Aqueous humor as eye lymph: A crossroad between venous and lymphatic system.

Aqueous humor (AQH) is a transparent fluid with characteristics similar to those of the interstitial fluid, which fills the eyeball posterior and anterior chambers and circulates in them from the sites of production to those of drainage. The AQH volume and pressure homeostasis is essential for the trophism of the ocular avascular tissues and their normal structure and function. Different AQH outflow pathways exist, including a main pathway, quite well defined anatomically and referred to as the conventional pathway, and some accessory pathways, more recently described and still not fully morphofunctionally understood, generically referred to as unconventional pathways. The conventional pathway is based on the existence of a series of conduits starting with the trabecular meshwork and Schlemm's Canal and continuing with a system of intrascleral and episcleral venules, which are tributaries to veins of the anterior segment of the eyeball. The unconventional pathways are mainly represented by the uveoscleral pathway, in which AQH flows through clefts, interstitial conduits located in the ciliary body and sclera, and then merges into the aforementioned intrascleral and episcleral venules. A further unconventional pathway, the lymphatic pathway, has been supported by the demonstration of lymphatic microvessels in the limbal sclera and, possibly, in the uvea (ciliary body, choroid) as well as by the ocular glymphatic channels, present in the neural retina and optic nerve. It follows that AQH may be drained from the eyeball through blood vessels (TM-SC pathway, US pathway) or lymphatic vessels (lymphatic pathway), and the different pathways may integrate or compensate for each other, optimizing the AQH drainage. The present review aims to define the state-of-the-art concerning the structural organization and the functional anatomy of all the AQH outflow pathways. Particular attention is paid to examining the regulatory mechanisms active in each of them. The new data on the anatomy and physiology of AQH outflow pathways is the key to understanding the pathophysiology of AQH outflow disorders and could open the way for novel approaches to their treatment.

Mast cells in meningiomas.

Meningioma represents the most frequent tumor of the central nervous system (CNS). Correlations between the presence of mast cells (MCs) and grade or other histological features of meningioma are still debated. Our study aimed to better understand the relationship between mast cells and meningiomas and to compare our results based on specific histological subtypes and novel 2021 CNS WHO grading system. We observed some differences as regards the number of MCs and meningioma grade. In low-grade (grade 1) meningiomas, MCs were observed in 7/22 cases, while they were consistently present in all eight high-grade cases (grade 2 and grade  3). Among the grade 1 meningiomas, we observed two "low-positive", two "intermediate-positive", and three "high-positive" cases. Among the group of high-grade meningiomas, the six cases grade 2 were considered as "low-positive", while the two grade 3 cases showed a higher number of MCs and were included in the "intermediate-positive" group. Even though with no statistical significance, due to the low number of cases, our results seem to confirm a sort of relationship between meningioma grading and the number of MCs, as demonstrated by the higher percentage of high-grade meningiomas showing MCs infiltrates, compared to low-grade meningiomas.

Is the Cerebellum Involved in the Nervous Control of the Immune System Function?

BACKGROUND: According to the views of psychoneuroendocrinoimmunology, many interactions exist between nervous, endocrine and immune system the purpose of which is to achieve adaptive measures restoring an internal equilibrium (homeostasis) following stress conditions. The center where these interactions converge is the hypothalamus. This is a center of the autonomic nervous system that controls the visceral systems, including the immune system, through both the nervous and neuroendocrine mechanisms. The nervous mechanisms are based on nervous circuits that bidirectionally connect hypothalamic neurons and neurons of the sympathetic and parasympathetic system; the neuroendocrine mechanisms are based on the release by neurosecretory hypothalamic neurons of hormones that target the endocrine cells and on the feedback effects of the hormones secreted by these endocrine cells on the same hypothalamic neurons. Moreover, the hypothalamus is an important subcortical center of the limbic system that controls through nervous and neuroendocrine mechanisms the areas of the cerebral cortex where the psychic functions controlling mood, emotions, anxiety and instinctive behaviors take place. Accordingly, various studies conducted in the last decades have indicated that hypothalamic diseases may be associated with immune and/or psychic disorders. OBJECTIVE: Various researches have reported that the hypothalamus is controlled by the cerebellum through a feedback nervous circuit, namely the hypothalamocerebellar circuit, which bi-directionally connects regions of the hypothalamus, including the immunoregulatory ones, and related regions of the cerebellum. An objective of the present review was to analyze the anatomical bases of the nervous and neuroendocrine mechanisms for the control of the immune system and, in particular, of the interaction between hypothalamus and cerebellum to achieve the immunoregulatory function. CONCLUSION: Since the hypothalamus represents the link through which the immune functions may influence the psychic functions and vice versa, the cerebellum, controlling several regions of the hypothalamus, could be considered as a primary player in the regulation of the multiple functional interactions postulated by psychoneuroendocrinoimmunology.

