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The lungs are major sites of metastases for several cancer types, including breast cancer (BC). Prognosis and quality of life of BC patients that develop pulmonary metastases are negatively impacted. The development of strategies to slow the growth and relieve the symptoms of BC lung metastases (BCLM) is thus an important goal in the management of BC. However, systemically administered first line small molecule chemotherapeutics have poor pharmacokinetic profiles and biodistribution to the lungs and significant off-target toxicity, severely compromising their effectiveness. In this work, we propose the local delivery of add-on immunotherapy to the lungs to support first line chemotherapy treatment of advanced BC. In a syngeneic murine model of BCLM, we show that local pulmonary administration (p.a.) of PLX-3397 (PLX), a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), is capable of overcoming physiological barriers of the lung epithelium, penetrating the tumor microenvironment (TME), and decreasing phosphorylation of CSF-1 receptors, as shown by the Western blot of lung tumor nodules. That inhibition is accompanied by an overall decrease in the abundance of protumorigenic (M2-like) macrophages in the TME, with a concomitant increase in the amount of antitumor (M1-like) macrophages when compared to the vehicle-treated control. These effects with PLX (p.a.) were achieved using a much smaller dose (1 mg/kg, every other day) compared to the systemic doses typically used in preclinical studies (40-800 mg/kg/day). As an additive in combination with intravenous (i.v.) administration of paclitaxel (PTX), PLX (p.a.) leads to a decrease in tumor burden without additional toxicity. These results suggested that the proposed immunochemotherapy, with regional pulmonary delivery of PLX along with the i.v. standard of care chemotherapy, may lead to new opportunities to improve treatment, quality of life, and survival of patients with BCLM.

Thin films (~ 150 nm) of amorphous As30Te70−xGax (where x = 0, 1, 3, 6, and 10 at%) are prepared through thermal evaporation of As30Te70−xGax bulk samples on glass substrates. X-ray powder diffraction (XRD) analysis reveals the amorphous nature of the as-prepared As30Te70−xGax thin films. The influence of Ga content on the As30Te70−xGax thin films’ linear and nonlinear optical properties is determined based on the optical reflectance and transmittance spectra. The estimated (direct or indirect) optical bandgap decreases with an increase in Ga content up to 3 at% and then increases, whereas the Urbach energy exhibits an opposite trend. The linear and nonlinear refractive indices, extension coefficient, optical conductivity, electrical conductivity and nonlinear susceptibility, optical density, inter-band transition strength, etc., are found to be significantly influenced by Ga content and the energy of incident waves. The As30Te67Ga3 composition can be considered as a puzzling compound as most of the investigated parameters in As30Te70−xGax alloys demonstrate opposite behaviors around that composition. Moreover, the optical surface resistance and thermal emission of As30Te70−xGax thin films are estimated from the investigated optical parameters and it was found that they are dependent on Ga content. The obtained results enhanced basic understanding and showed that the As–Te–Ga system qualifies for various optoelectronic applications.

During inflammatory, demyelinating diseases such as multiple sclerosis (MS) axonal damage is prevalent early in the disease course. Axonal damage includes swellings, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise the integrity of neurons and remyelination. Autophagy and the clearance of damaged cell components by the proteasome are important for the maintenance of normal cellular turnover; and the restoration of cellular homeostasis. The gradual accumulation of insoluble proteins in the brain is known to impair recovery from several neurodegenerative diseases. In this study, we used mass spectrometry to identify insoluble proteins within high-speed, mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with MS. We determined that insoluble transmembrane protein106B (TMEM106B), expressed in neurons and glia and normally lysosomal-associated, is increased in MS plaques relative to normal-appearing white matter from individuals with Alzheimer’s disease and non-neurologic controls. We found that decreased TMEM106B protein in mice results in significant axonal damage and lipid droplet accumulation in the spinal cord following chronic myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. When TMEM106Bt/t mice were treated with cuprizone to experimentally induce demyelination, a significant increase in lipid deposition was observed in the corpus callosum of TMEM106Bt/t mice post-cuprizone withdrawal. Our study shows that the brain and spinal cord from challenged TMEM106Bt/t mice accumulate OilRedO+/Perilipin2+ lipid droplets. We postulate that increased insolubility of TMEM106B in MS plaques limits debris clearance by the lysosome which over time contributes to failed remyelination and axonal defects.Abbreviated AbstractTransmembrane protein106B (TMEM106B), a lysosome-associated protein, is significantly less soluble in multiple sclerosis plaques than in white matter controls. Decreased TMEM106B produces significant axonal damage and lipid accumulation in mouse models of demyelinating diseases. TMEM106B insolubility and likely loss of function may limit lysosome transport and contribute to CNS pathology.

