Compensatory Genetic and Transcriptional Cytonuclear Coordination in Allopolyploid Lager Yeast (Saccharomyces pastorianus).

Cytonuclear coordination between biparental-nuclear genomes and uniparental-cytoplasmic organellar genomes in plants is often resolved by genetic and transcriptional cytonuclear responses. Whether this mechanism also acts in allopolyploid members of other kingdoms is not clear. Additionally, cytonuclear coordination of interleaved allopolyploid cells/individuals within the same population is underexplored. The yeast Saccharomyces pastorianus provides the opportunity to explore cytonuclear coevolution during different growth stages and from novel dimensions. Using S. pastorianus cells from multiple growth stages in the same environment, we show that nuclear mitochondria-targeted genes have undergone both asymmetric gene conversion and growth stage-specific biased expression favoring genes from the mitochondrial genome donor (Saccharomyces eubayanus). Our results suggest that cytonuclear coordination in allopolyploid lager yeast species entails an orchestrated and compensatory genetic and transcriptional evolutionary regulatory shift. The common as well as unique properties of cytonuclear coordination underlying allopolyploidy between unicellular yeasts and higher plants offers novel insights into mechanisms of cytonuclear evolution associated with allopolyploid speciation.

Q-switched vortex waveguide laser generation based on LNOI thin films with implanted Ag nanoparticles.

Lithium-niobate-on-insulator (LNOI) thin films have gained significant attention in integrated photonics due to their exceptional crystal properties and wide range of applications. In this paper, we propose a novel approach to realize a Q-switched vortex waveguide laser by incorporating integrated lithium niobate thin films with embedded silver nanoparticles (Ag:LNOI) as a saturable absorber. The saturable absorption characteristics of Ag:LNOI are investigated using a home-made Z-scan system. Additionally, we integrate Ag:LNOI as a saturable absorber into a Nd:YAG "ear-like" cladding waveguide platform, which is prepared via femtosecond laser direct writing. By combining this setup with helical phase plates for phase modulation in the resonator, we successfully achieve a passive Q-switched vortex laser with a high repetition rate and narrow pulse duration in the near-infrared region. This work demonstrates the potential applications of LNOI thin films towards on-chip integration of vortex waveguide laser sources.

Amino acid-stimulated insulin secretion: a path forward in type 2 diabetes.

Qualitative and quantitatively appropriate insulin secretion is essential for optimal control of blood glucose. Beta-cells of the pancreas produce and secrete insulin in response to glucose and non-glucose stimuli including amino acids. In this manuscript, we review the literature on amino acid-stimulated insulin secretion in oral and intravenous in vivo studies, in addition to the in vitro literature, and describe areas of consensus and gaps in understanding. We find promising evidence that the synergism of amino acid-stimulated insulin secretion could be exploited to develop novel therapeutics, but that a systematic approach to investigating these lines of evidence is lacking. We highlight evidence that supports the relative preservation of amino acid-stimulated insulin secretion compared to glucose-stimulated insulin secretion in type 2 diabetes, and make the case for the therapeutic potential of amino acids. Finally, we make recommendations for research and describe the potential clinical utility of nutrient-based treatments for type 2 diabetes including remission services.

CircZNF609 regulates pulmonary fibrosis via miR-145-5p/KLF4 axis and its translation function.

BACKGROUND: Pulmonary fibrosis is a growing clinical problem that develops as a result of abnormal wound healing, leading to breathlessness, pulmonary dysfunction and ultimately death. However, therapeutic options for pulmonary fibrosis are limited because the underlying pathogenesis remains incompletely understood. Circular RNAs, as key regulators in various diseases, remain poorly understood in pulmonary fibrosis induced by silica. METHODS: We performed studies with fibroblast cell lines and silica-induced mouse pulmonary fibrosis models. The expression of circZNF609, miR-145-5p, and KLF4 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6A RNA immunoprecipitation assays (MeRIP), Western blotting, immunofluorescence assays, and CCK8 were performed to investigate the role of the circZNF609/miR-145-5p/KLF4 axis and circZNF609-encoded peptides in fibroblast activation. RESULTS: Our data showed that circZNF609 was downregulated in activated fibroblasts and silica-induced fibrotic mouse lung tissues. Overexpression of circZNF609 could inhibit fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1). Mechanically, we revealed that circZNF609 regulates pulmonary fibrosis via miR-145-5p/KLF4 axis and circZNF609-encoded peptides. Furthermore, circZNF609 was highly methylated and its expression was controlled by N6-methyladenosine (m6A) modification. Lastly, in vivo studies revealed that overexpression of circZNF609 attenuates silica-induced lung fibrosis in mice. CONCLUSIONS: Our data indicate that circZNF609 is a critical regulator of fibroblast activation and silica-induced lung fibrosis. The circZNF609 and its derived peptides may represent novel promising targets for the treatment of pulmonary fibrosis.

