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Abstract Background Patients with cancer (PwC) who undergo specific treatments reported greater fatigue and reduced functional capacity as predominant outcomes, compromising their QoL during and following the treatment. Prehabilitation intervention, provided after diagnosis and before treatments, is to optimize the physiological reserve and address modifiable risk factors before surgery or chemotherapy to improve post-treatment results. The primary aim of this study is to obtain a common line of efficacy compared with prehabilitation treatment; the secondary endpoint is to assess the methodological quality of the studies eligible in the review. Methods The systematic review was conducted from September to February 2024, in accordance with PRISMA guidelines. Databases consulted were MEDLINE, Scopus, Web of science and CINAHL, RCTs related to Prehabilitation intervention on PwC were included. The methodological quality of the included studies was assessed through the RoB2 Cochrane tool and the PEDro scale. Meta-analysis was performed to estimate relative treatment effects among evaluated outcomes. Results Forty-two studies were included in the systematic review, 13 were included in the quantitative analysis. The results of the studies reporting reduced postoperative hospital stay, improved endurance, muscle strength, respiratory function, quality of life, and urinary incontinence. Critical analysis of the articles using the PEDro scale revealed 28 RCTs with a good rating, 9 with a fair rating, and 5 with a poor rating; in contrast, the Cochrane RoB2 tool revealed that all articles were at high risk of bias. Meta-analysis showed statistically significant values for 6MWT (38.53, 95%CI 33.03 - 44.04); HADS-depression (-0.71, 95%CI -0.93 -0.49) and HADS-anxiety (-0.49, 95%CI -0.76 -0.23). Conclusions Prehabilitation represents a specific intervention that aims to improve postoperative outcomes in fragile patients undergoing surgery, increasing their preoperative physiological reserve in anticipation of the stress they will face and facilitating the postoperative recovery of functional capacity. Prehabilitation is a good intervention to use, especially in terms of functional capacity and mental health, the latter being very impactful in terms of reduced levels of anxiety and depression. These data make it possible to justify supportive intervention by physical therapists aimed at improving and restoring health-related QoL especially in the short term.

Abstract Molecular dynamics (MD) simulation of the green ionic liquid [C₄mim][PF₆] mixed with polar benzonitrile (BNZ) solvent provides detailed insights into their structural and dynamic properties, essential for electrochemistry and materials science applications. The simulations we carried out at varying mole fractions (X BZN) reveal the mixtures’ physical, structural, and dynamic properties, with radial, spatial, and combined distribution functions, highlighting the effective interaction through H-bonding involved. The simulation indicates that BZN stacks on the cation butyl tail, providing a significant explanation for the unique experimental observations (following). Adding BZN causes the mixture’s liquid dynamics to increase linearly at low X BZN and exponentially at high X BZN, with a notable singular transition at 0.5X BZN. Comprehensive efforts were made to verify and support experimental sum frequency generation (SFG) spectroscopy by simulating the surface structure of the mixtures. Consequently, the simulated BZN stacking structure explains (1) the absence of the C≡N vibrational mode in the SFG spectrum for X BZN < 0.8, and (2) the gradual diminishing of the CH3 SFG signal, which disappears as X BZN approaches 0.5. Finally, this research removes a persistent ambiguity, proving that only the molecular moieties on the surface generate the SFG vibrational signal, while those in the subsurface do not.

Water-in-water (w/w) emulsions, comprising aqueous droplets within another continuous aqueous phase, rely on a low interfacial tension for stability. Thus far, it has been challenging to control their size and stability without the use of stabilizers. In this study, we introduce a microfluidic technique that addresses these challenges, producing stable w/w emulsions with precisely controlled size and uniformity. Results shows that using an acoustically actuated microfluidic mixer, PEG, Dextran, and alginate solutions (84.66 mPa.s viscosity difference) were homogenized rapidly, forming uniformly distributed w/w emulsions stabilized in alginate gels.The emulsion size, uniformity, and shear sensitivity can be tuned by modifying the alginate concentration. Biocompatibility was evaluated by monitoring the viability of kidney cells in the presence of emulsions and gels. In conclusion, this study not only showed emulsion formation with a high mixing efficiency exceeding 90 % for all viscosities, actuated at an optimized frequency of 1.064 MHz, but also demonstrated that an aqueous, solvent, and emulsifier-free composition exhibited remarkable biocompatibility, holding promise for precise drug delivery, cosmetics, and food applications.

