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We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.

The transition from fossil fuels to clean energy is a global priority to combat climate change, energy insecurity, and environmental degradation, with green hydrogen from renewable sources emerging as a promising and carbon‐free energy carrier. This study presents a comprehensive technoeconomic and environmental assessment of renewable energy–based hydrogen production systems, focusing on the coastal region of Marsa Matrouh, Egypt. In this regard, a fuzzy analytical hierarchy process (F‐AHP) integrated with multicriteria decision analysis (MCDA) is applied using four key criteria: commercial potential of hydrogen production, environmental impact of carbon dioxide (CO 2 ) mitigation, economic benefit, and social acceptance. Also, the photovoltaic (PV), wind turbine (WT), and alkaline (ALK) electrolysis are effectively modeled using their first‐order energy balance equations to estimate electricity and hydrogen output. The modeling approach is implemented via MATLAB simulation using the National Aeronautics and Space Administration (NASA) climate data of hourly solar radiation, temperature, and wind speed data to estimate energy output, hydrogen yield, and the levelized cost of hydrogen (LCOH). A case study is conducted in Marsa Matrouh, Egypt, to assess the technical and economic viability of five distinct scenarios: (SC 1 ) 100% PV, (SC 2 ) 100% WT, (SC 3 ) 50% PV + 50% WT, (SC 4 ) 70% PV + 30% WT, and (SC 5 ) 30% PV + 70% WT. Results show that the 100% wind scenario (SC 2 ) is optimal, delivering the highest annual energy (2417 MW h), hydrogen output (36 tons), CO 2 mitigation (769 tons/year), and the lowest LCOH ($2.66/kg), with the highest F‐AHP score (0.5360). These findings highlight the strategic value of wind energy for large‐scale hydrogen production and support Egypt’s Vision 2030 for green energy transformation.

Background: Vertical banded gastroplasty (VBG) was historically a popular restrictive bariatric procedure, but long‐term failure rates due to weight regain, stenosis, and gastroesophageal reflux have necessitated revisional interventions. One anastomosis gastric bypass (OAGB), also known as mini‐gastric bypass, has emerged as a viable revisional option due to its technical simplicity, lower complication rates, and promising metabolic outcomes. This study evaluates the safety, efficacy, and outcomes of OAGB as a revisional procedure following failed VBG, based on our center’s experience and a review of the current literature. Methods: Seventy‐one patients who underwent revisional OAGB after failed open VBG between February 2014 and February 2020 were included in this retrospective study. Three years outcomes regarding weight loss (the percentage of excess body weight loss (EBWL %) and change in body mass index (BMI)), co‐morbidities resolution, morbidity, and mortality were assessed. Results: The EBWL % after revisional OAGB was 68.2 ± 9.4%, 65.9 ± 2.5%, and 59.6 ± 7.4% after 1, 2, and 3 years, respectively. The mean BMI before revisional surgery was 41.8 ± 3.7 kg/m 2 ,which decreased to 31.9 ± 4.2 kg/m 2 3 years after the revisional surgery. After 1 year, there was a remarkable resolution of obesity‐related co‐morbidities, the remission of type 2 diabetes mellitus was 85.7%, and of hypertension was 80%. Remission of other comorbidities was also observed. Bile reflux was encountered in 6 cases (8.5%), two of them required surgical intervention. Conclusions: OAGB is a feasible and effective revisional procedure after failed open VBG. However, the risk of bile reflux should be considered to justify these findings; further prospective randomized controlled trials are required.

