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Colorectal cancer (CRC) is a devastating disease, ranking as the second leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) have emerged as promising treatments; however, their efficacy is largely restricted to a subgroup of microsatellite instable (MSI) CRCs. In contrast, microsatellite stable (MSS) CRCs, which account for the majority of cases, exhibit variable and generally weaker response to ICIs, with only a subset demonstrating exceptional responsiveness. Identifying novel cancer-specific tissue (CST) markers predictive of immunotherapy response is crucial for refining patient selection and overcoming treatment resistance. In this study, we developed clinically relevant CRC organoids and autologous immune system interaction platforms to model ICI response. We conducted a comprehensive molecular characterization of both responder and non-responder models, identifying CST markers that predict ICI response. Validation of these findings was performed using an independent cohort of patient specimens through multiplex immunofluorescence. Furthermore, we demonstrated that knocking out a key gene from the identified predictive signature in resistant organoids restored immune sensitivity and induced T-cell-mediated apoptosis. Overall, our results provide novel insights into the mechanisms underlying immunotherapy resistance and suggest new markers for enhancing patient selection. These findings may pave the way for new therapeutic options in MSS patients, potentially broadening the cohort of individuals eligible for immunotherapy.

Adriatic and Ionian seas are Mediterranean sub-basins linked through the Bimodal Oscillating System mechanism responsible for decadal reversals of the Ionian basin-wide circulation. Altimetric maps showed that the last cyclonic mode started in 2011 but unexpectedly in 2012 reversed to anticyclonic. We related this \"premature\" inversion to the extremely strong winter in 2012, which caused the formation of very dense Adriatic waters, flooding Ionian flanks in May and inverting the bottom pressure gradient. Using Lagrangian float measurements, the linear regression between the sea surface height and three isopycnal depths suggests that the southward deep-layer flow coincided with the surface northward geostrophic current and the anticyclonic circulation regime. Density variations at depth in the northwestern Ionian revealed the arrival of Adriatic dense waters in May and maximum density in September. Comparison between the sea level height in the northwestern Ionian and in the basin centre showed that in coincidence with the arrival of the newly formed Adriatic dense waters the sea level was lowered in the northwestern flank, inverting the surface pressure gradient. Toward the end of 2012, the density gradient between the basin flanks and its centre went to zero, coinciding with the weakening of the anticyclonic circulation and eventually with its return to the cyclonic pattern. Thus, the premature and transient reversal of Ionian surface circulation originated from the extremely harsh winter in the Adriatic, resulting in the formation and spreading of highly dense bottom waters. The present study highlights the remarkable sensitiveness of the Adriatic–Ionian BiOS to climatic forcing.

Temperature, salinity and oxygen data collected during April and June 2011 (M84/3 and P414 cruises respectively) are analysed to derive the oceanographic characteristics of the Eastern Mediterranean (EM) basin. These observed characteristics are compared with those from previous cruises over the period 1987–2011. As a result, the interannual and decadal variability of the EM thermohaline properties are discussed in the context of the evolution of the Eastern Mediterranean Transient (EMT) and of the general circulation of the basin. We found that the state of the EM is still far from the pre-EMT conditions, though the 2011 results possibly indicate a slow return to this status. In particular, a comparison between thermohaline property evolution deriving from interannual variability of the preconditioning and air–sea interaction (heat fluxes) in the South Adriatic and the Cretan Seas reveals aspects of the alternation of the two dense water sources (Adriatic and Aegean) during the last three decades, which have strong implications for the hydrographic characteristics of the intermediate and deep layers of the Ionian and Levantine basins.

Aspects of hydrography and large-scale circulation observed in the Mediterranean Sea during the M84/3 and P414 cruises (April and June 2011, respectively) are presented. In contrast to most of the recent expeditions, which were limited to special areas of the basin, these two cruises, especially the M84/3, offered the opportunity of delineating a quasi-synoptic picture of the distribution of the relevant physical parameters along a section extending through the whole Mediterranean, from the Lebanese coast up to the Strait of Gibraltar. The foci of our analysis are the observed water mass properties and velocity fields. The first are investigated through T–S diagrams and an optimum multiparameter (OMP) analysis and the results are discussed also in the context of recently identified modes of variability; the second are studied by comparing the velocity fields observed using a vessel-mounted Acoustic Doppler Current Profiler and those calculated from the observed density fields. Overall, a distribution of temperature, salinity and geostrophic velocities emerges, which is far from that observed before the beginning of the so-called \"Eastern Mediterranean Transient\", a major climatic shift in the hydrography and circulation of the Mediterranean Sea which began at the end of the 1980s. The picture which emerges helps to further address the complexity of long-term evolution of hydrography and large-scale circulation of the Mediterranean Sea.