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

The development of tolerance to the antinociceptive effect is a main problem associated with the repeated administration of opioids. The progressively higher doses required to relieve pain reduce safety and exacerbate the side effects of classical opioid receptor agonists like morphine. Nociceptin/orphanin FQ (N/OFQ) and its NOP receptor constitute the fourth endogenous opioid system that is involved in the control of broad spectrum of biological functions, including pain transmission. Aim of this work was to evaluate the relevance of the N/OFQ-NOP system in morphine antinociceptive action and in the development of morphine tolerance in the rat. Continuous spinal intrathecal infusion of morphine (1-3 nmol/h) evoked analgesic effects for 5 days in wild type animals. The same doses infused in NOP(-/-) rats showed a lower analgesic efficacy, while the onset of tolerance was delayed to day 9. N/OFQ (1-3 nmol/h), continuously infused in NOP(+/+) animals, showed an analgesic profile similar to morphine. Immunohistochemical analysis of the dorsal horn of the spinal cord of morphine tolerant NOP(+/+) rats showed an increased number of Iba1- and GFAP-positive cells (microglia and astrocytes, respectively). Interestingly, microglia but not astrocyte activation was observed in NOP(-/-) morphine tolerant rat. A selective activation of astrocytes was observed in the dorsal horn of wild type N/OFQ tolerant rats. The antinociceptive effect of morphine partially depends by the N/OFQ-NOP system that participates in the development of morphine tolerance. In particular, NOP receptors are involved in morphine-induced astrocyte activation, and N/OFQ per se increases astrocyte density.

The functional anatomy of the cerebrocerebellar circuit: A review and new concepts.

The cerebrocerebellar circuit is a feedback circuit that bidirectionally connects the neocortex and the cerebellum. According to the classic view, the cerebrocerebellar circuit is specifically involved in the functional regulation of the motor areas of the neocortex. In recent years, studies carried out in experimental animals by morphological and physiological methods, and in humans by magnetic resonance imaging, have indicated that the cerebrocerebellar circuit is also involved in the functional regulation of the nonmotor areas of the neocortex, including the prefrontal, associative, sensory and limbic areas. Moreover, a second type of cerebrocerebellar circuit, bidirectionally connecting the hypothalamus and the cerebellum, has been detected, being specifically involved in the regulation of the hypothalamic functions. This review analyzes the morphological features of the centers and pathways of the cerebrocerebellar circuits, paying particular attention to their organization in different channels, which separately connect the cerebellum with the motor areas and nonmotor areas of the neocortex, and with the hypothalamus. Actually, a considerable amount of new data have led, and are leading, to profound changes on the views on the anatomy, physiology, and pathophysiology of the cerebrocerebellar circuits, so much they may be now considered to be essential for the functional regulation of many neocortex areas, perhaps all, as well as of the hypothalamus and of the limbic system. Accordingly, clinical studies have pointed out an involvement of the cerebrocerebellar circuits in the pathophysiology of an increasing number of neuropsychiatric disorders.

Peptide welding technology - A simple strategy for generating innovative ligands for G protein coupled receptors.

Based on their high selectivity of action and low toxicity, naturally occurring peptides have great potential in terms of drug development. However, the pharmacokinetic properties of peptides, in particular their half life, are poor. Among different strategies developed for reducing susceptibility to peptidases, and thus increasing the duration of action of peptides, the generation of branched peptides has been described. However, the synthesis and purification of branched peptides are extremely complicated thus limiting their druggability. Here we present a novel and facile synthesis of tetrabranched peptides acting as GPCR ligands and their in vitro and vivo pharmacological characterization. Tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ), N/OFQ related peptides, opioid peptides, tachykinins, and neuropeptide S were generated with the strategy named peptide welding technology (PWT) and characterized by high yield and purity of the desired final product. In general, PWT derivatives displayed a pharmacological profile similar to that of the natural sequence in terms of affinity, pharmacological activity, potency, and selectivity of action in vitro. More importantly, in vivo studies demonstrated that PWT peptides are characterized by increased potency associated with long lasting duration of action. In conclusion, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.

