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A 31-year-old primiparous woman underwent non-invasive prenatal testing. The result was trisomy 13 (T13) positive. The chromosome 13 t-statistics (Z-score) was significantly high. The result of amniocentesis was normal karyotype (46,XX). Detailed ultrasound showed no fetal structural abnormalities. We suspected T13 confined placental mosaicism (CPM) and observed the course naturally. From the late second trimester, severe fetal growth restriction manifested followed by proteinuria and hypertension, diagnosing her with preeclampsia (PE). At 35 + 5 weeks, emergent cesarean section was required, yielding a 1480 g female infant. We sampled five locations of chorionic villi in the placenta. T13 cells dominated cells with normal karyotypes in all parts and the rate of trisomic cells ranged from 57% to 96%, which were generally high rate. None developed PE in reported T13 CPM cases and this is the first case of PE. The dominancy of T13 cells can be associated with PE development.
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A powder formulation for mucosal administration of mRNA-encapsulated lipid nanoparticles (mRNA-LNPs) is expected to be useful for respiratory diseases. Although freeze-drying is widely used to obtain solid formulations of mRNA-LNPs, highly hydrosoluble cryoprotectants, such as sucrose are necessary. However, sucrose is not a suitable excipient for inhalation powders because of its hygroscopic and deliquescence properties. Spray freeze-drying (SFD) is a method to produce inhalable powder formulation. In this study, we prepared inhalable powder formulations of mRNA-LNPs without deliquescence excipients using pH-modified SFD, which strengthens the interaction between mRNA and ionizable lipids of LNPs by acidic pH modifier, leading to retention of the encapsulated structure of mRNA-LNPs even after SFD. Powdered mRNA-LNPs were suitable for inhalation, and mRNA was encapsulated in LNPs after SFD. The mRNA encapsulation efficiency and mRNA transfection efficiency of pH-modified SFD-mediated powdered mRNA-LNPs were higher than those of conventional SFD, although they were significantly lower than those of liquid intact mRNA-LNPs. However, after long-term storage, the powdered formulation of the mRNA-LNPs exhibited higher mRNA transfection efficiency than liquid mRNA-LNP. Powdered mRNA-LNPs also exerted their function in air-liquid interface cultivation and in vivo intratracheal administration. Collectively, the powder formulation of mRNA-LNPs especially prepared by SFD is expected to be applied for dry powder inhalers.
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This study aimed to develop polyvinyl alcohol (PVA) nanofibers encapsulating 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/siRNA complexes via electrospinning for the delivery of nucleic acid-based drugs. It also focused on the influence of the intrinsic properties of PVA on the efficacy of the system. PVA nanofibers, with diameters of 300-400 nm, were obtained, within which the siRNA remained intact and the DOTAP/siRNA complexes were uniformly dispersed. By incorporating DOTAP/siRNA complexes into the PVA nanofibers and assessing the impact of their RNA interference (RNAi) activity in A549-Luc cells, a stable inhibition of luciferase expression was observed. An examination of the nanofiber preparation process revealed that even when DOTAP or siRNA were added separately to the PVA solution without forming complexes, the RNAi effect was retained. The DOTAP/siRNA complexes released from the PVA nanofibers were internalized by the cells, with some PVA residues remaining on their surfaces. The significance of the degree of hydrolysis and polymerization of PVA on the performance of nanofibers was highlighted. Notably, PVA with a low degree of hydrolysis substantially enhanced RNAi effects, with luciferase expression inhibition reaching 91.5 ± 0.7%. Nanofibers made of PVA grades with anionic or cationic modifications were also evaluated, suggesting that they affect the efficacy of siRNA delivery. The insights obtained suggest avenues for future research to optimize drug delivery systems further.
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Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(-)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins.
Assuntos
Aerossóis , Quimotripsina , Manitol , Nanofibras , Nanofibras/química , Nanofibras/administração & dosagem , Animais , Administração por Inalação , Manitol/química , Quimotripsina/química , Camundongos , Inaladores de Pó Seco , Álcool de Polivinil/química , Pós , Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Líquido da Lavagem Broncoalveolar/química , MasculinoRESUMO
Phytochemicals isolated from essential oils are effective alternatives for inhibiting microbial pathogens. Bovine protothecal mastitis is the cause of a reduction in milk production and the secretion of thin, watery milk with white flakes. In the present study, we performed in vitro susceptibility testing of the phytochemicals carvacrol, citral, and thymol in Prototheca strains isolated from cases of protothecosis in small animals and cow feces. The susceptibility of the algae to carvacrol, citral, and thymol was assessed using the modified CLSI M27-A3 broth microdilution method. The ranges of the minimum inhibitory concentrations (MIC%) of the phytochemicals in all isolates were 0.03% to 0.125% for carvacrol, 0.03% to 0.25% for citral, and 0.06% to 0.25% for thymol. Based on these results, carvacrol, citral, and thymol appear effective against Prototheca species at the tested concentrations, and may thus be useful for environmental disinfection in barns.
