Cyt c (cytochrome c) has been traditionally envisioned as rapidly diffusing in two dimensions at the surface of the mitochondrial inner membrane when not engaged in redox reactions with physiological partners. However, the discovery of the extended lipid anchorage (insertion of an acyl chain of a bilayer phospholipid into the protein interior) suggests that this may not be exclusively the case. The physical and structural factors underlying the conformational changes that occur upon interaction of ferrous cyt c with phospholipid membrane models have been investigated by monitoring the extent of the spin state change that result from this interaction. Once transiently linked by electrostatic forces between basic side chains and phosphate groups, the acyl chain entry may occur between two parallel hydrophobic polypeptide stretches that are surrounded by positively charged residues. Alteration of these charges, as in the case of non-trimethylated (TML72K) yeast cyt c and Arg91Nle horse cyt c (where Nle is norleucine), led to a decline in the binding affinity for the phospholipid liposomes. The electrostatic association was sensitive to ionic strength, polyanions and pH, whereas the hydrophobic interactions were enhanced by conformational changes that contributed to the loosening of the tertiary structure of cyt c. In addition to proposing a mechanistic model for the extended lipid anchorage of cyt c, we consider what, if any, might be the physiological relevance of the phenomenon.

As many as 30% to 40% of locally advanced rectal cancer (LARC) patients experience metastatic progression of the disease. Recognizing the potential of the genetic cargo in tumor-derived exosomes, we hypothesized that plasma exosomal microRNA (miRNA) may reflect biological aggressiveness in LARC and provide new markers for rectal cancer aggressiveness and risk stratification. In a prospective LARC cohort (NCT01816607), plasma samples were collected from 29 patients at the time of diagnosis, before neoadjuvant therapy and surgery. Exosomes, precipitated from plasma using a commercial kit, were verified by cryo-electron microscopy, nanoparticle tracking analysis, and western blotting. Expression of exosomal miRNAs was profiled using a miRCURY LNA miRNA microarray and validation of six miRNAs associated with pathological and clinical end-points was undertaken in plasma collected at the time of diagnosis from 64 patients in an independent prospective LARC cohort (NCT00278694). In both cohorts, exosomal miR-141-3p and miR-375 were higher in patients with synchronous liver metastasis than in those without (P = .010 and P = .017 respectively in the investigative cohort, and P < .001 for both in the validation cohort). Further, high exosomal miR-141-3p was associated with post-operative metastatic liver progression in the investigative cohort (P = .034). Because both miRNAs are associated with tumor angiogenesis and immune modulation, we propose that these miRNAs in circulating exosomes may reflect rectal cancer aggressiveness and accordingly be candidate biomarkers for further investigations.

Background: Antimicrobial resistance (AMR) is a major global health issue that exacerbates the burden of infectious diseases and healthcare costs. However, the scarcity of national-level AMR data in African countries hampers our understanding of its scale and contributing factors in the region. To gain insights into AMR prevalence in Africa, we collected and analyzed retrospective AMR data from 14 countries. Methods and findings: We estimated bacterial AMR prevalence, defined as the proportion of resistant human isolates tested from antimicrobial susceptibility (AST) data collected retrospectively for 2016–2019 from 205 laboratories across 14 African countries. We generated 95% confidence intervals (CIs) for aggregated AMR estimates to account for data quality disparities across countries; the median data quality score was 73.1%, ranging from 56.4% to 80.8%. We assessed 819,584 culture records covering 9,266 pathogen–drug combinations, of which 187,832 (22.9%) were positive cultures with AST results. The most frequently cultured specimens were urine (32.0%) and purulent samples (28.1%), and the most frequently isolated pathogens were Escherichia coli (22.2%) and Staphylococcus aureus (15.0%). Aggregated AMR estimates did not change significantly across the years studied (p > 0.337); however, there were significant variations in AMR prevalence estimates in culture-positive samples across countries, regions, patient departments (inpatient/outpatient), and specimen sources (p < 0.05). Male sex (adjusted odds ratio [aOR] 1.15; 95% CI [1.09,1.21]; p < 0.0001), ages above 65 (aOR 1.28; 95% CI [1.16–1.41]; p < 0.0001), and inpatient department (aOR 1.24; 95% CI [1.13–1.35]; p < 0.0001) were associated with higher AMR prevalence among culture-positive samples. The lack of routine testing, as reflected in the low data volume from most contributing laboratories, and the absence of patient clinical information, represent significant limitations of this study. Conclusion: Analysis of the largest retrospective AMR dataset in Africa indicates high variability in AMR prevalence across countries, coupled with differences in AMR testing capacities, data quality, and AMR estimates. Gaps in AST practices and inadequate digital infrastructures for data collection and reporting represent barriers to estimating the true AMR burden in the region. These barriers warrant large-scale investments to expand healthcare access and strengthen bacteriology laboratory capacities.

Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression.

Purpose: The aim of this study was to investigate the role of serotonin and protein 53 (p53) status of the cells in the radiation-induced bystander effects (RIBE). Materials and methods: The radiation-induced bystander response was investigated in human MCF-7 breast cancer cells and human HCT116 colorectal cancer cells employing medium-transfer experiments and micronuclei (MN) induction as an end-point. Irradiated cell conditioned medium (ICCM) from cells exposed to α-particle or γ-radiation was filtered and transferred to unirradiated cells 2 h following irradiation. MCF-7 cells were irradiated with 0.5 Gy α-particles, while HCT116 p53^+/+ and HCT116 p53^−/− cells were irradiated with 0.5 Gy γ-radiation. Results: Bystander MCF-7 cells, recipient of ICCM from 0.5 Gy α-particle irradiated MCF-7 cells grown in high serotonin conditions showed a modest but significant increase in MN, while MCF-7 cells receiving ICCM with low serotonin levels did not show any bystander effect. Added serotonin (100 ng/ml) led to a bystander effectin HCT116 p53^−/− cells recipient of ICCM from 0.5 Gy γ-irradiated HCT116 p53^+/+ cells, but had no effect when the ICCM was from γ-irradiated HCT116 P53^−/− cells. Conclusion: The results indicate that serotonin levels in the medium play a role in the RIBE and that there may be an interaction between the role of serotonin and the p53 status of the irradiated cells.