RESUMO
Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the anticancer effect of CDK9 inhibitors on HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ribonucleotídeo Redutases , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Ribonucleotídeo Redutases/genética , Quinase 9 Dependente de Ciclina , Difosfatos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Linhagem Celular TumoralRESUMO
BACKGROUNDS: Medical education has shifted from passive forms of teaching to more active learning strategies, particularly in response to the COVID-19 pandemic. Research has discussed the challenges and disadvantages associated with online education, but there is limited documentation on physicians' perceptions of this sudden and unexpected transformation in medical education. This study aimed to determine the effect of online interactive visual learning on physicians' perceptions of the effectiveness and their satisfaction with this online learning experience. METHODS: We routinely recruited 64 unclassified physicians in the hospital's postgraduate year (PGY) program between September 2021 and April 2022. PGY physicians received an online interactive visual learning course. Online (Google Form) testing and questionnaires before and after this course evaluated learning performance, learning attitude and satisfaction of these physicians. RESULTS: The interactive online learning tools facilitated the physicians' active learning processes by reducing their learning burden (burden vs. no burden: 4.69% vs. 68.75%) and increasing their learning interest (interest vs. no interest: 84.38% vs. 3.12%) in the online format. Post-test scores were significantly improved compared with pretest scores (post-test vs. pre-test: 5 vs. 4; p < 0.05) and their imaging recognition was markedly improved from baseline (post-test vs. pre-test: 85.19% vs. 61.11%). Levels of satisfaction correlated positively with the physicians' learning burden (rs = 0.541), learning interest (rs = 0.562), and perceived benefits of imaging recognition (post-course: rs = 0.508; future: rs = 0.563) (all p < 0.05). CONCLUSIONS: Our online course with interactive visual learning facilitated PGY physicians' learning performance, levels of satisfaction, interest, and perceived benefits of online learning. Hospitals and policymakers need to be aware that this learning approach can markedly enhance physicians' academic outcomes and levels of clinical practice.
Assuntos
COVID-19 , Educação a Distância , Médicos , Humanos , Educação a Distância/métodos , Taiwan , Pandemias , COVID-19/epidemiologia , Satisfação PessoalRESUMO
We tested the effect of 6-(Methylsulfinyl)hexyl Isothiocyanate (6-MITC) and derivatives (I7447 and I7557) on the differentiation and maturation of human myeloid dendritic cells (DCs) in vitro, and skin transplantation in vivo. Triggering of CD14+ myeloid monocyte development toward myeloid DCs with and without 6-MITC and derivatives to examine the morphology, viability, surface marker expression, and cytokine production. Stimulatory activity on allogeneic naive T cells was measured by proliferation and interferon-γ production. The skin allograft survival area model was used to translate the 6-MITC and derivatives' antirejection effect. All of the compounds had no significant effects on DC viability and reduced the formation of dendrites at concentrations higher than 10 µM. At this concentration, 6-MITC and I7557, but not I7447, inhibited the expression of CD1a and CD83. Both 6-MITC and I7557 exhibited T-cells and interferon-γ augmentation at lower concentrations and suppression at higher concentration. The 6-MITC and I7557 prolonged skin graft survival. Both the 6-MITC and I7557 treatment resulted in the accumulation of regulatory T cells in recipient rat spleens. No toxicity was evident in 6-MITC and I7557 treatment. The 6-MITC and I7557 induced human DC differentiation toward a tolerogenic phenotype and prolonged rat skin allograft survival. These compounds may be effective as immunosuppressants against transplant rejection.
