Dosimetric validation for prospective clinical trial on GRID collimator-based spatially fractionated radiation therapy: Dose metrics consistency and heterogeneous pattern reproducibility.

PURPOSE: The purpose of this study is to characterize the dosimetric properties of a commercial brass GRID collimator for high energy photon beams including 15 and 10 MV. Then, the difference in dosimetric parameters of GRID beams among different energies and linacs was evaluated. METHOD: A water tank scanning system was used to acquire the dosimetric parameters, including the percentage depth dose (PDD), beam profiles, peak to valley dose ratios (PVDRs), and output factors (OFs). The profiles at various depths were measured at 100 cm source to surface distance (SSD), and field sizes of 10 × 10 cm2 and 20 × 20 cm2 on three linacs. The PVDRs and OFs were measured and compared with the treatment planning system (TPS) calculations. RESULTS: Compared with the open beam data, there were noticeable changes in PDDs of GRID fields across all the energies. The GRID fields demonstrated a maximal of 3 mm shift in dmax (Truebeam STX, 15MV, 10 × 10 cm2). The PVDR decreased as beam energy increases. The difference in PVDRs between Trilogy and Truebeam STx using 6MV and 15MV was 1.5% ± 4.0% and 2.1% ± 4.3%, respectively. However, two Truebeam linacs demonstrated less than 2% difference in PVDRs. The OF of the GRID field was dependent on the energy and field size. The measured PDDs, PVDRs, and OFs agreed with the TPS calculations within 3% difference. The TPS calculations agreed with the measurements when using 1 mm calculation resolution. CONCLUSION: The dosimetric characteristics of high-energy GRID fields, especially PVDR, significantly differ from those of low-energy GRID fields. Two Truebeam machines are interchangeable for GRID therapy, while a pronounced difference was observed between Truebeam and Trilogy. A series of empirical equations and reference look-up tables for GRID therapy can be generated to facilitate clinical applications.

Heterogeneous bimetallic selenides encapsulated within graphene aerogel as advanced anodes for sodium ion batteries.

Metal selenides are promising anode candidates for sodium ion batteries (SIBs) because of their high theoretical capacity, low cost, and environmental friendship. However, the low rate capability at high current density due to its inherent low electrical conductivity and poor cycle stability caused by inevitable volume variations during cycling frustrate its practical applications. Herein, we have developed a simple metallic-organic frameworks (MOFs)-derived selenide strategy to synthesize a series of heterogeneous bimetallic selenides encapsulated within graphene aerogels (GA) as anodes for SIBs. The bimetallic selenides/GA composites have unique structural characteristics that can shorten the migration path for Na+/electrons and accommodate the volume variations via additional void space during cycling. The built-in electric fields induced at the heterointerfaces can greatly reduce the activation energy for rapid charge transfer kinetics and promote the diffusion of Na+/electrons. GA is also beneficial for accommodating the volume variations during cycling and improving conductivity. As an advanced anode for SIBs, the MoSe2-Cu1.82Se@GA with a special porous octahedron can deliver the highest capacity of 444.8 mAh/g at a high rate of 1 A/g even after 1000 cycles among the bimetallic selenides/GA composites.

Synthesis and characterization of core-shell high-nickel cobalt-free layered LiNi0.95Mg0.02Al0.03O2@Li2ZrO3 cathode for high-performance lithium ion batteries.

High-nickel cobalt-free layered cathode is regarded as a highly potential cathode material for the next generation lithium ion batteries (LIBs) because of its high energy density, low cost and environmentally benign. However, the poor cycle performance caused by its intrinsic unstable structure and chemo-mechanical instability frustrates its practical applications. Herein, we have developed a new core-shell high-nickel cobalt-free layered LiNi0.95Mg0.02Al0.03O2@Li2ZrO3 (LZO-NMA9523) cathode for high-performance LIBs. The Li2ZrO3 coating layer firstly helps to suppress and reduce the degree of Li+/Ni2+ cation mixing during the material preparation process. In addition, the Li2ZrO3 coating layer can not only accommodate the volume variations and enhance the electricity of the active materials, but also effectively inhibit the harmful irreversible phase transition during the charging/discharging process, thus greatly stabilizing the structure of the high-nickel cobalt-free cathode. As an advanced cathode for LIBs, the LZO-NMA9523 exhibits an excellent reversible capacity of 146.9 mAh g-1 after 100 cycles at 0.5 C with capacity retention of about 80%. This study provides a possible high-nickel cobalt-free layered cathode material for the next generation LIBs.