The long-term monitoring of basic hydrological parameters (temperature and salinity), collected as time series with adequate temporal resolution (i.e. with a sampling interval allowing the resolution of all important timescales) in key places of the Mediterranean Sea (straits and channels, zones of dense water formation, deep parts of the basins), constitute a priority in the context of global changes. This led CIESM (The Mediterranean Science Commission) to support, since 2002, the HYDROCHANGES programme (http//www.ciesm.org/marine/programs/hydrochanges.htm), a network of autonomous conductivity, temperature, and depth (CTD) sensors, deployed on mainly short and easily manageable subsurface moorings, within the core of a certain water mass. The HYDROCHANGES strategy is twofold and develops on different scales. To get information about long-term changes of hydrological characteristics, long time series are needed. But before these series are long enough they allow the detection of links between them at shorter timescales that may provide extremely valuable information about the functioning of the Mediterranean Sea. The aim of this paper is to present the history of the programme and the current set-up of the network (monitored sites, involved groups) as well as to provide for the first time an overview of all the time series collected under the HYDROCHANGES umbrella, discussing the results obtained thanks to the programme.

Abyssal temperature and velocity observations performed within the framework of the Neutrino Mediterranean Observatory, a project devoted to constructing a km 3 -scale underwater telescope for the detection of high-energy cosmic neutrinos, demonstrate cross-fertilization between subnuclear physics and experimental oceanography. Here we use data collected south of Sicily in the Ionian abyssal plain of the Eastern Mediterranean (EM) basin to show for the first time that abyssal vortices exist in the EM, at depths exceeding 2,500 m. The eddies consist of chains of near-inertially pulsating mesoscale cyclones/anticyclones. They are embedded in an abyssal current flowing towards North-Northwest. The paucity of existing data does not allow for an unambiguous determination of the vortex origin. A local generation mechanism seems probable, but a remote genesis cannot be excluded a priori . The presence of such eddies adds further complexity to the discussion of structure and evolution of water masses in the EM. Small-scale ocean dynamics can have wide reaching impacts on the larger-scale ocean circulation. Using temperature and velocity data, this study shows the presence of abyssal vortices in the Eastern Mediterranean basin, adding complexity to the structure and evolution of water masses in this region.

Current glacier melt rates in West Antarctica substantially exceed those around the East Antarctic margin. The exception is Wilkes Land, where for example Totten Glacier underwent significant retreat between 2000 and 2012, underlining its sensitivity to climate change. This process is strongly influenced by ocean dynamics, which in turn changes in accordance with the evolution of the ice caps. Here, we present new oceanographic data (temperature, salinity, and dissolved oxygen) collected during austral summer 2017 offshore the Sabrina Coast (East Antarctica) from the continental shelf break to ca 3000 m depth. This area is characterized by very few oceanographic in situ observations. The main water masses of the study area, identified by analysing thermohaline properties, are the Antarctic Surface Water with potential temperature θ>-1.5 ∘C and salinity S<34.2 (σθ<27.55 kg m−3), the Winter Water with -1.92<θ<-1.75 ∘C and 34.00 ∘C and S>34.5 (σθ>27.7 kg m−3), and Antarctic Bottom Water with -0.50<θ<0 ∘C and 34.6328.30 kg m−3). The latter is a mixture of dense waters from the Ross Sea and Adélie Land continental shelves. Such waters are influenced by the mixing processes they undergo as they move westward along the Antarctic margin, also interacting with the warmer Circumpolar Deep Water. The spatial distribution of water masses offshore the Sabrina Coast also appears to be strongly linked with the complex morpho-bathymetry of the slope and rise area, supporting the hypothesis that downslope processes contribute to shaping the architecture of the distal portion of the continental margin. Oceanographic data presented here can be downloaded from https://doi.org/10.25919/yyex-t381 (CSIRO; Van Graas, 2021).

