by tumour progression and three deaths caused by diseases other than cancer, while one patient was still undergoing followup. In terms of efficacy, the median DCR was 55.6%, while the median PFS and OS were 53.5 days and 134 days, respectively. Four patients (22.2%) experienced immunerelated adverse events, and none of the patients reported grade 3 or higher irAEs. Hyperthermia was followed by an increase in the number of tumour immuneactivated cells. CONCLUSIONS: HIT can provide survival benefits in patients with GITs by activating antitumour immune function and shows good safety and feasibility.
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Neoplasias Gastrointestinais , Hipertermia Induzida , Imunoterapia , Raios Infravermelhos , Humanos , Hipertermia Induzida/métodos , Raios Infravermelhos/uso terapêutico , Masculino , Terapia Combinada , Feminino , Imunoterapia/métodos , Neoplasias Gastrointestinais/terapia , Pessoa de Meia-Idade , Idoso , Água , Adulto , Qualidade de Vida , Resultado do TratamentoRESUMO
Cyanobacteria use a series of adaptation strategies and a complicated regulatory network to maintain intracellular iron (Fe) homeostasis. Here, a global activator named IutR has been identified through three-dimensional chromosome organization and transcriptome analysis in a model cyanobacterium Synechocystis sp. PCC 6803. Inactivation of all three homologous IutR-encoding genes resulted in an impaired tolerance of Synechocystis to Fe deficiency and loss of the responses of Fe uptake-related genes to Fe-deplete conditions. Protein-promoter interaction assays confirmed the direct binding of IutR with the promoters of genes related to Fe uptake, and chromatin immunoprecipitation sequencing analysis further revealed that in addition to Fe uptake, IutR could regulate many other physiological processes involved in intracellular Fe homeostasis. These results proved that IutR is an important transcriptional activator, which is essential for cyanobacteria to induce Fe-deficiency response genes. This study provides in-depth insights into the complicated Fe-deficient signaling network and the molecular mechanism of cyanobacteria adaptation to Fe-deficient environments.
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Regulação Bacteriana da Expressão Gênica , Homeostase , Ferro , Regiões Promotoras Genéticas , Synechocystis , Ferro/metabolismo , Synechocystis/metabolismo , Synechocystis/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Cianobactérias/metabolismo , Cianobactérias/genética , Perfilação da Expressão GênicaRESUMO
OBJECTIVES: The link between aging and pulmonary function decline is well-established, but the underlying mechanisms have yet to be fully revealed. Serum follistatin, a myokine implicated in muscle degeneration, may play a role in age-related pulmonary changes. This study aims to investigate the relationship between serum follistatin levels and pulmonary function decline in community-dwelling older adults, and evaluate their combined association with all-cause mortality. RESEARCH DESIGN AND METHODS: This longitudinal cohort study utilized data from 751 participants aged ≥50 years in the I-Lan Longitudinal Aging Study between 2018-2019. Serum follistatin levels, spirometry results, demographic and clinical data were retrieved. Participants were stratified based on their follistatin levels. Survival curves and group comparisons based on follistatin levels and decline in peak expiratory flow (PEF) using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards models were further used to identify independent predictors of all-cause mortality during the 52-month follow-up. RESULTS: Elevated follistatin levels significantly correlated with worse pulmonary function, particularly decreased PEF (p = 0.030). Kaplan-Meier analysis revealed the combination of elevated follistatin levels and decreased PEF was associated with increased risk of all-cause mortality (Log-rank p = 0.023). Cox proportional hazards models further identified that concurrent presence of higher follistatin levels and decreased PEF predicted higher risk of all-cause mortality (adjusted HR 3.58, 95% CI: 1.22-10.53, p = 0.020). CONCLUSION: Higher serum follistatin levels correlate with decreased pulmonary function, specifically PEF decline, in community-dwelling older adults. Furthermore, the coexistence of elevated follistatin levels and decreased PEF was associated with risk of all-cause mortality. Follistatin may serve as a biomarker for pulmonary aging and related adverse outcomes.