Synthesis of Bimetallic Palladium/Zinc Oxide Nanocomposites Using Crocus sativus and Its Anticancer Activity via the Induction of Apoptosis in Cervical Cancer.

Palladium (Pd) and zinc oxide (ZnO) (Pd/ZnO NPs) bimettalic nanocomposites still lag much too far behind other nanoparticles investigated for various biological uses in the area of cancer treatments. Chemically created nanoparticles agglomerate under physiological conditions, impeding their use in biomedical applications. In this study, a straightforward and environmentally friendly method for creating bimetallic nanoparticles (NPs) by combining palladium (Pd) and zinc oxide (ZnO) using Crocus sativus extract (CS-Pd/ZnO NCs) was reported; the bio-synthesize bimetallic palladium/zinc oxide nanocomposites and their antioxidant and anti-cancer properties were assessed. The developed Pd/ZnO NPs were characterized using different approaches, including UV-vis, DLS, FTIR, EDX, and SEM analyses. The present investigation shows how nanocomposites are made, their distinctive properties, antioxidant activity, anticancer mechanisms, and their potential therapeutic applications. DPPH and ABTS tests were used to investigate antioxidant activity. Further, the effects of CS-Pd/ZnO NCs on HeLa cells were assessed using the cell viability, ROS generation, MMP levels, and induced apoptosis. Apoptosis induction was measured using an Annexin V-fluorescein isothicyanate assay. Cell DNA was stained with propidium iodide to evaluate the impact upon this cell cycle. Time-dependent cell death was carried on by CS-Pd/ZnO NCs. The maximum inhibitory effect was 59 ± 3.2 when dosages of 4.5 µg/mL or higher were delivered after 24 h of treatment. Additionally, the CS-Pd/ZnO NCs caused HeLa cells to undergo apoptosis. Apoptotic HeLa cells were present in 35.64% of the treated cells at 4.5 µg/mL, and the cell cycle arrest at G0/G1 phase occurred concurrently. According to these findings, the CS-Pd/ZnO NCs may be a promising candidate for the creation of brand-new cervical cancer treatment.

Hippocampal sparing radiation therapy for brain metastases: treatment techniques and clinical implementation.

High doses of radiation to the hippocampus have been correlated with increased cognitive decline following radiation therapy for brain metastases. To mitigate these effects, a variety of hippocampal sparing techniques have been implemented for both whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). The goal of this review article is to provide a practical resource for the clinical implementation of hippocampal-sparing radiation therapy, starting with a brief background on the function and delineation of the hippocampal structure, as well as radiation effects on the hippocampus and the most widely recommended dose constraints. Considerations for treatment simulation are discussed, including options for cranial immobilization and optional head tilt. Hippocampal sparing has been demonstrated for WBRT using helical TomoTherapy, static intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) with a variety of patient setup positions, beam arrangements, and planning parameters. Tomotherapy has been shown to achieve slightly greater hippocampal sparing in some studies, while VMAT enables the most efficient treatment delivery. Hippocampal sparing has also been evaluated in a wide range of studies for both GammaKnife and linear accelerator (LINAC)-based SRS, with the proximity of metastases to the hippocampus being the most significant predictor of hippocampal dose. The methods and resulting hippocampal doses from these studies on both WBRT and SRS are discussed, as well as the role of automation in hippocampal sparing radiation therapy.

Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice.

Neuroinflammatory microglia secrete cytokines to induce neurotoxic reactive astrocytes, which are one of the major causes of neuronal death. However, the intrinsic key regulators underlying neurotoxic reactive astrocytes induction are unknown. Here we show that the transmembrane protein 164 (TMEM164) is an early-response intrinsic factor that regulates neurotoxic astrocyte reactivity. TMEM164 overexpression inhibits the induction of neurotoxic reactive astrocytes, maintains normal astrocytic functions and suppresses neurotoxic reactive astrocyte-mediated neuronal death by decreasing the secretion of neurotoxic saturated lipids. Adeno-associated virus-mediated, astrocyte-specific TMEM164 overexpression in male and female mice prevents the induction of neurotoxic reactive astrocytes, dopaminergic neuronal loss and motor deficits in a Parkinson's disease model. Notably, brain-wide astrocyte-specific TMEM164 overexpression prevents the induction of neurotoxic reactive astrocytes, amyloid ß deposition, neurodegeneration and memory decline in the 5XFAD Alzheimer's disease mouse model, suggesting that TMEM164 could serve as a potential therapeutic target for neurodegenerative disorders.