Osteosarcoma (OS) metastasizes primarily and almost exclusively to the lungs. The survival rate decreases significantly for patients who develop OS lung metastasis (OSLM). Purpose: To assess the safety and efficacy of colony-stimulating factor-1 receptor inhibitor (CSF-1Ri) (Pexidartinib; PLX) in shifting the OSLM tumor microenvironment (TME) to an anti-tumorigenic state upon local delivery to lungs of a syngeneic mouse model of OSLM. Methods: The safety of PLX upon repeated pulmonary administration (9 doses, every other day at 2 mg/kg) in healthy BALB/c mice was assessed using health scoring, pulmonary mechanics, molecular and cellular composition of bronchoalveolar lavage fluid (BALF), blood count and plasma biochemistry, and H&E of lungs and liver. To establish the OSLM model, murine OS cells, expressing bioluminescent and fluorescent genes (K7M2-Luc-tdT), were used. Mice bearing OSLM were randomized into two groups (vehicle and PLX) and treated over 3 weeks. Tumor burden was evaluated using bioluminescent imaging (BLI) and lung weight. The treatment impact on the abundance and phenotype of tumor-associated macrophages (TAMs) and their CSF-1R expression as well as on the abundance of tumor-infiltrating lymphocytes and their expression to PD-1 were investigated using immunofluorescence, flow cytometry, and western blot. Results: PLX is well tolerated upon local lung administration with all safety markers indicating no alteration compared to naïve and vehicle controls. Treatment did not affect health scores. We did not detect any functional or mechanical alteration on the lungs or systemically (including liver); no marked differences in pulmonary function parameters, proinflammatory cytokines, nor infiltrating differential cell count obtained from BALF were observed. Both total blood count and liver enzymes were within normal range. As a measure of efficacy, treatment with PLX via local lung administration reduced tumor burden, indicated by the in vivo BLI and lung weight. Notably, PLX significantly decreased the abundance of total TAMs, with a more pronounced effect on pro-tumorigenic alternatively-activated (M2-like) TAMs phenotype, thus leading to a 22-fold increase in M1/M2 ratio. PLX further led to a marked decrease in tumor-promoting T regulatory cells (Treg), increase in the CD8/Treg ratio, and decrease in PD-1+ percentage in CD8 T cells in the TME, indicating a shift to a more immunogenic tumor phenotype. Conclusions: We demonstrated that repeated doses of PLX is safe upon local delivery to the lungs of murine model of OSLM, with no alternations in lungs or liver tissue. We further showed that PLX reduces tumor burden, which correlates with a change in the immune phenotype of the OSLM toward a more anti-tumorigenic profile. These results are clinically relevant as PLX has been approved by the FDA, thus opening opportunities for its repurposing to support standard of care therapy in OSLM. Citation Format: Fatemah S. Sunbul, Sulaiman S. Alhudaithi, Rashed M. Almuqbil, Hanming Zhang, Raneem R. Aldaqqa, Shane Albin, Rebecca L. Heise, Valentina Robila, Matthew S. Halquist, Sarah W. Gordon, Paula D. Bos, Sandro R. da Rocha. Remodeling the microenvironment of osteosarcoma lung metastases with inhaled CSF-1Ri immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1991.

The study aimed at showing the effect of using Mental Imagination strategy in developing critical reading skills for ninth grade students in Gaza. The study used the experimental method and suitable critical reading skills for nine grade were identified. The sample of the study consisted of 81 students (ninth grade) distributed to an experimental group (41 students) and a controlled group (40 student), reading subjects were taught to the experimental group by using the Mental Imagination strategy which was applied by a teacher who received training related to this strategy. The controlled group were taught by using traditional methods. After a test was implemented to measure the critical reading skills and conducting statistical treatments by using Ancova, the study revealed that there was an effect on using the Mental Imagination strategy in developing targeted critical reading skills. It also clarified that there were significant differences at a ≤ 0.01 between the experimental and controlled group grades in the post test of critical reading skills attributed to the experimental group.

