Search

Introduction: The relationship between obstructive sleep apnea (OSA) and cancer has been recognized for some time now. However, little is known about the mechanisms by which sleep apnea promotes tumorigenesis and the impact of OSA on survival after cancer diagnosis. In the last few years, research has focused on the exploration of different biomarkers to understand the mechanisms underlying this relationship and miRNAs, non-coding single strands of about 22 nucleotides that post-transcriptionally regulate gene expression, have emerged as possible actors of this process.The aim of the study was to evaluate the impact of OSA on survival of metastatic colorectal cancer (mCRC) patients based on the expression of specific miRNAs. Methods: The expression of 6 miRNAs, respectively miR-21, miR-23b, miR-26a, miR-27b, miR-145 and miR-210, was analyzed by qRT-PCR in patients’ sera. Response to first-line therapy, Kaplan-Meier curves of overall and progression-free survival were used to evaluate survival in mCRC patients with and without OSA stratified for the expression of miRNAs. Results: The expression of miR-21, miR-23b, miR-26a and miR-210 was significantly upregulated in mCRCs with OSA compared to no OSA. In mCRC patients with OSA and increasing expression of miR-21, miR-23b, miR-26a and miR-210 risk of progression after first-line therapy was higher and both overall and progression-free survival were significantly worst. Conversely, as miR-27b and miR-145 expression increased, the life expectancy of patients diagnosed with OSA and mCRC improved markedly. Conclusions: This study highlights the relevance of specific miRNAs on OSA in mCRCs and their significance as non-invasive biomarkers in predicting the prognosis in patients with mCRC and OSA.

Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

Aberrations in the homologous recombination repair (HRR) pathway in prostate cancer (PCa) provide a unique opportunity to develop therapeutic strategies that take advantage of the reduced tumor ability to repair DNA damage. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have been shown to prolong the survival of PCa patients with HRR defects, particularly in those with Breast Cancer type 1 susceptibility protein/Breast Cancer type 2 susceptibility protein alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple preclinical and clinical studies are addressing potential synergies between PARPi and androgen receptor signaling inhibitors, and these strategies are also being evaluated in combination with other drugs such as immune checkpoint inhibitors. However, the effectiveness of these combining therapies could be hindered by multiple mechanisms of resistance, including also the role played by the immunosuppressive tumor microenvironment. In this review, we summarize the use of PARPi in PCa and the potential synergies with different molecular pathways. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi, expanding the use of genomic tests, and optimizing combination therapies.

Abstract The destructive (Mw 3.9) earthquake of 21 August 2017 re-opened the question on where magma resides at the Ischia island volcano. The peculiar complexity of the seismic source initiated the debate on the involvement of fluid-related processes, but the magmatic origin of the event remains uncertain. Here we use ground displacement and broadband seismic data to investigate the magmatic system of Ischia volcano, where progressive underplating of mafic material at mid-crustal depth feeds the deep structures, which are characterized by exceptionally high seismic velocity and are connected with a shallow crystal mush. Although no direct evidence of large molten volumes was found, strong anisotropy suggests that the crystal mush is pervaded by magma-intruded dykes. We propose that the 2017 event was due to a negative tensile deformation caused by depressurization of supercritical fluids along a shallow southwest (SW-)-dipping fault defined by receiver functions (RFs) data, which acted as a valve regulating the overpressure of deep magmatic fluids.

Abstract Background The NAPOLI‐I trial showed better outcome of nanoliposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (5‐FU/LV) compared to 5‐FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine‐based therapy. This study aims to explore the real‐world efficacy and safety of 5‐FU/LV‐nal‐IRI. Methods This is a retrospective multicenter analysis including advPDAC patients receiving 5‐FU/LV‐nal‐IRI after failure of gemcitabine‐based therapy. Survival analyses were performed using Kaplan–Meier method, univariate and multivariate analyses by Cox regression. Results A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine‐nabpaclitaxel as first line. 5‐FU/LV‐nal‐IRI was administered as second‐line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5‐FU/LV‐nal‐IRI initiation was 3.2 and 7.1 months, respectively. Conclusions These real‐world data confirm the 5‐FU/LV‐nal‐IRI efficacy and safety in advPDAC patients progressed to gemcitabine‐based therapy, with outcomes comparable to NAPOLI‐1, even in a less‐selected population and with more modern therapeutic algorithm.

