Search Results (35)

The c-Myc protein, a key regulator of cell proliferation, growth, and apoptosis in B-cell lymphocytes, is frequently dysregulated in Burkitt’s lymphoma. Zingiberaceae plants—galangal (Alpinia galanga), black turmeric (Curcuma aeroginosa), black ginger (Kaempferia parviflora), phlai lueang (Zingiber montanum), and phlai dum (Zingiber ottensii)—are traditionally used as herbal remedies and may serve as natural anti-lymphoma agents. In this study, extracts from these five plants were screened for cytotoxicity against Raji and Daudi lymphoma cell lines and compared with their effects on normal peripheral blood mononuclear cells (PBMCs). Galangal extract exhibited the strongest cytotoxic effects on lymphoma cells. Its major bioactive compounds, galangin and 1′-acetoxychavicol acetate (ACA), showed selective cytotoxicity, with ACA being more potent. ACA significantly suppressed both c-Myc and phosphorylated c-Myc (p-c-Myc) protein levels and induced dose-dependent apoptosis in lymphoma cells. Cell cycle analysis revealed arrest at specific phases, supporting its anti-proliferative action. Furthermore, network pharmacology and pathway enrichment analyses implicated ACA in the modulation of oncogenic PI3K-Akt and MAPK pathways. These findings highlight ACA as a promising plant-derived therapeutic candidate for lymphoma, acting through c-Myc suppression, cell cycle arrest, and apoptosis induction. Full article

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

Traditional construction of timber houses in Tanzania has been prevalent for years; however, inhabiting these structures has been a challenge due to the instability of the buildings under various loadings. This instability, despite its lightweight, is mainly controlled by mechanical joints within timber members. Parametric Python scripts were developed in Abaqus (version 6.13) to have a reliable joint between timber volume modules and assess their response when subjected to wind forces. Two timber volume modules, each with a height of 3.0 m, were subjected to a horizontal displacement of 10 mm. Results show that the screwed fasteners between the modules result in high shear resistance due to the embedded fastener’s threads in timber members increasing the rope effect. Additionally, with weak fastener stiffness, the openings in the longitudinal wall had no effect on resisting shear compared to strong joints between modules. Longitudinal walls with doors and window openings showed a decrease in shear force to 21.95 kN, which is 44% less than the 39 kN of walls without openings. In addition, for a single door in the wall, the shear force decreased to 17.9%, indicating that major shear forces in the wall are affected by the window opening due to its large size and proximity to the point of load application. Furthermore, the stresses were concentrated in the corners of the openings, subjecting the structure to failure during its in-service life and demanding the use of cross-diagonal timber members between the corners to redistribute corner stresses. It is recommended that these types of houses be adopted due to less slip deformation (less than 10 mm) caused by wind speed of 24 km/h. Full article

Feature detection is one of the hot topics in the weather radar research community. This study employed a convective–stratiform classification algorithm to detect features in polarimetric radar variables and Quantitative Precipitation Estimation (QPE) retrieval during a heavy precipitation event in Crossville, Tennessee, during warm-season convection. Analysis of polarimetric radar variables revealed that strong updrafts, mixed-phase precipitation, and large hailstones in the radar resolution volume during the event were driven by the existence of supercell thunderstorms. The results of feature detection highlight that the regions with convective–stratiform cores and strong–faint features in the reflectivity field are similar to those in the rainfall field, demonstrating how the algorithm more effectively detects features in both fields. The results of the estimates, accounting for uncertainty during feature detection, indicate that an offset of +2 dB overestimated convective features in the northeast in both the reflectivity and rainfall fields, while an offset of −2 dB underestimated convective features in the northwest part of both fields. The results highlight that convective cores cover a small area with high rainfall exceeding 50 mmh⁻¹, while stratiform cores cover a larger area with greater horizontal homogeneity and lower rainfall intensity. These findings are significant for nowcasting weather, numerical models, hydrological applications, and enhancing climatological computations. Full article

Traditional defect recovery methods rely on high-temperature annealing, often exceeding 750 °C for FeCrAl. In this study, we introduce electron wind force (EWF)-assisted annealing as an alternative approach to mitigate irradiation-induced defects at significantly lower temperatures. FeCrAl samples irradiated with 5 MeV Zr²⁺ ions at a dose of 10¹⁴ cm⁻² were annealed using EWF at 250 °C for 60 s. We demonstrate a remarkable transformation in the irradiated microstructure, where significant increases in kernel average misorientation (KAM) and low-angle grain boundaries (LAGBs) typically indicate heightened defect density; the use of EWF annealing reversed these effects. X-ray diffraction (XRD) confirmed these findings, showing substantial reductions in full width at half maximum (FWHM) values and a realignment of peak positions toward their original states, indicative of stress and defect recovery. To compare the effectiveness of EWF, we also conducted traditional thermal annealing at 250 °C for 7 h, which proved less effective in defect recovery as evidenced by less pronounced improvements in XRD FWHM values. Full article