SpoT-mediated NapA upregulation promotes oxidative stress-induced Helicobacter pylori biofilm formation and confers multidrug resistance.

Recently, there is increased incidence of drug-resistant Helicobacter pylori infection. Biofilm formation confers multidrug resistance to bacteria. Moreover, it has been found that the formation of biofilm on the surface of gastric mucosa is an important reason for the difficulty of eradication of H. pylori The mechanisms underlying H. pylori biofilm formation in vivo have not been elucidated. Reactive oxygen species (ROS) released by the host immune cells in response to H. pylori infection cannot effectively clear the pathogen. Moreover, the extracellular matrix of the biofilm protects the bacteria against ROS-mediated toxicity. This study hypothesized that ROS can promote H. pylori biofilm formation and treatment with low concentrations of hydrogen peroxide (H2O2) promoted this process in vitro The comparative transcriptome analysis of planktonic and biofilm-forming cells revealed that the expression of SpoT, a (p)ppGpp (guanosine 3'-diphosphate 5'-triphosphate and guanosine 3',5'-bispyrophosphate) synthetase/hydrolase, is upregulated in H2O2-induced biofilms and that knockout of spoT inhibited H. pylori biofilm formation. Additionally, this study examined the key target molecules involved in SpoT regulation using weighted gene co-expression network analysis. The analysis revealed that neutrophil-activating protein (NapA; HP0243) promoted H2O2-induced biofilm formation and conferred multidrug resistance. Furthermore, vitamin C exhibited anti-H. pylori biofilm activity and downregulated the expression of napA in vitro These findings provide novel insight into the clearance of H. pylori biofilms.

Nasturtium officinale L. and metformin alleviate the estradiol- induced polycystic ovary syndrome with synergistic effects through modulation of Bax/Bcl-2/p53/caspase-3 signaling pathway and anti-inflammatory and anti-oxidative effects.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, which is associated with metabolic, hereditary and hormonal disorders. The aim of this study was to evaluate the therapeutic effects of Nasturtium officinale L. (N. officinale) on biochemical and molecular parameters in estradiol-induced PCOS in rats. Seventy Wistar rats in 7 groups (n = 10) were randomly assigned to normal (NC), PCOS, metformin (MET - 300 mg/kg), N. officinale (50 and 100 mg/kg) and co-treatment with MET and N. officinale groups. After 21 days of treatment, biochemical parameters levels of estrogen, LH and FSH along with serum levels of (IL-6 and IL-1ß cytokines) and serum antioxidant parameters (enzymatic activity of catalase and superoxide dismutase) were measured. Finally, by measuring the expression of apoptosis related genes (Bax/Bcl-2/p53/caspase-3) with the help of real-time PCR and the expression of p53 with the help of immunohistochemistry in ovarian cells. N. officinale modulates hormones through its hypothalamic-pituitary-gonadal pathway with its synergistic effects along with MET. Also, in co-treatment groups (MET and N. officinale), the activity of serum antioxidant enzymes increased and also the serum level of inflammatory cytokines decreased. N. officinale, along with MET, amplified the Bax/Bcl2/p53/caspase-3 pathways, which eventually increased the number of p53 positive cells. These findings indicate that N. officinale extract along with MET can improve the physiological function of the ovaries in PCOS-induced disorders. PRACTICAL APPLICATIONS: Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, which is associated with metabolic, hereditary and hormonal disorders. The extract of Nasturtium officinale L. was able to intensify mitochondrial apoptotic pathway in cystic follicles and prevent their formation. It seems that pro-drugs containing N. officinale along with effective commercial drugs in PCOS can help ovulation and fertility in woman with this disease.

Effect of applicator removal from target volume for cervical cancer patients treated with Venezia high-dose-rate brachytherapy applicator.