Assuntos
Monoterpenos Acíclicos , Cimenos , Testes de Sensibilidade Microbiana , Óleos Voláteis , Compostos Fitoquímicos , Prototheca , Timol , Óleos Voláteis/farmacologia , Timol/farmacologia , Animais , Prototheca/efeitos dos fármacos , Cimenos/farmacologia , Compostos Fitoquímicos/farmacologia , Monoterpenos Acíclicos/farmacologia , Bovinos , Monoterpenos/farmacologia , Feminino , Mastite Bovina/microbiologia , Mastite Bovina/tratamento farmacológicoRESUMO
We present a unique case of transient global amnesia following intravenous administration of a non-ionic iodinated contrast agent for abdominal CT examination. Follow up MR imaging and MR angiography studies revealed hippocampal microinfarction and transient cerebral vasospasm. To our knowledge, this is the first reported case capturing arterial vasospasm following intravenous use of iodinated contrast. Medical professionals handling contrast agents should note the potential for these rare but serious adverse effects.
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Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell-fate decisions, resulting in an NE to non-NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non-SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Neoplasias Pulmonares , Receptores Notch , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Receptores Notch/metabolismo , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismoRESUMO
Polymeric nanofibers generated via electrospinning offer a promising platform for drug delivery systems. This study examines the application of electrospun polyvinyl alcohol (PVA) nanofibers for controlled lysozyme (LZM) delivery. By using various PVA grades, such as the degree of polymerization/hydrolysis, this study investigates their influence on nanofiber morphology and drug-release characteristics. LZM-loaded PVA monolithic nanofibers having 50% drug content exhibit efficient entrapment, wherein rapid dissolution is achieved within 30 min. The initial burst of LZM from the nanofiber was reduced as the LZM content was lowered. The initial dissolution is greatly influenced by the choice of PVA grade used; fully hydrolyzed PVA nanofibers demonstrate controlled release due to the reduced water solubility of PVA. Furthermore, coaxial electrospinning, which creates core-shell nanofibers with polycaprolactone as a controlled release layer, enables sustained LZM release over an extended period. This study confirms a correlation between PVA characteristics and controlled drug release and provides valuable insights into tailoring nanofiber properties for pharmaceutical applications.
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Nanofibras , Álcool de Polivinil , Preparações de Ação Retardada , Muramidase , Sistemas de Liberação de MedicamentosRESUMO
BACKGROUND: The impact of the distance from the root of splenic artery to tumor (DST) on the prognosis and optimal surgical procedures in the patients with pancreatic body/tail cancer has been unclear. METHODS: We retrospectively analyzed 94 patients who underwent distal pancreatectomy (DP) and 17 patients who underwent DP with celiac axis resection (DP-CAR) between 2008 and 2018. RESULTS: The 111 patients were assigned by DST length (in mm) as DST = 0: n = 14, 0Assuntos
Neoplasias Pancreáticas
, Artéria Esplênica
, Humanos
, Artéria Esplênica/cirurgia
, Prognóstico
, Estudos Retrospectivos
, Recidiva Local de Neoplasia/patologia
, Artéria Celíaca/cirurgia
, Artéria Celíaca/patologia
, Neoplasias Pancreáticas/patologia
, Pancreatectomia/métodos
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BACKGROUND: To compare the doses calculated by the analytical anisotropic algorithm (AAA) and two dose reporting modes of Acuros XB (AXB(Dm) and AXB(Dw)) with varied CT values on the Eclipse (Varian Medical Systems, Palo Alto, CA). MATERIALS AND METHODS: Virtual phantoms with a central layer of heterogeneous material (thickness = 2 or 5 cm) were created with Eclipse. Using single or opposed fields, the field sizes were 5 x 5 cm2 or 10 x 10 cm2. The photon energies were 6 or 10 MV, and the source-to-target distance was 100 cm. The relative doses at the center of the heterogeneous material layer were evaluated with varied CT values, from -1000 to 3000 HU. Values were normalized with the dose at 0 HU (100%) for comparative analysis. RESULTS: The results obtained from continuous data for a single field, 6 MV, 5 x 5 cm2, and the heterogeneous material 5 cm, where the differences between algorithms were most pronounced, were as follows. In the low-density region (-1000 HU and -800 HU), the dose differences for AXB with reference to AAA were, respectively, -54.5% and +4.6% (AXB(Dm)) and -47.0% and +3.5% (AXB(Dw)), and in the high-density regions (1000 HU and 3000 HU) were -5.7% and -8.8% (AXB(Dm)) and +7.4% and +3.5% (AXB(Dw)), respectively. Consequently, dose differences at arbitrary CT values could be obtained. CONCLUSION: Dose differences between these algorithms were clarified for heterogeneous materials. The risk of dose reduction or escalation in clinical use was clearly visible between CT values from -1000 to 3000 HU.