Strategies to increase the anti-tumor efficacy of cytokine-induced killer cells (CIKs) include genetic modification with chimeric antigen receptors (CARs) or the addition of soluble T-cell engaging bispecific antibodies (BsAbs). Here, CIKs were modified using a transposon system integrating two distinct anti-CD19 CARs (CAR-MNZ and CAR-BG2) or combined with soluble CD3xCD19 BsAb blinatumomab (CIK + Blina). CAR-MNZ bearing the CD28-OX40-CD3ζ signaling modules, and CAR-BG2, designed on the Tisagenlecleucel CAR sequence (Kymriah^®), carrying the 4-1BB and CD3ζ signaling elements, were employed. After transfection and CIK expansion, cells expressed CAR-CD19 to a similar extent (35.9% CAR-MNZ and 17.7% CAR-BG2). In vitro evaluations demonstrated robust proliferation and cytotoxicity (~50% cytotoxicity) of CARCIK-MNZ, CARCIK-BG2, and CIK + Blina against CD19⁺ target cells, suggesting similar efficacy. All effectors formed an increased number of synapses, activated NFAT and NFkB, and secreted IL-2 and IFN-ɣ upon encountering targets. CIK + Blina displayed strongest NFAT and IFN-ɣ induction, whereas CARCIK-BG2 demonstrated superior synapse formation. All the effectors have shown therapeutic activity in vivo against the CD19⁺ Daudi tumor model, with CARCIK cells showing a more durable response compared to CIK + Blina, likely due to the short half-life of Blina in this model. Full article

This study investigates the effectiveness of combined thermal and athermal stimuli in mitigating the extremely high-density nature of dislocation networks in the form of low-angle grain boundaries in FeCrAl alloy. Electron wind force, generated from very low duty cycle and high current density pulses, was used as the athermal stimulus. The electron wind force stimulus alone was unable to remove the residual stress (80% low-angle grain boundaries) due to cold rolling to 25% thickness reduction. When the duty cycle was increased to allow average temperature of 100 °C, the specimen could be effectively annealed in 1 min at a current density of 3300 A/mm². In comparison, conventional thermal annealing requires at least 750 °C and 1.5 h. For specimens with 50% thickness reduction (85% low-angle grain boundaries), the electron wind force was again unable to anneal the defects even at 3300 A/mm² current density and average temperature of 100 °C. Intriguingly, allowing average concurrent temperature of 200 °C eliminated almost all the low-angle grain boundaries at a current density of 700 A/mm², even lower than that required for the 25% thickness reduced specimens. Comprehensive electron and X-ray diffraction evidence show that alloys with extremely high defect density can be effectively annealed in less than a minute at approximately 200 °C, offering a substantial improvement over conventional high-temperature annealing. Full article

Low-angle grain boundaries (LAGBs) accommodate residual stress through the rearrangement and accumulation of dislocations during cold rolling. This study presents an electron wind force-based annealing approach to recover cold-rolling induced residual stress in FeCrAl alloy below 100 °C in 1 min. This is significantly lower than conventional thermal annealing, which typically requires temperatures around 750 °C for about 1.5 h. A key feature of our approach is the athermal electron wind force effect, which promotes dislocation movement and stress relief at significantly lower temperatures. The electron backscattered diffraction (EBSD) analysis reveals that the concentration of low-angle grain boundaries (LAGBs) is reduced from 82.4% in the cold-rolled state to a mere 47.5% following electropulsing. This level of defect recovery even surpasses the pristine material’s initial state, which exhibited 54.8% LAGBs. This reduction in LAGB concentration was complemented by kernel average misorientation (KAM) maps and X-ray diffraction (XRD) Full Width at Half Maximum (FWHM) measurements, which further validated the microstructural enhancements. Nanoindentation tests revealed a slight increase in hardness despite the reduction in dislocation density, suggesting a balance between grain boundary refinement and dislocation dynamics. This proposed low-temperature technique, driven by athermal electron wind forces, presents a promising avenue for residual stress mitigation while minimizing undesirable thermal effects, paving the way for advancements in various material processing applications. Full article

EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an EZH2 selective degrader, which successfully diminishes EZH2 levels in lymphoma cells. Additionally, lapatinib, a dual inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, targets a receptor protein that regulates cell growth and division. The overexpression of this protein is often observed in lymphoma cells. Our study aims to combine these two therapeutic targets to stimulate apoptosis pathways and potentially suppress Burkitt’s lymphoma cell survival and proliferation in a complementary and synergistic manner. We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt’s lymphoma. Full article

Applying deep learning models requires design and optimization when solving multifaceted artificial intelligence tasks. Optimization relies on human expertise and is achieved only with great exertion. The current literature concentrates on automating design; optimization needs more attention. Similarly, most existing optimization libraries focus on other machine learning tasks rather than image classification. For this reason, an automated optimization scheme of deep learning models for image classification tasks is proposed in this paper. A sequential-model-based optimization algorithm was used to implement the proposed method. Four deep learning models, a transformer-based model, and standard datasets for image classification challenges were employed in the experiments. Through empirical evaluations, this paper demonstrates that the proposed scheme improves the performance of deep learning models. Specifically, for a Virtual Geometry Group (VGG-16), accuracy was heightened from 0.937 to 0.983, signifying a 73% relative error rate drop within an hour of automated optimization. Similarly, training-related parameter values are proposed to improve the performance of deep learning models. The scheme can be extended to automate the optimization of transformer-based models. The insights from this study may assist efforts to provide full access to the building and optimization of DL models, even for amateurs. Full article

Natural killer (NK) cells are cytotoxic lymphocytes that are critical for the innate immune system. Engineering NK cells with chimeric antigen receptors (CARs) allows CAR-NK cells to target tumor antigens more effectively. In this report, we present novel CAR mRNA-LNP (lipid nanoparticle) technology to effectively transfect NK cells expanded from primary PBMCs and to generate functional CAR-NK cells. CD19-CAR mRNA and BCMA-CAR mRNA were embedded into LNPs that resulted in 78% and 95% CAR expression in NK cells, respectively. BCMA-CAR-NK cells after transfection with CAR mRNA-LNPs killed multiple myeloma RPMI8226 and MM1S cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner in vitro. In addition, CD19-CAR-NK cells generated with CAR mRNA-LNPs killed Daudi and Nalm-6 cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner. Both BCMA-CAR-NK and CD19-CAR-NK cells showed significantly higher cytotoxicity, IFN-gamma, and Granzyme B secretion compared with normal NK cells. Moreover, CD19-CAR-NK cells significantly blocked Nalm-6 tumor growth in vivo. Thus, non-viral delivery of CAR mRNA-LNPs can be used to generate functional CAR-NK cells with high anti-tumor activity. Full article

Background: SaferBirths Bundle of Care (SBBC) is a package of innovative clinical and training tools coupled with low-dose high-frequency simulation-based on-job training guided by local data. This bundle of care is a new initiative being implemented in 30 health facilities from five regions of Tanzania aiming at improving birth outcomes. Objective: To assess the perception of healthcare workers and facility leaders on the “SaferBirths Bundle of Care” towards saving women’s and newborns’ lives at birth. Method: We used a qualitative approach using focused group discussion (FGD) and individual interviews. A total of 21 FGD and 43 individual interviews were conducted between August and November 2022. In total, 94 midwives and 12 doctors were involved, some of whom were in leadership roles. The framework method for the analysis of qualitative data was used for analysis. Results: Healthcare workers and facility leaders received the bundle well and regarded it as effective in saving lives and improving healthcare provision. Five themes emerged as facilitators to the acceptance of the bundle: (1) the bundle is appropriate to our needs, (2) the training modality and data use fit our context, (3) use of champions and periodic mentorship, (4) learning from our mistakes, and (5) clinical and training tools are of high quality but can be further improved. Conclusion: The relevance of SaferBirths Bundle of Care in addressing maternal and perinatal deaths, the quality and modality of training, and the culture that enhances learning from mistakes were among the facilitators of the acceptability of the SBBC. A well-accepted intervention has huge potential for bringing the intended impact in health provision. Full article

