Atogepant for the Prevention of Episodic Migraine in Adults: A Systematic Review and Meta-Analysis of Efficacy and Safety

Introduction: The inhibition of the calcitonin gene-related peptide (CGRP) pathway has attracted interest in pharmacological research on migraine. Atogepant is a potent, selective, orally available antagonist of the CGRP receptor approved as a preventive treatment of episodic migraine. This systematic review with meta-analysis aims to evaluate the efficacy and safety of atogepant for the prevention of episodic migraine in adult patients. Methods: Randomized, placebo-controlled, single or double-blinded trials were identified through a systematic literature search (December week 4, 2021). Main outcomes included the changes from baseline in monthly migraine days and the incidence of adverse events (AEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated. Results: Two trials were included, overall enrolling 1550 patients. A total of 408 participants were randomized to placebo, 314 to atogepant 10 mg, 411 to atogepant 30 mg, and 417 to atogepant 60 mg once daily. The mean age of the patients was 41.0 years and 87.7% were women. The reduction in the mean number of migraine days from baseline across the 12-week treatment period was significantly greater among patients treated with atogepant at either the daily dose of 10 mg (MD − 1.16, 95% CI − 1.60 to − 0.73, p < 0.001), 30 mg (MD − 1.15, 95% CI − 1.54 to − 0.76, p < 0.001), or 60 mg (MD − 1.20, 95% CI − 2.18 to − 0.22, p = 0.016) than with placebo. There were no differences in the occurrence of AEs and drug withdrawal due to AEs between atogepant and placebo groups. Constipation was more commonly observed in patients treated with atogepant at 30 mg/day than placebo (RR 5.19, 95% CI 2.00–13.46; p = 0.001). Treatment with atogepant at the daily dose of 60 mg was associated with a higher risk of constipation (RR 4.92, 95% CI 1.89–12.79; p = 0.001) and nausea (RR 2.73, 95% CI 1.47–5.06; p = 0.001) than placebo. Conclusion: Atogepant is an efficacious and overall well-tolerated treatment for the prevention of episodic migraine in adults

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

Can anthocyanin presence ameliorate the photosynthetic performance of Prunus saplings subjected to polyethylene glycol-simulated water stress?

The aim was the evaluation of the biochemical and physiological responses of green- (GP) and red-leafed (RP) Prunus cerasifera mature leaves to 20 d of polyethylene glycol (PEG 6000)-induced water stress in order to elucidate a possible ameliorative role exerted by anthocyanins. At 10 d, the anthocyanin content remained unchanged in RP water-stressed leaves. Photosynthetic rate was lower in GP than that of RP (83.4 vs. 76.5%, respectively), paralleled by a higher degree of photoinhibition (Fv/Fm) in GP leaves. Leaves of GP accounted for higher content of soluble sugars at 10 d, when RP only showed a slight sucrose increase. At 20 d of stress, both morphs recovered their Fv/Fm values, suggesting the ability of both genotypes to adjust their photosynthetic metabolism under conditions of water stress. In conclusion, besides the sunscreen role served by anthocyanins, the carbon sink by these flavonoids might have further prevented sugar accumulation and the consequent sugar-promoted feedback regulation of photosynthesis in drought-stressed red leaves

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