AbstractDespite their protracted periods of inactivity, long-dormant volcanoes may be highly hazardous, as their reactivation can be characterized by violent explosive eruptions. An example of such volcanoes is the Colli Albani caldera, onto which deposits Rome Capital City is built, Italy. Its last volcanic activity was characterized by voluminous maar-forming phreatomagmatic eruptions dated between 36 and 25ka, but the volcano has produced several maar lake overflows during the Holocene till historical times. Presently, Colli Albani is affected by recurrent seismic events, anomalous heat flow, ground uplifts, hydrothermal circulation and gas emissions. For these reasons, the Italian Civil Protection has recently listed Colli Albani among the ten active volcanoes of Italy, but products for the evaluation of its volcanic hazards lacking. This work presents the first study on vent opening susceptibility mapping at Colli Albani. We explore the potential of an available geological dataset for building, through geographic information system analysis, an index that classifies areas at different vents opening susceptibility (low, moderate and high). Such result highlights as a solid geological mapping is a prerequisite for the volcanic hazard assessment, especially in remote or poorly studied long-dormant volcanoes such as caldera systems where the location of new vents could occur in different volcano sectors.

Abstract Diluted pyroclastic density currents are capable to cause huge devastation and mortality around volcanoes, and temperature is a crucial parameter in assessing their lethal power. Reflectance analysis on carbonized wood from ancient Herculaneum allowed a new reconstruction of the thermal events that affected buildings and humans during the 79CE Vesuvius eruption. Here we show that the first PDC entered the town was a short-lived, ash cloud surge, with temperatures of 555–495 °C, capable of causing instant death of people, while leaving only a few decimeters of ash on ground, which we interpret as detached from high concentration currents. The subsequent pyroclastic currents that progressively buried the town were mostly higher concentration PDCs at lower temperatures, between 465 and 390 and 350–315 °C. Charcoal proved to be the only proxy capable of recording multiple, ephemeral extreme thermal events, thus revealing for the first time the real thermal impact of the 79CE eruption. The lethal impact documented for diluted PDC produced during ancient and recent volcanic eruptions suggests that such hazard deserves greater consideration at Vesuvius and elsewhere, especially the underestimated hazard associated with hot detached ash cloud surges, which, though short lived, may expose buildings to severe heat damages and people to death.

Abstract Hydrothermal alteration is a common process in active geothermal systems and can significantly change the physiochemical properties of rocks. To improve reservoir assessment and modeling of high-temperature geothermal resources linked to active volcanic settings, a detailed understanding of the reservoir is needed. The Los Humeros Volcanic Complex, hosting the third largest exploited geothermal field in Mexico, represents a natural laboratory to investigate the impact of hydrothermal processes on the rock properties through andesitic reservoir cores and outcropping analogs. Complementary petrographic and chemical analyses were used to characterize the intensities and facies of hydrothermal alteration. The alteration varies from argillic and propylitic facies characterized by no significant changes of the REE budget indicating an inert behavior to silicic facies and skarn instead showing highly variable REE contents. Unaltered outcrop samples predominantly feature low matrix permeabilities ( 1.67 W m−1 K−1; > 0.91 10–6 m2 s−1), but a significant loss of magnetic susceptibility (10–3–10–6 SI). In particular, this latter characteristic appears to be a suitable indicator during geophysical survey for the identification of hydrothermalized domains and possible pathways for fluids. The lack of clear trends between alteration facies, alteration intensity, and chemical indices in the studied samples is interpreted as the response to multiple and/or repeated hydrothermal events. Finally, the proposed integrated field-based approach shows the capability to unravel the complexity of geothermal reservoir rocks in active volcanic settings.