Assuntos
Interferon gama , Isotiocianatos , Aloenxertos , Animais , Células Dendríticas , Sobrevivência de Enxerto , Humanos , Isotiocianatos/farmacologia , RatosRESUMO
Portal hypertension-related complications pose a significant risk for liver failure post-transplantation. Thus, accurate monitoring of intraoperative portal venous pressure (PVP) is crucial. However, current PVP monitoring techniques requiring direct percutaneous puncture carry the risk of graft damage. In this study, we present an innovative non-puncture PVP monitoring device (PVPMD) using a 3D-printed prototype. PVPMD design is inspired by the sphygmomanometer principle, and strategically encompasses the portal vein and enables precise PVP measurement through blood flow ultrasonography after temporary occlusion. By a series of mini-pig experiments, the prototype PVPMD demonstrated a strong correlation with invasive catheter measurements in the main trunk of the portal vein (rs = 0.923, p = 0.000). There was a significant repeatability and reproducibility between the prototype PVPMD- and invasive catheter-measured PVP. This indicates that the PVPMD holds immense potential for direct application in liver transplantation and surgery. Moreover, it has the potential to replace catheter-based central venous pressure (CVP) measurements, thereby mitigating catheter-related complications during many surgeries. In conclusion, our innovative device represents a significant advancement in PVP monitoring during liver transplantation, with comprehensive validation from principle exploration to successful animal experiments. We anticipate that this groundbreaking PVPMD will attract the attention of researchers and clinicians, propelling the noninvasive measurement of PVP or other venous/arterial pressures into a new era of clinical practice.
Assuntos
Hipertensão , Transplante de Fígado , Animais , Suínos , Transplante de Fígado/métodos , Pressão na Veia Porta/fisiologia , Reprodutibilidade dos Testes , Porco Miniatura , PunçõesAssuntos
Neoplasias da Mama , Icterícia Obstrutiva , Neoplasias Pancreáticas , Humanos , Feminino , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Icterícia Obstrutiva/etiologia , Pancreaticoduodenectomia , Tomografia Computadorizada por Raios X , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/cirurgiaRESUMO
BACKGROUND: Massive bleeding during liver transplantation (LT) is difficult to manage surgical event. Perihepatic packing (PP) and temporary abdominal closure (TAC) with delayed biliary reconstruction (DBR) can be applied in these circumstances. METHOD: A prospective database of LT in a major transplant center was analyzed to identify patients with massive uncontrollable bleeding during LT that was resolved by PP, TAC, and DBR. RESULTS: From January 2009 to July 2013, 20 (3.6%) of 547 patients who underwent LT underwent DBR. Mean intraoperative blood loss was 20,500 ml at the first operation. The DBR was performed with a mean of 55.2 h (16-110) after LT. Biliary reconstruction included duct-to-duct (n = 9) and hepatico-jejunostomy (n = 11). Complications occurred in eight patients and included portal vein thrombosis, cholangitis, severe bacteremia, pneumonia. There was one in-hospital death. In the follow-up of 18 to 33 months we have seen one patient died 9 months after transplantation. The remaining 18 patients are alive and well. CONCLUSIONS: In case of massive uncontrollable bleeding and bowel edema during LT, the combined procedures of PP, TAC, and DBR offer an alternatively surgical option to solve the tough situation.
Assuntos
Ductos Biliares/cirurgia , Perda Sanguínea Cirúrgica , Transplante de Fígado/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Estudos Prospectivos , Procedimentos de Cirurgia PlásticaRESUMO
INTRODUCTION: Conventional rigid endoscope requires a bundle of optic fibers for illumination and a set of camera for viewing body cavity. The design is bulky in the hand-held part and the laterally positioned optic fibers may hinder manipulation of instruments, especially in single port surgery. We designed a simplified unit to replace conventional endoscope. MATERIALS AND METHODS: We used an independent front image sensor along with six light emitting diode crystals. A wireless module working in 2.4 GHz and its antenna were integrated into the hand-help part. Two 800 mA batteries were used for power supply. The study was tested in two 35 kg pigs. Some simple thoracoscopic and laparoscopic operations were simulated to test the reliability and surgeon's acceptability. RESULTS: Signal Noise ratio can be controlled well in the setting of the operative room. Signal transmission was influenced significantly when covered by damped gauze or drape. The best quality of wireless transmission is through line-of-sight. Dropping frame is less than 1 frame per second in 99% time period during the test. CONCLUSION: Wireless modules in the design of rigid endoscope may be a plausible option with good acceptability.