Purpose: The volume of Venezia applicator with vaginal caps can be relatively large compared to target volumes. This study investigated the dosimetric and radiobiological effects of applicator volume removal for cervical cancer patients treated with Venezia (VZ) and tandem and split-ring (TSR) applicators used in the clinic. Material and methods: A total of 40 patients (101 plans) with stage IIA-IIIC cervical cancer were retrospectively reviewed. Thirty patients were treated with VZ and ten patients were treated with TSR. Applicators were contoured on planning CTs where target contours were involved. Applicator contours were subtracted from the target contours. External beam radiation therapy (EBRT) and brachytherapy doses were calculated in biologically equivalent doses in 2 Gy fractions (EQD2) and combined using full parameter addition for dose-volume histogram (DVH) parameters of composited dose. D90%, D50%, V100%, V150%, V200%, and tumor control probability (TCP) were evaluated and compared for targets after applicator exclusion. Results: The average volume changes in gross tumor volume (GTV), high-risk clinical target volume (HR-CTV), and intermediate-risk clinical target volume (IR-CTV) after VZ applicator exclusion were 1.4 ±1.5 cm3, 15.7 ±6.6 cm3, and 33.8 ±15.1 cm3, respectively. VZ exclusion resulted in significant changes (p < 0.05) in small volume parameters (D50%) and high-dose parameters (V150% and V200%) for HR-CTV and IR-CTV. Dosimetric impact of TSR exclusion on targets was not significant. There was no significant change in TCP after applicator exclusion. Conclusions: Venezia applicator with vaginal caps has significant impact on small volume and high-dose DVH parameters of the target. Applicator contour exclusion is recommended for dosimetric evaluation when Venezia applicator is used.

An AAV vaccine targeting the RBD of the SARS-CoV-2 S protein induces effective neutralizing antibody titers in mice and canines.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in catastrophic damage worldwide. Accordingly, the development of powerful, safe, easily accessible vaccines with long-term effectiveness is understood as an urgently needed countermeasure against this ongoing pandemic. Guided by this strong promise of using AAVs, we here designed, optimized, and developed an AAV-based vaccines (including AAV-RBD(max), AAV-RBD(wt), AAV-2xRBD, and AAV-3xRBD) that elicit strong immune responses against the RBD domain of the SARS-CoV-2 S protein. These immunogenic responses have proven long-lived, with near peak levels for at least six months in mice. Notably, the sera immunized with AAV-3xRBD vaccine contains powerful neutralizing antibodies against the SARS-CoV-2 pseudovirus. Further evidence proven that potent specific antibodies could also be elicited in canines after vaccination with AAV-3xRBD vaccine.

Automatic segmentation of high-risk clinical target volume for tandem-and-ovoids brachytherapy patients using an asymmetric dual-path convolutional neural network.

PURPOSES: Preimplant diagnostic magnetic resonance imaging is the gold standard for image-guided tandem-and-ovoids (T&O) brachytherapy for cervical cancer. However, high dose rate brachytherapy planning is typically done on postimplant CT-based high-risk clinical target volume (HR-CTVCT ) because the transfer of preimplant Magnetic resonance (MR)-based HR-CTV (HR-CTVMR ) to the postimplant planning CT is difficult due to anatomical changes caused by applicator insertion, vaginal packing, and the filling status of the bladder and rectum. This study aims to train a dual-path convolutional neural network (CNN) for automatic segmentation of HR-CTVCT on postimplant planning CT with guidance from preimplant diagnostic MR. METHODS: Preimplant T2-weighted MR and postimplant CT images for 65 (48 for training, eight for validation, and nine for testing) patients were retrospectively solicited from our institutional database. MR was aligned to the corresponding CT using rigid registration. HR-CTVCT and HR-CTVMR were manually contoured on CT and MR by an experienced radiation oncologist. All images were then resampled to a spatial resolution of 0.5 × 0.5 × 1.25 mm. A dual-path 3D asymmetric CNN architecture with two encoding paths was built to extract CT and MR image features. The MR was masked by HR-CTVMR contour while the entire CT volume was included. The network put an asymmetric weighting of 18:6 for CT: MR. Voxel-based dice similarity coefficient (DSCV ), sensitivity, precision, and 95% Hausdorff distance (95-HD) were used to evaluate model performance. Cross-validation was performed to assess model stability. The study cohort was divided into a small tumor group (<20 cc), medium tumor group (20-40 cc), and large tumor group (>40 cc) based on the HR-CTVCT for model evaluation. Single-path CNN models were trained with the same parameters as those in dual-path models. RESULTS: For this patient cohort, the dual-path CNN model improved each of our objective findings, including DSCV , sensitivity, and precision, with an average improvement of 8%, 7%, and 12%, respectively. The 95-HD was improved by an average of 1.65 mm compared to the single-path model with only CT images as input. In addition, the area under the curve for different networks was 0.86 (dual-path with CT and MR) and 0.80 (single-path with CT), respectively. The dual-path CNN model with asymmetric weighting achieved the best performance with DSCV of 0.65 ± 0.03 (0.61-0.70), 0.79 ± 0.02 (0.74-0.85), and 0.75 ± 0.04 (0.68-0.79) for small, medium, and large group. 95-HD were 7.34 (5.35-10.45) mm, 5.48 (3.21-8.43) mm, and 6.21 (5.34-9.32) mm for the three size groups, respectively. CONCLUSIONS: An asymmetric CNN model with two encoding paths from preimplant MR (masked by HR-CTVMR ) and postimplant CT images was successfully developed for automatic segmentation of HR-CTVCT for T&O brachytherapy patients.