Detecting crop rows from video frames in real time is a fundamental challenge in the field of precision agriculture. Deep learning based semantic segmentation method, namely U-net, although successful in many tasks related to precision agriculture, performs poorly for solving this task. The reasons include paucity of large scale labeled datasets in this domain, diversity in crops, and the diversity of appearance of the same crops at various stages of their growth. In this work, we discuss the development of a practical real-life crop row detection system in collaboration with an agricultural sprayer company. Our proposed method takes the output of semantic segmentation using U-net, and then apply a clustering based probabilistic temporal calibration which can adapt to different fields and crops without the need for retraining the network. Experimental results validate that our method can be used for both refining the results of the U-net to reduce errors and also for frame interpolation of the input video stream.

A new reflection only method for electromagnetic characterization of PEC-backed material is proposed. By exploiting waveguide high-order modes, this method can retrieve permittivity and permeability of dispersive and lossy materials. In contrast to similar researches, this method is mathematically simple and easy to implement. An example of retrieving/retrieval electromagnetic parameters of a dispersive material is carried out to show the applicability of the method.

The present framework reports the structural, fundamental parameters, and crystallization kinetics of the melt-quenched As30Te64Ga6 chalcogenide glass. The energy dispersive X-ray analysis of the As30Te64Ga6 glassy system reveals that the constituent element ratio of the investigated bulk sample agrees with the nominal composition. Also, X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) were used to characterize structural properties, and crystallization kinetics; respectively. Four characteristic temperatures related to various phenomena are observed in the investigated DSC traces. The first one is $$T_{g}$$ that corresponds to the glass transition temperature. The second one is ( $$T_{c1}$$ , and $$T_{c2}$$ ) that corresponds to the onset of the double crystallization temperatures. The third one ( $$T_{P1}$$ , and $$T_{P2}$$ ) identifies the double peak crystallization temperatures. The last characteristic temperature ( $$T_{m}$$ ) is the melting point. The XRD analysis indicates the amorphous structure of the as-prepared glassy alloy, while the annealed samples are polycrystalline. The crystallization kinetics of the As30Te64Ga6 bulk are studied under non-isothermal conditions. In addition, the values of various kinetic parameters such as the glass transition activation energy, weight stability standard, and Avrami exponent were determined. The activation energy of the crystallization process for As30Te64Ga6 glass alloy was calculated using classical methods. The results indicated that the rate of crystallization is related to thermal stability and the ability to form glass. Kinetic parameters have been estimated with some conventional methods and found to be dependent on heating rates (β).

Text classification has been recognized as an essential technique for handling and organizing text data. However, the classic text classifiers cannot clearly describe the difference between relevant and irrelevant information because of uncertainty. The underlying reason is that it is very hard for most text classifiers to explicitly describe the large uncertain boundary between two classes. A three-way decisions based framework is an interesting methodology for dealing with uncertainties in binary classification. However, it is not easy to effectively integrate the framework with a popular classifier (e.g. SVM). By integrating the distinct aspects of three-way decisions theory and the capacities of a support vector machine (SVM), a Multiple-SVMs classifier is proposed in this paper to address this issue. The proposed approach starts from the strategy of partitioning the training set into three regions, namely, positive, negative and boundary regions, to ensure the certainty of extracted knowledge for describing relevant information. Based on these three regions, an innovative and effective probabilistic feature-weighting approach has been proposed to accurately weight the representative terms. The model then organizes training samples to design a Multiple-SVMs classifier which is capable of predicting the classes of each document. Experimental results on the standard datasets RCVI and R21578 show that the proposed method significantly outperforms other state-of-the-art methods in different popular measures.

