Role of Etanercept and Infliximab on Nociceptive Changes Induced by the Experimental Model of Fibromyalgia

Background: Fibromyalgia is a clinical condition that affects 1% to 5% of the population. No proper therapy has been currently found. It has been described that inflammation plays a central role in the nerve sensitizations that characterize the pathology. Methods: This paper aimed to evaluate the efficacy of etanercept and infliximab in the management of pain sensitization. Fibromyalgia was induced by three injections once a day of reserpine at the dose of 1 mg/kg. Etanercept (3 mg/kg) and infliximab (10 mg/kg) were administered the day after the last reserpine injection and then 5 days after that. Behavioral analyses were conducted once a week, and molecular investigations were performed at the end of the experiment. Results: Our data confirmed the major effect of infliximab administration as compared to etanercept: infliximab administration strongly reduced pain sensitization in thermal hyperalgesia and mechanical allodynia. From the molecular point of view, infliximab reduced the activation of microglia and astrocytes and the expression of the purinergic P2X7 receptor ubiquitously expressed on glia and neurons. Downstream of the P2X7 receptor, infliximab also reduced p38-MAPK overexpression induced by the reserpine administration. Conclusion: Etanercept and infliximab treatment caused a significant reduction in pain. In particular, rats that received infliximab showed less pain sensitization. Moreover, infliximab reduced the activation of microglia and astrocytes, reducing the expression of the purinergic receptor P2X7 and p38-MAPK pathway.     

Measurement and Classification of Out-of-Sequence Packets in a Tier-1 IP Backbone

We present a classification methodology and a measurement study for out-of-sequence packets in TCP connections going over the Sprint IP backbone. Out-of-sequence packets can result from many events including loss, looping, reordering, or duplication in the network. It is important to quantify and understand the causes of such out-of-sequence packets since it is an indicator of the performance of a TCP connection, and the quality of its end-end path. Our study is based on passively observed packets from a point inside a large backbone network-as opposed to actively sending and measuring end-end probe traffic at the sender or receiver. A new methodology is thus required to infer the causes of a connection's out-of-sequence packets using only measurements taken in the "middle" of the connection's end-end path. We describe techniques that classify observed out-of-sequence behavior based only on the previously and subsequently-observed packets within a connection and knowledge of how TCP behaves. We analyze numerous several-hour packet-level traces from a set of OC-12 and OC-48 links for tens of millions connections generated in nearly 7600 unique ASes. We show that using our techniques, it is possible to classify almost all out-of-sequence packets in our traces and that we can quantify the uncertainty in our classification. Our measurements show a relatively consistent rate of out-of-sequence packets of approximately 4%. We observe that a majority of out-of-sequence packets are retransmissions, with a smaller percentage resulting from in-network reordering     

Circadian Regulation of Retinal Pigment Epithelium Function

The retinal pigment epithelium (RPE) is a single layer of cells located between the choriocapillaris vessels and the light-sensitive photoreceptors in the outer retina. The RPE performs physiological processes necessary for the maintenance and support of photoreceptors and visual function. Among the many functions performed by the RPE, the timing of the peak in phagocytic activity by the RPE of the photoreceptor outer segments that occurs 1–2 h. after the onset of light has captured the interest of many investigators and has thus been intensively studied. Several studies have shown that this burst in phagocytic activity by the RPE is under circadian control and is present in nocturnal and diurnal species and rod and cone photoreceptors. Previous investigations have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. However, the anatomical location of the circadian controlling this activity is not clear. Experimental evidence indicates that the circadian clock, melatonin, dopamine, and integrin signaling play a key role in controlling this rhythm. A series of very recent studies report that the circadian clock in the RPE controls the daily peak in phagocytic activity. However, the loss of the burst in phagocytic activity after light onset does not result in photoreceptor or RPE deterioration during aging. In the current review, we summarized the current knowledge on the mechanism controlling this phenomenon and the physiological role of this peak.     

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.     

New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent an unmet clinical need whose prognosis is still dismal. Alterations of immune response play a prominent role in AML/MDS pathogenesis, revealing novel options for immunotherapy. Among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 (TLR2) are major targets. Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death. Several other surface molecules, namely CD33, CD123, CD45, and CD70, can be targeted with monoclonal antibodies (mAbs) that exert different mechanisms of action and include naked and conjugated antibodies, bispecific T-cell engagers, trispecific killer engagers, and fusion proteins linked to toxins. These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment.     

