41
Background: The optimal threshold based on pre-treatment PET for patient selection for LuPSMA is yet to be defined. TheraP trial applied a high threshold for PSMA-expression on PSMA PET and ...utilized FDG PET to exclude FDG-avid/non-PSMA-avid disease while the VISION trial used only PSMA PET with a lower threshold of PSMA-expression. The stricter criteria in TheraP trial doubled the screening failure rate compared to VISION trial, 28% vs. 12.6%. In this study among VISION-eligible patients, we aimed to compare the outcome of those who were TheraP-Eligible (TheraP-E) to TheraP-Ineligible (TheraP-I). Further, the prognostic value of FDG-PET phenotyping is investigated. Methods: This retrospective cohort study evaluated consecutive VISION-eligible mCRPC patients who received at least one cycle of LuPSMA and had both PSMA- and FDG-PET within one month of each other between June 2022 and January 2023. Patients were blindly classified as TheraP-E vs. TheraP-I. We compared whole-body semiquantitative parameters including total tumor volume (TTV), SUVmean and SUVmax and outcomes including PSA decline of ≥50% relative to baseline (PSA50), PSA-progression-free survival (PSA-PFS), and overall survival (OS) between the groups. Separately, the patients were dichotomized to having dominant FDG-avid disease (uptake > liver in most sites of disease) vs. non-FDG-avid disease and OS were compared by Cox-regression. Results: 46 patients (median age: 72, ECOG 0-2: 89%, visceral disease: 28%) were included with a median follow-up of 10 months (IQR: 8-14). 14/46 (30%) patients assessed as TheraP-I and had lower PSMA-PET SUVmean and SUVmax compared to TheraP-E patients (5.6 vs. 8.8 and 23 vs. 53, p < 0.001 for both) while other PET parameters including PSMA TTV and FDG parameters (SUVmax, SUVmean and TTV) were not statistically different. TheraP-I patients had lower PSA50 response (21% vs. 56%, p = 0.029) but PSA-PFS and OS were not significantly different compared to TheraP-E patients (Table). 37/46 (80%) patients assessed as FDG-avid had an increased risk of death compared to non-FDG-avid counterparts (Table). Conclusions: In a VISION-eligible population receiving LuPSMA, TheraP imaging-based ineligibility was associated with worse PSA response but with no significant difference in PSA-PFS or OS. Clinical investigation of the more permissive VISION inclusion criteria and the importance of FDG-avid disease using a larger sample size is warranted. Table: see text
Despite significant advancements in material science, surgical site infection (SSI) rates remain high and prevention is key. This study aimed to demonstrate the in vivo safety and antibacterial ...efficacy of titanium implants treated with a novel broad‐spectrum biocidal compound (DBG21) against methicillin‐resistant Staphylococcus aureus (MRSA). Titanium (Ti) discs were covalently bound with DBG21. Untreated Ti discs were used as controls. All discs were implanted either untreated for 44 control mice or DBG21‐treated for 44 treated mice. After implantation, 1 × 107 colony forming units (CFU) of MRSA were injected into the operating site. Mice were killed at 7 and 14 days to determine the number of adherent bacteria (biofilm) on implants and in the peri‐implant surrounding tissues. Systemic and local toxicity were assessed. At both 7 and 14 days, DBG21‐treated implants yielded a significant decrease in MRSA biofilm (3.6 median log10 CFU 99.97% reduction p < 0.001 and 1.9 median log10 CFU 98.7% reduction p = 0.037, respectively) and peri‐implant surrounding tissues (2.7 median log10 CFU/g 99.8% reduction p < 0.001 and 5.6 median log10 CFU/g 99.9997% reduction p < 0.001, respectively). There were no significant differences between control and treated mice in terms of systemic and local toxicity. DBG‐21 demonstrated a significant decrease in the number of biofilm bacteria without associated toxicity in a small animal implant model of SSI. Preventing biofilm formation has been recognized as a key element of preventing implant‐related infections.