T and B cell receptor signaling involves the activation of Akt, MAPKs, and PKC as well as an increase in intracellular Ca²⁺ and calmodulin activation. While these coordinate the rapid turnover of gap junctions, also implicated in this process is Src, which is not activated as part of T and B cell receptor signaling. An in vitro kinase screen identified that Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) phosphorylate Cx43. Mass spectroscopy revealed that BTK and ITK phosphorylate Cx43 residues Y247, Y265, and Y313, which are identical to the residues phosphorylated by Src. Overexpression of BTK or ITK in the HEK-293T cells led to increased Cx43 tyrosine phosphorylation as well as decreased gap junction intercellular communication (GJIC) and Cx43 membrane localization. In the lymphocytes, activation of the B cell receptor (Daudi cells) or T cell receptor (Jurkat cells) increased the BTK and ITK activity, respectively. While this led to increased tyrosine phosphorylation of Cx43 and decreased GJIC, the cellular localization of Cx43 changed little. We have previously identified that Pyk2 and Tyk2 also phosphorylate Cx43 at residues Y247, Y265, and Y313 with a similar cellular fate to that of Src. With phosphorylation critical to Cx43 assembly and turnover, and kinase expression varying between different cell types, there would be a need for different kinases to achieve the same regulation of Cx43. The work presented herein suggests that in the immune system, ITK and BTK have the capacity for the tyrosine phosphorylation of Cx43 to alter the gap junction function in a similar manner as Pyk2, Tyk2, and Src. Full article

γδ T cells have the potential for adoptive immunotherapy since they respond to bacteria, viruses, and tumors. However, these cells represent a small fraction of the peripheral T-cell pool and require activation and proliferation for clinical benefits. In cord blood, there are some γδ T cells, which exhibit a naïve phenotype, and mostly include Vδ1+ T cells. In this study, we investigated the effect of CD3 signaling on cord blood γδ T-cell proliferation using K562-based artificial antigen presenting cells expressing costimulatory molecules. There were significantly more Vδ1+ T cells in the group stimulated with anti-CD3 antibody than in the group without. In cultured Vδ1+ T cells, DNAM-1 and NKG2D were highly expressed, but NKp30 and NKp44 showed low expression. Among various target cells, Vδ1+ T cells showed the highest cytotoxicity against U937 cells, but Daudi and Raji cells were not susceptible to Vδ1+ T cells. The major cytokines secreted by Vδ1+ T cells responding to U937 cells were Granzyme B, IFN-γ, and sFasL. Cytotoxicity by Vδ1+ T cells correlated with the expression level of PVR and Nectin of DNAM-1 ligands on the surface of target cells. Compared to Vδ2+ T cells in peripheral blood, cord blood Vδ1+ T cells showed varying cytotoxicity patterns depending on the target cells. Here, we determined the ideal conditions for culturing cord blood Vδ1+ T cells by observing that Vδ1+ T cells were more sensitive to CD3 signals than other subtypes of γδ T cells in cord blood. Cultured cord blood Vδ1+ T cells recognized target cells through activating receptors and secreted numerous cytotoxic cytokines. These results are useful for the development of tumor immunotherapy based on γδ T cells. Full article

Freeze-drying, also known as lyophilization, significantly improves the storage, stability, shelf life, and clinical translation of biopharmaceuticals. On the downside, this process faces complex challenges, i.e., the presence of freezing and drying stresses for the active compounds, the uniformity and consistency of the final products, and the efficiency and safety of the reconstituted lyophilized formulations. All these requirements can be addressed by adding specific excipients that can protect and stabilize the active ingredient during lyophilization, assisting in the formation of solid structures without interfering with the biological and/or pharmaceutical action of the reconstituted products. However, these excipients, generally considered safe and inert, could play an active role in the formulation interacting with the biological cellular machinery and promoting toxicity. Any side effects should be carefully identified and characterized to better tune any treatments in terms of concentrations and administration times. In this work, various concentrations in the range of 1 to 100 mg/mL of cellobiose, lactose, sucrose, trehalose, isoleucine, glycine, methionine, dextran, mannitol, and (2-hydroxypropyl)-β-cyclodextrin were evaluated in terms of their ability to create uniform and solid lyophilized structures. The freeze-dried products were then reconstituted in the appropriate cell culture media to assess their in vitro cytotoxicity on both a healthy cell line (B-lymphocytes) and their tumoral lymphoid counterpart (Daudi). Results showed that at 10 mg/mL, all the excipients demonstrated suitable lyophilized solid structures and high tolerability by both cell lines, while dextran was the only excipient well-tolerated also up to 100 mg/mL. An interesting result was shown for methionine, which even at 10 mg/mL, selectively affected the viability of the cancerous cell line only, opening future perspectives for antitumoral applications. Full article