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Change in HER2 status after neoadjuvant chemotherapy (NAC) with trastuzumab and pertuzumab (HP) in patients with HER2-positive early-stage breast cancer.
No full text e12614 Background: Combination of HP with NAC in the neoadjuvant setting leads to an high rate of pathological complete response (pCR) in patients with stage II-III HER2+ breast cancer (BC). The rate of change in HER2-status after NAC reported in literature is between 10-30%, although NAC comprises a various regimens, and the clinical significance of this phenomenon is unclear. Methods: We extracted data on patients with HER2+ BC treated with NAC and HP between September 1, 2013 to November 1, 2019. Only patients with internally verified HER2 status at our center were enrolled. The rate of pCR (ypT0/is ypN0) and the change in HER2 status on residual disease from baseline were evaluated. We used standard definition of HER2 status based on ASCO/CAP guidelines 2018. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+, FISH non-amplified. Results: Overall, 130 pts were identified. All patients received dose-dense AC-THP, except for 13 patients who received TCHP or other HP-based regimens. The pCR was achieved in 77/130 (59%) of patients and 53/130 (41%) had residual disease. Among 53 patients with residual disease, HER2 status was analyzed in 25 patients and was pending on the remaining patients. In the 25 analyzed patients, 13 had HER2-loss in residual disease. In 4/13 patients, HER2 expression was lost (IHC 0); in 9/13 patients, HER2-low profile was found (IHC 1+ in 6 patients, and IHC 2+, FISH non-amplified in 3). Details on HER2 status change are described in the table below. Conversely, 12/25 had concordant HER2 status after NAC. Conclusions: At single center, the change in HER2 status after NAC with HP appeared frequent. Pathological review of additional cases is ongoing. The clinical significance is still unclear but may open the possibility to investigate tailored approach in post-neoadjuvant setting based on the biological profile of residual disease. [Table: see text] </jats:p
Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade.
Get PDFPancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC
Identification of protein interactions of grapevine fanleaf virus RNA-dependent RNA polymerase during infection of by affinity purification and tandem mass spectrometry.
Get PDFThe RNA-dependent RNA polymerase (1E) is involved in replication of grapevine fanleaf virus (GFLV, , ) and causes vein clearing symptoms in . Information on protein 1E interaction with other viral and host proteins is scarce. To study protein 1E biology, three GFLV infectious clones, i.e. GHu (a symptomatic wild-type strain), GHu-1E (an asymptomatic GHu mutant) and F13 (an asymptomatic wild-type strain), were engineered with protein 1E fused to a V5 epitope tag at the C-terminus. Following -mediated delivery of GFLV clones in and protein extraction at seven dpi, when optimal 1E:V5 accumulation was detected, two viral and six plant putative interaction partners of V5-tagged protein 1E were identified for the three GFLV clones by affinity purification and tandem mass spectrometry. This study provides insights into the protein interactome of 1E during GFLV systemic infection in and lays the foundation for validation work
Aneuploidy as a promoter and suppressor of malignant growth.
No full textAneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell's genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy's distinct roles as both a tumour promoter and an anticancer vulnerability
Natural Genetic Diversity in Tomato Flavor Genes
Get PDFFruit flavor is defined as the perception of the food by the olfactory and gustatory systems, and is one of the main determinants of fruit quality. Tomato flavor is largely determined by the balance of sugars, acids and volatile compounds. Several genes controlling the levels of these metabolites in tomato fruit have been cloned, including LIN5, ALMT9, AAT1, CXE1, and LoxC. The aim of this study was to identify any association of these genes with trait variation and to describe the genetic diversity at these loci in the red-fruited tomato clade comprised of the wild ancestor Solanum pimpinellifolium, the semi-domesticated species Solanum lycopersicum cerasiforme and early domesticated Solanum lycopersicum. High genetic diversity was observed at these five loci, including novel haplotypes that could be incorporated into breeding programs to improve fruit quality of modern tomatoes. Using newly available high-quality genome assemblies, we assayed each gene for potential functional causative polymorphisms and resolved a duplication at the LoxC locus found in several wild and semi-domesticated accessions which caused lower accumulation of lipid derived volatiles. In addition, we explored gene expression of the five genes in nine phylogenetically diverse tomato accessions. In general, the expression patterns of these genes increased during fruit ripening but diverged between accessions without clear relationship between expression and metabolite levels
Novel tool to quantify with single-cell resolution the number of incoming AAV genomes co-expressed in the mouse nervous system.
Get PDFAdeno-associated viral (AAV) vectors are an established and safe gene delivery tool to target the nervous system. However, the payload capacity of <4.9 kb limits the transfer of large or multiple genes. Oversized payloads could be delivered by fragmenting the transgenes into separate AAV capsids that are then mixed. This strategy could increase the AAV cargo capacity to treat monogenic, polygenic diseases and comorbidities only if controlled co-expression of multiple AAV capsids is achieved on each transduced cell. We developed a tool to quantify the number of incoming AAV genomes that are co-expressed in the nervous system with single-cell resolution. By using an isogenic mix of three AAVs each expressing single fluorescent reporters, we determined that expression of much greater than 31 AAV genomes per neuron in vitro and 20 genomes per neuron in vivo is obtained across different brain regions including anterior cingulate, prefrontal, somatomotor and somatosensory cortex areas, and cerebellar lobule VI. Our results demonstrate that multiple AAV vectors containing different transgenes or transgene fragments, can efficiently co-express in the same neuron. This tool can be used to design and improve AAV-based interrogation of neuronal circuits, map brain connectivity, and treat genetic diseases affecting the nervous system
Causal Manipulation of Anterior Cingulate Neurons in Mice and Human Selectively Affects Approach during Reward-Threat Conflict
No full textAbstract 82: Identification of essential proliferation and trametinib resistance mechanisms in GNAQ-mutant uveal melanoma
No full textCancer as a tool for preclinical psychoneuroimmunology
Get PDFCancer represents a novel homeostatic challenge to the host system. How the brain senses and responds to changes in peripheral physiology elicited by tumor growth is a largely untapped area of research. This is especially relevant given the widespread prevalence of systemic problems that people with various types of cancer experience. These include disruptions in sleep/wake cycles, cognitive function, depression, and changes in appetite/food intake, among others. Critically, many of these problems are evident prior to diagnosis, indicating that their etiology is potentially distinct from the effects of cancer treatment or the stress of a cancer diagnosis. Psychoneuroimmunology (PNI) is well equipped to tackle these types of problems, as it uses approaches from multiple disciplines to understand how specific stimuli (endogenous and environmental) are transduced into neural, endocrine, and immune signals that ultimately regulate health and behavior. In this article, I first provide a brief historical perspective of cancer and PNI, introduce the idea of cancer as a systemic homeostatic challenge, and provide examples from preclinical literature supporting this hypothesis. Given the rise of advanced tools in neuroscience (e.g., calcium imaging), we can now monitor and manipulate genetically defined neural circuits over the extended time scales necessary to disentangle distal communication between peripheral tumors and the brai