Angiogenesis versus arteriogenesis.

In the vascular system, angiogenesis and arteriogenesis play a unique yet equally important role in both health and disease. Angiogenesis, the formation of new blood vessels from a preexisting vascular bed, occurs naturally during wound healing, the female menstrual cycle and pregnancy. It plays a critical role in tissue growth and repair, and is a highly controlled process that is dependent on an intricate balance of both pro-angiogenic (to stimulate) and anti-angiogenic (to negatively regulate the phenomenon) factors. Otherwise, the term arteriogenesis refers to anatomic transformation of preexisting arterioles with increasing lumen area and wall thickness, due to a thick muscular layer and purchasing of visco-elastic and vasomotor capacities. Arteriogenesis differs from angiogenesis in several aspects, the most important being the dependence of angiogenesis on hypoxia and the dependence of arteriogenesis on inflammation. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis.

GEMOX: An Active Regimen for the Treatment of Luminal and Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

BACKGROUND: Pretreated metastatic breast cancer (MBC) remains a formidable challenge with unmet needs both in terms of prolonged survival and quality-of-life-related issues. METHODS: We collected data from 27 MBC patients treated with gemcitabine and oxaliplatin (GEMOX) at our institution between June 2009 and April 2015. The patients were heavily pretreated, and all had previously been exposed to anthracyclines and taxanes. RESULTS: We achieved a complete response in 1 patient (4%), a partial response in 7 patients (26%) and stable disease in 12 patients (44%), while 6 patients (22%) experienced progressive disease. The response of 1 patient (4%) could not be evaluated because she interrupted her treatment during the first cycle due to a major reaction to oxaliplatin. We observed grade 4 hypertransaminasaemia in only 1 patient (4%) and grade 2 neuropathy in 16 patients (59%). Grade 3 leuconeutropenia was observed in 5 patients (18%). The median progression-free survival was 5.9 months and the median overall survival was 9.6 months. CONCLUSIONS: GEMOX is an efficient and well-tolerated salvage regimen for MBC patients.

Parents with cancer: Searching for the right balance between telling the truth and protecting children.

OBJECTIVE: Recent scientific approaches to cancer patients draw attention to the psychological aspects of the disease and the involvement of their families, who are forced to reorganize themselves in order to manage the patient's illness. Functional responses to a stressful event facilitate open communication between family members and empathy for the patient's children, who need to be involved and informed about the illness in a clear and open fashion. The primary goal of this observational study was to explore the communication styles used by cancer-stricken parents with their children and to identify a correlation with the patient's levels of anxiety and depression and their ability to cope. We also sought to understand whether location, severity, and time from diagnosis influenced communication, coping, anxiety, or depression. METHOD: From September of 2011 to July of 2015, 151 questionnaires were given to patients who had received at least one course of chemotherapy. The instruments that we employed were the Openness to Discuss Cancer in the Nuclear Family Scale, the Hospital Anxiety and Depression Scale, and the Mini-Mental Adjustment to Cancer Scale. Our sample included patients with children aged from 3 to 18 years. The patients had different types of cancer, mainly gastrointestinal and breast cancer. Their disease was at the metastatic stage in approximately 20% of patients. RESULTS: Our results showed statistically significant correlations between higher levels of anxiety and depression and more closed communication styles. The coping styles "hopelessness/helplessness," "cognitive avoidance," and "anxious preoccupation" were associated with a closed communication style that is correlated with higher levels of anxiety and depression. Tumor location, time from diagnosis, and stage of disease did not show statistically significant correlations with anxiety, depression, coping mechanisms, or communication styles. SIGNIFICANCE OF RESULTS: Our study confirmed what has been reported in the literature: high levels of anxiety and depression affect communication among family members. Not surprisingly, the "fighting spirit" coping style engenders open communication.

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13).

