Search

The American Association of Physicists in Medicine’s Task Group No.43 has provided a standardised dose calculation methodology that is now the international benchmark for all brachytherapy dosimetry publications and treatment planning systems. However, limitations in this methodology has seen the development of Model-Based Dose Calculation Algorithms (MBDCA). In 2009, Varian (Varian Medical Systems, Palo Alto, CA, USA) released Acuros$$^{\text {TM}}$$ TM BrachyVision (ABV) which calculates dose by explicitly solving the Linear Boltzmann Transport Equation. In this study we have assessed the accuracy of ABV dose calculations within a range of materials relevant to high dose rate brachytherapy with an iridium-192 ($$^{\text {192}}$$ 192 Ir) source. Accuracy assessment has been achieved by implementing a modelled GamaMed Plus $$^{\text {192}}$$ 192 Ir source within a series of phantoms using the GEANT4 Application for Emission Tomography (GATE) to calculate dose for comparison with dose as determined by ABV. Comparisons between GATE and ABV were made using point-to-point profile comparisons and 1D gamma analysis. Source validation results yielded good agreement with published data. Spectrum and TG43U1 comparisons showed no major differences, with TG43U1 comparisons agreeing within ± 1%. Point-to-point comparisons showed large differences between GATE and ABV near the source and in low density materials. 1D gamma analysis pass criteria of 2%/1 mm and 2%/2 mm yielded passing rates ranging between 51.72–100% and 62.07–100% respectively. A critical analysis of this study’s results suggest that ABV is unable to accurately calculate doses in low density materials. Furthermore, spatial accuracy of dose near the source is within 2 mm.

Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3–stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt+ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083–96. ©2017 AACR.

Supplementary Methods described

Time lapse microscopy experiment of sorted NKp46-ILC3 cells (CD3-, CD11c-, B220, NKp46-, CD127+, CD90.2+) co-cultured with MSC cells as described in Figure 2B. Low magnification (Ã-10) video shows the general clustering pattern of NKp46-ILC3 cells around the MSC cells over a duration of 10 hours.

Figure S1, Related to Figure 1 FACS and immunofluorescence validation of Lin-CD127+CD90.2+NKP46- gated ILC3 cells Figure S2, Related to Figure 2 ELISA quantification of CXCL13 and CCL21 chemokines levels in conditioned media (CM) obtained from the bone marrow derived MSC cell line (HS-5) and from the breast cancer cell line 4T1.2 cell line is shown. Figure S3, Related to Figure 2 Proliferation assay of ILC3 cells and ELISA quantification of CXCL13 and CCL21 from siRNA transfected MSC cells. Figure S4, Related to Figure 4 CXCR5 expression on MSC cells. Figure S5, Related to Figure 5 Identification of a RORγT+CD127+CD3- ILC3 cells within the tertiary lymphoid structures within breast cancers. Figure S6, Related to Figure 5 Expression of lymphoid chemokine and chemokine receptor genes in breast cancer datasets. Table S1, Related to Figure 5 Table S1: Clinico-pathological characteristics for the METABRIC sample.

Supplementary Figure legends

Objective To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region. Methods This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators. Results A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81–1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%. Conclusion This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.

High-intensity focused ultrasound (HIFU) ablation, also known as focused ultrasound surgery, is the latest advancement in treating uterine fibroids and adenomyosis. Limited evidence, in terms of case series only, suggest that ultrasound-guided focused ultrasound/magnetic resonance-guided focused ultrasound treatment for fibroids and adenomyosis could be a safe alternative to myomectomy or uterine artery embolisation for females who wish to have babies. It also appears that this non-invasive HIFU treatment can shorten the treatment to pregnancy interval after HIFU ablation. Further studies are needed to confirm such findings.