Dose uncertainty due to needle-tip localization error in prostate seed implantation.

Purpose: This study quantified the dosimetric uncertainty caused by needle-tip detection errors in ultrasound images due to bevel-tip orientation differences, with respect to the location on template grid. Material and methods: Trans-rectal ultrasound (TRUS) system with physical template grid and 18-gauge bevel-tip brachytherapy needles were used. TRUS was set at 6.5 MHz in water phantom, and measurements were taken with 50% and 100% B-mode TRUS gains. Needle-tip localization errors were then retrospectively applied back to 45 prostate seed implant plans to evaluate the important planning parameters for the prostate (D90, V100, V150, and V200), urethra (D10 and D30), and rectum (V100, D2cc, and D0.1cc), following the ABS and AAPM TG-137 guidelines. Results: The needle-tip detection errors for 50% and 100% TRUS gains were 3.7 mm (max) and 5.2 mm (max), respectively. The observed significant decrease in prostate coverage (mean D90 lower by 12.8%, and V100 lower by 3.9% for smaller prostates) after seed placements were corrected by compensating the needle-tip detection errors. Apex of the prostate was hotter, and the base was cooler. Dosimetric difference for urethral and rectal parameters were not statistically significant. Conclusions: This study revealed that the beveled needle-tip orientation could considerably impact the needle tips detection accuracy, based on which the seeds might be delivered. These errors can lead to significant dosimetric uncertainty in prostate seed implantation.

Zileuton inhibits arachidonate-5-lipoxygenase to exert antitumor effects in preclinical cervical cancer models.

BACKGROUND: Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study evaluated the efficacy of zileuton in cervical cancer, determined the molecular mechanism of action, and assessed ALOX5 expression in cervical cancer patients. METHODS: The effects of zileuton were evaluated using cervical cancer cell lines and xenograft mouse models. Loss-of-function analysis of ALOX5 was performed using siRNA. The levels of ALOX5 and 5-HETE were determined using immunohistochemistry and ELISA. RESULTS: Zileuton resulted in cell proliferation inhibition and apoptosis induction in a dose-dependent manner, regardless of cellular origin or HPV infection. In two independent cervical cancer xenograft mouse models, zileuton at nontoxic doses significantly prevented tumor formation and decreased tumor growth. Zileuton acts on cervical cancer cells by inhibiting the ALOX5-5-HETE axis. Of note, ALOX5-5-HETE was significantly upregulated in cervical cancer compared with normal tissue. Inhibition of ALOX5 via the siRNA approach mimics the inhibitory effects of zileuton and confirms the roles of ALOX5 in cervical cancer. CONCLUSIONS: Our work demonstrates that the ALOX5-5-HETE axis is activated in cervical cancer, with important roles in growth and survival, and this can be therapeutically targeted by zileuton. Our findings also provide preclinical evidence to assess the efficacy of zileuton in cervical cancer in clinical settings.

Copy Number Signatures and Clinical Outcomes in Upper Tract Urothelial Carcinoma.