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Background: We clarified the dose difference between the anisotropic analytical algorithm (AAA) and Acuros XB (AXB) with increasing target's air content using a virtual phantom and clinical cases. Materials and methods: Whole neck volumetric modulated arc therapy (VMAT) plan was transferred into a virtual phantom with a cylindrical air structure at the center. The diameter of the air structure was changed from 0 to 6 cm, and the target's air content defined as the air/planning target volume (PTV) in percent (air/PTV) was varied. VMAT plans were recalculated by AAA and AXB with the same monitor unit (MU) and multi-leaf collimator (MLC) motions. The dose at each air/PTV (5%-30%) was compared between each algorithm with D98%, D95%, D50% and D2% for the PTV. In addition, MUs were also compared with the same MLC motions between the D95% prescription with AAA (AAA_D95%), AXB_D95%, and the prescription to 100% minus air/PTV (AXB_D100%-air/PTV) in clinical cases of head and neck (HNC). Results: When air/PTV increased (5-30%), the dose differences between AAA and AXB for D98%, D95%, D50% and D2% were 3.08-15.72%, 2.35-13.92%, 0.63-4.59%, and 0.14-6.44%, respectively. At clinical cases with air/PTV of 5.61% and 28.19%, compared to AAA_D95%, the MUs differences were, respectively, 2.03% and 6.74% for AXB_D95% and 1.80% and 0.50% for AXB_D100%-air/PTV. Conclusion: The dose difference between AAA and AXB increased as the target's air content increased, and AXB_D95% resulted in a dose escalation over AAA_D95% when the target's air content was ≥ 5%. The D100%-air/PTV of PTV using AXB was comparable to the D95% of PTV using AAA.
Assuntos
Educação em Farmácia , Farmácia , Humanos , Previsões , Pesquisadores , Preparações FarmacêuticasRESUMO
Biopharmaceuticals, including therapeutic genes and proteins, are characterized by highly-targeted, specific action and flexible pharmacological design and have a rapidly growing market share; however, because of high molecular weight and low stability, injection is the most common delivery route of biopharmaceuticals. Thus, pharmaceutical innovations are required to provide alternative delivery routes for biopharmaceuticals. Pulmonary drug delivery via inhalation is a promising approach, particularly for targeting local diseases of the lung, because it can exert therapeutic effects in small doses and can noninvasively and directly deliver drugs to airway surfaces. However, biopharmaceutical inhalers must ensure that the biopharmaceuticals maintain their integrity as they are subjected to several types of physicochemical stress, such as hydrolysis, ultrasound, and heating, at various stages during the process from manufacturing to administration. In this symposium, I present a novel dry powder inhaler (DPI) preparation method without heat-drying, with the goal of developing biopharmaceutical DPIs. Spray-freeze-drying is a nonthermal drying technique that produces a powder with porous shapes; this powder has suitable inhalation characteristics for DPI. A model drug, plasmid DNA (pDNA), was stably prepared as a DPI using the spray-freeze-drying process. Under dry conditions, the powders maintained high inhalation characteristics and maintained pDNA integrity for 12 months. The powder induced pDNA expression in mouse lungs that exceeded at higher levels than the solution did. This novel preparation method is suitable for DPI preparation for various drugs and may help expand the clinical application of DPIs.
