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1.
ACS Appl Mater Interfaces ; 16(20): 26025-26033, 2024 May 22.
Article En | MEDLINE | ID: mdl-38717862

Bi-Sb-Te-based thermoelectric materials have the best room-temperature thermoelectric properties, but their inherent brittleness and rigidity limit their application in the wearable field. In this study, W-doped p-type Bi0.5Sb1.5Te3 (W-BST) thin films were prepared using magnetron sputtering on polyimide substrates to create thermoelectric generators (TEGs). Bending tests showed that the thin film has excellent flexibility and mechanical durability, meeting the flexible requirements of wearable devices. W doping can significantly increase the carrier concentration, Seebeck coefficient, and electrical conductivity of BST thin films. At 300 K, the power factor of the W-BST film is 2.25 times higher than that of the undoped film, reaching 13.75 µW cm-1 K-2. First-principles calculations showed that W doping introduces significant impurity peaks in the bandgap, in which W d electrons remarkably hybridize with the Sb and Te p electrons, leading to an improved electrical conductivity of BST films. Furthermore, W doping significantly reduces the work function of BST films, thereby improving the carrier mobility. A TEG module fabricated from four layers of W-BST thin films achieved a maximum output power density of 6.91 mW cm-2 at a temperature difference of 60 K. Application tests showed that the flexible TEG module could power a portable clock using the temperature difference between body temperature and room temperature. At a medium temperature of 439 K, the assembled TEG module can provide a stable output voltage of 1.51 V to power a LED. This study demonstrates the feasibility of combining inorganic thermoelectric materials with flexible substrates to create high-performance flexible TEGs.

2.
Natl Sci Rev ; 11(6): nwae146, 2024 Jun.
Article En | MEDLINE | ID: mdl-38741713

Lithiated organic cathode materials show great promise for practical applications in lithium-ion batteries owing to their Li-reservoir characteristics. However, the reported lithiated organic cathode materials still suffer from strict synthesis conditions and low capacity. Here we report a thermal intermolecular rearrangement method without organic solvents to prepare dilithium hydroquinone (Li2Q), which delivers a high capacity of 323 mAh g-1 with an average discharge voltage of 2.8 V. The reversible conversion between orthorhombic Li2Q and monoclinic benzoquinone during charge/discharge processes is revealed by in situ X-ray diffraction. Theoretical calculations show that the unique Li-O channels in Li2Q are beneficial for Li+ ion diffusion. In situ ultraviolet-visible spectra demonstrate that the dissolution issue of Li2Q electrodes during charge/discharge processes can be handled by separator modification, resulting in enhanced cycling stability. This work sheds light on the synthesis and battery application of high-capacity lithiated organic cathode materials.

3.
Insect Biochem Mol Biol ; 170: 104130, 2024 May 10.
Article En | MEDLINE | ID: mdl-38734116

Agmatine N-acetyltransferase (AgmNAT), which catalyzes the formation of N-acetylagmatine from acetyl-CoA and agmatine, is a member of the GCN5-related N-acetyltransferase family. So far, knowledge of the physiological roles of AgmNAT in insects is limited. Here, we identified one gene encoding protein homologous to that of Drosophila AgmNAT using sequence information from an activity-verified Drosophila AgmNAT in a BLAST search of the Bactrocera dorsalis genome. We expressed and purified B. dorsalis AgmNAT in Escherichia coli and used the purified enzyme to define the substrate specificity for acyl-CoA and amine substrates. Our application of the screening strategy to BdorAgmNAT led to the identification of agmatine as the best amine substrate for this enzyme, with the highest kcat/Km value. We successfully obtained a BdorAgmNAT knockout strain based on a wild-type strain (WT) using the CRISPR/Cas9 technique. The ovary development of the BdorAgmNAT knockout mutants was delayed for 10 days compared with the WT specimens. Moreover, mutants had a much smaller mature ovary size and laid far fewer eggs than WT. Loss of function of BdorAgmNAT caused by RNAi with mature WT females did not affect their fecundity. These findings indicate that BdorAgmNAT is critical for oogenesis. Our data provide the first evidence for AgmNAT in regulating ovary development.