Lung cancers remain the leading cause of cancer-related death in both men and women. Infiltrating immune cells in the tumor microenvironment (TME) play a critical role in the formation, progression, and the response of solid tumors to therapy, including in lung cancers. Clinical studies have established that tumor-associated macrophages (TAMs) and their phenotypical composition are critical immune infiltrates in the lung TME, with the abundance of the M2-like phenotype negatively correlating with patient survival. Colony-Stimulating Factor 1 (CSF-1) receptor (CSF-1R) is a type III protein tyrosine kinase receptor that plays an important role in the recruitment and differentiation of monocytes into tumor-promoting M2-like TAMs and their survival. In this work we evaluated the therapeutic potential of PLX 3397 (PLX), a small molecule CSF-1R inhibitor (CSF-1Ri), upon local lung administration in an immune-competent mouse model of lung cancer. The efficacy of local lung delivered PLX as single therapy was investigated first. As assessed by immunofluorescence of sections of lung tumor nodules, a statistically significant reduction in M2-like TAMs and an increase in M1-like TAMs was observed, thus leading to a shift in the (M1/M2) balance. Those changes in abundance of immune infiltrates correlated with a significant decrease in tumor burden when compared to control. When combined with systemically administered cisplatin (CIS) PLX treatment provided further benefits, leading to a significant decrease in tumor burden when compared to either PLX or CIS treatments alone, as measured by bioluminescence intensity (BLI) in vivo (thoracic area) and ex vivo (lung tissue). This combination therapy led to the most pronounced increase in M1/M2 ratio, followed by a significant decrease in M2-like TAMs with the CIS therapy. This work is clinically relevant as it demonstrates the potential of local lung administration of PLX to support standard of care chemotherapy for lung cancer management. This is important as the pulmonary route of administration is a plausible strategy for reducing the total dose of CSF-1Ris as the tissue of interest (lungs) can be locally targeted. Because the major off-target effect of CSF-1Ris is liver toxicity, reducing systemic concentration will support translation of those therapies, especially in combination with standard of care chemotherapy that has significant off-target toxicity and patient attrition itself. This work is scientifically relevant as we demonstrate for the first time that local administration of a CSF-1Ri to the lungs leads to a shift in the balance of TAMs in the TME of a model of lung tumor, adding to the sparse literature of CSF-1Ris related to lung cancers.

Nanobodies have been progressively replacing traditional antibodies in various immunological methods. However, the use of nanobodies as capture antibodies is greatly hampered by their poor performance after passive adsorption to polystyrene microplates, and this restricts the full use of double nanobodies in sandwich enzyme-linked immunosorbent assays (ELISAs). Herein, using the human soluble epoxide hydrolase (sEH) as a model analyte, we found that both the immobilization format and the blocking agent have a significant influence on the performance of capture nanobodies immobilized on polystyrene and the subsequent development of double-nanobody sandwich ELISAs. We first conducted epitope mapping for pairing nanobodies and then prepared a horseradish-peroxidase-labeled nanobody using a mild conjugation procedure as a detection antibody throughout the work. The resulting sandwich ELISA using a capture nanobody (A9, 1.25 μg/mL) after passive adsorption and bovine serum albumin (BSA) as a blocking agent generated a moderate sensitivity of 0.0164 OD·mL/ng and a limit of detection (LOD) of 0.74 ng/mL. However, the introduction of streptavidin as a linker to the capture nanobody at the same working concentration demonstrated a dramatic 16-fold increase in sensitivity (0.262 OD·mL/ng) and a 25-fold decrease in the LOD for sEH (0.03 ng/mL). The streptavidin-bridged double-nanobody ELISA was then successfully applied to tests for recovery, cross-reactivity, and real samples. Meanwhile, we accidentally found that blocking with skim milk could severely damage the performance of the capture nanobody by an order of magnitude compared with BSA. This work provides guidelines to retain the high effectiveness of the capture nanobody and thus to further develop the double-nanobody ELISA for various analytes.

Introduction: Dysplasia Epiphysealis Hemimelica (DEH)is a rare developmental epiphyseal disease characterized by asymmetri cover growth of cartilage in the epiphysis, histologically mimics osteochondroma of the joints. The disease mainly involves ankle, knee and tarsal bones. Small number of cases is reported in literature particularly those managed arthroscopically. Case Report: The present study reports a case of Dysplasia Epiphysealis Hemimelica (DEH) developed in the talus in male child presented with swelling, pain, and inability to put weight. Radiographs showed irregularities of the talar body with a large loose body in the anterior joint compartment with excessive overgrowth of the anteromedial and posteromedial aspects of the talus managed by combined anterior and posterior ankle arthroscopy in a single session and showed improvement of both pain and range of motion in the short-term follow-up. Conclusion: Trevor disease of the ankle is a rare disease that needs high index of suspicion for diagnosis and arthroscopy can be a minimally invasive option to improve pain and range of motion. This case report demonstrates basis on which such a rare disease can be diagnosed and shows the arthroscopic surgical technique details and its possible value in the outcome of these cases.

