Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment
. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic ...therapy
. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery
were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
Lobular carcinoma in situ (LCIS) is a non-invasive proliferation of discohesive cells arising in the terminal duct lobular unit. LCIS was initially described as a marker of bilateral increased risk ...of invasive breast carcinoma, however more recently it is recognized to act as a non-obligate precursor of invasive lobular carcinoma. There are 3 main types of LCIS; classical LCIS, florid LCIS and pleomorphic LCIS. The morphological characteristics of the 3 subtypes are described, along with differences in tumour biology. LCIS is associated with loss of expression of E-cadherin protein, part of the cadherin:catenin cell adhesion complex. Immunohistochemistry for E-cadherin can assist in the diagnosis of LCIS, but important caveats apply in its interpretation and other markers such as beta catenin and p120 may also be of use. Classical LCIS has a low upgrade rate and recommended management is regular follow up, however pleomorphic and florid LCIS have a higher risk of associated invasive cancer and are managed like DCIS with therapeutic excision aiming for clear margins.
The effect of level and frequency on the audibility of partials was measured for complex tones with partials uniformly spaced on an equivalent rectangular bandwidth (ERB(N)) number scale. On each ...trial, subjects heard a sinusoidal "probe" followed by a complex tone. The probe was mistuned downwards or upwards (at random) by 4.5% from the frequency of one randomly selected partial in the complex. The subject indicated whether the probe was higher or lower in frequency than the nearest partial in the complex. The frequencies were roved from trial to trial, keeping frequency ratios fixed. In experiment 1, the level per partial, L, was 40 or 70 dB SPL and the mean frequency of the central partial, f(c), was 1201 Hz. Scores for the highest and lowest partials in the complexes were generally high for all spacings. Scores for the inner partials were close to chance at 0.75-ERB(N) spacing, and improved as the spacing was increased up to 2 ERB(N). For intermediate spacings, performance was better for the lower level used. In experiment 2, L was 70 dB SPL and f(c) was 3544 Hz. Performance worsened markedly for partial frequencies above 3544 Hz, consistent with a role of phase locking.
Obstructive Eustachian tube dysfunction (OETD) is a common condition resulting from inadequate opening of the Eustachian tube (ET). A new surgical treatment involves high-pressure inflation of a ...balloon within the ET, with the aim of dilating the soft tissue structure. However, the mechanical effects of this intervention have not been established, nor the impact of changing device size or other technical parameters. A novel experimental technique allowed quantification of plastic and elastic tissue deformation in model materials and then human cadaver ETs during balloon dilation, based on the measured balloon inflation pressure-volume relationship. Plastic tissue deformation was found to be greater using larger balloons and deeper device insertion, but increasing the inflation pressure had a more limited effect, with most deformation occurring well below the clinically used pressures. Histological assessment of ET tissue suggested that mucosal tearing and cartilage cracking were in part responsible for the mechanical changes. Balloon dilation of the ET has huge potential if found to be clinically effective, but currently there is a need to understand and develop the technique further. The novel methods employed in this study will be valuable in future laboratory and in vivo studies of ET balloon dilation. Pressures are reported in Bar as this unit is used for medical balloon dilation procedures in clinical practice. 1 Bar = 100,000 Pa.
Graphical abstract caption
Dilation of the Eustachian tube for obstructive dysfunction is performed clinically with 3- and 6-mm-diameter balloons of approximately the same overall length. Our data suggest that dilation with a 6-mm balloon causes greater deformation of the soft tissue structure than dilation with a 3-mm balloon. This difference has yet to be demonstrated clinically. Plastic deformation was measured in terms of energy (J) dissipated during balloon inflation.
Abstract
Background
Transglutaminase 2 (TGM2) is a protein expressed in several isoforms in both intra- and extra-cellular tissue compartments. It has multiple functions that are important in cancer ...biology and several small studies have suggested expression of TGM2 in breast cancers is associated with a poorer prognosis. The aim of this study was to evaluate the role of intra-cellular and extra-cellular TGM2 expression in breast cancer and to determine whether there were any differences by hormone receptor status.
Methods
We carried out TGM2 immunostaining of tissue micro-arrays comprising 2169 tumour cores and scored these for both intra- and extra-cellular and expression.