Previous findings indicated that the laser photobiomodulation is more effective than the control or placebo in preserving the alveolar socket. This study aimed to compare two different lasers regarding their effectiveness in aiding alveolar socket preservation. Twenty extraction sockets were selected then divided into two equal groups. Group A was exposed to 650 nm Diode laser, and Group B to 810 nm Diode laser following the same protocol and parameters after a standard alveolar socket preservation procedure with collagen plug. Radiographic analysis with cone beam computed tomography was done to compare the alveolar bone surface area immediately after extraction and three months post-operatively, while bone samples collected before implant drilling were histologically examined for newly formed bone evaluation and histomorphometric analysis in terms of percentage of new bone surface area, percentage of unmineralized bone and finally, immunohistochemical analysis of Osteocalcin reaction surface area as well as optical density. Radiographically, infrared (810 nm) Diode effect on alveolar bone surface area has significantly exceeded the red laser, while histologically, red (650 nm) Diode has demonstrated statistical significance regarding all parameters; newly formed bone surface area percentage, unmineralized bone area percentage and finally Osteocalcin bone marker reaction surface area percentage and optical density. Under the specified conditions and laser parameters, photobiomodulation using the 810 nm Diode got the upper hand radiographically, yet histologically, the red 650 nm Diode managed to dominate all histological parameters when both employed as an adjunct to alveolar socket preservation procedures.

BackgroundIn this study, we describe the generation of a fully human monoclonal antibody (named ‘7NP2’) targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.Methods7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in Cynomolgus monkeys.ResultsBiodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.ConclusionsThe results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.

Advanced central bronchogenic carcinoma often accompanies adjacent obstructive consolidation. Differentiation between bronchogenic carcinoma and Post obstructive consolidation (POC) is necessary to determine the true tumor size and field of radiation therapy or post-therapeutic evaluation. 15 cases with lung carcinoma were compared to 15 participants (control group) who were diagnosed as non-tumoral consolidation. Tumor and POC differentiation in CT was reported in 9 (60%) cases. Tumor and POC differentiation in T2 was reported in 11 (73.3%) cases. Tumor and POC differentiation in DWI was reported in 15 (100%) cases. Mean ADC values in lung carcinoma mass was significantly lower when compared to mean ADC values in lung consolidation (P < 1 x 10.sup.-3). Cut off value less than 1.85 x 10.sup.-3 mm.sup.2/s of ADC value had significant differentiation ability to detect malignant mass from consolidation with area under curve 0.936 (P < 1 x 10.sup.-3), with 100% sensitivity and 66.7% specificity.

Neutralizing monoclonal antibodies have achieved great efficacy and safety for the treatment of numerous infectious diseases. However, their neutralization potency is often rapidly lost when the target antigen mutates. Instead of isolating new antibodies each time a pathogen variant arises, it can be attractive to adapt existing antibodies, making them active against the new variant. Potential benefits of this approach include reduced development time, cost, and regulatory burden. Here a methodology is described to rapidly evolve neutralizing antibodies of proven activity, improving their function against new pathogen variants without losing efficacy against previous ones. The reported procedure is based on structure‐guided affinity maturation using combinatorial mutagenesis and phage display technology. Its use against the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is demonstrated, but it is suitable for any other pathogen. As proof of concept, the method is applied to CoV‐X2, a human bispecific antibody that binds with high affinity to the early SARS‐CoV‐2 variants but lost neutralization potency against Delta. Antibodies emerging from the affinity maturation selection exhibit significantly improved neutralization potency against Delta and no loss of efficacy against the other viral sequences tested. These results illustrate the potential application of structure‐guided affinity maturation in facilitating the rapid adaptation of neutralizing antibodies to pathogen variants.