Doxorubicin (DOX) is a chemotherapeutic agent broadly used in the treatment of a range of solid tumors. In spite of its high potency, as is the case for many other chemotherapeutic drugs, there are many challenges associated with the use of DOX in clinical oncology. This is particularly true for DOX in the treatment of lung cancer, where in vitro potency is shown to be very high, but low lung distribution and off-target toxicity (particularly cardiotoxicity) restrict its use. Nanocarrier-based drug delivery systems (nanoDDS) have been shown to help alter biodistribution and alleviate off-target toxicity associated with DOX. While significant understanding exists regarding the design parameters to achieve those clinical benefits, much less is known regarding the design of nanoDDS capable of enhancing tumor penetration of DOX (and other drugs), which is another major factor leading to DOX's reduced efficacy. The purpose of this study was to design a dendrimer-based nanoDDS capable of enhancing the penetration of DOX as measured in an in vitro 3D lung tumor model and to correlate those results with its efficacy. Spheroids formed with the A549 human lung adenocarcinoma cells/murine fibroblast cell line (NIH/3T3 cell line) are shown to produce the essential components of the extracellular matrix (ECM), which is known as a physical barrier that hinders the transport of DOX. DOX was conjugated to generation 4 succinamic acid-terminated poly(amido-amine) (PAMAM) dendrimers (G4SA) through an enzyme-liable tetrapeptide (G4SA-GFLG-DOX), resulting in a nanoDDS with ∼5.5 DOX, -17 mV surface (ζ) potential, and a 10 nm hydrodynamic diameter (HD). The penetration of DOX to the core of the spheroid in terms of DOX fluorescence was determined to be 3.1-fold greater compared to free DOX, which positively correlated with enhanced efficacy as measured by the Caspase 3/7 assay. This improved penetration happens as the interactions between the G4SA-GFLG-DOX and the highly negatively charged ECM are minimized by shielding the protonatable amine of DOX upon conjugation, and the HD of the conjugate is kept smaller than the estimated mesh size of the ECM. Interestingly, the conjugate provided more specificity for DOX to tumor cells compared to fibroblasts, while free DOX is equally distributed in both tumor and fibroblasts as assessed in the coculture spheroids. Growth inhibition studies show that the released DOX maintains its activity and leads to tumor reduction to the same extent as free DOX. The results obtained here are of relevance for the design of dendrimer-based nanoDDS and for the treatment of solid tumors as they provide critical information regarding desirable surface characteristics and sizes for efficient tumor penetration.

Effect of annealing temperature on the structural and optical properties of As30Te60Ga10 thin film was studied using various techniques such as differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The DSC analysis revealed that the As30Te60Ga10 glass has a single glass transition and crystallization peak while XRD results confirmed that the as-prepared and annealed films have crystalline nature. The coexistence of the crystalline phases in the investigated films could be attributed to the formation of orthorhombic As, hexagonal Ga7Te10, and monoclinic As2Te3 phases. It was found that the average crystallite size and optical parameters of the studied films depend on the annealing temperature. For example, the optical band gap decreased from 1.54 eV to 1.11 eV as the annealing temperature increased from 300 K to 433 K.

Background and study aim: Hepatitis C virus (HCV) infection is a major public health problem worldwide. Blood donations screening achieved mainly by serological identification of HCV-Antibody (Ab), has largely reduced HCV transmission. HCV Core Antigen (CAg) tests have been introduced to supplement anti-HCV tests and HCV PCR analyses. CAg may be a useful screening test for identifying window phase of HCV infected patients whom are candidate for blood donations. The study aimed to evaluate diagnostic performance of HCV core antigen in comparison to HCV-RNA quantification and anti-HCV-Ab analyses in attendances of blood bank of Zagazig University hospitals. Patients and Methods: The study was performed on 92 participants attending the blood banks of Zagazig University Hospitals for blood donation between May 2015 to November 2017. The participants were classified into two groups; group A, which included 46 donors (32 males and 14 females) with negative HCV antibody and group B, which Included 46 patients (30 males and 16 females) with positive HCV antibody. Clinical assessment, HCV AB detection by ELISA, Prototype ELISA for HCV core antigen for presence of HCV core antigen and HCV RNA Quantitative were done for all participants. Results: No significant differences between both studied regarding sex and age. A high significant relation between HCV AB positivity and negativity as regard HCV PCR was found in both groups. A high significant relation between HCV core antigen positivity and negativity as regard HCV PCR. There was high significant relation between HCV core antigen positivity and HCV PCR in group A patients. There was a high significant relation between HCV core antigen positivity and HCV PCR in positive HCV antibody patients and statistically a high significant relation between HCV core antigen negativity and HCV PCR in group B patients. Conclusion: HCV core Ag can be identified by serological ELISA. This assay is cheap, easily performed, and compatible with HCV PCR. Its application may prevent the vast majority of HCV transmissions caused by the transfusion of window phase donations.