Abstract The Roccamonfina volcano is located within the Garigliano Graben (southern Apennines, Italy) and has been active throughout the Middle‐Late Pleistocene. Along its polyphase volcanic history (630–55 ka), including several caldera‐forming eruptions (385–230 ka), several effusive/mildly explosive monogenetic events occurred along the volcano slopes, within the summit caldera, and along the graben‐bounding carbonate reliefs. In this paper, we present a multidisciplinary study of a mafic magmatic feeder dike intruded within the Meso‐Tertiary carbonates and overlying Lower Pleistocene breccias of Mt Cesima, northeast of the Roccamonfina volcano. We performed a stratigraphic and structural survey of the area and petrographic analyses on several samples of the dike. Results indicate that a ∼1 km long fissure fed an eruption that also emplaced a Strombolian pyroclastic sequence. Petrological data show that an open‐system mafic recharge fueled the tephritic magma that fed the eruption, whereas no evidence of significant pre/syn‐eruptive assimilation of carbonate has been identified. Stratigraphic and petrological data do not allow to firmly constrain the timing of the eruption, which could belong both to the pre‐Brown Leucitic Tuff (>354 ka) and to the post‐White Trachytic Tuffs (

Abstract In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC). RNA mediated gene silencing of regulatory genes, and treatment with MEK and p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical adenoma-carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression. RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing trametinib’s anti-inflammatory effects. Patients treated with FOLFOX-based first-line therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that cancer-specific immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of colorectal cancer.

Summary: Ribonucleoprotein (RNP) condensates are crucial for controlling RNA metabolism and splicing events in animal cells. We used spatial proteomics and transcriptomic to elucidate RNP interaction networks at the centrosome, the main microtubule-organizing center in animal cells. We found a number of cell-type specific centrosome-associated spliceosome interactions localized in subcellular structures involved in nuclear division and ciliogenesis. A component of the nuclear spliceosome BUD31 was validated as an interactor of the centriolar satellite protein OFD1. Analysis of normal and disease cohorts identified the cholangiocarcinoma as target of centrosome-associated spliceosome alterations. Multiplexed single-cell fluorescent microscopy for the centriole linker CEP250 and spliceosome components including BCAS2, BUD31, SRSF2 and DHX35 recapitulated bioinformatic predictions on the centrosome-associated spliceosome components tissue-type specific composition. Collectively, centrosomes and cilia act as anchor for cell-type specific spliceosome components, and provide a helpful reference for explore cytoplasmic condensates functions in defining cell identity and in the origin of rare diseases.

AimThe aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens.Study design and methodsClinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1–2), and intensity of chemotherapy regimen (doublet vs. triplet).ResultsAmong 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users.ConclusionIn patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.

Background: Relevant improvement in first-line treatment of metastatic pancreatic cancer (mPC) was provided by FOLFIRINOX and by gemcitabine (gem) plus nab-paclitaxel (Nab-p) regimens. Regardless of the first-line treatment survival benefit, most patients survive less than 1 year. Aim: The objectives of this multicenter phase I/II study were to evaluate as first-line chemotherapy (CT) two modified regimens of FOLFIRINOX, replacing either oxaliplatin (Oxa) or irinotecan with Nab-p, in patients with mPC. Methods: The primary objectives of phase 1 were the definition of the dose limit binations, while for phase II they were the characterization of safety and activity of Nab-FOLFIRI and Nab-FOLFOX in mPC. Results: Sixty-three patients received Nab-FOLFIRI or Nab-FOLFOX in phase I. We defined MTD at 120 mg/m2 for Nab-p with FOLFIRI and 160 mg/m2 with FOLFOX. In phase II, we randomized 42 patients for each arm with the following results: (1) overall response rate (ORR) was 31% for both schedules; (2) a clinical benefit rate (CBR) of 69% and 71%; (3) 1-year survival was 41% and 50%; (4) progression free survival (PFS) was 6 months and 5.6 months; (5) median overall survival (OS) was 10.2 and 10.4 months for Nab-FOLFIRI and Nab-FOLFOX, respectively. (6) Neutropenia was the most common grade ≥3 adverse event in our regimens, significantly lower than that reported for the FOLFIRINOX triplet. Conclusion: Nab-FOLFIRI and Nab-FOLFOX might be hopeful first-line CT options for mPC patients, with promising activity and a good safety profile.

In this study, Smith and colleagues employ analogue experiments to show the controlling parameters on sediment bedforms in pyroclastic density current deposits. The findings are applied and validated on natural deposits.