DNA-encoded chemical libraries (DELs) consist of large chemical compound collections individually linked to DNA barcodes, facilitating pooled construction and screening. However, screening campaigns often fail if the molecular arrangement of the building blocks is not conducive to an efficient interaction with a protein target. Here we postulated that the use of rigid, compact and stereo-defined central scaffolds for DEL synthesis may facilitate the discovery of very specific ligands capable of discriminating between closely related protein targets. We synthesized a DEL comprising 3,735,936 members, featuring the four stereoisomers of 4-aminopyrrolidine-2-carboxylic acid as central scaffolds. The library was screened in comparative selections against pharmaceutically relevant targets and their closely related protein isoforms. Hit validation results revealed a strong impact of stereochemistry, with large affinity differences between stereoisomers. We identified potent isozyme-selective ligands against multiple protein targets. Some of these hits, specific to tumour-associated antigens, demonstrated tumour-selective targeting in vitro and in vivo. Collectively, constructing DELs with stereo-defined elements contributed to high library productivity and ligand selectivity.The design and construction of a stereo-defined DNA-encoded chemical library, featuring the four different 4-amino-proline stereoisomers as a central scaffold, has now enabled the discovery of potent ligands to proteins of pharmaceutical interest. Parallel screening with closely related isoforms (anti-targets) facilitated the isolation of hits with high selectivity ratios.

Existence rectangles of positive eigenvalues with corresponding positive eigenfunctions of 2 p -order and 2 q -order nonlinear coupled multiparameter systems of ordinary differential equations are introduced. The boundary conditions are related to the Abel–Whittaker interpolation problem f ( 2 k ) ( 1 ) = a k , f ( 2 k + 1 ) ( 0 ) = b k , k ≥ 0 . The multiplicity of the eigenvalues are also investigated. Under standard conditions, we prove the existence of rectangles of non-simple eigenvalues with multiplicities greater than or equal to two.

BackgroundFibroblast Activation Protein (FAP) has been described as the “next billion-dollar nuclear theranostics target”1, since more than 28 different tumor types have successfully been imaged in patients with radiolabeled FAP ligands. 2-3 FAP can be found in the tumor microenvironment (TME) of most malignant solid tumors, while being absent in most healthy tissues. Thus, it is an attractive target for both imaging and therapeutic applications. Monoclonal antibodies targeting TME antigens have been considered for the delivery of bioactive payloads, such as proinflammatory cytokines. Antibody-cytokine fusions (also called immunocytokines) may exploit the tumor-homing properties of the antibody moiety, in order to concentrate the cytokine payload at the site of disease and enhance the therapeutic index.4 Interleukin-12 (IL12) have been extensively studied in oncology. IL12 strongly promotes NK cells, CD4+ and CD8+ T cells to produce interferon-gamma (IFN-g), one of the most relevant mediators of anti-cancer immunity.5MethodsIn this work, we describe the generation of a novel anti-FAP antibody, called 7NP2. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin-12 was generated and the anti-cancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. To prepare for future clinical trials, a fusion protein consisting of human IL12 linked to the 7NP2 antibody was further investigated in a toxicology study in Cynomolgus monkeys.ResultsBiodistribution analysis in tumor bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent anti-tumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.ConclusionsThe results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.ReferencesCalais J. FAP: The next billion dollar nuclear theranostics target?. Journal of Nuclear Medicine 2020;61(2). doi:10.2967/jnumed.119.241232.Kratochwil C, et al, 68Ga-FAPI PET/CT: Tracer uptake in 28 different kinds of cancer. Journal of Nuclear Medicine 2019;60(6). doi: 10.2967/jnumed.119.227967.Backhaus P, et al.Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA. European Journal of Nuclear Medicine and Molecular Imaging 2022;49(6). doi:10.1007/s00259-021-05653-0.Neri D. Antibody–Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity. Cancer Immunology Research 2019. doi: 10.1158/2326-6066.CIR-18-0622.Puca E, et al. The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors. International Journal of Cancer 2019. doi:10.1002/ijc.32603.Ethics ApprovalMouse experiments were performed under a project license (license number 04/2018) granted by the Veterinäramt des Kantons Zürich, Switzerland, in compliance with the Swiss Animal Protection Act (TSchG) and the Swiss Animal Protection Ordinance (TSchV).Procedures on Cynomolgus monkeys (including housing, health monitoring, restrain, dosing, etc) and ethical revision were performed according to the current Italian legislation (Legislative Decree March 4th, 2014 n. 26) enforcing the 2010/63/EU Directive on the protection of animals used for biomedical research.