Background:Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis, and biomarkers that predict response to treatment are highly desirable. The primary aim was to predict progression-free survival (PFS) with a multivariate risk prediction model.Methods:Experimental covariates were derived from blood samples of 56 HNSCC patients which were prospectively obtained within a Phase 2 clinical trial (NCT02633800) at baseline and after the first treatment cycle of combined platinum-based chemotherapy with cetuximab treatment. Clinical and experimental covariates were selected by Bayesian multivariate regression to form risk scores to predict PFS.Results:A ‘baseline’ and a ‘combined’ risk prediction model were generated, each of which featuring clinical and experimental covariates. The baseline risk signature has three covariates and was strongly driven by baseline percentage of CD33+CD14+HLADRhigh monocytes. The combined signature has six covariates, also featuring baseline CD33+CD14+HLADRhigh monocytes but is strongly driven by on-treatment relative change of CD8+ central memory T cells percentages. The combined model has a higher predictive power than the baseline model and was successfully validated to predict therapeutic response in an independent cohort of nine patients from an additional Phase 2 trial (NCT03494322) assessing the addition of avelumab to cetuximab treatment in HNSCC. We identified tissue counterparts for the immune cells driving the models, using imaging mass cytometry, that specifically colocalized at the tissue level and correlated with outcome.Conclusions:This immune-based combined multimodality signature, obtained through longitudinal peripheral blood monitoring and validated in an independent cohort, presents a novel means of predicting response early on during the treatment course.Funding:Daiichi Sankyo Inc, Cancer Research UK, EU IMI2 IMMUCAN, UK Medical Research Council, European Research Council (335326), Merck Serono. Cancer Research Institute, National Institute for Health Research, Guy’s and St Thomas’ NHS Foundation Trust and The Institute of Cancer Research.Clinical trial number:NCT02633800.

Bactericidal antibiotics kill bacteria by perturbing various cellular targets and processes. Disruption of the primary antibiotic-binding partner induces a cascade of molecular events, leading to overproduction of reactive metabolic by-products. It remains unclear, however, how these molecular events contribute to bacterial cell death. Here, we take a single-cell physical biology approach to probe antibiotic function. We show that aminoglycosides and fluoroquinolones induce cytoplasmic condensation through membrane damage and subsequent outflow of cytoplasmic contents as part of their lethality. A quantitative model of membrane damage and cytoplasmic leakage indicates that a small number of nanometer-scale membrane defects in a single bacterium can give rise to the cellular-scale phenotype of cytoplasmic condensation. Furthermore, cytoplasmic condensation is associated with the accumulation of reactive metabolic by-products and lipid peroxidation, and pretreatment of cells with the antioxidant glutathione attenuates cytoplasmic condensation and cell death. Our work expands our understanding of the downstream molecular events that are associated with antibiotic lethality, revealing cytoplasmic condensation as a phenotypic feature of antibiotic-induced bacterial cell death., The detailed mechanisms of action of bactericidal antibiotics remain unclear. Here, Wong et al. show that these antibiotics induce cytoplasmic condensation through membrane damage and outflow of cytoplasmic contents, as well as accumulation of reactive metabolic by-products and lipid peroxidation, as part of their lethality.

High Intensity Focused Ultrasound ablation therapy for fibroids and adenomyoma has been increasingly applied in Gynecology. It is now considered a safe surgery with effectiveness compatible to open or laparoscopic myomectomy. However, to further minimize its potential risks of skin burn to the buttocks and nerve injury, this paper studied the skin temperature changes as monitored by infrared thermography in an attempt to identify the risks during HIFU treatment. Although the infrared imaging technology is safe and feasible to monitor the skin temperature changes during HIFU ablation, there isn’t enough conclusive evidence to prove it can be used to avoid skin burn at the buttock or nerve injury.

The American Association of Physicists in Medicine's Task Group No.43 has provided a standardised dose calculation methodology that is now the international benchmark for all brachytherapy dosimetry publications and treatment planning systems. However, limitations in this methodology has seen the development of Model-Based Dose Calculation Algorithms (MBDCA). In 2009, Varian (Varian Medical Systems, Palo Alto, CA, USA) released Acuros[Formula: see text] BrachyVision (ABV) which calculates dose by explicitly solving the Linear Boltzmann Transport Equation. In this study we have assessed the accuracy of ABV dose calculations within a range of materials relevant to high dose rate brachytherapy with an iridium-192 ([Formula: see text]Ir) source. Accuracy assessment has been achieved by implementing a modelled GamaMed Plus [Formula: see text]Ir source within a series of phantoms using the GEANT4 Application for Emission Tomography (GATE) to calculate dose for comparison with dose as determined by ABV. Comparisons between GATE and ABV were made using point-to-point profile comparisons and 1D gamma analysis. Source validation results yielded good agreement with published data. Spectrum and TG43U1 comparisons showed no major differences, with TG43U1 comparisons agreeing within ± 1%. Point-to-point comparisons showed large differences between GATE and ABV near the source and in low density materials. 1D gamma analysis pass criteria of 2%/1 mm and 2%/2 mm yielded passing rates ranging between 51.72-100% and 62.07-100% respectively. A critical analysis of this study's results suggest that ABV is unable to accurately calculate doses in low density materials. Furthermore, spatial accuracy of dose near the source is within 2 mm.