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Folistatina , Vida Independente , Humanos , Masculino , Estudos Longitudinais , Folistatina/sangue , Feminino , Idoso , Vida Independente/estatística & dados numéricos , Pessoa de Meia-Idade , Envelhecimento/fisiologia , Envelhecimento/sangue , Mortalidade , Pulmão/fisiopatologia , China/epidemiologia , Causas de Morte , Biomarcadores/sangueRESUMO
Atom-interferometer gyroscopes have attracted much attention for their long-term stability and extremely low drift. For such high-precision instruments, self-calibration to achieve an absolute rotation measurement is critical. In this work, we propose and demonstrate the self-calibration of an atom-interferometer gyroscope. This calibration is realized by using the detuning of the laser frequency to control the atomic velocity, thus modulating the scale factor of the gyroscope. The modulation determines the order and the initial phase of the interference stripe, thus eliminating the ambiguity caused by the periodicity of the interferometric signal. This self-calibration method is validated through a measurement of the Earth's rotation rate, and a relative uncertainty of 162 ppm is achieved. Long-term stable and self-calibrated atom-interferometer gyroscopes have important applications in the fields of fundamental physics, geophysics, and long-time navigation.
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Tamoxifen (TAM) is a classical anti-estrogenic drug that antagonizes estrogen by competitively binding to estrogen receptor α (ERα). However, drug resistance to TAM remains a significant challenge in breast cancer treatment. In this study, we aimed to design an actively targeted drug delivery system to enhance the proliferation inhibitory effects of TAM on ER positive breast cancer cells. Herein, chitosan (CS) was modified with genistein (GEN) to obtain the actively targeted GEN-CS. The TAM-loaded nanoparticles (TAM-GEN-CS-NPs) were constructed using an ionic-crosslinking method, with GEN-CS as the carrier material and sodium tripolyphosphate (TPP) as the crosslinking agent. As a result, TAM-GEN-CS-NPs exhibited a spherical morphology with an average size of 299.8 nm. The encapsulation efficiency and drug loading content were 85.77% and 14.13 µg/mg, respectively. Compared with free TAM, TAM-GEN-CS-NPs displayed obvious slow-release performance. In vitro cellular assays demonstrated that TAM-GEN-CS-NPs had active targeting and proliferation inhibitory effects on MCF-7 cells. The IC50 of TAM and TAM-GEN-CS-NPs were 10.25 µg/mL and 7.22 µg/mL, respectively. More importantly, the combination index (CI) value of TAM and GEN was less than 1, indicating synergistic effects. Therefore, TAM-GEN-CS-NPs hold the potential to enhance TAM therapy for breast cancer through active targeting and synergistic treatment strategies.
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BACKGROUND: Despite vaccines' effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure. METHODS: This retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not. RESULTS: A total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RTâPCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815). CONCLUSIONS: Vaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.
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COVID-19 , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Vacinas , Humanos , COVID-19/prevenção & controle , COVID-19/complicações , Síndrome do Desconforto Respiratório/etiologia , Insuficiência Respiratória/etiologia , Estudos Retrospectivos , SARS-CoV-2 , Resultado do Tratamento , VacinaçãoRESUMO
PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.
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Adenocarcinoma , Hipertermia Induzida , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Células PC-3 , Espécies Reativas de Oxigênio/metabolismo , Micro-Ondas , Proteína Supressora de Tumor p53/metabolismo , Hipertermia Induzida/métodos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/metabolismo , Reparo do DNA , Apoptose , Estresse Oxidativo , Hipertermia , Adenocarcinoma/radioterapia , DNA/metabolismo , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
BACKGROUND: Adult patients with biliary acute pancreatitis (BAP) or choledocholithiasis who do not undergo cholecystectomy on index admission have worse outcomes. Given the paucity of data on the impact of cholecystectomy during index hospitalization in children, we examined readmission rates among pediatric patients with BAP or choledocholithiasis who underwent index cholecystectomy versus those who did not. METHODS: Retrospective study of children (< 18 years old) admitted with BAP, without infection or necrosis (ICD-10 K85.10), or choledocholithiasis (K80.3x-K80.7x) using the 2018 National Readmission Database (NRD). Exclusion criteria were necrotizing pancreatitis with or without infected necrosis and death during index admission. Multivariable logistic regression was performed to identify factors associated with 30-day readmission. RESULTS: In 2018, 1122 children were admitted for index BAP (n = 377, 33.6%) or choledocholithiasis (n = 745, 66.4%). Mean age at admission was 13 (SD 4.2) years; most patients were female (n = 792, 70.6%). Index cholecystectomy was performed in 663 (59.1%) of cases. Thirty-day readmission rate was 10.9% in patients who underwent cholecystectomy during that index admission and 48.8% in those who did not (p < 0.001). In multivariable analysis, patients who underwent index cholecystectomy had lower odds of 30-day readmission than those who did not (OR 0.16, 95% CI 0.11-0.24, p < 0.001). CONCLUSIONS: Index cholecystectomy was performed in only 59% of pediatric patients admitted with BAP or choledocholithiasis but was associated with 84% decreased odds of readmission within 30 days. Current guidelines should be updated to reflect these findings, and future studies should evaluate barriers to index cholecystectomy.
