Pen shell Pinna nobilis L. (Mollusca: Bivalvia) from different peculiar environments: adaptive mechanisms of osmoregulation and neurotransmission

The pen shell Pinna nobilis (Linnaeus, 1758) is the largest endemic bivalve mollusc of the Mediterranean Sea, listed as an endangered species in the European Union. Because no information is available about the adaptation of pen shells to different habitats, herein the fundamental conditions of adaptation of P. nobilis to peculiar natural environments, such as the Strait of Messina (SM) and the meromictic Faro Lake (FL; Sicily, Italy), were explored by assessing the morphology, mucous production, osmoregulation and neurotransmission of their gills. Although gills of the pen shells from both sites exhibited a regular morphology, a higher presence of acid mucous cells was detected in P. nobilis from FL than SM, as well as higher levels of osmolytes but without interfering the osmoregulatory processes. About the functioning of gills, the cholinergic (i.e. acetylcholine and AChE) neuronal system was unaltered between individuals from the two sites, whereas the GABAergic neurotransmission (i.e. 4-aminobutyrate or GABA) was significantly augmented in gills of P. nobilis from FL than SM. This may be an adaptive response to hypoxic conditions in FL, as supported by the increased hypoxia-inducible factor (HIF-1α) in gills of pen shells from FL than SM. Noteworthy, this study reports for the first time the presence of the GABA neurotransmitter within the metabolite profile, obtained by application of a protonic Nuclear Magnetic Resonance (1H NMR)-based metabolomics approach, of a marine bivalve. Therefore, GABA may be suggested as a metabolite biomarker in pen shells. Overall, findings from this study provide new insights on the behavioural and adaptive responses of the pen shell Pinna nobilis settled in different peculiar environments

Extremely fast Holocene coastal landscape evolution in the Kachchh Upland (NW India): Clues from a multidisciplinary review

The coastal landscape of the Kachchh Upland (KU) region (NW-India) changed over the last few thousand years from a shallow marine gulf to a salty desert (1-4 meters asl). In this area, bordered to the south by the Northern Hill Range (NHR), the tectonic-climatic interaction triggered the sea level fall from +2/4 m circa (6000-2000 BP) to zero. An ancient river pattern deposited a tidally regulated delta area during the sea level fall that stopped 2000-3000 years ago due to tectonic activity and a dry climate. Deltaic-alluvial fans (DAF) in front of the NHR suggest that the KU's tectonic activity led to fast landscape evolution. We explored such drastic changes by integrating scientific information from a multidisciplinary literature review, identifying terraces and DAFs, and inferring faults through landform recognition, quantitative morphometry, and field surveys. Our interpretation, summarized in a map, provides new information on active processes along the NHR

ReptIslands: Mediterranean islands and the distribution of their reptile fauna

Aim: Analyses of biogeographical patterns and macroecology of islands require large datasets reporting the occurrence of species. The Mediterranean region is a biodiversity hotspot, which hosts a large number of reptile species and has been the focus of many studies. Nevertheless, comprehensive inventories describing the features and biodiversity of these environments are lacking. We gathered a dataset summarizing data on reptile distribution on islands of the Mediterranean basin and Macaronesia, also including detailed information on the geographical features. Location: Islands from the Mediterranean Basin, the Atlantic Ocean within the Mediterranean biogeographical region, and Macaronesia (Canary and Savage Islands, Azores, Madeira and Cape Verde). Time period: Present. Taxon: Reptiles (squamates and turtles). Methods: Initially, we developed a geographical database describing islands of the study region, then gathered information on reptile occurrences from 757 bibliographical sources, including atlases, published papers and the grey literature. Through a critical review of these sources, we also obtained information on the status of populations (native, island endemic or non-native) and on the reliability of occurrence data. Results: We obtained basic geographical information from 1875 islands covering the whole study region and with a very broad range of geographical features. We gathered >4150 records of reptile occurrence on islands, referring to 198 taxonomic units (species or species complexes); information on population status was available for 84.9% of records. Data are provided as comma-delimited text files. Main conclusions: The database provides a key resource for biogeographical analyses and can also serve as a backbone for conservation studies. The availability of a large database on island features can also be useful for biogeographers working on other taxonomic groups. Nevertheless, more data are required for some geographical areas, in order to ascertain the status (e.g., native vs. non-native) of many populations and to understand the interplay between natural and human-driven processes