Genetic Basis of ACTH-Secreting Adenomas

Cushing’s disease represents 60–70% of all cases of Cushing’s syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing’s disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets.     

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing’s disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic–pituitary–adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth.     

One and two port piezoelectric higher order contour-mode MEMS resonators for mechanical signal processing

This paper reports on the design, fabrication and testing of novel one and two port piezoelectric higher order contour-mode MEMS resonators that can be employed in RF wireless communications as frequency reference elements or arranged in arrays to form banks of multi-frequency filters. The paper offers a comparison of one and two port resonant devices exhibiting frequencies approximately ranging from 200 to 800 MHz, quality factor of few thousands (1000–2500) and motional resistances ranging from 25 to 1000 Ω. Fundamental advantages and limitations of each solution are discussed. The reported experimental results focus on the response of a higher order one port resonator under different environmental conditions and a new class of two port contour resonators for narrow band filtering applications. Furthermore, an overview of novel frequency synthesis schemes that can be enabled by these contour-mode resonators is briefly presented.     

Printed Solar Cells and Energy Storage Devices on Paper Substrates

Paper is a flexible material, commonly used for information storage, writing, packaging, or specialized purposes. It also has strong appeal as a substrate in the field of flexible printed electronics. Many applications, including safety, merchandising, smart labels/packing, and chemical/biomedical sensors, require an energy source to power operation. Here, progress regarding development of photovoltaic and energy storage devices on cellulosic substrates, where one or more of the main material layers are deposited via solution processing or printing, is reviewed. Paper can be used simply as the flexible substrate or, exploiting its porous fiber‐like nature, as an active film by infiltration or copreparation with electronic materials. Solar cells with efficiencies of up to 9% on opaque substrates and 13% on transparent substrates are demonstrated. Recent developments in paper‐based supercapacitors and batteries are also reviewed with maximum achieved capacity of 1350 mF cm^?2 and 2000 mAh g^?1, respectively. Analyzing the literature, it becomes apparent that more work needs to be carried out in continuing to improve peak performance, but especially stability and the application of printing techniques, even roll‐to‐roll processing, over large areas. Paper is not only environmentally friendly and recyclable, but also thin, flexible, lightweight, biocompatible, and inexpensive.     

Major element chemistry in inner alpine snowpacks (Aosta Valley Region,NW Italy)

Major element chemistry of the snow cover was investigated at 15 sampling sites at about 2000 m a.s.l. in the Aosta Valley Region (North Western Italy), an inner alpine region characterized by a continental climate, during late winter 2005–2006. Snowfall in winter 2005–2006 was primarily due to westerly, Atlantic air flows, while southerly flows were not a significant source of precipitation. These two factors (i.e. the inner alpine topography and the peculiar air flow patterns) determined a unique ion distribution compared to rest of the Alps. Calcium and magnesium concentrations in snowpacks were low, consistent with the absence of Saharan dust events and local geological sources. Sodium and chloride concentrations were higher than the average for the Alps, supporting the influence of the Atlantic air masses on the ionic composition of snowfall. Sulfate concentrations were in the range of background concentrations reported for high altitude and latitude sites, indicating that industrial emissions were not a main source of chemicals in Aosta Valley snowpacks for winter 2005–2006. Ammonium and nitrate values were comparable to concentrations found in other sites of the Alps for low-emission winters. We estimated dissolved inorganic nitrogen stored in snow to range between 0.25 and 0.75 kg N ha^? 1, corresponding to about 2–6% of the over-winter-N mineralization in Alpine soils in the Western Alps. In the Aosta Valley, local biogenic pollution rather than long-range transport may contribute substantially to the ionic load in the snowpack when westerly air masses are the main source of precipitation. Although conducted over only one winter season, this study suggests a peculiar and previously unreported pattern of snowpack chemistry, that may be representative of the inner alpine, continental valleys in the absence of strong anthropogenic pollution or dust deposition. Due to the fact that inner alpine valleys cover a non-negligible surface of the Alps, we suggest these patterns to be taken into account while modeling ion depositions at a global scale.