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Current tumor diagnostics rely on fluorodeoxyglucose (FDG)-PET imaging, but FDG’s short half-life and high cost limit its widespread use. Infrared (IR) probes are emerging as non-radioactive alternatives to conventional tracers for tissue section and other in vitro imaging applications. Because cells and tissues are relatively free of absorption peaks between 1800 and 2200 cm−1, metal-carbonyl complexes, especially cyclopentadienylrhenium(I) tricarbonyl (Cp[Re(CO)3]) derivatives, absorb strongly in this window and provide robust platforms for bioconjugation. Furthermore, Cp[Re(CO)3] fragments can be introduced into organic substrates via an elegant three-component reaction that simultaneously forges the cyclopentadienyl-metal and cyclopentadienyl-substituent bonds. As a result, the functionalized half-sandwich complex is obtained in a single step without any special handling issues. We have therefore properly modified a glucose molecule with that complex and developed a novel glucoconjugated Cp[Re(CO)3] probe that enables IR-based visualization of diseased cells at 2100 cm−1, offering a non-invasive, non-radioactive histological tool and a promising basis for future medical imaging devices.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited effective therapeutic options due to late diagnosis, aggressive progression, and rapid development of drug resistance. In pursuit of novel treatments, this study reports the design, synthesis, and biological evaluation of a new series of topsentin derivatives, featuring a 1,2,4-oxadiazole core. The newly synthesized derivatives were screened for antiproliferative activity against multiple PDAC cell lines (SUIT-2, Patu-T, and PANC-1), identifying several compounds with potent growth-inhibitory effects, particularly on SUIT-2 and Patu-T cells. Further studies demonstrated that these compounds also significantly inhibited cell migration and reduced clonogenic potential, with IC50 values in the micromolar range. The results suggest that these marine-inspired 1,2,4-oxadiazole derivatives effectively target key hallmarks of PDAC, including proliferation, migration, and colony formation, supporting their further development as promising candidates for overcoming drug resistance and metastatic progression in pancreatic cancer.

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDDL) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDDS) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDDL, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDDS, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDDS-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDDL or CDDS in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment.

Background Nucleoside analogues are crucial in treating non-small cell lung cancer (NSCLC), but resistance hampers patient outcomes. The cytidine analogue RX-3117 shows promise in gemcitabine-resistant cancers, yet mechanisms underlying acquired resistance to this drug remain unexplored. This study includes a comprehensive investigation into RX-3117 resistance mechanisms by leveraging new preclinical models and cutting-edge genomic tools, including a CRISPR-Cas9 knockout screen and transcriptomics. Methods NSCLC cell lines A549 and SW1573 were exposed to stepwise increasing concentrations of RX-3117 to establish stable resistant subclones, confirmed by SRB and clonogenic assays. Intracellular RX-3117 nucleotide levels were measured via LC/MS-MS, prompting the evaluation and modulation of the expression of key metabolic enzymes by Western blot and siRNA. A CRISPR-Cas9 screen identified genes whose loss increased RX-3117 sensitivity, while RNA-sequencing with differential expression analyses revealed resistance-related pathways, further investigated through cell cycle distribution, knock-out, and ELISA assays. Results Resistant clones exhibited decreased accumulation of RX-3117 nucleotides, which however, was not associated to reduced expression of activation enzymes (UCK2, UMPK, CMPK, NME1/NDPK, RR1 and RR2). Instead, increased expression was observed in certain DNA repair and deactivation enzymes (NT5C3) but pharmacological inhibition and silencing of the latter did not circumvent resistance. Remarkably, a comprehensive approach with CRISPR-Cas9 screen highlighted DNA-repair and cell cycle determinants as key sensitizing genes. XL-PCR and RNA-sequencing confirmed aberrations in DNA-repair and pathways involved in cell cycle regulation. Knock-out and pharmacological inhibition validated the role of PKMYT1, a protein kinase involved in G2/M transition and genomic stability. RX-3117-resistant A549 cells showed enhanced sensitivity to the PKMYT1 inhibitor lunresertib and its synergism with RX-3117, suggesting further studies, especially in patients with high PKMYT1 expression who have significantly shorter survival rates, as observed in public databases and validated in an internal cohort of NSCLC patients. Conclusion By integrating CRISPR-Cas9 with functional assays and transcriptomics, our study established a framework for decoding resistance mechanisms and highlights potential therapeutic strategies to enhance RX-3117 efficacy in NSCLC. We demonstrated for the first time that aberrant DNA repair and cell cycle dysregulation led resistance, identifying PKMYT1 as a promising target.

IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate.Materials and methodsWe scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case–Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase.ResultsThe C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10−8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1.ConclusionWe identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Using lower limb exoskeletons provides potential advantages in terms of productivity and safety associated with reduced stress. However, complex issues in human–robot interactions are still open, such as the physiological effects of exoskeletons and the impact on the user’s subjective experience. In this work, an innovative exoskeleton, the Wearable Walker, is assessed using the EXPERIENCE benchmarking protocol from the EUROBENCH project. The Wearable Walker is a lower-limb exoskeleton that enhances human abilities, such as carrying loads. The device uses a unique control approach called Blend Control that provides smooth assistance torques. It operates two models simultaneously, one in the case in which the left foot is grounded and another for the grounded right foot. These models generate assistive torques combined to provide continuous and smooth overall assistance, preventing any abrupt changes in torque due to model switching. The EXPERIENCE protocol consists of walking on flat ground while gathering physiological signals, such as heart rate, its variability, respiration rate, and galvanic skin response, and completing a questionnaire. The test was performed with five healthy subjects. The scope of the present study is twofold: to evaluate the specific exoskeleton and its current control system to gain insight into possible improvements and to present a case study for a formal and replicable benchmarking of wearable robots.

•Cardiac magnetic resonance (CMR) should be repeated every 2 years in patients with hypertrophic cardiomyopathy because the extent of late gadolinium enhancement (LGE) may increase rapidly in a relevant percentage of patients.•In hypertrophic cardiomyopathy, LGE extent ≥15% of the left ventricular mass is considered a marker of risk of sudden cardiac death; however, some patients with a lower extent of LGE at baseline CMR may present a ≥15% extent at the follow-up examination.•The finding of an LGE extent ≥15% of the left ventricular mass at the follow-up CMR allows a significant reclassification of the risk of major arrhythmic events compared with the same finding at baseline CMR.•The high rate of progression of LGE, defined as the increase of LGE extent >0.07 g/month between 2 consecutive CMR examinations, is the best independent predictor of major arrhythmic events. In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) extent ≥15% of left ventricular mass is considered a prognostic risk factor. LGE extent increases over time and the clinical role of the progression of LGE over time (LGE rate) was not prospectively evaluated. We sought to evaluate the prognostic role of the LGE rate in HCM. We enrolled 105 patients with HCM who underwent cardiac magnetic resonance (CMR) at baseline (CMR-I) and after ≥2 years of follow-up (CMR-II). LGE rate was defined as the ratio between the increase of LGE extent (grams) and the time interval (months) between examinations. A combined end point of sudden cardiac death, resuscitated cardiac arrest, appropriate Implanted Cardioverter Defibrillator (ICD) intervention, and sustained ventricular tachycardia was used (hard events). The percentage of patients with LGE extent ≥15% increased from 9% to 20% from CMR-I to CMR-II (p = 0.03). During a median follow-up of 52 months, 25 hard events were recorded. The presence of LGE ≥15% at CMR-II allowed a significant reclassification of the risk of patients than at LGE ≥15% at CMR-I (net reclassification improvement 0.21, p = 0.046). On the MaxStat analysis, the optimal prognostic cut point for LGE rate was >0.07 g/month. On the Kaplan–Meier curve, patients with LGE rate >0.07 had worse prognosis than those without (p <0.0001). LGE rate >0.07 allowed a significant reclassification of the risk compared with LGE ≥15% at CMR-I and at CMR-II (net reclassification improvement 0.49, p = 0.003). In the multivariable models, LGE rate >0.07 was the best independent predictor of hard events. In conclusion, CMR should be repeated after 2 years to reclassify the risk for sudden death of those patients. A high LGE rate may be considered a novel prognostic factor in HCM.

FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1-2.9 months) and median overall survival was 6.2 months (95% CI: 5.3-7.1 months). At multivariate analysis, CA19.9 level ≥59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12-4.78; p = 0.023). Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions’ longest diameters (SLD) after 6–8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group; p = 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months, p < 0.001) and OS (13.2 vs. 9.7 months, p = 0.001). Median DoR was −27.5% (−29.4% with FOLFOXIRI and −21.4% with GemNab, p = 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months, p < 0.001) and OS (14.3 vs. 11.1 months, p = 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy.

Introduction. Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. Methods. Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. Results. In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. Discussion. The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.