HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Optimizing Image Fidelity with Arrays

Through simulations, I have investigated the limitations imposed upon the image fidelity of interferometric observations by primary beam errors. Significant antenna surface and pointing errors lead to the greatest reduction in fidelity for most cases, but, when present, imaginary beam components dominate the degradation. Beam errors were addressed by optimizing the antenna surfaces and aligning the optics and then determining baseline based primary beams. Methods for applying these measured patterns to actual data were discussed. Pointing errors were reduced by improving the fit to the pointing model. Further reduction was achieved by integrating the use of optical pointing observations into standard radio observing. The greatest benefit was seen during daytime observations, but general reduction in pointing error was seen. The dense uv-coverage of the Combined Array for Research in Millimeter-wave Astronomy (CARMA) coupled with the techniques described above make it an ideal instrument for imaging extended regions with high fidelity. The NGC 7538 star-forming cloud contains dense peaks, many high-mass stars and associated accretion disks, and multiple outflows. I obtained CARMA images at the requisite fidelity, employing the above techniques. These mosaiced, spectral-line, and 3-mm band continuum observations provide a clearer picture of the bulk morphology of the region and the fine-scale structures within it than has hitherto been possible. For the first time in the region, infall signatures were found towards two sources, allowing comparison of the infall and outflow mass and verifying that significant accretion (>10−4M⊙ yr−1) continues well into the stage where a massive protostar has formed. One of the sources, NGC 7538IRS1, shows one of the few definitive signatures of an inverse PCygni profile towards a massive protostar. Three outflows were found centered on sources that are separated by 10,000-20,000 AU in projection. The calculated energy injection rate provides constraints for models of outflow feedback. The NGC 7538 results demonstrate clearly the capability of CARMA to provide high quality images over wide-fields and the benefits of the techniques I developed. While work to improve CARMA image fidelity continues, the program described here lays the groundwork and should help guide further enhancements of image fidelity at CARMA and at other radio facilities.</p

Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits

International audienceCellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics

Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits.

Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics

Cell death induced in a murine mastocytoma by 42-47°C heating in vitro: Evidence that the form of death changes from apoptosis to necrosis above a critical heat load

The pathogenesis of heat-induced cell death is controversial. Categorizing the death occurring after various heat loads as either apoptosis or necrosis might help to elucidate this problem, since it has been shown that these two processes differ in their mode of initiation as well as in their morphological and biochemical features. Log-phase cultures of mastocytoma P-815 x 2.1 were heated at temperatures ranging from 42 to 47°C for 30 min. After 42°C heating a slight increase in apoptosis was observed morphologically. However, after heating at 43, 43.5 and 44°C, there was marked enhancement of apoptosis, and electrophoresis of DNA showed characteristic internucleosomal cleavage. With heating at 45°C both apoptosis and necrosis were enhanced, whereas at 46 and 47°C only necrosis was produced. DNA extracted from the 46 and 47°C cultures showed virtually no degradation, which contrasts with the random DNA breakdown observed in necrosis produced by other types of injury; lysosomal enzymes released during heat-induced necrosis may be inactivated at the higher temperatures. It is suggested that apoptosis following heating may be triggered either by a limited increase in cytosolic calcium levels resulting from mild membrane changes or by DNA damage. Necrosis, on the other hand, is likely to be a consequence of severe membrane disruption