4.
Front Microbiol ; 15: 1362089, 2024.
Article En | MEDLINE | ID: mdl-38756732

Entomopathogenic fungi (EPF) are economical and environmentally friendly, forming an essential part of integrated pest management strategies. We screened six strains of Beauveria bassiana (B1-B6) (Hypocreales: Cordycipitaceae), of which B4 was the most virulent to Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). We further assessed the biological characteristics of strain B4 and the environmental factors influencing its ability to infect B. dorsalis. We also evaluated the effects of B4 on two of the natural predators of B. dorsalis. We found that strain B4 was the most virulent to 3rd instar larvae, pupae, and adult B. dorsalis, causing mortality rates of 52.67, 61.33, and 90.67%, respectively. B4 was not toxic to B. dorsalis eggs. The optimum B4 effects on B. dorsalis were achieved at a relative humidity of 91-100% and a temperature of 25°C. Among the six insecticides commonly used for B. dorsalis control, 1.8% abamectin emulsifiable concentrate had the strongest inhibitory effect on B4 strain germination. B4 spraying affected both natural enemies (Amblyseius cucumeris and Anastatus japonicus), reducing the number of A. cucumeris and killing A. japonicus adults. We found a valuable strain of EPF (B4) that is virulent against many life stages of B. dorsalis and has great potential for the biological control of B. dorsalis. We also provide an important theoretical and practical base for developing a potential fungicide to control B. dorsalis.

5.
J Nanobiotechnology ; 22(1): 289, 2024 May 27.
Article En | MEDLINE | ID: mdl-38802863

By integrating magnetic resonance-visible components with scaffold materials, hydrogel microspheres (HMs) become visible under magnetic resonance imaging(MRI), allowing for non-invasive, continuous, and dynamic monitoring of the distribution, degradation, and relationship of the HMs with local tissues. However, when these visualization components are physically blended into the HMs, it reduces their relaxation rate and specificity under MRI, weakening the efficacy of real-time dynamic monitoring. To achieve MRI-guided in vivo monitoring of HMs with tissue repair functionality, we utilized airflow control and photo-crosslinking methods to prepare alginate-gelatin-based dual-network hydrogel microspheres (G-AlgMA HMs) using gadolinium ions (Gd (III)), a paramagnetic MRI contrast agent, as the crosslinker. When the network of G-AlgMA HMs degrades, the cleavage of covalent bonds causes the release of Gd (III), continuously altering the arrangement and movement characteristics of surrounding water molecules. This change in local transverse and longitudinal relaxation times results in variations in MRI signal values, thus enabling MRI-guided in vivo monitoring of the HMs. Additionally, in vivo data show that the degradation and release of polypeptide (K2 (SL)6 K2 (KK)) from G-AlgMA HMs promote local vascular regeneration and soft tissue repair. Overall, G-AlgMA HMs enable non-invasive, dynamic in vivo monitoring of biomaterial degradation and tissue regeneration through MRI, which is significant for understanding material degradation mechanisms, evaluating biocompatibility, and optimizing material design.


Alginates , Contrast Media , Gadolinium , Hydrogels , Magnetic Resonance Imaging , Microspheres , Magnetic Resonance Imaging/methods , Gadolinium/chemistry , Animals , Alginates/chemistry , Hydrogels/chemistry , Contrast Media/chemistry , Wound Healing/drug effects , Cross-Linking Reagents/chemistry , Gelatin/chemistry , Mice , Tissue Scaffolds/chemistry
6.
Mol Carcinog ; 2024 May 09.
Article En | MEDLINE | ID: mdl-38725218

It's been long thought that CD8+ cytotoxic T cells play a major role in T cell-mediated antitumor responses, whereas CD4+ T cells merely provide some assistance to CD8+ T cells as the "helpers." In recent years, numerous studies support the notion that CD4+ T cells play an indispensable role in antitumor responses. Here, we summarize and discuss the current knowledge regarding the roles of CD4+ T cells in antitumor responses and immunotherapy, with a focus on the molecular and cellular mechanisms behind these observations. These new insights on CD4+ T cells may pave the way to further optimize cancer immunotherapy.