A crucial feature to manage a volcanic crisis is the ability of volcanologists to promptly detect an impending eruption. This is often affected by significant uncertainty, mainly for the difficulty in interpreting the monitoring signals in terms of the exact timing of a possible eruption. Here we contribute to this problem, focusing on the states of active volcanoes with closed conduit, as deduced from monitoring data. Four main states can be identified. In the quiescence state 1) the monitoring data lie on a baseline, suggesting the lack of shallow magma/fluid movement. The unrest state is highlighted by minor 2) to major 3) variations in the intensity and rate of monitoring data; in both cases, radial ground deformation pattern and non-migrating seismicity imply shallow magma and/or fluid accumulation. The state of impending eruption 4) is characterised by non-radial, asymmetric ground deformation pattern and migrating seismicity, which suggest that magma approaches the surface through a propagating dyke. As early recognition of this distinctive state is crucial for timely eruption forecast, monitoring activity should be aimed at its prompt detection. The application of this rationale to two types of active volcanoes in densely inhabited areas, a restless caldera (Campi Flegrei) and a quiescent stratovolcano (Vesuvio), highlights its feasibility and importance in eruption forecasting. This rationale may foster a general reference framework to be adopted in case of unrest, supporting in interpreting the monitoring data, as well as more effective: 1) operationally-oriented, monitoring system; 2) probabilistic forecast; 3) use of volcanic alert levels.

Pyroclastic density currents (PDCs) are a major threat during explosive volcanic eruptions, hence the possibility to forecast them would be a vital improvement for risk mitigation. Here the authors present a 3D flow model to quantify the thermal patterns leading to volcanic ash plume collapse conditions.

Abstract Background Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically “cold” tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear. Methods We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies. Results We identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC. Conclusions Combined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC.

Current treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail the first lines of treatment and present signs of progressive disease. With most recurrences being located within the margins of the previously resected lesion, a comprehensive molecular and genetic profiling of rGBM revealed substantial differences compared with newly diagnosed disease. In the present comprehensive review, we sought to examine the current treatment guidelines and the new perspectives that polarize the field of neuro-oncology, strictly focusing on progressive disease. For this purpose, updated PRISMA guidelines were followed to search for pivotal studies and clinical trials published in the last five years. A total of 125 articles discussing locoregional management, radiotherapy, chemotherapy, and immunotherapy strategies were included in our analysis, and salient findings were critically summarized. In addition, an in-depth description of the molecular profile of rGBM and its distinctive characteristics is provided. Finally, we integrate the above-mentioned evidence with the current guidelines published by international societies, including AANS/CNS, EANO, AIOM, and NCCN.

Malignant Brenner Tumor (mBT) is extremely rare. Although BT are almost exclusive ovarian neoplasms, they may constitute a highly unusual tumor of the testis; in fact, only seven fully documented cases have been reported to date. Because of their rarity, the pathogenesis of these tumors has not been clarified and there is no standard therapeutic approach. We report the first case of epididymal mBT with synchronous, multiple, liver metastases and a very dramatic clinical course. Both primary tumor and metastasis were subjected to mutational analysis of 20 cancer associated genes. Primary tumor showed FGFR3 Tyr375Cys and PIK3CA His1047Arg missense mutations. Both mutations are reported as pathogenic in ClinVar database. The same FGFR3 mutation was present in liver metastasis. Based on these results we believe that the FGFR pathway could be an ideal candidate for personalized treatment, offering hope to a subset of patients with mBT. Personalized approach, including mutational analysis and molecular testing should be required in patients with rare tumors in order to clarify diagnosis and improve therapeutic strategies.