An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt1]N/OFQ(1-13)-NH2 acts as a universal agonist for nociceptin/orphanin FQ (N/OFQ) and classical opioid receptors. The present study investigated the pharmacological profile of the PWT derivative of [Dmt1]N/OFQ(1-13)NH2 (PWT2-[Dmt1]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt1] mimicked the effects of [Dmt1]N/OFQ(1-13)-NH2 displaying full agonist activity, similar affinity/potency and selectivity at human recombinant N/OFQ (NOP) and opioid receptors in receptor binding, stimulation of [35S]GTPγS binding, calcium mobilization in cells expressing chimeric G proteins, and BRET studies for measuring receptor/G-protein and receptor/ß-arrestin 2 interaction. In vivo in monkeys PWT2-[Dmt1] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt1]N/OFQ(1-13)-NH2. The analgesic action of PWT2-[Dmt1] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt1]N/OFQ(1-13)-NH2 obtained with the PWT technology maintains the in vitro pharmacological profile of the parent peptide but displays higher potency and longer lasting action in vivo.

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations.

Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [35S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65-6570) and the NOP selective antagonist SB-612111. AT compounds displayed high NOP affinity and behaved as NOP agonists in all the functional assays consistently showing the following rank order of potency AT-127≥AT-090≥AT-035>AT-004= AT-001. AT compounds behaved as NOP full agonists in the calcium mobilization and mouse colon assays and as partial agonists in the [35S]GTPγS and BRET assays. Interestingly AT-090 and AT-127, contrary to standard nonpeptide agonists that display G protein biased agonism, behaved as an unbiased agonists. AT-090 and AT-127 displayed higher NOP selectivity than Ro 65-6570 at native mouse receptors. AT-090 and AT-127 might be useful pharmacological tools for investigating the therapeutic potential of NOP partial agonists.

Eribulin in Male Patients With Breast Cancer: The First Report of Clinical Outcomes.

BACKGROUND: Evidence on the management and treatment of male breast cancer is scant. We report the analysis of a multicenter Italian series of patients with male breast cancer treated with eribulin. To our knowledge, this is the first report on the use or eribulin in this setting. PATIENTS AND METHODS: Patients were retrospectively identified in 19 reference centers. All patients received eribulin treatment, according to the standard practice of each center. Data on the identified patients were collected using a standardized form and were then centrally reviewed by two experienced oncologists. RESULTS: A total of 23 patients (median age, 64 years; range, 42-80) were considered. The median age at the time of diagnosis of breast cancer was 57 years (range, 42-74). HER2 status was negative in 14 patients (61%), and 2 patients (9%) had triple-negative disease. The most common metastatic sites were the lung (n = 14; 61%) and bone (n = 13; 56%). Eribulin was administered for a median of 6 cycles (range, 3-15). All patients reported at least stable disease; two complete responses (9%) were documented. Eribulin was well-tolerated, with only four patients (17%) reporting grade 3 adverse events and two (9%) with treatment interruptions because of toxicity. Eight subjects (35%) did not report any adverse event during treatment. For patients with a reported fatal event, the median overall survival from the diagnosis of metastatic disease was 65 months (range, 22-228). CONCLUSION: Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer. IMPLICATIONS FOR PRACTICE: Evidence on the management and treatment of male breast cancer is eagerly awaited. Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer.

Mast cells in human digestive tube in normal and pathological conditions.

Mast cells (MCs) are localized in connective tissues and are more numerous near the boundaries between the external environment and the internal milieu including the skin, the respiratory tract, the gastrointestinal tract and the conjunctiva. In the gastrointestinal tract, MCs represent 1-5% of mononuclear cells in the lamina propria of the mucosa and in the submucosa, and they are also found inside the epithelium and deep in the muscle and serosal layers. The gastrointestinal MCs perform their biological functions, releasing mediators, as amines (histamine, serotonin), cytokines, proteases, lipid mediators (leukotrienes, prostaglandins), and heparin. MCs are involved in the pathogenesis of different inflammatory conditions and tumors of the gastrointestinal tract. The use of MCs' tryptase inhibitors or c-KitR tyrosine kinase inhibitors could represent a potential anti-MC therapeutic approach in all the inflammatory and tumor pathological conditions of the digestive tube in which MCs are involved.

Adjuvant Carboplatin Treatment in 115 Patients With Stage I Seminoma: Retrospective Multicenter Survey.