Tumor staging of upper tract urothelial carcinomas (UTUCs) is relatively difficult to assert accurately before surgery. Here, we used copy number (CN) signatures as a tool to explore their clinical significance of molecular stratification in UTUC. CN signatures were extracted by non-negative matrix factorization from the whole-genome sequencing (WGS) data of 90 Chinese UTUC primary tumor samples. A validation UTUC cohort (n = 56) and a cohort from urinary cell-free DNA (cfDNA) of urothelial cancer patients (n = 94) and matched primary tumors were also examined. Survival analyses were measured using the Kaplan-Meier, and Cox regression was used for multivariate analysis. Here, we identified six CN signatures (Sig1-6). Patients with a high contribution of Sig6 (Sig6high) were associated with higher microsatellite instability level and papillary architecture and had a favorable outcome. Patients with a low weighted genome integrity index were associated with positive lymph node and showed the worst outcome. Sig6high was identified to be an independently prognostic factor. The predictive significance of CN signature was identified by a validation UTUC cohort. CN signatures retained great concordance between primary tumor and urinary cfDNA. In conclusion, our results reveal that CN signature assessment for risk stratification is feasible and provides a basis for clinical studies that evaluate therapeutic interventions and prognosis.

Permanent Interstitial Cesium-131 Brachytherapy in Treating High-Risk Recurrent Head and Neck Cancer: A Prospective Pilot Study.

PURPOSE/OBJECTIVES: To establish the feasibility and safety of intraoperative placement of cesium-131 (Cs-131) seeds for re-irradiation in recurrent head and neck cancer (HNC). METHODS: Patients with resectable recurrent HNC who were deemed to have a high risk of second recurrence were eligible. Immediately after tumor extirpation, seeds were implanted in the surgical bed based on the preoperative treatment plan with intraoperative adjustment. The surgical bed and the seeds were covered with a regional flap or microvascular free flap. A CT of the neck was obtained on postoperative day 1 for evaluation of the postoperative dose distribution. Patients were followed 1 and 3 months after surgery, then every 3 months in the first 2 years. RESULTS: From November 2016 to September 2018, 15 patients were recruited and 12 patients received treatment per protocol. For the patients who had implants, the sites of initial recurrence included 10 neck alone, 1 neck and larynx, and 1 neck/peristomal. The median follow-up was 21.4 months. After surgery, patients remained hospitalized for a median of 6 days. There were no high-grade toxicities except two patients with wound complications requiring wound care. Eight patients had recurrences, three locoregional alone, three distant alone, and two with both locoregional and distant recurrences. Only one patient had an in-field failure. Five patients died, with 1- and 2-year overall survival of 75 and 58%. CONCLUSIONS: Cs-131 implant after surgical resection in recurrent HNC is feasible and safe. There were no unexpected severe toxicities. Most failures were out-of-field or distant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02794675.

Feasibility of improving patient's safety with in vivo dose tracking in intracavitary and interstitial HDR brachytherapy.

PURPOSE: The in vivo dosimetric monitoring in HDR brachytherapy is important for improving patient safety. However, there are very limited options available for clinical application. In this study, we present a new in vivo dose measurement system with a plastic scintillating detector (PSD) for GYN HDR brachytherapy. METHODS: An FDA approved PSD system, called OARtrac (AngioDynamics, Latham, NY), was used with various applicators for in vivo dose measurements for GYN patients. An institutional workflow was established for the clinical implementation of the dosimetric system. Action levels were proposed based on the measurement and system uncertainty for measurement deviations. From October 2018 to September 2019, a total of 75 measurements (48 fractions) were acquired from 14 patients who underwent HDR brachytherapy using either a multichannel cylinder, Venezia applicator, or Syed-Neblett template. The PSDs were placed in predetermined catheters/channels. A planning CT was acquired for treatment planning in Oncentra (Elekta, Version-4.5.2) TPS. The PSDs were contoured on the CT images, and the PSD D90% values were used as the expected doses for comparison with the measured doses. RESULTS: The mean difference from patient measurements was -0.22% ± 5.98%, with 26% being the largest deviation from the expected value (Syed case). Large deviations were observed when detectors were placed in the area where dose rates were less than 1 cGy/s. CONCLUSIONS: The establishment of clinical workflow for the in vivo dosimetry for both the intracavitary and interstitial GYN HDR brachytherapy will potentially improve the safety of the patient treatment.