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Produtos Biológicos , Temperatura Alta , Animais , Camundongos , Pós , Administração por Inalação , Composição de Medicamentos/métodos , DNA/genética , Inaladores de Pó Seco/métodos , Tamanho da Partícula , AerossóisRESUMO
Tumor-initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial-mesenchymal transition (EMT)-like signature marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis. Mechanistically, ROR1 induces the expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance PDAC proliferation. Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role for ROR1high cells as tumor-initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Nucleares/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/genética , Transição Epitelial-Mesenquimal , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias PancreáticasRESUMO
BACKGROUND/AIM: This study compared two types of parallel-plate ionization chamber to clarify the pitfalls of dosimetry in electron radiation therapy. MATERIALS AND METHODS: The ion recombination correction factor and polarity effect correction factor, sensitivity, and percentage depth doses (PDDs) of PPC05 and PPC40 parallel-plate ionization chambers were compared in a small-field electron beam. The output ratios were measured for 4-20 MeV electron beams with field sizes of 10 cm × 10 cm, 6 cm × 6 cm, and 4 cm × 4 cm. Furthermore, the films were placed in water and positioned in the beam with their surface perpendicular to the beam axis, and lateral profiles were obtained for each beam energy and each field. RESULTS: Regarding PDDs, at depths greater than the peak dose, the percentage depth dose for PPC40 was smaller than that for PPC05 in small fields and at beam energies greater than 12 MeV, which could be attributed to the lack of lateral electron equilibrium at small depths and multiple scattering events at large depths. The output ratio of PPC40 was approximately 0.025-0.038, which was lower than that of PPC05 in a 4 cm × 4 cm field. For large fields, the lateral profiles were similar, regardless of the beam energy, however, for small fields, the flatness of the lateral profile was beam energy dependent. CONCLUSION: The PPC05 chamber, which has a smaller ionization volume, is therefore more suitable than the PPC40 chamber for small-field electron dosimetry, in particular at high beam energies.
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Elétrons , Radiometria , Humanos , ÁguaRESUMO
Objective.The purpose of this study was to develop a new bolus (HM bolus), with tissue equivalence, transparency, reusability, and free shaping at approximately 40 °C for excellent adhesion, and to evaluate the feasibility of clinically using this bolus as an ideal bolus.Approach.We summarized the advantages and disadvantages of existing boluses. To evaluate dose characteristics, a vinyl gel sheet bolus (Gel bolus) and HM bolus placed on a water-equivalent phantom were used to obtain the percentage depth dose (PDD) of electron (6 MeV, 9 MeV) and photon (4 MV, 6 MV) beams. The average dose difference of the HM bolus and Gel bolus was calculated. The Gel bolus, a soft rubber bolus (SR bolus), and HM bolus were placed in adherence to a pelvic phantom. CT images taken after shaping and 1, 2, and 3 weeks after shaping were used to evaluate the adhesion and reproducibility using air gap and dice similarity coefficient (DSC).Main results.The average dose difference for electron beams was 0.16% ± 0.79% and photon beams was 0.06% ± 0.34%, both within 1% of the PDD results. The HM bolus showed the same build-up effect and dose characteristics as the Gel bolus. The mean air gap values for the Gel bolus, SR bolus, and HM bolus were 96.02 ± 43.77 cm3, 34.93 ± 21.44 cm3, and 4.40 ± 1.50 cm3, respectively. The mean DSC values compared to initial images for the Gel bolus, SR bolus, and HM bolus were 0.363 ± 0.035, 0.556 ± 0.042, and 0.837 ± 0.018, respectively. Excellent adhesion was observed in the CT simulation and during the treatment period.Significance.The HM bolus has unique features, such as tissue equivalence, transparency, reusability, and free shaping for excellent adhesion, and is thus an ideal bolus for use in clinical cases.
