Her2 signaling and breast cancer stem cells: The bridge behind her2-positive breast cancer aggressiveness and therapy refractoriness

HER2 overexpression/amplification occurs in 15–20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/β-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control

An Unusual Cause of Dementia: Essential Diagnostic Elements of Corticobasal Degeneration—A Case Report and Review of the Literature

Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease

Weighing the prognostic role of hyponatremia in hospitalized patients with metastatic solid tumors: the HYPNOSIS study

Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P < 0.001). In the multivariable model, hyponatremia was independently associated with poorer OS (HR, 1.66; P < 0.001). According to the multivariable model, a nomogram system was developed and validated in an external set of patients. We weighed over time the influence of hyponatremia on survival of patients with metastatic solid tumors and pointed out the possibility to exploit serum sodium assessment to design integrated prognostic tools. Our study also highlights the need for a deeper characterization of the biological role of extracellular sodium levels in tumor development and progression

Creedy, Jean Iris

The final stage of leaf ontogenesis is represented by senescence, a highly regulated process driven by a sequential cellular breakdown involving, as the first step, chloroplast dismantling with consequent reduction of photosynthetic efficiency. Different processes, such as pigment accumulation, could protect the vulnerable photosynthetic apparatus of senescent leaves. Although several studies have produced transcriptomic data on foliar senescence, just few works have attempted to explain differences in red and green leaves throughout ontogenesis. In this work, a transcriptomic approach was used on green and red leaves of Prunus cerasifera to unveil molecular differences from leaf maturity to senescence. Our analysis revealed a higher gene regulation in red leaves compared to green ones, during leaf transition. Most of the observed DEGs were shared and involved in transcription factor activities, senescing processes and cell wall remodelling. Significant differences were detected in cellular functions: genes related to photosystem I and II were highly down-regulated in the green genotype, whereas transcripts involved in flavonoid biosynthesis, such as UDP glucose-flavonoid-3-O-glucosyltransferase (UFGT) were exclusively up-regulated in red leaves. In addition, cellular functions involved in stress response (glutathione-S-transferase, Pathogen-Related) and sugar metabolism, such as three threalose-6-phosphate synthases, were activated in senescent red leaves. In conclusion, data suggests that P. cerasifera red genotypes can regulate a set of genes and molecular mechanisms that cope with senescence, promoting more advantages during leaf ontogenesis than compared to the green ones

Supplemental red LED light promotes plant productivity, “photomodulate” fruit quality and increases Botrytis cinerea tolerance in strawberry

This work provides new evidences on the effect of pre-harvest red (R), green (G), blue (B), and white (W - R:G:B; 1:1:1) LED light supplementation on production, nutraceutical quality and Botrytis cinerea control of harvested strawberry fruit. Yield, fruit color, firmness, soluble solid content, titratable acidity, primary and specialized metabolites, expression of targeted genes and mold development were analyzed in fruit from light-supplemented plants, starting from the strawberry flowering, radiating 250 mu mol m-2 s-1 of light for five hours per day (from 11:00 to 16:00 h), until the fruit harvest. Briefly, R light induced the highest productivity and targeted antho-cyanin accumulation, whilst B and G lights increased the accumulation of primary and secondary metabolites especially belonging to ellagitannin and proanthocyanidin classes. R light also promoted pathogen tolerance in fruit by the upregulation of genes involved in cell wall development (F x aPE41), inhibition of fungus poly-galacturonases (F x aPGIP1) and the degradation of B. cinerea beta-glucans (F x aBG2-1). Our dataset highlights the possibility to use red LED light to increase fruit yield, "photomodulate" strawberry fruit quality and increase B. cinerea tolerance. These results can be useful in terms of future reduction of agrochemical inputs through the use of R light, enhancing, at the same time, fruit production and quality. Finally, further analyses might clarify the effect of pre-harvest supplemental G light on postharvest fruit quality

Combination of baseline LDH, performance status and age as integrated algorithm to identify solid tumor patients with higher probability of response to anti PD-1 and PD-l1 monoclonal antibodies

Predictive biomarkers of response to immune-checkpoint inhibitors (ICIs) are an urgent clinical need. The aim of this study is to identify manageable parameters to use in clinical practice to select patients with higher probability of response to ICIs. Two-hundred-and-seventy-one consecutive metastatic solid tumor patients, treated from 2013 until 2017 with anti-Programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) ICIs, were evaluated for baseline lactate dehydrogenase (LDH) serum level, performance status (PS), age, neutrophil-lymphocyte ratio, type of immunotherapy, number of metastatic sites, histology, and sex. A training and validation set were used to build and test models, respectively. The variables\u2019 effects were assessed through odds ratio estimates (OR) and area under the receive operating characteristic curves (AUC), from univariate and multivariate logistic regression models. A final multivariate model with LDH, age and PS showed significant ORs and an AUC of 0.771. Results were statistically validated and used to devise an Excel algorithm to calculate the patient\u2019s response probabilities. We implemented an interactive Excel algorithm based on three variables (baseline LDH serum level, age and PS) which is able to provide a higher performance in response prediction to ICIs compared with LDH alone. This tool could be used in a real-life setting to identify ICIs in responding patients

Photosynthetic traits and biochemical responses in strawberry (Fragaria × ananassa duch.) leaves supplemented with led lights

Selected light wavebands promote plant development and/or the biosynthesis of targeted metabolites. This work offers new insights on the effects of red (R), green (G), blue (B), and white (W – R:G:B; 1:1:1) LED light supplementation on physiochemical traits of strawberry leaves. Gas exchange and chlorophyll fluorescence parameters, photosynthetic pigments, and superoxide anion (•O2–) content were analysed in plants grown for 1 (T1) and 17 (T17) d with light supplementations. At T1, light supplementations resulted in the enhancement of the de-epoxidation state of xanthophylls and nonphotochemical quenching, but no changes were observed in maximal photosynthetic rate (PNmax), irrespective of light spectra. At T17, xanthophyll contents remained higher only in R-supplemented plants. Overall, W light resulted in higher photosynthesis, whilst R and B light depressed PNmax values and promoted•O2 – formation at T17. G light did not induce variations in photosynthetic traits nor induced oxidative stress at both T1 and T17