Uterine fibroids are a common gynecological disorder affecting a large number of infertile women. Their pregnancy outcomes may also be poor because of complications such as miscarriage, preterm labor, obstructed labor, or postpartum bleeding. Myomectomy was traditionally used to enhance women’s reproductive ability or reduce the above complications. However, operative myomectomy, either laparoscopic or open approach, may cause operative morbidity and raise hysterectomy risks. After myomectomy, women would also require a Caesarean section because of uterine ruptures’ risks. High Intensity Focused Ultrasound ablation (Focused Ultrasound Surgery - FUS) is currently increasingly used as a new technology to treat fibroids. Therefore, the impact of HIFU ablation on patients’ fertility and pregnancy outcomes has become a topic of interest. This paper reviewed the currently existing but limited evidence of this issue in the literature. It showed that USgHIFU/MRgFUS treatment for fibroids could be a safe alternative to myomectomy or UAE for women who wish to have babies. It also appears that FUS treatment can shorten the treatment to pregnancy interval after FUS ablation. Given the large number of women developing fibroids before childbearing, addressing this important issue in a large clinical trial is critical.

Vulvar intraepithelial neoplasia is a premalignant skin lesion of the vulva that often presents with severe vulvar pruritus, pain, and psychosexual disorders. The technology of non-invasive focused ultrasound surgery has improved over the years. Today its potential to treat these irritating diseases noninvasively is a relatively new area of clinical research interest. Increasing studies in China revealed that FUS treatment is effective and safe. This paper describes the preparation, technique, postoperative care, and results of this focused ultrasound surgery for treating vulvar non-neoplastic epithelial disease. Therefore it could be a future alternative treatment for benign vulvar diseases, replacing many invasive surgical treatments.

BackgroundAdvanced Head and Neck Squamous Cell Cancer (HNSCC) is associated with a poor prognosis, and biomarkers that predict response to treatment are highly desirable. The primary aim was to predict Progression Free Survival (PFS) with a multivariate risk prediction model.MethodsBlood samples from 56 HNSCC patients were prospectively obtained within a Phase 2 clinical trial (NCT02633800), before and after the first treatment cycle of platinum-based chemotherapy, to identify biological covariates predictive of outcome. A total of 42 baseline covariates were derived pre-treatment, which were combined with 29 covariates after one cycle of treatment. These covariates were ranked and selected by Bayesian multivariate regression to form risk scores to predict PFS, producing “baseline” and “combined” risk prediction models respectively.ResultsThe baseline model comprised of CD33+CD14+ monocytes, Double Negative B cells and age, in a weighted risk signature which predicted PFS with a concordance index (C-index) of 0.661. The combined model composed of baseline CD33+CD14+ monocytes, baseline Tregs, after-treatment changes in CD8 effector memory T cells, CD8 Central memory T cells and CD3 T Cells, along with the hypopharyngeal primary tumor subsite. This weighted risk signature exhibited an improved C-index of 0.757. There was concordance between levels of CD33+CD14+ myeloid cells in tumor tissue, as demonstrated by imaging mass cytometry, and peripheral blood in the same patients. This monocyte subpopulation also had univariate predictive value (log-rank p value = 0.03) but the C-index was inferior to the combined signature.ConclusionsThis immune-based combined multimodality signature, obtained through longitudinal peripheral blood monitoring, presents a novel means of predicting response early on during the treatment course.FundingDaiichi Sankyo Inc, Cancer Research UK, EU IMI2 IMMUCAN, UK Medical Research Council, European Research Council (335326), National Institute for Health Research and The Institute of Cancer Research.