7.
J Am Chem Soc ; 146(18): 12743-12749, 2024 May 08.
Article En | MEDLINE | ID: mdl-38652821

Aqueous batteries, with the advantages of high safety and low cost, are highly promising for large-scale energy storage. However, freezing of the aqueous electrolyte limits the low-temperature operation. Here, we propose and achieve a highly dispersed solvation structure in the electrolyte by coupling nonaggregated Cl- anions, which reduces the water cluster size and prevents the solidification of the aqueous electrolyte until -136.3 °C. The low-temperature LiCl electrolyte exhibits a high ionic conductivity (1.0 mS cm-1) at -80 °C and enables a stable low-temperature Ag/AgCl reference electrode at -50 °C. Moreover, the polyaniline-based battery can work at an extremely low temperature of -100 °C and shows superior cycling performance of 4000 cycles at -40 °C with 95.7% capacity retention. This work elucidates the correlation between the anion effect and the thermodynamic transition of the electrolyte, offering a novel approach for designing low-temperature electrolytes.

8.
Nanoscale ; 16(19): 9496-9508, 2024 May 16.
Article En | MEDLINE | ID: mdl-38651386

"Transition" metal-coordinated plant polyphenols are a type of promising antitumor nanodrugs owing to their high biosafety and catalytic therapy potency; however, the major obstacle restricting their clinical application is their poor tumor accumulation. Herein, Fe-doped ZIF-8 was tailored using tannic acid (TA) into a hollow mesoporous nanocarrier for gallic acid (GA) loading. After hyaluronic acid (HA) modification, the developed nanosystem of HFZIF-8/GA@HA was used for the targeted delivery of Fe ions and GA, thereby intratumorally achieving the synthesis of an Fe-GA coordinated complex. The TA-etching strategy facilitated the development of a cavitary structure and abundant coordination sites of ZIF-8, thus ensuring an ideal loading efficacy of GA (23.4 wt%). When HFZIF-8/GA@HA accumulates in the tumor microenvironment (TME), the framework is broken due to the competitive protonation ability of overexpressed protons in the TME. Interestingly, the intratumoral degradation of HFZIF-8/GA@HA provides the opportunity for the in situ "meeting" of GA and Fe ions, and through the coordination of polyhydroxyls assisted by conjugated electrons on the benzene ring, highly stable Fe-GA nanochelates are formed. Significantly, owing to the electron delocalization effect of GA, intratumorally coordinated Fe-GA could efficiently absorb second near-infrared (NIR-II, 1064 nm) laser irradiation and transfer it into thermal energy with a conversion efficiency of 36.7%. The photothermal performance could speed up the Fenton reaction rate of Fe-GA with endogenous H2O2 for generating more hydroxyl radicals, thus realizing thermally enhanced chemodynamic therapy. Overall, our research findings demonstrate that HFZIF-8/GA@HA has potential as a safe and efficient anticancer nanodrug.


Gallic Acid , Gallic Acid/chemistry , Gallic Acid/pharmacology , Mice , Animals , Humans , Cell Line, Tumor , Tannins/chemistry , Hyaluronic Acid/chemistry , Iron/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Tumor Microenvironment/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , Catalysis , Drug Carriers/chemistry , Nanoparticles/chemistry , Imidazoles
9.
Org Biomol Chem ; 22(19): 3904-3909, 2024 May 15.
Article En | MEDLINE | ID: mdl-38656504

A method for the α-oxidation and sulfonation of benzyl secondary amines was developed utilizing Ir(III) or Eosin Y as the photocatalyst in the presence of O2 as a green oxidant. Using commercial substrates, 37 products from cyclic and acyclic benzylamines were achieved with good functional group compatibility in 48-87% yields. Furthermore, tetrahydroisoquinoline protected by an Ac or a Boc group was oxidized under standard conditions.