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Colecistectomia , Coledocolitíase , Pancreatite , Readmissão do Paciente , Humanos , Readmissão do Paciente/estatística & dados numéricos , Feminino , Masculino , Estudos Retrospectivos , Coledocolitíase/cirurgia , Coledocolitíase/complicações , Adolescente , Criança , Colecistectomia/estatística & dados numéricos , Pancreatite/cirurgia , Doença Aguda , Pré-EscolarRESUMO
The gut-islets axis is an important endocrine signaling axis that regulates the function of islets by modulating the gut micro-environment and its endocrine metabolism. The discovery of intestinal hormones, such as GLP-1 and GIP, has established a preliminary link between the gut and the islet, paving the way for the development of GLP-1 receptor agonists based on the regulation theory of the gut-islets axis for diabetes treatment. This discovery has created a new paradigm for diabetes management and rapidly made the regulation theory of the gut-islets axis a focal point of research attention. Recent years, with in-depth study on gut microbiota and the discovery of intestinal-derived extracellular vesicles, the concept of gut endocrine and the regulation theory of the gut-islets axis have been further expanded and updated, offering tremendous research opportunities. The gut-islets axis refers to the complex interplay between the gut and the islet, which plays a crucial role in regulating glucose homeostasis and maintaining metabolic health. The axis involves various components, including gut microbiota, intestinal hormones, amino acids and ACE2, which contribute to the communication and coordination between the gut and the islet.
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BACKGROUND: Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) is a rare leukemia subtype first classified by the World Health Organization in 2016. The incidence of Ph+ AML is approximately 0.5 - 3%, and its prognosis is poor. Ph+ AML with additional chromosomal abnormalities in children has rarely been reported, and its treatment and prognosis remain uncertain. METHODS: We retrospectively analyzed 649 patients with AML from 2006 - 2021. Six (0.9%) patients with Ph+ AML were identified and treated with conventional chemotherapy. The clinical features and prognoses were retrospectively analyzed. RESULTS: Six cases of AML with a Ph chromosome were reported. One of the six individuals exhibited a biphenotypic immunophenotype, one exhibited a simple myeloid immunophenotype, and the other four exhibited myeloid and lymphoid expression. Karyotypic analysis (R banding) was performed in six cases, four of which were classical Ph chromosomal abnormalities, two of which had additional abnormalities outside the Ph chromosome. Fluorescence in situ hybridization (FISH) analysis using the BCR/ABL fusion gene distinguished that the BCR major breakpoint break in three cases was type P210 and the BCR minor breakpoint break in three cases was type P190. The complete remission rate of the six patients in this study using conventional chemotherapy was 60%, with a median survival time of 7.5 months. CONCLUSIONS: In summary, Ph+ AML is a heterogeneous disease often associated with additional chromosomal abnormalities. Ph+ AML is seen with a lymphoid immunophenotype and alterations in associated genes such as the IGH gene. Adults were predominantly P210 and two cases in children were both P190. Conventional treatments are less effective, and there are no standard treatment regimens.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Adulto , Criança , Humanos , Cromossomo Filadélfia , Prognóstico , Hibridização in Situ Fluorescente , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Aberrações Cromossômicas , Proteínas de Fusão bcr-abl/genéticaRESUMO
Background: We aim to investigate the prevalence, patterns, risk factors, and outcomes of peritoneal metastases (PM) after curative laparoscopic hepatectomy (LH) for hepatocellular carcinoma (HCC). Methods: A multicenter cohort of 2,138 HCC patients who underwent curative LH from August 2010 to December 2016 from seven hospitals in China was retrospectively analyzed. The incidence of PM following LH was evaluated and compared with that in open hepatectomy (OH) after 1:1 propensity score matching (PSM). Results: PM prevalence was 5.1% (15/295) in the early period [2010-2013], 2.6% (47/1,843) in the later period [2014-2016], and 2.9% (62/2,138) in all LH patients, which was similar to 4.0% (59/1,490) in the OH patients. The recurrence patterns, timing, and treatment did not significantly vary between the LH and OH patients (P>0.05). Multivariate logistic regression revealed that tumor diameter >5 cm, non-anatomical resection, presence of microvascular invasion, and lesions <2 cm from major blood vessels were independent risk factors of PM after LH. Of the 62 cases with PM, 26 (41.9%) had PM only, 34 (54.9%) had intrahepatic recurrence (IHR) and PM, and 2 (3.2%) had synchronous extraperitoneal metastases (EPM). Patients with resectable PM had a 5-year overall survival (OS) of 65.0% compared to 9.0% for unresectable PM (P=0.001). Conclusions: The prevalence, patterns and independent risk factors of PM were identified for HCC patients after LH. LH was not associated with increased incidence of PM in HCC patients for experienced surgeons. Surgical re-excision of PM was associated with prolonged survival.