An Integrated Multiscale Method for the Characterisation of Active Faults in Offshore Areas. The Case of Sant\u2019Eufemia Gulf (Offshore Calabria, Italy)

Diagnostic morphological features (e.g., rectilinear seafloor scarps) and lateral offsets of the Upper Quaternary deposits are used to infer active faults in offshore areas. Although they deform a significant seafloor region, the active faults are not necessarily capable of producing large earthquakes as they correspond to shallow structures formed in response to local stresses. We present a multiscale approach to reconstruct the structural pattern in offshore areas and distinguish between shallow, non-seismogenic, active faults, and deep blind faults, potentially associated with large seismic moment release. The approach is based on the interpretation of marine seismic reflection data and quantitative morphometric analysis of multibeam bathymetry, and tested on the Sant\u2019Eufemia Gulf (southeastern Tyrrhenian Sea). Data highlights the occurrence of three major tectonic events since the Late Miocene. The first extensional or transtensional phase occurred during the Late Miocene. Since the Early Pliocene, a right-lateral transpressional tectonic event caused the positive inversion of deep (>3 km) tectonic features, and the formation of NE-SW faults in the central sector of the gulf. Also, NNE-SSW to NE-SW trending anticlines (e.g., Maida Ridge) developed in the eastern part of the area. Since the Early Pleistocene (Calabrian), shallow (<1.5 km) NNE-SSW oriented structures formed in a left-lateral transtensional regime. The new results integrated with previous literature indicates that the Late Miocene to Recent transpressional/transtensional structures developed in an 3cE-W oriented main displacement zone that extends from the Sant\u2019Eufemia Gulf to the Squillace Basin (Ionian offshore), and likely represents the upper plate response to a tear fault of the lower plate. The quantitative morphometric analysis of the study area and the bathymetric analysis of the Angitola Canyon indicate that NNE-SSW to NE-SW trending anticlines were negatively reactivated during the last tectonic phase. We also suggest that the deep structure below the Maida Ridge may correspond to the seismogenic source of the large magnitude earthquake that struck the western Calabrian region in 1905. The multiscale approach contributes to understanding the tectonic imprint of active faults from different hierarchical orders and the geometry of seismogenic faults developed in a lithospheric strike-slip zone orthogonal to the Calabrian Arc

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases

Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis

Objectives: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. Methods: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks’ double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. Results: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. Conclusion: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

Background: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. Methods: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. Results: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. Conclusions: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Introduction: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients’ subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach

Demographic and Clinical Factors Associated with Response to Smallpox Vaccine in Preimmunized Volunteers

CONTEXT: In March 2003, the French Ministry of Health implemented a program on preparedness and response to a biological attack using smallpox as weapon. This program included the establishment of a preoutbreak national team that could be revaccinated against smallpox. OBJECTIVE: To identify demographic and clinical factors associated with vaccination success defined as the presence of a pustule at the inoculation site at day 8 (days 7-9), with an undiluted vaccinia virus derived from a Lister strain among preimmunized volunteers. VOLUNTEERS AND METHODS: From March 2003 to November 2006, we have studied prospectively 226 eligible volunteers. Demographic data were recorded for each volunteer (age, sex, number of previously smallpox vaccinations and date of the last vaccination). Smallpox vaccine adverse reactions were diagnosed on the basis of clinical examination performed at days 0, 7, 14, 21 and 28 after revaccination. RESULTS: A total of 226 volunteers (sex ratio H/F = 2.7) were revaccinated. Median age was 45 years (range: 27-63 yrs). All volunteers completed follow-up. Median number of vaccinations before revaccination was 2 (range: 1-8). The median delay between time of the study and the last vaccination was 29 years (range; 18-60 yrs). Sixty-one volunteers (27%) experienced one (n = 40) or more (n = 21) minor side effects during the 2-14 days after revaccination. Successful vaccination was noted in 216/226 volunteers (95.6%) at day 8 and the median of the pustule diameter was 5 mm (range: 1-20 mm). Size of the pustule at day 8 was correlated with age (p = 0.03) and with the presence of axillary adenopathy after revaccination (p = 0.007). Sex, number of prior vaccinations, delay between the last vaccination and revaccination, and local or systemic side effects with the exception of axillary adenopathy, were not correlated with the size of the pustule at day 8. CONCLUSIONS: Previously vaccinated volunteers can be successfully revaccinated with the Lister strain