High-pressure processing (HPP) has been employed in the food and pharmaceutical industries for multiple applications, such as microbial inactivation, shelf life extension, homogenizing/stabilizing emulsions, suspensions, gels, and other colloidal systems, cold extraction of meat in crustaceans, the opening of mollusks, etc. However, high pressure is known to affect the stability and the quality of barosensitive (i.e., sensitivity because of the level of pressure) components of the bioproducts, such as proteins. In general, Le Chatelier's principle dictates the fate of high molecular weight polymeric compounds like proteins under high pressure, suggesting a tendency to degrade into simpler monomers. From a structural analysis point of view, this generally results in increased tendencies for the protein to denature from its native state and possibly affect its ability to renature. Protein crystallization is also affected favorably or unfavorably by pressure, depending on the effect of pressure on nucleation and crystal growth steps for the particular type of protein. Protein refolding is another effect whose kinetics can be optimized by pressure. This work discusses the mechanisms of the impact of pressure on protein structure, crystallization refolding, and unfolding, with examples of the application of these processes in recent literature.

We prove an existence result for a p-Laplacian problem set in the whole Euclidean space and exhibiting a critical term perturbed by a singular, convective reaction. The approach used combines variational methods, truncation techniques, and concentration compactness arguments, together with set-valued analysis and fixed point theory. De Giorgi’s technique, a priori gradient estimates, and nonlinear regularity theory are employed to obtain local C1,α{C}^{1,\alpha } regularity of solutions, as well as their pointwise decay at infinity. The result is new even in the non-singular case, also for the Laplacian.

Abstract Background Tumor heterogeneity is a main contributor of resistance to anti-cancer targeted agents though it has proven difficult to study. Unfortunately, model systems to functionally characterize and mechanistically study dynamic responses to treatment across coexisting subpopulations of cancer cells remain a missing need in oncology. Methods Using single cell cloning and expansion techniques, we established monoclonal cell subpopulations (MCPs) from a commercially available epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer cell line. We then used this model sensitivity to the EGFR inhibitor osimertinib across coexisting cell populations within the same tumor. Pathway-centered signaling dynamics associated with response to treatment and morphological characteristics of the MCPs were assessed using Reverse Phase Protein Microarray. Signaling nodes differentially activated in MCPs less sensitive to treatment were then pharmacologically inhibited to identify target signaling proteins putatively implicated in promoting drug resistance. Results MCPs demonstrated highly heterogeneous sensitivities to osimertinib. Cell viability after treatment increased > 20% compared to the parental line in selected MCPs, whereas viability decreased by 75% in other MCPs. Reduced treatment response was detected in MCPs with higher proliferation rates, EGFR L858R expression, activation of EGFR binding partners and downstream signaling molecules, and expression of epithelial-to-mesenchymal transition markers. Levels of activation of EGFR binding partners and MCPs’ proliferation rates were also associated with response to c-MET and IGFR inhibitors. Conclusions MCPs represent a suitable model system to characterize heterogeneous biomolecular behaviors in preclinical studies and identify and functionally test biological mechanisms associated with resistance to targeted therapeutics.

Abstract Background Intravenous fosfomycin (IVFOF) is gaining interest in severe infections. Its use may be limited by adverse events (AEs). Little experience exists on IVFOF therapeutic drug monitoring (TDM) in real-life setting. Patients and methods Retrospective study of patients receiving IVFOF for > 48 h at Policlinico Hospital (Milan, Italy) from 01/01/2019 to 01/01/2023. AEs associated to IVFOF graded CTCAE ≥ II were considered. Demographic and clinical risk factors for IVFOF-related AEs were analysed with simple and multivariable regression models. The determination of IVFOF TDM was made by a rapid ultraperformance liquid chromatography mass spectrometry method (LC-MS/MS) on plasma samples. The performance of TDM (trough levels (Cmin) in intermittent infusion, steady state levels (Css) in continuous infusion) in predicting AEs ≤ 5 days after its assessment was evaluated. Results Two hundred and twenty-four patients were included. At IVFOF initiation, 81/224 (36.2%) patients were in ICU and 35/224 (15.7%) had septic shock. The most frequent infection site was the low respiratory tract (124/224, 55.4%). Ninety-five patients (42.4%) experienced ≥ 1AEs, with median time of 4.0 (2.0–7.0) days from IVFOF initiation. Hypernatremia was the most frequent AE (53/224, 23.7%). Therapy discontinuation due to AEs occurred in 38/224 (17.0%). ICU setting, low respiratory tract infections and septic shock resulted associated with AEs (RRadjusted 1.59 (95%CI:1.09–2.31), 1.46 (95%CI:1.03–2.07) and 1.73 (95%CI:1.27–2.37), respectively), while IVFOF daily dose did not. Of the 68 patients undergone IVFOF TDM, TDM values predicted overall AEs and hypernatremia with AUROC of 0.65 (95%CI:0.44–0.86) and 0.91 (95%CI:0.79-1.0) respectively for Cmin, 0.67 (95%CI:0.39–0.95) and 0.76 (95%CI:0.52-1.0) respectively for Css. Conclusions We provided real world data on the use of IVFOF-based regimens and associated AEs. IVFOF TDM deserves further research as it may represent a valid tool to predict AEs. Key points Real world data on intravenous fosfomycin for severe bacterial infections. AEs occurred in over 40% (therapy discontinuation in 17%) and were related to baseline clinical severity but not to fosfomycin dose. TDM showed promising results in predicting AEs.