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ATP-dependent energy-consuming enzymatic reactions are widely used in cell-free biocatalysis. However, the direct addition of large amounts of expensive ATP can greatly increase cost, and enzymatic production is often difficult to achieve as a result. Although a polyphosphate kinase (PPK)-polyphosphate-based ATP regeneration system has the potential to solve this challenge, the generally poor thermal stability of PPKs limits the widespread use of this method. In this paper, we evaluated the thermal stability of a PPK from Sulfurovum lithotrophicum (SlPPK2). After directed evolution and computation-supported design, we found that SlPPK2 is very recalcitrant and cannot acquire beneficial mutations. Inspired by the usually outstanding stability of ancestral enzymes, we reconstructed the ancestral sequence of the PPK family and used it as a guide to construct three heat-stable variants of SlPPK2, of which the L35F/T144S variant has a half-life of more than 14 h at 60°C. Molecular dynamics simulations were performed on all enzymes to analyze the reasons for the increased thermal stability. The results showed that mutations at these two positions act synergistically from the interior and surface of the protein, leading to a more compact structure. Finally, the robustness of the L35F/T144S variant was verified in the synthesis of nucleotides at high temperature. In practice, the use of this high-temperature ATP regeneration system can effectively avoid byproduct accumulation. Our work extends the temperature boundary of ATP regeneration and has great potential for industrial applications.IMPORTANCEATP regeneration is an important basic applied study in the field of cell-free biocatalysis. Polyphosphate kinase (PPK) is an enzyme tool widely used for energy regeneration during enzymatic reactions. However, the thermal stability of the PPKs reported to date that can efficiently regenerate ATP is usually poor, which greatly limits their application. In this study, the thermal stability of a difficult-to-engineer PPK from Sulfurovum lithotrophicum was improved, guided by an ancestral sequence reconstruction strategy. The optimal variant has a 4.5-fold longer half-life at 60°C than the wild-type enzyme, thus enabling the extension of the temperature boundary for ATP regeneration. The ability of this variant to regenerate ATP was well demonstrated during high-temperature enzymatic production of nucleotides.