BACKGROUND: The administration of carboplatin AUC 7 has become a standard adjuvant option for patients undergoing orchiectomy for stage I seminoma, in alternative to radiotherapy on retroperitoneal lymphnodes or surveillance. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial of Oliver et al, but dose ranges were not reported. Fear of toxicity may induce arbitrary dose reductions, which may potentially compromise patients' outcome. PATIENTS AND METHODS: We reviewed adjuvant carboplatin administration in 115 stage I seminoma patients followed in 11 Italian medical oncology centers since 2005. Clinical and pathological data, modality of carboplatin dose calculation, dose reductions, toxicities, and relapses were recorded. RESULTS: Median age was 35 years (range, 18-65 years), adverse prognostic factors were either T ≥ 4 cm (17.4%) or rete testis invasion (28.7%), both of them (35.7%), none or unspecified (18.3%). GFR was estimated mainly by Cockroft-Gault formula (55.7%) or Jeliffe formula (26.1%), with a median of 105 mL/min (range, 75-209 mL/min). The median dose of carboplatin was 900 mg (range, 690-1535 mg). A dose reduction > 10% was applied to 14 patients. Toxicities were mild fatigue, moderate nausea/vomiting, 5.2% of grade 3 to 4 thrombocytopenia. After a median follow-up of 22.1 months, 5.2% of patients have relapsed in the retroperitoneal lymph nodes. None of the patients that relapsed were treated with reduced dose. All but one achieved complete remission with salvage chemotherapy. CONCLUSIONS: Adjuvant AUC 7 carboplatin reduce relapses of stage I seminoma patients to 5.2%, with manageable toxicities. Dose reductions should be proscribed.

Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist.

The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein and ß-arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G-protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP-ß-arrestin 2 interactions and displayed reduced potency at mu/ß-arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long-lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB-612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.

Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity.

Oxaliplatin and paclitaxel are considered central components in the treatment of colorectal and breast cancer, respectively. The development of neuropathy during chronic treatment represents the major dose-limiting side effect that leads to discontinuation or interruption of therapies. The management of neuropathy is a challenge to individuate innovative therapeutic strategies based on new targets and correct routes of administration. We evaluated the hypersensitivity reliever effect of different opioid receptor agonists in rat models of oxaliplatin and paclitaxel-induced neuropathy. Compounds were spinally infused by intrathecal catheter. In oxaliplatin-treated rats, 0.3 nmol morphine induced the reversion of the mechanical hypersensitivity (Paw-pressure test), nociceptin/orphanin FQ (N/OFQ; 0.3-3 nmol) significantly increased the pain threshold without reaching the values of the control animals. The N/OFQ peptide (NOP) receptor full agonist UFP-112 reverted pain threshold alterations at lower dosage (0.1 nmol) vs morphine and N/OFQ, the partial agonist UFP-113 (0.1-1 nmol) was similar to N/OFQ. The higher efficacy of morphine vs N/OFQ was highlighted also in paclitaxel-treated rats. The mechanical hypersensitivity was fully reverted by 0.1 nmol UFP-112 and UFP-113. In conclusion, intrathecal µ opioid peptide (MOP) and NOP receptor agonists relieved chemotherapy-induced neuropathic pain. The synthetic peptides showed valuable potency and efficacy suggesting the NOP system as an exploitable target.

A fractal analysis of the spatial distribution of tumoral mast cells in lymph nodes and bone marrow.

The spatial distribution of mast cells inside the tumor stroma has been little investigated. In this study, we have evaluated tumor mast cells distribution through the analysis of the morphological features of the spatial patterns generated by these cells, including size, shape, and architecture of the cell pattern. We have compared diffuse large B cells lymphoma (DLBCL) and systemic mastocytosis in two different anatomical localizations (lymph nodes for DLBCL and, respectively, bone marrow for mastocytosis). Results have indicated that, despite the high difference in size exhibited by the mast cells patterns in the two conditions, the spatial relationship between the mast cells forming the aggregates resulted similar, characterized by a significant tendency of the mast cells to self-organize in clusters.

Gemcitabine Plus Nab-Paclitaxel as Second-Line and Beyond Treatment for Metastatic Pancreatic Cancer: a Single Institution Retrospective Analysis.

Metastatic pancreatic cancer still represent one of the most deadly disease for which there are few therapeutic options, especially in second line and beyond setting. Nabpaclitaxel plus gemcitabine activity was demonstrated in first line setting, but there are no clear evidence suggesting its use after that. We report a retrospective data analysis of 23 patients who received nab-paclitaxel plus gemcitabine after first line treatment at our Oncology Department. We observed a significant clinical benefit (43,5%) with a median overall survival of 5 months. In addition, manageable side effects were reported. Our data, despite the small sample, seem to indicate that nab- paclitaxel plus gemcitabine is an active and well tolerated regimen even in pretreated patients.