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Abstract Background Pancreatic ductal adenocarcinoma (PDAC) requires innovative therapeutic strategies to counteract its progression and metastatic potential. Since the majority of patients are diagnosed with advanced metastatic disease, treatment strategies targeting not only the primary tumor but also metastatic lesions are needed. Tumor-Associated Macrophages (TAMs) have emerged as central players, significantly influencing PDAC progression and metastasis. Our objective was to validate an innovative therapeutic strategy involving the reprogramming of TAMs using lipid nanosystems to prevent the formation of a pro-metastatic microenvironment in the liver. Results In vitro results demonstrate that M2-polarized macrophages lose their M2-phenotype following treatment with lipid nanoemulsions composed of vitamin E and sphingomyelin (VitE:SM), transitioning to an M0/M1 state. Specifically, VitE:SM nanoemulsion treatment decreased the expression of macrophage M2 markers such as Arg1 and Egr2, while M1 markers such as Cd86, Il-1b and Il-12b increased. Additionally, the TGF-βR1 inhibitor Galunisertib (LY2157299) was loaded into VitE:SM nanoemulsions and delivered to C57BL/6 mice orthotopically injected with KPC PDAC tumor cells. Treated mice showed diminished primary tumor growth and reduced TAM infiltration in the liver. Moreover, we observed a decrease in liver metastasis with the nanoemulsion treatment in an intrasplenic model of PDAC liver metastasis. Finally, we validated the translatability of our VitE:SM nanosystem therapy in a human cell-based 3D co-culture model in vivo, underscoring the pivotal role of macrophages in the nanosystem’s therapeutic effect in the context of human PDAC metastasis. Conclusions The demonstrated effectiveness and safety of our nanosystem therapy highlights a promising therapeutic approach for PDAC, showcasing its potential in reprogramming TAMs and mitigating the occurrence of liver metastasis. Graphical abstract

Abstract Background Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. Methods The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. Conclusions Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Abstract Background Most microbiota studies in microscopic colitis patients are performed after diagnostic colonoscopy without considering the potential effect of colonic lavage. Patients may achieve clinical remission after colonoscopy and it is unknown whether lavage-induced changes play a role. Aim To assess the effect of polyethylene glycol (PEG) colonic lavage on clinical remission rate, microbial diversity, microbial dysbiosis index and specific microbial changes in patients with active microscopic colitis as compared to other diarrhoeal diseases and healthy controls. Methods Fifty-five consecutive patients presenting chronic watery diarrhoea and 12 healthy controls were included. Faecal samples were collected three days before and 30 days after PEG in patients and controls for microbiome analysis. Results Clinical remission was observed in 53% of microscopic colitis patients, and in 32% of non-microscopic colitis patients (p = 0.16). Considering patients with persisting diarrhoea after colonoscopy, 71% of non-microscopic colitis patients had bile acid diarrhoea. Baseline Shannon Index was lower in diarrhoea groups than in healthy controls (p = 0.0025); there were no differences between microscopic colitis, bile-acid diarrhoea and functional diarrhoea. The microbial dysbiosis index was significantly higher in microscopic colitis than in bile acid diarrhoea plus functional diarrhoea (p = 0.0095), but no bacterial species showed a significantly different relative abundance among the diarrheal groups. Conclusions Dysbiosis is a feature in active microscopic colitis, but loss of microbial diversity was similar in all diarrheal groups, suggesting that faecal microbial changes are not due to microscopic colitis itself but associated with stool form. A considerable number of microscopic colitis patients achieved clinical remission after colonoscopy, but we were unable to demonstrate related PEG-induced changes in faecal microbiome.

