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Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti‐MM activity of engineered toxin body MT‐0169, a next‐generation immunotoxin comprising a CD38‐specific antibody fragment linked to a de‐immunized Shiga‐like toxin A subunit (SLTA) payload. We show that specific binding of MT‐0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co‐culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT‐0169. In the preclinical setting, MT‐0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT‐0169 showed efficient in vivo anti‐MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow‐like niche. These findings support clinical investigation of MT‐0169 in relapsed/refractory MM patients, including those refractory to CD38‐targeting immunotherapies.

BackgroundPD-L1 targeting mAbs have had success in the clinic for a variety of solid tumors and specific patient subsets. To date, all PD-L1 mAbs rely on blocking the PD-1/PD-L1 axis through steric hindrance for their activity. MT-6402 is a clinical stage ETB that binds to PD-L1, triggers receptor internalization, and induces cell death of PD-L1+ cells through ribosomal destruction. MT-6402 represents a wholly novel approach to targeting PD-L1 expressing immune and tumor cells built upon the clinical hypothesis that elimination rather than blocking of PD-L1+ tumor and immune cells could transform immune tolerant tumor microenvironments (TME) to immune augmenting phenotypes. To this end, MT-6402 also carries a CMVpp65 peptide capable of HLA-A*02 restricted antigen presentation designed to redirect CMV-specific cytotoxic T cells to tumor tissue. Thus far, MT-6402 has completed three dosage cohorts (n=16) in a phase 1 dose escalation trial. Here we show changes in serum vascular endothelial growth factor (VEGF) correlate with peripheral reductions in monocyte derived suppressor cells (MDSCs), both biomarkers of potential TME alterations and a unique peripheral effect not seen with αPD-L1 blocking mAbs.MethodsPeripheral blood mononuclear cells (PBMC) from MT-6402-dosed patients were stained with surface antibodies and acquired on a flow cytometer to identify CD11b+CD14+HLA-DR-/low Monocytic MDSCs. Luminex was used to quantify VEGF concentrations in patient matched serum.ResultsA sawtooth pattern of peripheral VEGF levels emerged in 5/7 patients with higher pre-dose VEGF levels (>125pg/ml) following multiple doses of MT-6402 and indicative of a tumor remodeling response. A gradual VEGF increase in cohort 1 cycle 1 correlated with peripheral MDSC extravasation into tissue or TME. For cohorts 2 and 3, an inverse relationship between VEGF concentrations and MDSC frequencies emerged, where spikes in MDSCs correlated to sharp reductions in serum VEGF levels. Overall, PBMC phenotyping and cytokine data demonstrated an inverse correlation of MDSC frequencies and VEGF concentrations across dosage cohorts.ConclusionsPD-L1 expression on tumor and immune cells have non-redundant contributions to the maintenance of the TME and disease progression. Current PD-L1 antibodies physically inhibit PD-L1 and PD-1 interaction but do not fully inhibit PD-L1+ immune cell functions that contribute to TME maintenance (i.e., cytokine/chemokine secretion). Unlike PD-L1 antibodies, MT-6402 was designed to destroy PD-L1+ immune cells in a target-specific manner. We demonstrate here that MDSCs are depleted in the periphery of patients treated with MT-6402 and that this depletion appears related to peripheral changes in VEGF and alterations of the TME.Trial RegistrationNCT04795713Ethics ApprovalThis study was conducted in compliance with current Good Clinical Practice (GCP) standards as defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for GCP, all applicable national, state , and local laws and regulations, and the applicable Institutional Review Board/Independent Ethics Committee (IRB/IEC) and other institutional requirements.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

The p107 protein, a member of the pocket protein family of tumor suppressors, is an important regulator of normal cell cycle progression and growth. The small DNA tumor viruses (adenovirus, human papilomavirus, and SV40) all encode a viral protein that specifically targets p107 for regulation through direct binding of the protein in order to facilitate viral DNA replication by inducing an exit from quiescence and the creation of an S-phase like environment. We demonstrate here that the IE1-72 gene product of the human cytomegalovirus (HCMV) also binds the p107 protein during infection and functionally alters its biological effects. Expression of the IE1-72 gene product results in the alleviation of p107-mediated transcriptional repression of an E2F-responsive promoter and presumably allows for the activation of a series of E2F-responsive promoters involved in DNA replication. This model is supported by data demonstrating that IE1-72 expression alone is sufficient to induce DNA replication in quiescent cells. Mapping studies have revealed that the IE1-72 protein binds p107 in the cyclin-binding region of the protein suggesting that IE1-72 expression effects the ability of p107 to bind and regulate both E2F and the cyclin/cdk2 complexes it is normally associated with. Infection by HCMV or expression of the IE1-72 protein alone is capable of overcoming a p107-mediated block in cell growth further supporting the notion that IE1-72 expression plays a pivotal role during HCMV infection in creating an environment favorable to viral DNA replication.