Results
Intra-cellular (tumour cell) TGM2 positivity was associated with a better prognosis (HR = 0.74, 95% CI 0.59–0.92) with a larger effect stronger in hormone-receptor-negative cases (HR = 0.56, 95% CI 0.37–0.85). Extra-cellular (stromal) TGM2 expression was associated with a poorer prognosis (HR = 1.47, 95% CI 1.06–2.03) with a stronger association in hormone-receptor-positive cases (HR = 1.60, 95% CI 1.09–2.34).
Conclusion
Tissue compartment and hormone receptor status differences in the effect of TGM2 expression on clinical outcomes of breast cancer may reflect the different functions of TGM2.
We report the case of a 97-year-old woman who had a prolonged hospital admission for the treatment of right-sided heart failure. During her stay she experienced a rapid deterioration, characterised ...by shortness of breath, cardiovascular compromise and a hot, red, swollen calf. Post-mortem examination demonstrated that this was caused by necrotising fasciitis due to Serratia marcescens as a single pathogen. This is only the second reported case of this condition in the absence of diabetes or immunosuppression, and clinical deterioration was much more rapid. The case underlines the importance of circumspection and regular review in the diagnosis of the elderly patient. It reminds us that these patients should be viewed as functionally immunosuppressed, and that some or all of the haematological markers of infection can be absent even in severe disease.
► We measured auditory temporal processing children with Autism Spectrum Disorder (ASD). ► Results were compared with age and IQ-matched typically developing controls. ► ASD group had higher ...modulation-depth thresholds than controls. ► Results are consistent with reduced temporal-processing efficiency in the ASD group.
Individuals with Autism Spectrum Disorder (ASD) perform worse than controls when listening to speech in a temporally modulated noise (Alcántara, Weisblatt, Moore, & Bolton, 2004; Groen et al., 2009). The current study examined whether this is due to poor auditory temporal-envelope processing. Temporal modulation transfer functions were measured in 6 high-functioning children with ASD and 6 control listeners, using sinusoidal amplitude modulation of a broadband noise. Modulation-depth thresholds at low modulation rates were significantly higher for the ASD group than for the Control group, and generally higher at all modulation rates tested. Low-pass filter model estimates of temporal-envelope resolution and temporal-processing efficiency showed significant differences between the groups for modulation-depth threshold values at low modulation rates. Intensity increment-detection thresholds, measured on a subset of individuals in the ASD and Control groups, were not significantly different. The results are consistent with ASD individuals having reduced processing efficiency of temporal modulations. Possible neural mechanisms that might underlie these findings are discussed.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGVHD) is still the major ...complication causing mortality. MicroRNAs (miRNAs) play a significant role in inflammation and have potential as prognostic and diagnostic biomarkers. This study investigated the role of two immune-specific miRNAs (miR-146a and miR-155) as biomarkers for aGVHD incidence in the peripheral blood of allo-HSCT patients prior to disease onset. The study showed that miR-146a and its statistical interaction with miR-155 at day +28 were predictive of aGVHD incidence. Interestingly, the expression levels of miR-146a and miR-155 negatively correlated with the transcription factor, SPI1 (PU.1gene) mRNA expression.
The discovery of interchromosomal interactions in higher eukaryotes points to a functional interplay between genome architecture and gene expression, challenging the view of transcription as a ...one-dimensional process. However, the extent of interchromosomal interactions and the underlying mechanisms are unknown. Here we present the first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues. Our results show that the active globin genes associate with hundreds of other transcribed genes, revealing extensive and preferential intra- and interchromosomal transcription interactomes. We show that the transcription factor Klf1 mediates preferential co-associations of Klf1-regulated genes at a limited number of specialized transcription factories. Our results establish a new gene expression paradigm, implying that active co-regulated genes and their regulatory factors cooperate to create specialized nuclear hot spots optimized for efficient and coordinated transcriptional control.
An exploratory qualitative study was performed to evaluate the experiences of nursing staff (
= 10) working in a residential aged care facility (RACF) during the coronavirus disease 2019 (COVID-19) ...pandemic lockdown. Semi-structured, in-person interviews were performed, and thematic analysis was used to analyze the data. Care staff had little or no knowledge of how to cope with a lockdown necessitated by a pandemic. However, management developed proactive plans as they aligned with the changing care circumstances and ongoing government directives. Five major themes were identified:
;
;
;
; and
. RACF staff described working under stressful conditions during the initial COVID-19 pandemic lockdown; yet with experience, care staff and the management team adapted to pandemic requirements to meet the needs of residents in their care. RACFs should be prepared for the impact of pandemics on staff and ensure care resources and support are available for the continuity of safe and quality care of residents.
(3), 34-39..
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