Abstract Background Staphylococcus pseudintermedius (SP) and Staphylococcus aureus (SA) are common colonizers of companion animals, but they are also considered opportunistic pathogens, causing diseases of diverse severity. This study focused on the identification and characterization of 33 coagulase-positive staphylococci isolated from diseased pets (28 dogs and five cats) during 2009–2011 in a veterinary hospital in Spain in order to stablish the circulating lineages and their antimicrobial resistance profile. Results Twenty-eight isolates were identified as SP and five as SA. Nine methicillin-resistant (MR) isolates (27%) carrying the mecA gene were detected (eight MRSP and one MRSA). The 55% of SP and SA isolates were multidrug-resistant (MDR). MRSP strains were typed as ST71-agrIII-SCCmecII/III-(PFGE) A (n=5), ST68-agrIV-SCCmecV-B1/B2 (n=2), and ST258-agrII-SCCmecIV-C (n=1). SP isolates showed resistance to the following antimicrobials [percentage of resistant isolates/resistance genes]: penicillin [82/blaZ], oxacillin [29/mecA] erythromycin/clindamycin [43/erm(B)], aminoglycosides [18–46/aacA-aphD, aphA3, aadE], tetracycline [71/tet(M), tet(K)], ciprofloxacin [29], chloramphenicol [29/cat pC221], and trimethoprim-sulfamethoxazole [50/dfrG, dfrK]. The dfrK gene was revealed as part of the radC-integrated Tn559 in two SP isolates. Virulence genes detected among SP isolates were as follow [percentage of isolates]: siet [100], se-int [100], lukS/F-I [100], sec canine [7], and expB [7]. The single MRSA-mecA detected was typed as t011-ST398/CC398-agrI-SCCmecV and was MDR. The methicillin-susceptible SA isolates were typed as t045-ST5/CC5 (n=2), t10576-ST1660 (n=1), and t005-ST22/CC22 (n=1); the t005-ST22 feline isolate was PVL-positive and the two t045-ST45 isolates were ascribed to Immune Evasion Cluster (IEC) type F. Moreover, the t10576-ST1660 isolate, of potential equine origin, harbored the lukPQ and scneq genes. According to animal clinical history and data records, several strains seem to have been acquired from different sources of the hospital environment, while some SA strains appeared to have a human origin. Conclusions The frequent detection of MR and MDR isolates among clinical SP and SA strains with noticeable virulence traits is of veterinary concern, implying limited treatment options available. This is the first description of MRSA-ST398 and MRSP-ST68 in pets in Spain, as well the first report of the dfrK-carrying Tn559 in SP. This evidences that current transmissible lineages with mobilizable resistomes have been circulating as causative agents of infections among pets for years.

Abstract Background Gender-based violence among young women is a growing problem worldwide. The consequences of this victimization have been well reported in the scientific literature, among which negative health outcomes stand out. The factors influencing this problem are many; one highlighted by research is socialization into a dominant coercive discourse that associates sexual-affective attraction to males with violent attitudes and behaviors, while in turn, such discourse empties males with egalitarian behaviors from sexual attractiveness. This coercive discourse may be shaping the sexual preferences of female youth. The current paper explores young women’s preferences for different types of sexual relationships and, more particularly, for what type of sexual affective relationships they coercively preferred men with violent attitudes and behavior. Methods A quantitative, mixed-design vignette study was conducted with 191 college females in Spain. We focused the analysis only on responses about vignettes including narratives of men with violent attitudes and behaviors. In addition, we examined whether participants would report higher coerced preferences for violent men when asked about the coerced preferences of their female friends than when asked about their own preferences. Results Only 28.95% of participants responded that their female friends would prefer a young man with violent behavior for a stable relationship, meanwhile 58.42% would do it for hooking up. When reporting about themselves, the difference was greater: 28.42% would prefer a young man with violent behavior for hooking up and just 5.78% for a stable relationship. Conclusions The dominant coercive discourse that links attractiveness to people with violent attitudes and behaviors may be explaining the results obtained in this study. The findings can help eliminate the stereotype largely adopted by some intervention and prevention programs which assume that gender-based violence occurs mainly in stable relationships, considering that falling in love is the reason that lead women to suffer from violence. Our results can also support health professionals and others serving young women to enhance their identification of gender violence victimization, as well as our findings point to the need to include the evidence of gender violence in sporadic relationships in prevention programs and campaigns addressed to young women.