10.
Mitochondrial DNA B Resour ; 9(3): 411-414, 2024.
Article En | MEDLINE | ID: mdl-38562438

Hemiboea pterocaulis is a unique species only found in Guilin, Guangxi, China. In this study, we sequenced and assembled the complete chloroplast genome of H. pterocaulis and revealed its phylogenetic relationship with other Hemiboea species. The chloroplast genome sequence of H. pterocaulis is 153,159 bp in length and comprises a large single-copy (LSC) region of 84,178 bp, a small single-copy (SSC) region of 18,087 bp, and a pair of inverted repeat (IR) regions, each with a length of 25,447 bp. It has a total GC content of 37.6% and encodes 132 genes, including 87 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The phylogenetic relationships based on the complete chloroplast genome sequences of Hemiboea taxa indicate that H. pterocaulis is most closely related to H. suiyangensis, indicating that H. pterocaulis is an independent species and is separated from the H. subcapitata complex. These results provide valuable insights into the phylogeny, species divergence, and delimitation of the Hemiboea genus.

11.
bioRxiv ; 2024 Apr 08.
Article En | MEDLINE | ID: mdl-38645259

The crab-eating macaques ( Macaca fascicularis ) and rhesus macaques ( M. mulatta ) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is ∼42% lower, while centromeres are ∼3.7 times longer than those in humans. The characterization of ∼2 Mbp fixed genetic variants and ∼240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1 ). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO ). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2 ). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1 , SEMA3F , and HOXD13 ). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.

12.
Nat Commun ; 15(1): 2512, 2024 Mar 21.
Article En | MEDLINE | ID: mdl-38509084

Linear bosonic modes offer a hardware-efficient alternative for quantum information processing but require access to some nonlinearity for universal control. The lack of nonlinearity in photonics has led to encoded measurement-based quantum computing, which relies on linear operations but requires access to resourceful ('nonlinear') quantum states, such as cubic phase states. In contrast, superconducting microwave circuits offer engineerable nonlinearities but suffer from static Kerr nonlinearity. Here, we demonstrate universal control of a bosonic mode composed of a superconducting nonlinear asymmetric inductive element (SNAIL) resonator, enabled by native nonlinearities in the SNAIL element. We suppress static nonlinearities by operating the SNAIL in the vicinity of its Kerr-free point and dynamically activate nonlinearities up to third order by fast flux pulses. We experimentally realize a universal set of generalized squeezing operations, as well as the cubic phase gate, and exploit them to deterministically prepare a cubic phase state in 60 ns. Our results initiate the experimental field of polynomial quantum computing, in the continuous-variables notion originally introduced by Lloyd and Braunstein.

13.
Small ; : e2309801, 2024 Mar 25.
Article En | MEDLINE | ID: mdl-38528431

Solid-state lithium batteries (SSLBs) are regarded as next-generation energy storage devices because of their advantages in terms of safety and energy density. However, the poor interfacial compatibility and low ionic conductivity seriously hinder their development. Electrospinning is considered as a promising method for fabricating solid-state electrolytes (SSEs) with controllable nanofiber structures, scalability, and cost-effectiveness. Numerous efforts are dedicated to electrospinning SSEs with high ionic conductivity and strong interfacial compatibility, but a comprehensive summary is lacking. Here, the history of electrospinning SSEs is overeviewed and introduce the electrospinning mechanism, followed by the manipulation of electrospun nanofibers and their utilization in SSEs, as well as various methods to improve the ionic conductivity of SSEs. Finally, new perspectives aimed at enhancing the performance of SSEs membranes and facilitating their industrialization are proposed. This review aims to provide a comprehensive overview and future perspective on electrospinning technology in SSEs, with the goal of guiding the further development of SSLBs.