Assuntos
Fótons , Planejamento da Radioterapia Assistida por Computador , Reprodutibilidade dos Testes , Método de Monte Carlo , Planejamento da Radioterapia Assistida por Computador/métodos , Simulação por Computador , Imagens de Fantasmas , Dosagem Radioterapêutica , Radiometria/métodos , RadioterapiaRESUMO
The present study investigated the expression and role of ROR2 in small cell lung cancer (SCLC). To examine the expression of ROR2, 27 surgically resected SCLC tissue samples were immunostained for ROR2. Sixteen tissue samples were positive and some showed intratumor heterogeneity in staining intensity. The heterogeneity of ROR2 expression was also observed in tumor tissues from a PDX model of SCLC, in which there were cells with high ROR2 expression (ROR2high cells) and without its expression (ROR2low cells). These cells were subjected to a RNA sequence analysis. GSEA was performed and the results obtained revealed the enrichment of molecules such as G2M checkpoint, mitotic spindle, and E2F targets in ROR2high cells. The rate of EdU incorporation was significantly higher in ROR2high cells than ROR2low cells from the PDX model and the SCLC cell lines. Cell proliferation was suppressed in ROR2 KO SBC3 cells in vitro and in vivo. Comparisons of down-regulated differentially expressed genes in ROR2 KO SBC3 cells with up-regulated DEG in ROR2high cells from the PDX model revealed 135 common genes. After a Metascape analysis of these genes, we focused on Aurora kinases. In SCLC cell lines, the knockdown of ROR2 suppressed Aurora kinases. Therefore, ROR2 appears to regulate the cell cycle through Aurora kinases. The present results reveal a role for ROR2 in SCLC and afford a candidate system (ROR2-Aurora kinase) accompanying tumor heterogeneity in SCLC.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Linhagem Celular Tumoral , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Aurora QuinasesRESUMO
Purpose: The purpose of the study is to investigate the impact of large target offset distances on the dose distribution and gamma passing rate (GPR) in single-isocenter multiple-target stereotactic radiosurgery (SIMT SRS) using volumetric modulated arc therapy (VMAT) with a flattening filter-free (FFF) beam from a linear accelerator. Methods: Two targets with a diameter of 1 cm were offset by "±2, ±4, and ±6 cm from the isocenter in a verification phantom for head SRS (20 Gy/fr). The VMAT plans were created using collimator angles that ensured the two targets did not share a leaf pair from the multi-leaf collimator. To evaluate the low-dose spread intermediate dose spill (R50%), GPRs were measured with a criterion of 3%/2 mm using an electronic portal imaging device and evaluated using monitor unit (MU), modulation complexity score for VMAT (MCSv), and leaf travel (LT) parameters. Results: For offsets of 2, 4, and 6 cm, the respective parameters were: R50%, 4.75 ± 0.36, 5.13 ± 0.36, and 5.11 ± 0.33; GPR, 95.01%, 93.82%, and 90.67%; MU, 5893 ± 186, 5825 ± 286, and 5810 ± 396; MCSv, 0.24, 0.16, and 0.13; and LT, 189.21 ± 36.04, 327.69 ± 67.01, and 430.39 ± 114.34 mm. There was a spread in the low-dose region from offsets of ≥4 cm and the GPR negatively correlated with LT (r = -0.762). There was minimal correlation between GPR and MU or MCSv. Conclusions: In SIMT SRS VMAT plans with an FFF beam from a linear accelerator, target offsets of <4 cm from the isocenter can minimize the volume of the low-dose region receiving 10 Gy or more. During treatment planning, it is important to choose gantry, couch, and collimator angles that minimize LT and thereby improve the GPR.
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BACKGROUND & AIMS: Recently, a decrease in skeletal muscle, termed sarcopenia, has been reported to be associated with poorer survival of patients in several types of cancer. However, few studies have investigated the association between sarcopenia and the survival of patients with gallbladder cancer. METHODS: A total of 88 patients undergoing curative resection for advanced gallbladder cancer were included in this study. The quality of skeletal muscle was assessed by the intramuscular adipose tissue content (IMAC), and the quantity of skeletal muscle was assessed by the psoas muscle index (PMI), measured on preoperative computed tomography. The optimum cutoff values for IMAC and PMI for predicting the overall survival in each sex were determined using a minimum p value approach. Clinicopathological factors, IMAC and PMI were retrospectively analyzed to identify the predictors of overall survival (OS). RESULTS: The cutoff values for IMAC were -0.3 in males and 0.04 in females. The numbers of patients with low IMAC and high IMAC were 42 and 46, respectively. The cutoff values for PMI were 7.3 cm2/m2 in males and 5.0 cm2/m2 in females. The numbers of patients with low PMI and high PMI were 22 and 66, respectively. A multivariate analysis revealed that pT stage (pT3/4, hazard ratio [HR] = 6.72, p = 0.004), high IMAC (HR = 4.12, p < 0.001), Bile duct infiltration (present, HR = 2.82, p = 0.046), high age (≥72 years old, HR = 2.64, p = 0.010), major hepatectomy (performed, HR = 2.50, p = 0.031) and pN1/2 (HR = 2.17, p = 0.010) as independent prognostic factors. CONCLUSION: IMAC was independent prognostic factor for resected advanced gallbladder cancer, so the quality of skeletal muscle more strongly predicted survival than the quantity of skeletal muscle.
Assuntos
Neoplasias da Vesícula Biliar , Sarcopenia , Masculino , Feminino , Humanos , Idoso , Sarcopenia/complicações , Neoplasias da Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/complicações , Neoplasias da Vesícula Biliar/patologia , Estudos Retrospectivos , Fatores de Risco , Músculos Psoas/diagnóstico por imagemRESUMO
Sirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.