Abstract Background In conflict-afflicted areas, pregnant women and newborns often have higher rates of adverse health outcomes. Objective To describe maternal and child health indicators and interventions between 1998 and 2016 comparing high and low conflict areas in Colombia. Methods Mixed study of convergent triangulation. In the quantitative component, 16 indicators were calculated using official, secondary data sources. The victimization rate resulting from armed conflict was calculated by municipality and grouped into quintiles. In the qualitative component, a comparative case study was carried out in two municipalities of Antioquia: one with high rates of armed conflict and another with low rates. A total of 41 interviews and 8 focus groups were held with local and national government officials, health professionals, community informants, UN agencies and NGOs. Results All of the indicators show improvement, however, four show statistically significant differences between municipalities with high victimization rates versus low ones. The maternal mortality ratio was higher in the municipalities with greater victimization in the periods 1998–2004, 2005–2011 and 2012–2016. The percentage of cesarean births and women who received four or more antenatal visits was lower among women who experienced the highest levels of victimization for the period 1998–2000, while the fertility rate for women between 15 and 19 years was higher in these municipalities between 2012 and 2016. In the context of the armed conflict in Colombia, maternal and child health was affected by the limited availability of interventions given the lack of human resources in health, supplies, geographical access difficulties and insecurity. The national government was the one that mostly provided the programs, with difficulties in continuity and quality. UN Agencies and NGOs accessed more easily remote and intense armed conflict areas. Few specific health interventions were identified in the post-conflict context. Conclusions In Colombia, maternal and child health indicators have improved since the conflict, however a pattern of inequality is observed in the municipalities most affected by the armed conflict.

Abstract Background Food-producing animals can be a vehicle for staphylococcal species as well as their virulence and antimicrobial resistance genes. This work aimed to analyse the diversity of staphylococcal species in food-producing animals in Dakar/Senegal, and to determine the antimicrobial resistance phenotype/genotype and virulence factors of recovered isolates. Nasal samples of 149 cows and 199 chickens (348 animals) were collected from one slaughterhouse and a local market respectively, and were inoculated on selective media for staphylococci recovery. For S. aureus isolates, molecular typing (spa-type, MLST) was performed by PCR/sequencing, and the presence of 27 virulence genes (exfoliative and toxic shock toxins, PVL, haemolysins and enterotoxins) as well as the gene scn were analysed by PCR. Susceptibility to twelve antibiotics was studied by disc-diffusion method for all staphylococci; the resistance genes involved were screened by PCR. Results Staphylococcus spp. was present in 3 and 26.8% of chicken and cow nasal samples, respectively. Seven S. aureus isolates and forty isolates of other staphylococcal species were identified. S. aureus isolates were recovered from cow (n = 6) and chicken (n = 1) samples, belonging to four genetic lineages: t084/ST15 (n = 1); t10579/ST291 (n = 3); t355, t4690/ST152 (n = 2); and t6618/ST6 (n = 1). All S. aureus were methicillin-susceptible, penicillin-resistant (blaZ), and two of them were also tetracycline-resistant [tet(K)]. All the isolates carried at least one of the virulence genes tested. The PVL genes were detected in three ST15 and ST152 isolates. They all harboured haemolysins encoding genes and lacked the scn gene. The other staphylococci recovered were S. sciuri (n = 16), S. simulans (n = 11), S. hyicus (n = 5), S. haemolyticus (n = 4), S. chromogenes (n = 3), and S. hominis (n = 1); they were all methicillin-susceptible and 27.5% tetracycline-resistant [tet(K) and tet(L)]. Conclusions A low prevalence of S. aureus was detected among food-producing animals, all susceptible to methicillin. However, the presence of virulence genes (lukF/lukS-PV, eta, tst, sea and see) is worrisome to the extent that they could be transferred to derived food and therefore, to humans.

Abstract Background The frequency of mild forms of hepatitis A, especially in children, could lead to underreporting. The objective of the study was to investigate the sensitivity of two surveillance systems, mandatory Statutory Disease Reports and the Microbiological Reporting System of Catalonia, using capture-recapture techniques. Methods The study was conducted in Catalonia between 2011 and 2015. Hepatitis A cases reported to two independent surveillance systems were included: Statutory Disease Reports (SDR) and Microbiological Reporting System of Catalonia (MRS). The variables collected were: age, sex, year of declaration, size of municipality ( 15 years (25.5%; 22.8–28.3 vs. 12.1%; 10–14.2). For those born in Spain, the sensitivity was 57.2% (49.6–67.4) in the SDR and 27.1% (23.5–31.9) in the MRS, lower than that for foreign-born patients (58%; 51.2–66.8 vs. 49.1%; 43.4–56.6). In electronically-reported cases, the sensitivity was much higher in the SDR than in the MRS (47.2%; 42.3–52.1 vs. 9.4%; 6.5–12.3). No differences were observed according to sex, size of municipality, and year of declaration or reporting centre. The estimated total number of cases using the Chapman formula was very similar to the adjusted estimate (1121; 985–1258 vs. 1120; 876–1525), indicating the robustness of the results. Conclusions The sensitivity of the SDR was greater than that of MRS, especially in patients aged