Abstract Background Listeria monocytogenes is a foodborne pathogen, which can cause a severe illness, especially in people with a weakened immune system or comorbidities. The interactions between host and pathogens and between pathogens and tumor cells have been debated in recent years. However, it is still unclear how bacteria can interact with tumor cells, and if this interaction can affect tumor progression and therapy. Methods In this study, we evaluated the involvement of L. monocytogenes in pre-neoplastic and colorectal cancer cell proliferation and tumorigenic potential. Results Our findings showed that the interaction between heat-killed L. monocytogenes and pre-neoplastic or colorectal cancer cells led to a proliferative induction; furthermore, by using a three-dimensional cell culture model, the obtained data indicated that L. monocytogenes was able to increase the tumorigenic potential of both pre-neoplastic and colorectal cancer cells. The observed effects were then confirmed as L. monocytogenes-specific, using Listeria innocua as negative control. Lastly, data suggested the Insulin Growth Factor 1 Receptor (IGF1R) cascade as one of the possible mechanisms involved in the effects induced by L. monocytogenes in the human colorectal adenocarcinoma cell line. Conclusions These findings, although preliminary, suggest that the presence of pathogenic bacterial cells in the tumor niches may directly induce, increase, and stimulate tumor progression.

Antivirulence agents are considered a promising strategy to treat bacterial infections. Fluoropyrimidines possess antivirulence and antibiofilm activity against Gram-negative bacteria; however, their mechanism of action is yet unknown. Consistent with their known antibiofilm activity, fluoropyrimidines, particularly 5-fluorocytosine (5-FC), impair curli-dependent surface adhesion by Escherichia coli MG1655 via downregulation of curli fimbriae gene transcription. Curli inhibition requires fluoropyrimidine conversion into fluoronucleotides and is not mediated by c-di-GMP or the ymg-rcs envelope stress response axis, previously suggested as the target of fluorouracil antibiofilm activity in E. coli. In contrast, 5-FC hampered the transcription of curli activators RpoS and stimulated the expression of Fis, a curli repressor affected by nucleotide availability. This last observation suggested a possible perturbation of the de novo pyrimidine biosynthesis by 5-FC: indeed, exposure to 5-FC resulted in a ca. 2-fold reduction of UMP intracellular levels while not affecting ATP. Consistently, expression of the de novo pyrimidine biosynthesis genes carB and pyrB was upregulated in the presence of 5-FC. Our results suggest that the antibiofilm activity of fluoropyrimidines is mediated, at least in part, by perturbation of the pyrimidine nucleotide pool. We screened a genome library in search of additional determinants able to counteract the effects of 5-FC. We found that a DNA fragment encoding the unknown protein D8B36_18,480 and the N-terminal domain of the penicillin-binding protein 1b (PBP1b), involved in peptidoglycan synthesis, could restore curli production in the presence of 5-FC. Deletion of the PBP1b-encoding gene mrcB, induced csgBAC transcription, while overexpression of the gene encoding the D8B36_18,480 protein obliterated its expression, possibly as part of a coordinated response in curli regulation with PBP1b. While the two proteins do not appear to be direct targets of 5-FC, their involvement in curli regulation suggests a connection between peptidoglycan biosynthesis and curli production, which might become even more relevant upon pyrimidine starvation and reduced availability of UDP-sugars needed in cell wall biosynthesis. Overall, our findings link the antibiofilm activity of fluoropyrimidines to the redirection of at least two global regulators (RpoS, Fis) by induction of pyrimidine starvation. This highlights the importance of the de novo pyrimidines biosynthesis pathway in controlling virulence mechanisms in different bacteria and makes the pathway a potential target for antivirulence strategies.