The North Ionian Gyre (NIG) displays prominent inversions on decadal scales. We investigate the role of internal forcing induced by changes in the horizontal pressure gradient due to the varying density of Adriatic Deep Water (AdDW), which spreads into the deep layers of the northern Ionian Sea. In turn, the AdDW density fluctuates according to the circulation of the NIG through a feedback mechanism known as the bimodal oscillating system. We set up laboratory experiments with a two-layer ambient fluid in a circular rotating tank, where densities of 1000 and 1015 kg m−3 characterize the upper and lower layers, respectively. From the potential vorticity evolution during the dense-water outflow from a marginal sea, we analyze the response of the open-sea circulation to the along-slope dense-water flow. In addition, we show some features of the cyclonic and anticyclonic eddies that form in the upper layer over the slope area. We illustrate the outcome of the experiments of varying density and varying discharge rates associated with dense-water injection. When the density is high (1020 kg m−3) and the discharge is large, the kinetic energy of the mean flow is stronger than the eddy kinetic energy. Conversely, when the density is lower (1010 kg m−3) and the discharge is reduced, vortices are more energetic than the mean flow – that is, the eddy kinetic energy is larger than the kinetic energy of the mean flow. In general, over the slope, following the onset of dense-water injection, the cyclonic vorticity associated with current shear develops in the upper layer. The vorticity behaves in a two-layer fashion, thereby becoming anticyclonic in the lower layer of the slope area. Concurrently, over the deep flat-bottom portion of the basin, a large-scale anticyclonic gyre forms in the upper layer extending partly toward a sloping rim. The density record shows the rise of the pycnocline due to the dense-water sinking toward the flat-bottom portion of the tank. We show that the rate of increase in the anticyclonic potential vorticity is proportional to the rate of the rise of the interface, namely to the rate of decrease in the upper-layer thickness (i.e., the upper-layer squeezing). The comparison of laboratory experiments with the Ionian Sea is made for a situation when the sudden switch from cyclonic to anticyclonic basin-wide circulation took place following extremely dense Adriatic water overflow after the harsh winter in 2012. We show how similar the temporal evolution and the vertical structure are in both laboratory and oceanic conditions. The demonstrated similarity further supports the assertion that the wind-stress curl over the Ionian Sea is not of paramount importance in generating basin-wide circulation inversions compared with the internal forcing.

In September 2021, as part of the Italian Arctic research programme, a multidisciplinary cruise along the 75th parallel north through the Greenland Sea Gyre was conducted aboard the Italian icebreaker Laura Bassi in the framework of the CASSANDRA project, which also contributed to the Synoptic Arctic Survey (SAS) 2020/22. The cruise took place during the period of the lowest summer sea ice extent ever measured. The data show strong horizontal gradients with temperatures between 1.5 and 9.0 °C and salinity between 30 and 35. Warm and salty Atlantic Water (AW, θ > 3.0 °C, S around 35) dominates on the eastern side of the transect in the upper 500 m with surface temperatures of 4.5–9.0 °C, while Polar Water (PW, θ < 0 °C, S < 33) occupies the surface layer (50–80 m) in the west. The intermediate layer (100–500 m) consists of mixed water, and below 500 m the deep water of the Greenland Sea and the Norwegian Sea predominates. The oxygen enrichment is higher in the intermediate layers, while the values in deep layers and western regions are lower (<300 µmol kg−1). A stratified upper layer (30–50 m deep) with low surface nutrients, especially nitrate, is observed, while an accumulation of silicate occurs in deep water masses. The surface water in the eastern part of the transect has high pHT and total alkalinity values due to photosynthesis and the presence of salty AW, while the fresh PW in the west has a lower alkalinity. Respiratory activity and organic matter concentrations (particulate/dissolved organic carbon) vary horizontally at the surface, decrease with depth, and increase slightly near the seafloor. A west–east gradient is also observed for δ18O and δD, with the ratios indicating the influence of freshwater at the surface near the Greenland coast. The abundance of prokaryotes decreases from the photic zone (<100 m depth) to the sea floor. Carbohydrates and carboxylic acids are identified as well-utilised polymers at every station and in every layer. Overall, the microbial enzyme patterns show a decrease from the surface to deeper layers, with some hotspots of metabolic activity at 20–40 m and in the aphotic layer. The enzyme patterns vary spatially, with activity peaks at the ends and in the middle of the transect. Phytoplankton biomass, expressed as chlorophyll a, varies across the transect, with higher values at the westernmost and easternmost stations. The micro-phytoplankton fraction dominates in PW, while the nano-phytoplankton fraction predominates in AW, even at the interface between the two water masses. Data of phytoplankton communities show low abundances and a dominance of nano-sized organisms, with diatoms being more abundant in the western part. Microzooplankton represents an important fraction of the planktonic community in this area, with tintinnids being the most important groups along the transect. Micrometazoans and aloricate ciliates are more abundant in the AW, resulting in higher biomass values at the eastern stations. Copepods are the most abundant mesozooplanktonic taxon both at the surface and in the upper 100 m water layer (97 % and 94 % of total mesozooplankton abundance, respectively), mainly represented by the genus Calanus. The data are publicly available at the Italian Arctic Data Centre (IADC), see https://doi.org/10.71761/c082c3ca-40bf-42b1-a61a-7b3697ab2c5a (Bensi et al., 2024), https://doi.org/10.71761/f7474404-3331-43e5-883b-25755e94956d (Azzaro et al., 2024).