TMPRSS6 is a regulated gene, with a crucial role in the regulation of iron homeostasis by inhibiting hepcidin expression. The main regulator of iron homeostasis, the antimicrobial peptide hepcidin, ...which also has a role in immunity, is directly upregulated by inflammation. In this study, we analyzed whether inflammation is also a modulator of TMPRSS6 expression in vitro and in vivo and we determined the mechanism of this regulation A Human Hepatoma cell line was treated with interleukin-6 and mice were injected with lipopolysaccharide and TMPRSS6 expression and the regulatory mechanism were addressed. In this study, we demonstrate that inflammation downregulates TMPRSS6 expression in vitro and in vivo. The downregulation of Tmprss6 by inflammation in mice is not dependent on the Bmp-Smad pathway but occurs through a decrease in Stat5 phosphorylation. Moreover, Stat5 positively regulates Tmprss6 expression directly by binding to a Stat5 element located on the Tmprss6 promoter. Importantly, our results highlight the functional role of inflammatory modulation of TMPRSS6 expression in the regulation of hepcidin. TMPRSS6 inhibition via decreased STAT5 phosphorylation may be an additional mechanism by which inflammation stimulates hepcidin expression to regulate iron homeostasis and immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
5055
Background: LuPSMA, a radioligand targeting the cell surface protein PSMA, is approved for men with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) following an androgen ...receptor (AR)-signaling inhibitor (ARSI) and docetaxel. DNA damage repair gene (DDR) mutations are common in mCRPC, and given that ionizing radiation induces DNA damage, we hypothesized that the presence of these alterations could associate with improved clinical outcomes to LuPSMA. Data also suggests that the presence of DDR mutations may correlate with PSMA expression, providing further motivation to evaluate if DDR alterations are associated with the clinical activity of LuPSMA. Methods: We abstracted retrospective data from all patients at our center who received at least one cycle of LuPSMA per the FDA label and who had panel-based sequencing performed (e.g. UW-Oncoplex, Foundation One). Patients with somatic or germline alterations in a DDR gene were assigned to the DDR deficient cohort, while patients with somatic testing negative for a DDR gene mutation were assigned to the DDR intact cohort. Mutations in any DDR gene were considered for the purpose of stratifying between genomic subgroups. Differences in baseline PSMA SUVmean and PSA
50
responses (i.e. ≥50% decline in PSA) were compared between cohorts. Results: Of 91 patients who received ≥1 cycle of LuPSMA, 54 had genetic testing. 35 (64%) received ≥2 lines of prior ARSI therapy, 30 (56%) received ≥2 lines of prior chemotherapy and 15 (28%) received prior PARP inhibitor. 21 patients had alterations in a DDR gene and the remaining 33 patients had somatic testing without an identifiable DDR mutation. PSMA SUVmean was similar between groups: 8.04 (95% CI: 6.95 - 9.12) (DDR intact) vs. 7.32 (95% CI: 6.23 – 8.41) (DDR deficient), p = 0.37. 7/33 (21%) patients in the DDR intact group achieved PSA
50
response compared to 11/21 (52%) in the DDR group (p= 0.018). Survival data is immature but will be presented at the meeting. Rapid autopsy (RA) was performed in one subject with a BRCA2 mutation (baseline PSMA SUVmean 5.6) and immunohistochemistry analysis revealed profound loss of PSMA following progression on LuPSMA. Conclusions: Mutations in DDR genes were associated with a higher PSA
50
response rate following LuPSMA compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that higher response rates in the DDR cohort may have been mediated primarily by increased sensitivity to ionizing radiation. Evaluation for associations between DDR mutational status and survival endpoints is needed and will require a larger sample size and longer follow up. RA post-LuPSMA revealed loss of PSMA expression, suggesting that antigen loss may be a relevant resistance mechanism. Table: see text
Pb, Hf, Nd and Sr isotopes of basaltic lavas from the two Réunion Island volcanoes are reported in order to examine the origin of the sources feeding these volcanoes and to detect possible changes ...through time. Samples, chosen to cover the whole lifetime of the two volcanoes (from 2 Ma to present), yield a chemically restricted (compared to OIB lavas) but complex distribution. Réunion plume isotopic characteristics have been defined on the basis of the composition of uncontaminated shield-building lavas from the Piton de la Fournaise volcano. The average
ɛ
Nd,
ɛ
Hf,
87Sr/
86Sr and
206Pb/
204Pb,
207Pb/
204Pb, and
208Pb/
204Pb isotope ratios calculated for this component are +
4.4, +
9.1, 0.70411, 18.97, 15.59 and 39.03, respectively. In Pb–Pb isotope space, each volcano defines a distinct linear trend but slight variations are also detected within the various volcanic sequences. The Piton des Neiges volcano yields a distinct and significantly more scattered isotopic distribution than Piton de la Fournaise for both Pb, Hf and Nd isotope tracers. A principal component analysis of the Pb isotope data from Piton de la Fournaise reveals a major contribution of the C and EM-1 components (with a clear Dupal flavor) as main components for the modern Réunion plume. The same components have been identified for Piton des Neiges but with a stronger participation of a depleted mantle component and a weaker EM-1 contribution. The compositional change of the lavas erupted by the Piton des Neiges and Piton de la Fournaise volcanoes is attributed to the impingement of two small-scale blobs of plume material at the base of the Réunion lithosphere. Compared to other hot-spots worldwide, in particular Hawaii and Kerguelen, magmas beneath Réunion are generated from a considerably more homogeneous, compositionally more primitive plume higher in
206Pb. Although shallow-level contamination processes have been locally detected they did not alter significantly the composition of the plume magmas. This is tentatively attributed to mantle dynamics producing small, high-velocity blobs that ascend rapidly through the lithosphere, and to the lack of a well-developed magma chamber at depth in the lithosphere.