Background:. Modern surgical therapy of chronic headaches/migraines is essentially based on the release/neurolysis of extracranial nerves, which, when compressed or inflamed, act as trigger points and, as such, trigger headache attacks. The aim of this article was to describe a novel maneuver we use as an aid in the preoperative planning of occipital trigger sites. Methods:. In the period of January 2021–September 2023, we operated on 32 patients (11 men, 21 women, age range: 26–68 years), who underwent migraine surgery for occipital trigger point release. All patients were evaluated using the described preoperative maneuver. In a dedicated card, the levels of tenderness at each point were marked accordingly, differentiating them by intensity as nothing (−), mild (+), medium (++), or high (+++). Patients were then operated on at the points corresponding only to the ++ and +++ signs. Results:. At 6-month follow-up, we observed significant improvement (>50%) in 29 patients (91%), with complete recovery in 25 patients (78%). Conclusions:. In our experience, the maneuver described, in addition to being very simple, has been shown to have good sensitivity and reproducibility. We therefore recommend its use, especially for those surgeons beginning their practice in this particular area of plastic surgery.

Abstract Glioblastoma is a fast‐growing and aggressive form of brain cancer. Even with maximal treatment, patients show a low median survival and are often subjected to a high recurrence incidence. The currently available treatments require multimodal management, including maximal safe surgical resection, followed by radiation and chemotherapy. Because of the infiltrative glioblastoma nature, intraoperative differentiation of cancer tissue from normal brain parenchyma is very challenging, and this accounts for the low rate of complete tumor resection. For these reasons, clinicians have increasingly used various intraoperative adjuncts to improve surgical results, such as fluorescent agents. However, most of the existing fluorophores show several limitations such as poor selectivity, photostability, photosensitization and high costs. This could limit their application to successfully improve glioblastoma resection. In the present perspective, we highlight the possibility to develop next‐generation fluorescent tools able to more selectively label cancer cells during surgical resection.

BackgroundUlcerative colitis (UC) is a multifactorial chronic inflammatory bowel disease (IBD) that affects the large intestine with superficial mucosal inflammation. A dysbiotic gut microbial profile has been associated with UC. Our study aimed to characterize the UC gut bacterial, fungal, and metabolic fingerprints by omic approaches.MethodsThe 16S rRNA- and ITS2-based metataxonomics and gas chromatography–mass spectrometry/solid phase microextraction (GC–MS/SPME) metabolomic analysis were performed on stool samples of 53 UC patients and 37 healthy subjects (CTRL). Univariate and multivariate approaches were applied to separated and integrated omic data, to define microbiota, mycobiota, and metabolic signatures in UC. The interaction between gut bacteria and fungi was investigated by network analysis.ResultsIn the UC cohort, we reported the increase of Streptococcus, Bifidobacterium, Enterobacteriaceae, TM7-3, Granulicatella, Peptostreptococcus, Lactobacillus, Veillonella, Enterococcus, Peptoniphilus, Gemellaceae, and phenylethyl alcohol; and we also reported the decrease of Akkermansia; Ruminococcaceae; Ruminococcus; Gemmiger; Methanobrevibacter; Oscillospira; Coprococus; Christensenellaceae; Clavispora; Vishniacozyma; Quambalaria; hexadecane; cyclopentadecane; 5-hepten-2-ol, 6 methyl; 3-carene; caryophyllene; p-Cresol; 2-butenal; indole, 3-methyl-; 6-methyl-3,5-heptadiene-2-one; 5-octadecene; and 5-hepten-2-one, 6 methyl. The integration of the multi-omic data confirmed the presence of a distinctive bacterial, fungal, and metabolic fingerprint in UC gut microbiota. Moreover, the network analysis highlighted bacterial and fungal synergistic and/or divergent interkingdom interactions.ConclusionIn this study, we identified intestinal bacterial, fungal, and metabolic UC-associated biomarkers. Furthermore, evidence on the relationships between bacterial and fungal ecosystems provides a comprehensive perspective on intestinal dysbiosis and ecological interactions between microorganisms in the framework of UC.