Understanding how bactericidal antibiotics kill bacteria remains an open question. Previous work has proposed that primary drug-target corruption leads to increased energetic demands, resulting in the generation of reactive metabolic byproducts (RMBs), particularly reactive oxygen species, that contribute to antibiotic-induced cell death. Studies have challenged this hypothesis by pointing to antibiotic lethality under anaerobic conditions. Here, we show that treatment of Escherichia coli with bactericidal antibiotics under anaerobic conditions leads to changes in the intracellular concentrations of central carbon metabolites, as well as the production of RMBs, particularly reactive electrophilic species (RES). We show that antibiotic treatment results in DNA double-strand breaks and membrane damage and demonstrate that antibiotic lethality under anaerobic conditions can be decreased by RMB scavengers, which reduce RES accumulation and mitigate associated macromolecular damage. This work indicates that RMBs, generated in response to antibiotic-induced energetic demands, contribute in part to antibiotic lethality under anaerobic conditions.

Transportation authorities are always looking for ways to improve road safety since vehicle collisions cost Canada 25 billion dollars of capital loss and around 2800 deaths each year. An important step in improving road safety is to sieve out the problem sites through network screening processes. screening for specific accident types is discussed in this thesis, using signalized intersections in Toronto in an illustrative application. each such collision type is associated with corresponding countermeasures, which allows the engineer to rank the entities with specific remedies in mind. In this way, the effectiveness of road network screening can improved through targeted treatments. Three different screening methods are introduced and compared; procedures for selecting entities from screening results by different methods are also presented. A process for ranking jurisdictions by regions is proposed. This is a method which combines the conventional network screening techniques with geographic information system (GIS) tools. The GIS can integrate the spatial information of a selected area with the conventional accident and road characteristic data and facilitate network screening by region.

Integration of binding information by macromolecular entities is fundamental to cellular functionality. Recent work has shown that such integration cannot be explained by pairwise cooperativities, in which binding is modulated by binding at another site. Higher-order cooperativities (HOCs), in which binding is collectively modulated by multiple other binding events, appear to be necessary but an appropriate mechanism has been lacking. We show here that HOCs arise through allostery, in which effective cooperativity emerges indirectly from an ensemble of dynamically interchanging conformations. Conformational ensembles play important roles in many cellular processes but their integrative capabilities remain poorly understood. We show that sufficiently complex ensembles can implement any form of information integration achievable without energy expenditure, including all patterns of HOCs. Our results provide a rigorous biophysical foundation for analysing the integration of binding information through allostery. We discuss the implications for eukaryotic gene regulation, where complex conformational dynamics accompanies widespread information integration.

High-intensity focused ultrasound (HIFU) surgery is a noninvasive thermal ablation treatment modality, and its clinical application is increasingly introduced into gynecological practices in China and Asia. To further strengthen the technology's standardized management, the Asia-Pacific Association for Gynecologic Endoscopy and Minimally Invasive Therapy (APAGE) collected the consensus of well-known experts in the field. They shared opinions on the management standards of the basic requirements for developing this HIFU technology in medical institutions, operators' training requirements, technical management, HIFU training program, etc., Based on the recommendations from APAGE, Hong Kong Focused Ultrasound Surgery Association developed its proposed HIFU training program for gynecologists in Hong Kong. This paper will present the training requirements and hopefully share its training and credentialing rationales with other HIFU medical institutes.

Membrane lysis, or rupture, is a cell death pathway in bacteria frequently caused by cell wall-targeting antibiotics. Although previous studies have clarified the biochemical mechanisms of antibiotic action, a physical understanding of the processes leading to lysis remains lacking. Here, we analyze the dynamics of membrane bulging and lysis in Escherichia coli, in which the formation of an initial, partially subtended spherical bulge (“bulging”) after cell wall digestion occurs on a characteristic timescale of 1 s and the growth of the bulge (“swelling”) occurs on a slower characteristic timescale of 100 s. We show that bulging can be energetically favorable due to the relaxation of the entropic and stretching energies of the inner membrane, cell wall, and outer membrane and that the experimentally observed timescales are consistent with model predictions. We then show that swelling is mediated by the enlargement of wall defects, after which cell lysis is consistent with both the inner and outer membranes exceeding characteristic estimates of the yield areal strains of biological membranes. These results contrast biological membrane physics and the physics of thin, rigid shells. They also have implications for cellular morphogenesis and antibiotic discovery across different species of bacteria.