Staphylococcus aureus gamma-hemolysin CB (HlgCB) is a core-genome-encoded pore-forming toxin that targets the C5a receptor, similar to the phage-encoded Panton-Valentine leucocidin (PVL). Absolute ...quantification by mass spectrometry of HlgCB in 39 community-acquired pneumonia (CAP) isolates showed considerable variations in the HlgC and HlgB yields between isolates. Moreover, although HlgC and HlgB are encoded on a single operon, their levels were dissociated in 10% of the clinical strains studied. To decipher the molecular basis for the variation in
expression and protein production among strains, different regulation levels were analyzed in representative clinical isolates and reference strains. Both the HlgCB level and the HlgC/HlgB ratio were found to depend on
promoter activity and mRNA processing and translation. Strikingly, only one single nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of
mRNA strongly impaired
translation in the USA300 strain, leading to a strong decrease in the level of HlgC but not in HlgB. Finally, we found that high levels of HlgCB synthesis led to mortality in a rabbit model of pneumonia, correlated with the implication of the role of HlgCB in severe S. aureus CAP. Taken together, this work illustrates the complexity of virulence factor expression in clinical strains and demonstrates a butterfly effect where subtle genomic variations have a major impact on phenotype and virulence.
S. aureus virulence in pneumonia results in its ability to produce several virulence factors, including the leucocidin PVL. Here, we demonstrate that HlgCB, another leucocidin, which targets the same receptors as PVL, highly contributes to S. aureus virulence in
-negative strains. In addition, considerable variations in HlgCB quantities are observed among clinical isolates from patients with CAP. Biomolecular analyses have revealed that a few SNPs in the promoter sequences and only one SNP in the 5' UTR of
mRNA induce the differential expression of
, drastically impacting
mRNA translation. This work illustrates the subtlety of regulatory mechanisms in bacteria, especially the sometimes major effects on phenotypes of single nucleotide variation in noncoding regions.
In the last decade, the microfluidic community has witnessed an evolution in fabrication methodologies that deviate from using conventional glass and polymer-based materials. A leading example within ...this group is the print, cut and laminate (PCL) approach, which entails the laser cutting of microfluidic architecture into ink toner-laden polyester sheets, followed by the lamination of these layers for device assembly. Recent success when applying this method to human genetic fingerprinting has highlighted that it is now ripe for the refinements necessary to render it amenable to mass-manufacture. In this communication, we detail those modifications by identifying and implementing a suitable heat-sensitive adhesive (HSA) material to equip the devices with the durability and resilience required for commercialization and fieldwork. Importantly, this augmentation is achieved without sacrificing any of the characteristics which make the PCL approach attractive for prototyping. Exemplary HSA-devices performed DNA extraction, amplification and separation which, when combined, constitute the complete sequence necessary for human profiling and other DNA-based analyses.
Despite significant technological advancements in material science, a high level of hand-hygiene and systematic use of antiseptics and antibiotics, surgical site infections (SSI) are still to date ...the number one complication seen after surgery in the United States. Methicillin-resistant Staphylococcus aureus (MRSA) is the largest purveyor of health care-acquired infections (HCAI) and is responsible for significant morbidity and mortality.
This study aimed to demonstrate the in-vivo safety and antibacterial efficacy of non-eluting titanium implants covalently bound with a novel broad-spectrum biocidal quaternary ammonium compound (DBG21) against MRSA biofilm.
Subcutaneous MRSA infection mouse model comparing the antimicrobial efficacy of untreatedversusDBG21-treated titanium alloy discs. A separate comparative safety study was performed in the absence of infection.
Sixty-five 11-week-old balb/c mice.
Efficacy study: Number of adherent bacteria on implants (CFU) and in the surrounding tissue (CFU/g) at days 7 and 14. Safety study: systemic and subacute toxicity (clinical tolerance, blood tests and histology).