Abstract Translational research for the evaluation of physical activity habits and lifestyle modifications based on nutrition and exercise has recently gained attention. In this study, we evaluated the effects of serum samples obtained before and after a 12-week home-based lifestyle intervention based on nutrition and exercise in breast cancer survivors in terms of modulation of the tumorigenic potential of breast cancer cells. The home-based lifestyle intervention proposed in this work consisted of educational counselling on exercise and nutritional behaviors and in 12 weeks of structured home-based exercise. Triple-negative breast cancer cell line MDA-MB-231 was cultured in semi-solid medium (3D culture) with sera collected before (PRE) and after (POST) the lifestyle intervention program. Spheroid formation was evaluated by counting cell colonies after 3 weeks of incubation. Results show a slight but significant reduction of spheroid formation induced by serum collected POST in comparison to those obtained PRE. Moreover, statistical analyses aimed to find physiologic and metabolic parameters associated with 3D cell proliferation revealed the proliferative inducer IGF-1 as the only predictor of cell tumorigenic potential. These results highlight the importance of lifestyle changes for cancer progression control in a tertiary prevention context. Translational research could offer a useful tool to identify metabolic and physiological changes induced by exercise and nutritional behaviors associated with cancer progression and recurrence risk.

Abstract Recent advances in peptide delivery and nanotechnology has resulted in emergence of several non-parenteral administration routes that replace subcutaneous injections associated with patient discomfort. Thiolated biopolymers are relatively new materials being explored to enhance mucoadhesivity and permeability in these efforts, yet their pH dependent reactivity remains an obstacle. This work focussed on improving the mucoadhesivity of thiolated chitosans by activating them with mercaptonicotinic acid, in a bid to create a novel thiomerized chitosan that can open cell tight junctions for application in oral delivery. The synthesized mercaptonicotinic acid activated thiolated chistoan (MNA-TG-chitosan), along with thiolated chitosan (TG-chitosan) and unmodified chitosan were then used to create insulin nanoparticles (insNPs) using spray drying encapsulation process. Use of MNA-TG-chitosan in place of chitosan resulted in reduction of particle size of insNPs from 318 to 277 nm with no significant changes in polydispersity index (~ 0.2), encapsulation efficiency (~ 99%), insulin loading content (~ 25%) and morphology. Results from in-vitro cytotoxicity on TR146, CaCo2 and HepG2 cell lines revealed no significant effects on cell viability at 50–1000 μg/mL concentration. insNPs encapsulated with the new material, MNA-TG-chitosan, resulted in a 1.5-fold and 4.4-fold higher cellular uptake by HepG2 liver cells where insulin is metabolized, approximately 40% and 600% greater insulin transport through TR146 buccal cell monolayers, and 40% and 150% greater apparent permeability than insNPs encapsulated with unmodified chitosan and TG-chitosan respectively. The higher permeation achieved on using MNA-TG chitosan was attributed to the greater opening of the cell tight junction evidenced by reduction of transepithelial electrical resistance of TR146 buccal cell monolayers. This study demonstrates MNA-TG-chitosan as a promising material for improved peptide oral delivery.

Despite copious data linking brain function with changes to social behavior and mental health, little is known about how puberty relates to brain functioning. We investigated the specificity of brain network connectivity associations with pubertal indices and age to inform neurodevelopmental models of adolescence. We examined how brain network connectivity during a peer evaluation fMRI task related to pubertal hormones (dehydroepiandrosterone and testosterone), pubertal timing and status, and age. Participants were 99 adolescents assigned female at birth aged 9–15 (M = 12.38, SD = 1.81) enriched for the presence of internalizing symptoms. Multivariate analysis revealed that within Salience, between Frontoparietal – Reward and Cinguloopercular – Reward network connectivity were associated with all measures of pubertal development and age. Specifically, Salience connectivity linked with age, pubertal hormones, and status, but not timing. In contrast, Frontoparietal – Reward connectivity was only associated with hormones. Finally, Cinguloopercular – Reward connectivity related to age and pubertal status, but not hormones or timing. These results provide evidence that the salience processing underlying peer evaluation is jointly influenced by various indices of puberty and age, while coordination between cognitive control and reward circuitry is related to pubertal hormones, pubertal status, and age in unique ways.