Transporters HP0939, HP0497, and HP0471 participate in intrinsic multidrug resistance and biofilm formation in Helicobacter pylori by enhancing drug efflux.

BACKGROUND: The multidrug resistance of Helicobacter pylori is becoming an increasingly serious issue. It is therefore necessary to study the mechanism of multidrug resistance of H pylori. We have previously identified that the HP0939, HP0497, and HP0471 transporters affect the efflux of drugs from H pylori. As efflux pumps participate in bacterial multidrug resistance and biofilm formation, we hypothesized that these transporters could be involved in the multidrug resistance and biofilm formation of H pylori. MATERIALS AND METHODS: We therefore constructed three knockout strains, Δhp0939, Δhp0497, and Δhp0471, and three high-expression strains, Hp0939he , Hp0497he , and Hp0471he , using the wild-type (WT) 26 695 strain of H pylori as the template. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of wild strains, knockout strains, and high-expression strains to amoxicillin, metronidazole, and other antibiotics were measured. The efflux capacity of high-expression strains and wild strains was compared by Hoechst 33 342 accumulation assay. RESULTS: Determination of the MIC and MBC of the antibiotics revealed that the knockout strains were more sensitive to antibiotics, while the high-expression strains were less sensitive to antibiotics, compared to the WT. The ability of the high-expression strains to efflux drugs was significantly higher than that of the WT. We also induced H pylori to form biofilms, and observed that the knockout strains could barely form biofilms and were more sensitive to several antibiotics, compared to the WT. The mRNA expression of hp0939, hp0497, and hp0471 in the clinically sensitive and multidrug-resistant strains was determined, and it was found that these genes were highly expressed in the multidrug-resistant strains that were isolated from the clinics. CONCLUSIONS: In this study, we found three transporters involved in intrinsic multidrug resistance of H pylori.

Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing.

BACKGROUND: Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity. METHODS: We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients. RESULTS: Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients. CONCLUSIONS: Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.

Appropriate Methodology for EBRT and HDR Intracavitary/Interstitial Brachytherapy Dose Composite and Clinical Plan Evaluation for Patients With Cervical Cancer.

PURPOSE: This study assessed the appropriateness of full parameter addition (FPA) methods with respect to the 3-dimensional deformable dose composite method for evaluating combined external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICBT). METHODS AND MATERIALS: A total of 22 patients who received EBRT and high-dose-rate ICBT were retrospectively evaluated. Split-ring and tandem applicators were used for all patients. Additional interstitial needles were used for 5 patients to supplement the implant. Deformable image registrations were performed to deform the secondary EBRT and ICBT planning computed tomography (CT) images onto the reference CT from the third fraction of ICBT. The Dice similarity coefficient was used to evaluate the quality of deformable registration. Doses were transferred to the reference CT, scaled to the equivalent dose in 2-Gy fractions and combined to create the dose composite. Eight dose-accumulation methods were evaluated and compared. D2cc and D0.1cc for organs at risk were investigated. RESULTS: The differences in D2cc for rectum, bladder, sigmoid, and bowel between the FPA method for whole-pelvis EBRT and ICBT, calculated using an old American Brachytherapy Society worksheet (FPA_Eh + I_old) and deformable composite for EBRT with boosts and ICBT (Def_E + B + I) were -2.19 ± 1.37 Gyα/ß = 3, -0.64 ± 1.13 Gyα/ß = 3, -2.06 ± 2.71 Gyα/ß = 3, and -1.59 ± 0.89 Gyα/ß = 3, respectively. The differences in D2cc for rectum, bladder, sigmoid, and bowel between the new ABS worksheet (FPA_Eh + B + I_abs) and the Def_E + B + I method were 1.21 ± 1.22 Gy α/ß = 3, 1.93 ± 1.38 Gyα/ß = 3, 0.72 ± 1.12 Gyα/ß = 3, and 1.19 ± 1.46 Gyα/ß = 3, respectively. Differences in dose-volume histogram parameter values among Def_E + B + I and other FPA methods were not statistically significant (P > .05). CONCLUSIONS: Compared with the FPA-based method, deformable registration-based dose composites demonstrated lower OAR D2cc and D0.1cc values; however, the differences were not statistically significant. The current ABS-recommended FPA-based sheet can serve as an acceptable plan evaluation tool for clinical purposes.