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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

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.

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.

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.

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.

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.

β-Lactam antibiotics disrupt the assembly of peptidoglycan (PG) within the bacterial cell wall by inhibiting the enzymatic activity of penicillin-binding proteins (PBPs). It was recently shown that β-lactam treatment initializes a futile cycle of PG synthesis and degradation, highlighting major gaps in our understanding of the lethal effects of PBP inhibition by β-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the β-lactam mecillinam and show that lethality from PBP2 inhibition is a specific consequence of toxic metabolic shifts induced by energy demand from multiple catabolic and anabolic processes, including accelerated protein synthesis downstream of PG futile cycling. Resource allocation into these processes is coincident with alterations in ATP synthesis and utilization, as well as a broadly dysregulated cellular redox environment. These results indicate that the disruption of normal anabolic-catabolic homeostasis by PBP inhibition is an essential factor for β-lactam antibiotic lethality.