In advanced pancreatic ductal adenocarcinoma (PDAC), first-line chemotherapy is the standard of care. Due to the absence of head-to-head comparisons in clinical trials, we performed this systematic review and network meta-analysis to compare treatment options for PDAC in terms of their efficacy and toxicity. PubMed, the Cochrane Central Register of Controlled Trials, Embase, and oncological meetings websites were searched until Nov 15, 2023. We included phase 2–3 randomised controlled trials published after Jan 1, 2000, evaluating first-line treatments in patients with previously untreated, unresectable, locally advanced or metastatic PDAC. Primary endpoints assessed were progression-free survival and overall survival. Summary data were extracted from published reports. The deviance information criterion was used to choose between a random-effects or fixed-effects model. Hazard ratios (HRs) with 95% credible intervals were estimated using a Bayesian approach. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and studies were graded as low, some concerns, or high risk of bias. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. This systematic review and network meta-analysis is registered with PROSPERO, CRD42023450330. 6050 records were screened and 79 randomised controlled trials (22 168 patients) were included in the analysis. Gemcitabine was the most frequent comparator (in 50 [63%] of 79 trials) and was considered as the reference treatment. A fixed-effect model was used to analyse the primary outcomes. Regarding progression-free survival (71 trials, 19 479 patients), the most effective treatments were gemcitabine plus nab-paclitaxel alternating folinic acid, fluorouracil, and oxaliplatin ([FOLFOX] HR 0·32, 95% credible interval 0·22–0·47), cisplatin, nab-paclitaxel, capecitabine, and gemcitabine ([PAXG] 0·35, 0·22–0·55), and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin ([NALIRIFOX] 0·43, 0·34–0·54), followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin ([FOLFIRINOX] 0·55, 0·47–0·65) and gemcitabine plus nab-paclitaxel (0·62, 0·54–0·72). Similar results were observed for overall survival (79 trials, 22 104 patients): PAXG (HR 0·40, 95% credible interval 0·25–0·65), gemcitabine plus nab-paclitaxel alternating FOLFOX (0·46, 0·32–0·66), and NALIRIFOX (0·56, 0·45–0·70) had the highest benefit, followed by FOLFIRINOX (0·66, 0·56–0·78) and gemcitabine plus nab-paclitaxel (0·67, 0·59–0·77). The overall risk of bias was low to some concerns. Certainty of evidence was low. Our findings suggest that NALIRIFOX and FOLFIRINOX should be the preferred options for patients who can tolerate these regimens, with gemcitabine plus nab-paclitaxel remaining a viable alternative, particularly in patients unfit for triplet therapy. Phase 3 randomised controlled trials investigating concomitant or sequential quadruplets are warranted. None.