The calculation of the magnitude of an eruption needs the accurate estimate of its deposit volume. This is particularly critical for ignimbrites as no methods for their volume calculations and associated errors and uncertainties are consolidated in the literature, although invariably the largest magnitude eruptions on Earth are made of ignimbrites. The 39.8 ka Campanian Ignimbrite (CI) eruption is the largest of the Campi Flegrei caldera (Italy). The global cooling following the CI eruption and its widespread tephra affected the paleoenvironment and the migration of hominids in Europe at that time. Despite the large number of studies, the estimates of the Dense Rock Equivalent volume of the CI range between 60 and 300 km3, because of the lack of clear and reproducible methods for its calculation. Here we present a new calculation of the volume of the CI, grounded on a clear and reproducible method that can be applied universally and which provides an accurate estimation of the volume of the deposits on ground and their uncertainties and errors, allowing a strong base for further estimates of the amount of deposits eroded, covered, elutriated, which are essential for the final computation of the eruption magnitude. In order to calculate the CI volume, we reconstructed the first total isopach map of the pyroclastic density current deposit preserved on land, developed through a method that reconstructs the paleo-topography during the eruption, which is reproducible for all topographically controlled ignimbrites and allows the calculation of well-defined uncertainties in the on-land ignimbrite deposits. The preserved total extra-caldera bulk volume of the ignimbrite is estimated at 68.2 ± 6.6 km3. The total pyroclastic density current deposit volume is then corrected for erosion, ash elutriation, the intracaldera deposit volume, and the volume of tephra deposited in the sea, whereas volumes of the basal fallout deposits are taken from other studies. The total Dense Rock Equivalent volume of the eruption is 181–265 km3, whose range accounts for errors and uncertainties. This value corresponds to a mass of 4.7–6.9 × 1014 kg, a magnitude (M) of 7.7–7.8 and a volcanic Explosivity Index (VEI) of 7.

Detecting the ultrastructure of brain tissue in human archaeological remains is a rare event that can offer unique insights into the structure of the ancient central nervous system (CNS). Yet ancient brains reported in the literature show only poor preservation of neuronal structures. Using scanning electron microscopy (SEM) and advanced image processing tools, we describe the direct visualization of neuronal tissue in vitrified brain and spinal cord remains which we discovered in a male victim of the AD 79 eruption in Herculaneum. We show exceptionally well preserved ancient neurons from different regions of the human CNS at unprecedented resolution. This tissue typically consists of organic matter, as detected using energy-dispersive X-ray spectroscopy. By means of a self-developed neural image processing network, we also show specific details of the neuronal nanomorphology, like the typical myelin periodicity evidenced in the brain axons. The perfect state of preservation of these structures is due to the unique process of vitrification which occurred at Herculaneum. The discovery of proteins whose genes are expressed in the different region of the human adult brain further agree with the neuronal origin of the unusual archaeological find. The conversion of human tissue into glass is the result of sudden exposure to scorching volcanic ash and the concomitant rapid drop in temperature. The eruptive-induced process of natural vitrification, locking the cellular structure of the CNS, allowed us to study possibly the best known example in archaeology of extraordinarily well-preserved human neuronal tissue from the brain and spinal cord.

The study of the structural order of charcoals embedded in pyroclastic density currents provides information on their emplacement temperature during volcanic eruptions. In the present work, a set of charcoals from three distinct pyroclastic density currents deposits whose temperatures have been previously estimated by charcoal reflectance analyses to lie between 250 °C and 550 °C, was studied by means of Raman spectroscopy. The analyses reveal a very disordered structural ordering of the charcoals, similar to kerogen matured under diagenetic conditions. Changes in Raman spectra at increasing temperatures reflect depolymerization and an increase of aromaticity and can be expressed by parameters derived from a simplified fitting method. Based on this approach, a second order polynomial regression with a high degree of correlation and a minimum error was derived to predict paleotemperatures of pyroclastic deposits. Our results show that Raman spectroscopy can provide a reliable and powerful tool for volcanological studies and volcanic hazard assessment given its advantage of minimum samples preparation, rapid acquisition processes and high precision.

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.

Immunotherapy targeting the PD-1–PD-L1 axis yielded good results in treating different immunologically ‘‘hot’’ tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11–41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

Abstract The aspect ratio of ignimbrites is a commonly used parameter that has been related to the energy of the parent pyroclastic density currents (PDCs). However this parameter, calculated as the ratio between the average thickness and the average lateral extent of ignimbrites, does not capture fundamental differences in pyroclastic flow mobility nor relates to lithofacies variations of the final deposits. We herein introduce the “topological aspect ratio” (ARt) as the ratio of the local deposit thickness (Ht) to the distance between the local site and the maximum runout distance (Lt), where Ht is a proxy for the PDC tendency to deposit, and Lt a proxy for the PDC mobility or its tendency to further transport the pyroclastic material. The positive versus negative spatial gradient d(ARt)/dx along flow paths discriminate zones where PDCs are forced (i.e. where they transport the total energy under the action of mass discharge rate) from zones where they are inertial (i.e. where they transport the total energy under the action of viscous or turbulent fluidization). Though simple to apply, the topological aspect ratio and its spatial gradient are powerful descriptors of the interplay between sedimentation and mobility of PDCs, and of the resulting lithofacies variations.