Targeted delivery of ZNF416 siRNA-loaded liposomes attenuates experimental pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is a chronic progressive fibrotic interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition caused by activated fibroblasts. Increasing evidence shows that matrix stiffness is essential in promoting fibroblast activation and profibrotic changes. Here, we investigated the expression and function of matrix stiffness-regulated ZNF416 in pulmonary fibrotic lung fibroblasts. METHODS: 1 kappa (soft), 60 kappa (stiff) gel-coated coverslips, or transforming growth factor-beta 1 (TGF-ß1)-cultured lung fibroblasts and the gain- or loss- of the ZNF416 function assays were performed in vitro. We also established two experimental pulmonary fibrosis mouse models by a single intratracheal instillation with 50 mg/kg silica or 6 mg/kg bleomycin (BLM). ZNF416 siRNA-loaded liposomes and TGF-ß1 receptor inhibitor SB431542 were administrated in vivo. RESULTS: Our study identified that ZNF416 could regulate fibroblast differentiation, proliferation, and contraction by promoting the nuclear accumulation of p-Smad2/3. Besides, ZNF416 siRNA-loaded liposome delivery by tail-vein could passively target the fibrotic area in the lung, and co-administration of ZNF416 siRNA-loaded liposomes and SB431542 significantly protects mice against silica or BLM-induced lung injury and fibrosis. CONCLUSION: In this study, our results indicate that mechanosensitive ZNF416 is a potential molecular target for the treatment of pulmonary fibrosis. Strategies aimed at silencing ZNF416 could be a promising approach to fight against pulmonary fibrosis.

Corticosteroid treatment in severe patients with SARS-CoV-2 and chronic HBV co-infection: a retrospective multicenter study.

BACKGROUND: The impact of corticosteroids on patients with severe coronavirus disease 2019 (COVID-19)/chronic hepatitis B virus (HBV) co-infection is currently unknown. We aimed to investigate the association of corticosteroids on these patients. METHODS: This retrospective multicenter study screened 5447 confirmed COVID-19 patients hospitalized between Jan 1, 2020 to Apr 18, 2020 in seven centers in China, where the prevalence of chronic HBV infection is moderate to high. Severe patients who had chronic HBV and acute SARS-cov-2 infection were potentially eligible. The diagnosis of chronic HBV infection was based on positive testing for hepatitis B surface antigen (HBsAg) or HBV DNA during hospitalization and a medical history of chronic HBV infection. Severe patients (meeting one of following criteria: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 ≤ 93% on room air; or oxygen index < 300 mmHg) with COVID-19/HBV co-infection were identified. The bias of confounding variables on corticosteroids effects was minimized using multivariable logistic regression model and inverse probability of treatment weighting (IPTW) based on propensity score. RESULTS: The prevalence of HBV co-infection in COVID-19 patients was 4.1%. There were 105 patients with severe COVID-19/HBV co-infections (median age 62 years, 57.1% male). Fifty-five patients received corticosteroid treatment and 50 patients did not. In the multivariable analysis, corticosteroid therapy (OR, 6.32, 95% CI 1.17-34.24, P = 0.033) was identified as an independent risk factor for 28-day mortality. With IPTW analysis, corticosteroid treatment was associated with delayed SARS-CoV-2 viral RNA clearance (OR, 2.95, 95% CI 1.63-5.32, P < 0.001), increased risk of 28-day and in-hospital mortality (OR, 4.90, 95% CI 1.68-14.28, P = 0.004; OR, 5.64, 95% CI 1.95-16.30, P = 0.001, respectively), and acute liver injury (OR, 4.50, 95% CI 2.57-7.85, P < 0.001). Methylprednisolone dose per day and cumulative dose in non-survivors were significantly higher than in survivors. CONCLUSIONS: In patients with severe COVID-19/HBV co-infection, corticosteroid treatment may be associated with increased risk of 28-day and in-hospital mortality.

ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1.

BACKGROUND: N6-methyladenosine (m6A) is the most common and abundant internal modification of RNA. Its critical functions in multiple physiological and pathological processes have been reported. However, the role of m6A in silica-induced pulmonary fibrosis has not been fully elucidated. AlkB homolog 5 (ALKBH5), a well-known m6A demethylase, is upregulated in the silica-induced mouse pulmonary fibrosis model. Here, we sought to investigate the function of ALKBH5 in pulmonary fibrosis triggered by silica inhalation. METHODS: We performed studies with fibroblast cell lines and silica-induced mouse pulmonary fibrosis models. The expression of ALKBH5, miR-320a-3p, and forkhead box protein M1 (FOXM1) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6A RNA immunoprecipitation assays (MeRIP), western bolt, immunofluorescence assays, and 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining were performed to explore the roles of ALKBH5, miR-320a-3p, and FOXM1 in fibroblast activation. RESULTS: ALKBH5 expression was increased in silica-inhaled mouse lung tissues and transforming growth factor (TGF)-ß1-stimulated fibroblasts. Moreover, ALKBH5 knockdown exerted antifibrotic effects in vitro. Simultaneously, downregulation of ALKBH5 elevated miR-320a-3p but decreased pri-miR-320a-3p. Mechanically, ALKBH5 demethylated pri-miR-320a-3p, thus blocking the microprocessor protein DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p. We further demonstrated that miR-320a-3p could regulate fibrosis by targeting FOXM1 messenger RNA (mRNA) 3'-untranslated region (UTR). Notably, our study also verified that ALKBH5 could also directly regulate FOXM1 in an m6A-dependent manner. CONCLUSIONS: Our findings suggest that ALKBH5 promotes silica-induced lung fibrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1 directly. Approaches aimed at ALKBH5 may be efficacious in treating lung fibrosis.

Micronutrient Level Is Negatively Correlated with the Neutrophil-Lymphocyte Ratio in Patients with Severe COVID-19.

Aim: To explore the potential relationship between NLR and micronutrient deficiency in patients with severe COVID-19 infection. Methods: Sixteen patients were categorized into the mild group (mild COVID-19) and severe group (severe COVID-19) based on the guideline of the management of COVID-19. The lactate dehydrogenase (LDH); superoxide dismutase (SOD), the inflammatory markers (neutrophil lymphocyte ratio (NLR)), erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), selenium (Se), iron (Fe), zinc (Zn), nickel (Ni), copper (Cu), chromium (Cr), cadmium (Cd), arsenic (As), and manganese (Mn) were measured in the blood. Results: Compared to the mild group, the NLR (P < 0.05) and the level of Se (P < 0.01), Fe (P < 0.05), and Zn (P < 0.05) were significantly decreased in the severe group. The level of Se, Fe, and Zn was significantly correlated to NLR levels. Furthermore, close positive correlation was found between NLR and severity of COVID-19. Conclusion: The micronutrient deficiency in the blood is associated with NLR in the severity of COVID-19 patients.

PTX3 alleviates hard metal-induced acute lung injury through potentiating efferocytosis.