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Trifosfato de Adenosina , Epsilonproteobacteria , Fosfotransferases (Aceptor do Grupo Fosfato) , Trifosfato de Adenosina/metabolismo , Temperatura , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , NucleotídeosRESUMO
Tetrabromobisphenol A (TBBPA) analogues have been investigated for their prevalent occurrence in environments and potential hazardous effects to humans and wildlife; however, there is still limited knowledge regarding their toxicokinetics and trophic transfer in aquatic food chains. Using a developed toxicokinetic model framework, we quantified the bioaccumulation, biotransformation and trophic transfer of tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A di(allyl ether) (TBBPA-DAE) during trophic transfer from brine shrimp (Artemia salina) to zebrafish (Danio rerio). The results showed that the two TBBPA analogues could be readily accumulated by brine shrimp, and the estimated bioconcentration factor (BCF) value of TBBPS (5.68 L kg-1 ww) was higher than that of TBBPA-DAE (1.04 L kg-1 ww). The assimilation efficiency (AE) of TBBPA-DAE in zebrafish fed brine shrimp was calculated to be 16.3%, resulting in a low whole-body biomagnification factor (BMF) in fish (0.684 g g-1 ww). Based on the transformation products screened using ultra-high-performance liquid chromatograph-high resolution mass spectrometry (UPLC-HRMS), oxidative debromination and hydrolysis were identified as the major transformation pathways of TBBPS, while the biotransformation of TBBPA-DAE mainly took place through ether bond breaking and phase-II metabolism. Lower accumulation of TBBPA as a metabolite than its parent chemical was observed in both brine shrimp and zebrafish, with metabolite parent concentration factors (MPCFs) < 1. The investigated BCFs for shrimp of the two TBBPA analogues were only 3.77 × 10-10 - 5.59 × 10-3 times of the theoretical Kshrimp-water based on the polyparameter linear free energy relationships (pp-LFERs) model, and the BMF of TBBPA-DAE for fish was 0.299 times of the predicted Kshrimp-fish. Overall, these results indicated the potential of the trophic transfer in bioaccumulation of specific TBBPA analogues in higher trophic-level aquatic organisms and pointed out biotransformation as an important mechanism in regulating their bioaccumulation processes. ENVIRONMENTAL IMPLICATION: The internal concentration of a pollutant in the body determines its toxicity to organisms, while bioaccumulation and trophic transfer play important roles in elucidating its risks to ecosystems. Tetrabromobisphenol A (TBBPA) analogues have been extensively investigated for their adverse effects on humans and wildlife; however, there is still limited knowledge regarding their toxicokinetics and trophic transfer in aquatic food chains. This study investigated the bioaccumulation, biotransformation and trophic transfer of TBBPS and TBBPA-DAE in a simulated di-trophic food chain. This state-of-art study will provide a reference for further research on this kind of emerging pollutant in aquatic environments.
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Poluentes Ambientais , Perciformes , Bifenil Polibromatos , Poluentes Químicos da Água , Animais , Humanos , Cadeia Alimentar , Bioacumulação , Ecossistema , Peixe-Zebra/metabolismo , Biotransformação , Perciformes/metabolismo , Poluentes Ambientais/análise , Éteres , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected individuals worldwide, and patients with cancer are particularly vulnerable to COVID-19-related severe illness, respiratory failure, and mortality. The relationship between COVID-19 and cancer remains a critical concern, and a comprehensive investigation of the factors affecting survival among patients with cancer who develop COVID-19-related respiratory failure is warranted. We aim to compare the characteristics and outcomes of COVID-19-related acute respiratory failure in patients with and without underlying cancer, while analyzing factors affecting in-hospital survival among cancer patients. METHODS: We conducted a retrospective observational study at Taipei Veterans General Hospital in Taiwan from May to September 2022, a period during which the omicron variant of the severe acute respiratory syndrome coronavirus 2 was circulating. Eligible patients had COVID-19 and acute respiratory failure. Clinical data, demographic information, disease severity markers, treatment details, and outcomes were collected and analyzed. RESULTS: Of the 215 enrolled critically ill patients with COVID-19, 65 had cancer. The patients with cancer were younger and had lower absolute lymphocyte counts, higher ferritin and lactate dehydrogenase (LDH) concentrations, and increased vasopressor use compared with those without cancer. The patients with cancer also received more COVID-19 specific treatments but had higher in-hospital mortality rate (61.5% vs 36%, P = 0.002) and longer viral shedding (13 vs 10 days, P = 0.007) than those without cancer did. Smoking [odds ratio (OR): 5.804, 95% confidence interval (CI): 1.847-39.746], elevated LDH (OR: 1.004, 95% CI: 1.001-1.012), vasopressor use (OR: 5.437, 95% CI: 1.202-24.593), and new renal replacement therapy (OR: 3.523, 95% CI: 1.203-61.108) were independent predictors of in-hospital mortality among patients with cancer and respiratory failure. CONCLUSION: Critically ill patients with cancer experiencing COVID-19-related acute respiratory failure present unique clinical features and worse clinical outcomes compared with those without cancer. Smoking, elevated LDH, vasopressor use, and new renal replacement therapy were risk factors for in-hospital mortality in these patients.
Assuntos
COVID-19 , Neoplasias , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Humanos , COVID-19/complicações , SARS-CoV-2 , Estado Terminal , Neoplasias/complicações , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. OBJECTIVES: This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. DESIGN: This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). METHODS: The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. RESULTS: We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. CONCLUSION: By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.