Floods represent the most frequent natural hazard, generating significant impacts on people as well as considerable economic and environmental losses worldwide. These events are particularly exacerbated by extreme climatic phenomena, such as the 2017 Coastal El Niño, the most intense in the past century, with the Piura region of Peru being the most affected. Flood susceptibility mapping (FSM) are essential for mitigating the negative impacts of floods through land-use planning, policy and plan formulation, and fostering community resilience for the sustainable occupation and use of floodplains. This study aimed to develop FSM in northern Peru, particularly in the Piura region, using a hybrid methodology integrating optical and radar remote sensing (RS), GIS, and machine learning (ML) techniques. Sentinel-1 data were used to map flood extent using the Normalized Difference Flood Index (NDFI), while flood susceptibility was modeled using ten topographic variables (derived from a DEM), the Normalized Difference Vegetation Index (NDVI), geology, and geomorphology; issues related to correlation and multicollinearity among topographic variables were addressed through Principal Component Analysis (PCA), selecting four principal components that explained 75.4% of the variance. Six FSMs were generated using Support Vector Machine (SVM) and Random Forest (RF), combined with different methods to estimate the quantitative relationship between variables and flood occurrence: Quantiles (q), Frequency Ratio (FR), and Weights of Evidence (WoE) (SVM-q, SVM-FR, SVM-WoE, RF-q, RF-FR, and RF-WoE). Model validation was performed using metrics such as the Area Under the ROC Curve (AUC), F1-score, and Accuracy, along with a cross-validation analysis. The results revealed that the RF ensemble model with WoE (RF-WoE) exhibited the best performance (AUC = 0.988 in training and >0.907 in validation), outperforming the SVM-based models; the SHAP analysis confirmed the significance of geology, geomorphology, and aspect in flood prediction. The resulting susceptibility maps identified the lower Piura River basin as the most vulnerable area, particularly during the 2017 Coastal El Niño event, due to morphological factors and inadequate land occupation. This study contributes to the field by demonstrating the effectiveness of a hybrid methodology that combines PCA, machine learning, and SHAP analysis, providing a more robust and interpretable approach to flood susceptibility mapping. Finally, the findings provide valuable inputs for local authorities, decision-makers, and organized communities to strengthen resilience, reduce vulnerability, and enhance preparedness against future floods, while also supporting the formulation of public policies and the integration of flood susceptibility into land-use planning for sustainable territorial management.

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in d-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.

In the original publication of the article, the names of the COVID-19 Task Force were not listed as contributors.

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34–1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01–1.34); Ca × P product from 58 to 48 (p = 0.001, 95% CI 4.2–15.7); and intact PTH (iPTH) from 426 ± 274 to 300 ± 228 pg/ml (p = 0.03, 95% CI 19.3–401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).

Samples of two characteristic semiconductor sensor materials, silicon and germanium, have been irradiated with neutrons produced at the RP-10 Nuclear Research Reactor at 4.5 MW. Their radionuclides photon spectra have been measured with high resolution gamma spectroscopy, quantifying four radioisotopes (\\(^{28}\\)Al, \\(^{29}\\)Al for Si and \\(^{75}\\)Ge and \\(^{77}\\)Ge for Ge). We have compared the radionuclides production and their emission spectrum data with Monte Carlo simulation results from FLUKA. Thus we have tested FLUKA's low energy neutron library (ENDF/B-VIIR) and decay photon scoring with respect to the activation of these semiconductors. We conclude that FLUKA is capable of predicting relative photon peak amplitudes, with gamma intensities greater than 1%, of produced radionuclides with an average uncertainty of 13%. This work allows us to estimate the corresponding systematic error on neutron activation simulation studies of these sensor materials.