Wiley最新文献

Multiple myeloma (MM), one of the most frequent haematological malignancies, significantly increases the risk of bacterial infections due to treatment-related side effects, comorbidities and cancer-induced immune deficiencies. Recently, CD71⁺ erythroid cells (CECs) have been identified as key immunomodulators in neonates and cancer patients, but their role in MM progression remains unclear. Using a murine MM model, closely resembling human disease, we observed that MM progression is associated with anaemia and an increase in immature CECs, which are characterized by elevated arginase 2 (ARG2) expression. These MM-associated CECs suppress T-cell proliferation, contributing to impaired immune responses. Notably, ARG2 deficiency in mice led to slower MM progression and improved survival. Furthermore, MM-bearing mice exhibited higher susceptibility to Listeria monocytogenes infections, mirroring the increased infection risk in MM patients. Our findings suggest that ARG2-expressing CECs play a critical role in MM-associated immune suppression and infection susceptibility, pointing out ARG2 as a potential therapeutic target to enhance immune function and reduce infection risks in MM patients.

The combination of magnetic resonance imaging (MRI)/near-infrared (NIR) fluorescence signals and chemotherapy agents has been developed for cancer diagnosis and treatment. In this work, we investigated the impacts of NIR Cyanine 5.5 fluorescence and Doxorubicin on cell cycle arrest, magnetic resonance, and NIR fluorescence optical imaging for Fe3O4-encapsulated nanosystems based on poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS) copolymer. Although Cyanine 5.5 and Fe3O4 nanoparticles (NPs) are less cytotoxic than Doxorubicin, they present a cytostatic effect, inducing cell cycle arrest at the G2/M phase in human brain adenocarcinoma (CCF-STTG1) cells. For MRI applications, the permeability of the PLA-TPGS copolymer coating layer to water molecules might lengthen the translational diffusion time (τD), causing the high relaxivity ratio (r2/r1) in Fe3O4 bare NPs under an applied magnetic field (7 Tesla). Astonishingly, the chemical structures of Cyanine 5.5 and Doxorubicin significantly contribute to the enhancement of the T2 relaxivities of Fe3O4 NPs through π-π and p-π conjugation. Furthermore, the radiance ratio and signal-to-noise ratio enhancement and a slight blue shift in the optimal excitation and emission wavelengths were recorded. These findings show the potential for in vivo MRI and NIR bioimaging experiments of the nanoparticles.

Childhood obesity leads to early puberty development in girls, but its effect in boys remains unclear. We conducted a systematic review and meta-analysis to study the association between childhood obesity and puberty development in boys. We included 14 cohort studies with 114,822 boys. Meta-analysis showed that childhood overweight (RR, 1.44; 95%CI, 1.08-1.93; the number of studies [N] = 4) and obesity (RR, 1.35; 95%CI, 1.11-1.64; N = 5) were associated with the earlier occurrence of testicular volume ≥4 mL (Tanner stage 2). Age reaching Tanner stage 2 in overweight boys was earlier than normal-weight boys (mean difference: -0.23 years, 95% CI: -0.37 to -0.08; N = 2); a similar trend was observed in obese boys, but the effect estimate did not reach significance level (mean difference: -0.27 years, 95% CI: -0.59 to 0.05; N = 3). Similarly, the age at pubarche in boys with overweight/obesity was earlier than those with normal weight. Qualitative analysis shows first nocturnal emission; change in voice and peak height velocity in boys with overweight/obesity appeared to develop earlier than those with normal weight. These findings suggest overweight/obesity is associated with earlier pubertal development in boys. Due to the limited number of studies identified in this review, further studies are warranted to confirm these associations.

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, has renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte growth factor, thrombopoietin (TPO) and second generation TPO agents using multiple animal models including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (e.g., thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non-invasive measures such as magnetic resonance imaging proton density fat fraction (MRI-PDFF) and FibroScan® controlled attenuation parameter (CAP™) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure-response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic/pharmacodynamic (PK/PD) modeling of both liver fat measurements simultaneously. Population pharmacokinetic and exposure-response models using individual predictions of average concentrations were used to describe ervogastat/clesacostat PKPD. Due to both liver fat endpoints being continuous-bounded outcomes on different scales, a dynamic transform-both-sides approach was used to link a common latent factor representing liver fat to each endpoint. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described by the model. The clinical trial simulation was able to adequately predict the results of a recent Phase 2 study, where subjects given ervogastat/clesacostat 300/10 mg BID for 6 weeks had a LS means and model-predicted median (95% confidence intervals) percent change from baseline MRI-PDFF of -45.8% and -45.6% (-61.6% to -31.8%), respectively. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies.

The transformation of carbon dioxide (CO2) into high-value chemicals is a significant step towards achieving the goal of "carbon neutrality". α-methylene cyclic carbonate, as an intermediate for the synthesis of many important organic compounds, is widely employed in industrial productions. In this work, a series of ionic porous organic polymers (IPOPs) with different basic-functionalized anions were successfully synthesized and adjusted to have certain BET surface areas and high contents of ion sites by post-modification. These basic-functionalized IPOPs could exhibit excellent catalytic performance for carboxylative cyclization of CO2 at 30 oC and 1 bar in presence of silver salts, eliminating the use of extra organic bases. In the whole catalytic reaction, the basic-functionalized anions could play triple roles: enriching CO2 for further transformation, activating the hydroxyl groups of substrates to improve the catalytic performance, while coordinating with Ag atom to stabilize and regenerate catalyst. Notably, the catalytic system of DCX-4-Tet/Ag2O exhibited excellent recyclability, and the yield of α-alkylidene cyclic carbonate was well maintained at 99% after 5 cycles. To the best of our knowledge, the catalytic system was the first example of basic-functionalized IPOPs that played multiple roles for highly efficient CO2 cyclization under mild conditions without any extra organic bases.

In the recent two decades, the multidisciplinary field of medicinal chemistry has undergone several conceptual and technology-driven paradigm changes with significant impact on the skill set medicinal chemists need to acquire during their education. Considering the need for academic medicinal chemistry teaching, this article aims at identifying important skills, competences, and basic knowledge as general learning outcomes based on an analysis of the relevant stakeholders and concludes effective teaching strategies preparing students for a future career as medicinal chemists and drug designers.

Aqueous zinc-metal batteries (AZMBs) represent a promising frontier in battery technology, offering sustainable and safe alternatives to traditional non-aqueous batteries. Despite their potential, understanding the kinetics of zinc electrodeposition-a critical factor in AZMB performance-remains underexplored. Utilizing voltammetry on ultramicroelectrodes, we investigate how scan rate influences key processes of nucleation and growth during Zn²⁺ electrodeposition. The findings highlight the efficacy of the Butler-Volmer formulation in capturing electron-transfer kinetics, contrasting with complex electron transfer kinetic models used for non-aqueous battery chemistries. We clearly demonstrate that there is a strong dependence of scan rate on the measured value of kinetic parameters (exchange current). To accurately probe the charge transfer kinetics, it is essential to apply fast scan voltammetry to decouple the influence of mass transfer, ensuring that the measured current is independent of the scan rate. Furthermore, by studying a model electrolyte additive, the intricate balance between charge transfer and mass transfer dynamics is unveiled, and this information is crucial for enhancing the stability of zinc metal anodes. These insights pave the way for developing advanced electrolyte and current collector formulations, promising enhanced cyclability and sustainability in zinc metal batteries.