Prolonged exposure to hard metal dust results in hard metal lung disease (HMLD) characterized by respiratory symptoms. Understanding the pathogenesis and pathological process of HMLD would be helpful for its early diagnosis and treatment. In this study, we established a mouse model of hard metal-induced acute lung injury through one-time intratracheal instillation of WC-Co dust suspension. We found that WC-Co treatment damaged the lungs of mice, leading to increased production of IL-1ß, TNF-α, IL-6 and IL-18, inflammatory cells infiltration and apoptosis. In vitro, WC-Co induced cytotoxicity, inflammatory response and apoptosis in macrophages (PMA-treated THP-1) and epithelial cells (A549) in a dose-dependent manner. Moreover, RNA-sequence and validation experiments verified that Pentraxin 3 (PTX3), an important mediator in the regulation of inflammation, was elevated both in vivo and in vitro induced by WC-Co. Functional experiments confirmed the PTX3, which was located on the membrane of apoptotic cells, promoted macrophage efferocytosis efficiently. This progress could help block the lung inflammation and contribute to the rapid recovery of WC-Co-induced acute lung injury. These observations provide a further understanding of the molecular mechanism of WC-Co-induced pulmonary injury and disclose PTX3 as a new potential therapeutic approach to relieve WC-Co-induced acute lung injury via efferocytosis.

Data driven adaptive Gaussian mixture model for solving Fokker-Planck equation.

The Fokker-Planck (FP) equation provides a powerful tool for describing the state transition probability density function of complex dynamical systems governed by stochastic differential equations (SDEs). Unfortunately, the analytical solution of the FP equation can be found in very few special cases. Therefore, it has become an interest to find a numerical approximation method of the FP equation suitable for a wider range of nonlinear systems. In this paper, a machine learning method based on an adaptive Gaussian mixture model (AGMM) is proposed to deal with the general FP equations. Compared with previous numerical discretization methods, the proposed method seamlessly integrates data and mathematical models. The prior knowledge generated by the assumed mathematical model can improve the performance of the learning algorithm. Also, it yields more interpretability for machine learning methods. Numerical examples for one-dimensional and two-dimensional SDEs with one and/or two noises are given. The simulation results show the effectiveness and robustness of the AGMM technique for solving the FP equation. In addition, the computational complexity and the optimization algorithm of the model are also discussed.

LncRNA-ATB regulates epithelial-mesenchymal transition progression in pulmonary fibrosis via sponging miR-29b-2-5p and miR-34c-3p.

Dysregulation of non-coding RNAs (ncRNAs) has been proved to play pivotal roles in epithelial-mesenchymal transition (EMT) and fibrosis. We have previously demonstrated the crucial function of long non-coding RNA (lncRNA) ATB in silica-induced pulmonary fibrosis-related EMT progression. However, the underlying molecular mechanism has not been fully elucidated. Here, we verified miR-29b-2-5p and miR-34c-3p as two vital downstream targets of lncRNA-ATB. As opposed to lncRNA-ATB, a significant reduction of both miR-29b-2-5p and miR-34c-3p was observed in lung epithelial cells treated with TGF-ß1 and a murine silicosis model. Overexpression miR-29b-2-5p or miR-34c-3p inhibited EMT process and abrogated the pro-fibrotic effects of lncRNA-ATB in vitro. Further, the ectopic expression of miR-29b-2-5p and miR-34c-3p with chemotherapy attenuated silica-induced pulmonary fibrosis in vivo. Mechanistically, TGF-ß1-induced lncRNA-ATB accelerated EMT as a sponge of miR-29b-2-5p and miR-34c-3p and shared miRNA response elements with MEKK2 and NOTCH2, thus relieving these two molecules from miRNA-mediated translational repression. Interestingly, the co-transfection of miR-29b-2-5p and miR-34c-3p showed a synergistic suppression effect on EMT in vitro. Furthermore, the co-expression of these two miRNAs by using adeno-associated virus (AAV) better alleviated silica-induced fibrogenesis than single miRNA. Approaches aiming at lncRNA-ATB and its downstream effectors may represent new effective therapeutic strategies in pulmonary fibrosis.

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling.

BACKGROUND: Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. METHODS: The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-ß1)-induced differentiated lung fibroblasts were used for in vitro models. RESULTS: At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2-10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-ß1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. CONCLUSIONS: In this study, we identified that metformin might be a potential drug for silicosis treatment.

Respiratory traits and coal workers' pneumoconiosis: Mendelian randomisation and association analysis.