Background: No clinical trial has directly compared nab-paclitaxel/gemcitabine (nab-P/G) with FOLFIRINOX (fluorouracil/leucovorin/oxaliplatin/irinotecan) in metastatic or advanced pancreatic cancer (mPC or aPC). We conducted a systematic review of real-world studies comparing these regimens in the first-line setting. Methods: Embase and MEDLINE databases through 22 January 2019, and Gastrointestinal Cancers Symposium 2019 abstracts were searched for real-world, retrospective studies comparing first-line nab-P/G versus FOLFIRINOX in mPC or aPC that met specific parameters. Studies with radiotherapy were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Results: Of 818 records initially identified, 35 were duplicates and 749 did not meet the eligibility criteria, mostly because they were either not comparative ( n = 356) or not first line ( n = 245). The remaining 34 studies (21 mPC; 13 aPC) assessed >6915 patients who received nab-P/G or FOLFIRINOX. In the studies identified, the median overall survival (OS) reached 14.4 and 15.9 months with nab-P/G and FOLFIRINOX, respectively, and median progression-free survival reached 8.5 and 11.7 months, respectively. Safety data were reported in 14 studies (2205 patients), including 8 single-institutional studies. In most single-institutional studies that reported safety data, rates were higher with FOLFIRINOX versus nab-P/G for grade 3/4 neutropenia (five of six studies) and febrile neutropenia (all three studies), while rates of grade 3/4 peripheral neuropathy were higher with nab-P/G in four of seven studies. Conclusions: Although FOLFIRINOX was associated with slightly longer median OS in more studies, the differences, when available, were not statistically significant. Therefore, a randomized, controlled trial is warranted. Toxicity profile differences represent key considerations for treatment decisions.

Metastasis is a process by which cancer cells escape from the location of the primary tumor invading normal tissues at distant organs. Chromosomal instability (CIN) is a hallmark of human cancer, associated with metastasis and therapeutic resistance. The centrosome plays a major role in organizing the microtubule cytoskeleton in animal cells regulating cellular architecture and cell division. Loss of centrosome integrity activates the p38-p53-p21 pathway, which results in cell-cycle arrest or senescence and acts as a cell-cycle checkpoint pathway. Structural and numerical centrosome abnormalities can lead to aneuploidy and CIN. New findings derived from studies on cancer and rare genetic disorders suggest that centrosome dysfunction alters the cellular microenvironment through Rho GTPases, p38, and JNK (c-Jun N-terminal Kinase)-dependent signaling in a way that is favorable for pro-invasive secretory phenotypes and aneuploidy tolerance. We here review recent data on how centrosomes act as complex molecular platforms for Rho GTPases and p38 MAPK (Mitogen activated kinase) signaling at the crossroads of CIN, cytoskeleton remodeling, and immune evasion via both cell-autonomous and non-autonomous mechanisms.

This paper presents a detailed geological map at the 1:20,000 scale of the Tocomar basin in the Central Puna (north-western Argentina), which extends over an area of about 80 km2 and displays the spatial distribution of the Quaternary deposits and the structures that cover the Ordovician basement and the Tertiary sedimentary and volcanic units. The new dataset includes litho-facies descriptions, stratigraphic and structural data and new 234U/230Th ages for travertine rocks. The new reconstructed stratigraphic framework, along with the structural analysis, has revealed the complex evolution of a small extensional basin including a period of prolonged volcanic activity with different eruptive centres and styles. The geological map improves the knowledge of the geology of the Tocomar basin and the local interplay between orogen-parallel thrusts and orogen-oblique fault systems. This contribution represents a fundamental support for in depth research and also for encouraging geothermal exploration and exploitation in the Puna Plateau region.

Pancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials.

Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells “immune resistance,” combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign “myeloid” cells, macrophages, and neutrophils, respectively. The development of cancer-specific “immune resistance” can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy.

In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC) treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF)/vascular endothelial growth factor receptor 1 (VEGFR1) axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.

Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.