Efficacy Study: TiAl6V4 discs, 6mm ø, 0.5 mm thick, were activated, dip-coated in a polymer solution, and baked to produce covalently bound DBG21-treated discs. Untreated TiAl6V4 discs were used as controls. All discs underwent subsequent sterilization by 25kGy gamma-irradiation, were implanted either untreated for control mice or DBG21-treated for treated mice, and were challenged with a high-bacterial inoculum of MRSA (ATCC43300) in a well-established subcutaneous infection mouse model (11-week-old balb/c) in the absence of antibiotics. A veterinary ethics committee validated the protocol. Sixty-five mice (33 controls, 32 treated) were included in an antibacterial efficacy study. After implantation of one disc in a posterior subcutaneous pocket and closure of the skin for each mouse, 7 log10CFU (colony forming units) of MRSA were injected through a catheter into the operating site. Mice were sacrificed after either 7 days (18 treated, 18 controls) or 14 days (15 controls, 14 treated) to determine the number of adherent bacteria (biofilm) on implants and in the peri-implant surrounding tissues. Results were expressed respectively as median log10CFU reduction on implants and median log10CFU/g reduction in tissue compared with untreated control mice. The statistical significance (p) was determined using Mann-Whitney tests. Safety Study: Ten mice implanted with either control (5 mice) or DBG-21 treated (5 mice) discs were assessed in a safety study in the absence of infection (ISO 10993-11:2017 for systemic and subacute toxicity including clinical tolerance, blood tests and local histology).
Efficacy Study: At both 7 and 14 days, DBG21-treated implants yielded a significant decrease in MRSA biofilm (respectively 3.6 median log10CFU (99.97%) reduction (p < 0.001) and 1.9 median log10CFU (98.7%) reduction (p = 0.037)) and peri-implant surrounding tissues (respectively 2.7 median log10CFU/g (99.8%) reduction (p < 0.001) and 5.6 median log10CFU/g (99.9997%) reduction (p < 0.001)). At day 7, three treated mice (16.6%) were completely sterilized on both tissue and implant. At day 14, 10 treated mice (71.4%) had sterile peri-implant tissue. Safety Study: There were no significant differences between control and treated mice in terms of clinical scores, blood tests and local histology after up to 11 days from implantation.
Preventing biofilm formation has been recognized as a key element of SSI prevention. Yet, no biofilm-resistant titanium implants are available in clinical practice to prevent and mitigate the burden of SSIs. This small animal safety and efficacy trial suggests that DBG-21 is a promising candidate for antimicrobial surface modification of titanium implants.
DBG21 antimicrobial surface modification (Not approved for this indication).
This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC).
Female patients with ...advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m
) and carboplatin (dose in mg calculated by area under the curve mg/mL/min × (glomerular filtration rate mL/min + 25 mL/min) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient.
Patients received lacnotuzumab + gem-carbo (
= 34) or gem-carbo (
= 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months 90% confidence interval (CI), 4.47-8.64 in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand.
Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC.
The availability of iron (Fe) to marine microbial communities is enhanced through complexation by ligands. In Fe limited environments, measuring the distribution and identifying the likely sources of ...ligands is therefore central to understanding the drivers of marine productivity. Antarctic coastal marine environments support highly productive ecosystems and are influenced by numerous sources of ligands, the magnitude of which varies both spatially and seasonally. Using competitive ligand exchange adsorptive cathodic stripping voltammetry (CLE-AdCSV) with 2-(2-thiazolylazo)-
p
-cresol (TAC) as a competing artificial ligand, this study investigates Fe-binding ligands (FeL) across the continental shelf break in the Mertz Glacier Region, East Antarctica (64 - 67°S; 138 - 154°E) during austral summer of 2019. The average FeL concentration was 0.86 ± 0.5 nM Eq Fe, with strong conditional stability constants (Log K
FeL
) averaging 23.1 ± 1.0. The strongest binding ligands were observed in modified circumpolar deep water (CDW), thought to be linked to bacterial Fe remineralisation and potential siderophore release. High proportions of excess unbound ligands (L’) were observed in surface waters, as a result of phytoplankton Fe uptake in the mixed layer and euphotic zone. However, FeL and L’ concentrations were greater at depth, suggesting ligands were supplied with dissolved Fe from upwelled CDW and particle remineralisation in benthic nepheloid layers over the shelf. Recent sea-ice melt appeared to support bacterial production in areas where Fe and ligands were exhausted. This study is included within our newly compiled Southern Ocean Ligand (SOLt) Collection, a database of publicly available Fe-binding ligand surveys performed south of 50°S. A review of the SOLt Collection brings attention to the paucity of ligand data collected along the East Antarctic coast and the difficulties in pinpointing sources of Fe and ligands in coastal environments. Elucidating poorly understood ligand sources is essential to predicting future Fe availability for microbial populations under rapid environmental change.
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