OBJECTIVES: Susceptibility loci of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were also significantly associated with the predisposition of coal worker's pneumoconiosis (CWP) in recent studies. However, only a few genes and loci were targeted in previous studies. METHODS: To systematically evaluate the genetic associations between CWP and other respiratory traits, we reviewed the reported genome-wide association study loci of five respiratory traits and then conducted a Mendelian randomisation study and a two-stage genetic association study. RESULTS: Interestingly, we found that for each SD unit, higher lung function was associated with a 66% lower risk of CWP (OR=0.34, 95% CI: 0.15 to 0.77, p=0.010) using conventional Mendelian randomisation analysis (inverse variance weighted method). Moreover, we found susceptibility loci of interstitial lung disease (rs2609255, OR=1.29, p=1.61×10-4) and lung function (rs4651005, OR=1.39, p=1.62×10-3; rs985256, OR=0.73, p=8.24×10-4 and rs6539952, OR=1.28, p=4.32×10-4) were also significantly associated with the risk of CWP. Functional annotation showed these variants were significantly associated with the expression of FAM13A (rs2609255, p=7.4 ×10-4), ANGPTL1 (rs4651005, p=5.4 ×10-7), SPATS2L (rs985256, p=1.1 ×10-5) and RP11-463O9.9 (rs6539952, p=7.1 ×10-6) in normal lung tissues, which were related to autophagy pathway simultaneously according to enrichment analysis. CONCLUSIONS: These results provided a deeper understanding of the genetic predisposition basis of CWP.

LncRNA-PVT1 activates lung fibroblasts via miR-497-5p and is facilitated by FOXM1.

It is little known about the lncRNA-PVT1 effect on occupational pulmonary fibrosis, although researches show it plays an essential role in cancer. Studies reveal that lung fibroblast activation is one of the key events in silica-induced fibrosis. Here, we found that lncRNA-PVT1 promoted the proliferation, activation, and migration of lung fibroblasts. The isolation of cytoplasmic and nuclear RNA assay and fluorescence in situ hybridization experiment showed that lncRNA-PVT1 was abundantly expressed in the cytoplasm. Luciferase reporter gene assay and RNA pull-down experiment indicated that the cytoplasmic-localized lncRNA-PVT1 could competitively bind miR-497-5p. MiR-497-5p was further observed to attenuate silica-induced pulmonary fibrosis by targeting Smad3 and Bcl2. Moreover, the transcription factor FOXM1 acted as a profibrotic factor by elevating lncRNA-PVT1 transcription in lung fibroblasts. Inhibition of FOXM1 expression with thiostrepton alleviated silica-induced pulmonary fibrosis in vivo. Collectively, we revealed that FOXM1-facilitated lncRNA-PVT1 activates lung fibroblasts via miR-497-5p during silica-induced pulmonary fibrosis, which may provide potential therapeutic targets for pulmonary fibrosis.

Risk factors for severe COVID-19 in middle-aged patients without comorbidities: a multicentre retrospective study.

BACKGROUND: Information regarding characteristics and risk factors of COVID-19 amongst middle-aged (40-59 years) patients without comorbidities is scarce. METHODS: We therefore conducted this multicentre retrospective study and collected data of middle-aged COVID-19 patients without comorbidities at admission from three designated hospitals in China. RESULTS: Among 119 middle-aged patients without comorbidities, 18 (15.1%) developed into severe illness and 5 (3.9%) died in hospital. ARDS (26, 21.8%) and elevated D-dimer (36, 31.3%) were the most common complications, while other organ complications were relatively rare. Multivariable regression showed increasing odds of severe illness associated with neutrophil to lymphocyte ratio (NLR, OR, 11.238; 95% CI 1.110-1.382; p < 0.001) and D-dimer greater than 1 µg/ml (OR, 16.079; 95% CI 3.162-81.775; p = 0.001) on admission. The AUCs for the NLR, D-dimer greater than 1 µg/ml and combined NLR and D-dimer index were 0.862 (95% CI, 0.751-0.973), 0.800 (95% CI 0.684-0.915) and 0.916 (95% CI, 0.855-0.977), respectively. SOFA yielded an AUC of 0.750 (95% CI 0.602-0.987). There was significant difference in the AUC between SOFA and combined index (z = 2.574, p = 0.010). CONCLUSIONS: More attention should be paid to the monitoring and early treatment of respiratory and coagulation abnormalities in middle-aged COVID-19 patients without comorbidities. In addition, the combined NLR and D-dimer higher than 1 µg/ml index might be a potential and reliable predictor for the incidence of severe illness in this specific patient with COVID-19, which could guide clinicians on early classification and management of patients, thereby relieving the shortage of medical resource. However, it is warranted to validate the reliability of the predictor in larger sample COVID-19 patients.

Intraoperative Radiotherapy for Breast Cancer Treatment in a Rural Community.

BACKGROUND: Access to health care poses particular challenges for patients living in rural communities. Intraoperative radiotherapy (IORT) offers a treatment alternative to traditional whole-breast radiation therapy (WBRT) for select patients. This study aimed to analyze the use of IORT for patients undergoing breast-conserving surgery at an academic institution located in a rural state. METHODS: A retrospective review analyzed all patients at a single institution with a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer from April 2012 to January 2017 who were undergoing breast-conserving surgery with either IORT or WBRT. Student's t test or Fisher's exact test was used to make statistical comparisons. RESULTS: Patients undergoing IORT (n = 117) were significantly older than patients treated with WBRT (n = 191) (65.6 vs 58.6 years; p < 0.001) and had smaller tumors on both preoperative imaging (1.04 vs 1.66 cm; p < 0.05) and final pathology (0.99 vs 1.48 cm; p < 0.05). Patients receiving IORT lived farther from the treating facility than patients treated with WBRT (67.2 vs 30.8 miles; p < 0.05). To account for biases created in the IORT selection criteria, subgroup analysis was performed for women receiving WBRT who fulfilled IORT selection criteria, and distance traveled remained significant (67.2 vs 31.4 miles; p < 0.05). Neither recurrence nor survival differed between the IORT and WBRT groups. Medicare reimbursement for IORT was approximately 50% more than for WBRT. CONCLUSIONS: For women from rural communities, IORT appears to be an attractive option because these women tend to be older and to live farther from the treatment facility.

Does the apex optimization line matter for single-channel vaginal cylinder brachytherapy planning?

The objective of this study is to test the impact of the use of the apex optimization line for new vaginal cylinder (VC) applicators. New single channel VC applicators (Varian) that have different top thicknesses but the same diameters as the old VC applicators (2.0 cm diameter, 2.3, 2.6, 3.0, and 3.5 cm) were compared using phantom studies. Old VC applicator plans without the apex optimization line were also compared to the plans with an apex optimization line. The apex doses were monitored at 5 mm depth doses (eight points) where a prescription dose (Rx) of 6 Gy was prescribed. VC surface doses (eight points) were also analyzed. The new VC applicator plans without apex optimization line presented significantly lower 5-mm depth doses over the Rx (on average -31 ± 7%, P < 0.00001) due to thicker VC tops (3.4 ± 1.1 mm thicker with the range of 1.2-4.4 mm) than the old VC applicators. Old VC applicator plans also showed a statistically significant reduction (P < 0.00001) due to the Ir-192 source anisotropic effect at the apex region, but the percent reduction over the Rx was only -7 ± 9%. However, by adding the apex optimization line to the new VC applicator plans, the plans improved 5-mm depth doses (-7 ± 9% over Rx) that were not statistically different from old VC applicator plans (P = 0.923), along with apex VC surface doses (-22 ± 10% over old VC vs -46 ± 7% without using apex optimization line). The use of the apex optimization line is important in order to avoid significant additional cold doses (-24 ± 2%) at the prescription depth (5 mm) of the apex, specifically for the new VC applicators that have thicker tops. A template-based vaginal cylinder planning reduced the intra- and inter-planner variations of manual generation of apex optimization line, along with treatment time.

Patient's specific integration of OAR doses (D2 cc) from EBRT and 3D image-guided brachytherapy for cervical cancer.

The objective of this study was to assess the recommended DVH parameter (e.g., D2 cc) addition method used for combining EBRT and HDR plans, against a reference dataset generated from an EQD2-based DVH addition method. A revised DVH parameter addition method using EBRT DVH parameters derived from each patient's plan was proposed and also compared with the reference dataset. Thirty-one biopsy-proven cervical cancer patients who received EBRT and HDR brachytherapy were retrospectively analyzed. A parametrial and/or paraaortic EBRT boost were clinically performed on 13 patients. Ten IMRT and 21 3DCRT plans were determined. Two different HDR techniques for each HDR plan were analyzed. Overall D2 cc and D0.1 cc OAR doses in EQD2 were statistically analyzed for three different DVH parameter addition methods: a currently recommended method, a proposed revised method, and a reference DVH addition method. The overall D2 ccEQD2 values for all rectum, bladder, and sigmoid for a conformal, volume optimization HDR plan generated using the current DVH parameter addition method were significantly underestimated on average -5 to -8% when compared to the values obtained from the reference DVH addition technique (P < 0.01). The revised DVH parameter addition method did not present statistical differences with the reference technique (P > 0.099). When PM boosts were considered, there was an even greater average underestimation of -8~-10% for overall OAR doses of conformal HDR plans when using the current DVH parameter addition technique as compared to the revised DVH parameter addition. No statistically significant differences were found between the 3DCRT and IMRT techniques (P > 0.3148). It is recommended that the overall D2 cc EBRT doses are obtained from each patient's EBRT plan.

Correlations of p53 expression with transvaginal color Doppler ultrasound findings of cervical cancer after radiotherapy.

PURPOSE: To investigate the correlations of p53 expression with transvaginal color Doppler ultrasound findings of cervical cancer after radiotherapy (RT). METHODS: A total of 78 patients with cervical cancer (stage II and III) treated in the Oncology Department of our hospital from March 2011 to September 2017 were enrolled, and another 10 normal cervical tissue specimens were taken from the Pathology Department as controls. RT was performed to the 78 enrolled patients. Morphological features of tumor tissues after RT were detected via hematoxylineosin (HE) staining, the mutant p53 protein level was detected via immunohistochemistry (IHC), and imaging signs and blood flow resistance index (RI) of cervical cancer were detected via transvaginal color Doppler ultrasound. Finally, the correlations of p53 protein with transvaginal color Doppler ultrasound findings were analyzed. RESULTS: After RT, most cervical cancer tissues showed nuclear degeneration, karyolysis, cytoplasmic keratosis (vacuolization), and regeneration and fibrosis of cancer tissues. The expression of p53 was negative in normal cervix, while there were 48 p53-positive cases (61.54%) and 30 p53-negative cases (38.46%) in patients with cervical cancer (p<0.05). No echo was detected in 2 out of 78 patients, and there were 4 cases of equal echo, 36 cases of low echo and 36 cases of high echo. Results of x2 test showed that the positive rate of p53 protein was significantly correlated with cervical space-occupying lesion and mass diameter shown in transvaginal color Doppler ultrasound (p<0.05), but it had no significant correlation with pelvic lymph node metastasis (p>0.05). The p53 protein expression level was significantly correlated with color Doppler flow imaging (CDFI) grading and RI (p<0.05). CONCLUSIONS: The p53 protein expression in cervical cancer after RT is significantly correlated with cervical space-occupying lesion and tumor size shown in transvaginal color Doppler ultrasound, CDFI grading and RI. p53 level and transvaginal color Doppler ultrasound can provide certain valuable clinical information for the treatment and monitoring of cervical cancer.

Comparative assessment of orthogonal polynomials for wavefront reconstruction over the square aperture.

Four orthogonal polynomials for reconstructing a wavefront over a square aperture based on the modal method are currently available, namely, the 2D Chebyshev polynomials, 2D Legendre polynomials, Zernike square polynomials and Numerical polynomials. They are all orthogonal over the full unit square domain. 2D Chebyshev polynomials are defined by the product of Chebyshev polynomials in x and y variables, as are 2D Legendre polynomials. Zernike square polynomials are derived by the Gram-Schmidt orthogonalization process, where the integration region across the full unit square is circumscribed outside the unit circle. Numerical polynomials are obtained by numerical calculation. The presented study is to compare these four orthogonal polynomials by theoretical analysis and numerical experiments from the aspects of reconstruction accuracy, remaining errors, and robustness. Results show that the Numerical orthogonal polynomial is superior to the other three polynomials because of its high accuracy and robustness even in the case of a wavefront with incomplete data.