14.
Zool Res ; 45(2): 292-298, 2024 Mar 18.
Article En | MEDLINE | ID: mdl-38485499

Mutations in mitochondrial DNA (mtDNA) are maternally inherited and have the potential to cause severe disorders. Mitochondrial replacement therapies, including spindle, polar body, and pronuclear transfers, are promising strategies for preventing the hereditary transmission of mtDNA diseases. While pronuclear transfer has been used to generate mitochondrial replacement mouse models and human embryos, its application in non-human primates has not been previously reported. In this study, we successfully generated four healthy cynomolgus monkeys ( Macaca fascicularis) via female pronuclear transfer. These individuals all survived for more than two years and exhibited minimal mtDNA carryover (3.8%-6.7%), as well as relatively stable mtDNA heteroplasmy dynamics during development. The successful establishment of this non-human primate model highlights the considerable potential of pronuclear transfer in reducing the risk of inherited mtDNA diseases and provides a valuable preclinical research model for advancing mitochondrial replacement therapies in humans.


Mitochondrial Diseases , Rodent Diseases , Mice , Humans , Female , Animals , Mitochondrial Diseases/genetics , Mitochondrial Diseases/prevention & control , Mitochondrial Diseases/veterinary , Haplorhini/genetics , Mitochondria/genetics , DNA, Mitochondrial/genetics , Primates/genetics
15.
J Colloid Interface Sci ; 665: 181-187, 2024 Jul.
Article En | MEDLINE | ID: mdl-38522158

Carbonyl or imine-based compounds have received a great deal of attention due to their high specific capacity and designability as cathodes for aqueous rechargeable organo-aluminum batteries. However, the inherent low conductivity and high solubility of carbonyl and imine-based compounds severely affect the cycling stability of aluminum batteries. Therefore, it is urgent to find an organic cathodes material with low solubility and good cycling performance. In this work, dibenzo[a,c]dibenzo[5,6:7,8]quinoxalino[2,3-i]phenazine-10,21-dione (DDQP) were synthesized by simple dehydration condensation to form new imine covalent bonds, which led to the synthesis of imine-conjugated backbone structures with carbonyl, extended π-conjugation planes, and increased active sites, resulting in increased specific capacities. Its storage mechanism with Al(OTF)2+ has also been confirmed. This monovalent ion usually possesses a lower coulombic interaction, which leads to a reduced solubility of DDQP during redox processes and improves its cyclic stability. The specific capacity of DDQP is 252.22 mAh/g at a current density of 400 mA g-1. After cycling, the discharge specific capacity remains at 219 mAh/g. Surprisingly, the conductivity of the battery also is improved by this structure of multiple active sites. And it can be further confirmed by theoretical calculations that the synthesis of DDQP realigns the arrangement of the electron cloud, enhances the electron affinity, and reduces the energy gap. This study provides a new reference for improving the performance of aqueous organic aluminum batteries.

16.
J Am Chem Soc ; 146(14): 10167-10176, 2024 Apr 10.
Article En | MEDLINE | ID: mdl-38536043

The π-bond enrichment frameworks not only serve as a crucial building block in organic synthesis but also assume a pivotal role in the fields of materials science, biomedicine, photochemistry, and other related disciplines owing to their distinctive structural characteristics. The incorporation of various substituents into the C═C double bonds of tetrasubstituted alkenes is currently a highly significant research area. However, the synthesis of tetrasubstituted alkenes with diverse substituents on double bonds poses a significant challenge in achieving stereoselectivity. Here, we reported an efficient and convergent route of Cu-catalyzed borylalkynylation of both symmetrical and unsymmetrical 1,3-diynes, B2pin2, and acetylene bromide to the construction of boronated phenyldiethynylethylene (BPDEE) derivatives with excellent chemo-, stereo-, and regioselectivities. BPDEE derivatives could transform into novel tetrasubstituted organic π-conjugated gem-diphenyldiethynylethylene (DPDEE), vinylphenyldiethynylethylene (VPDEE), and phenyltriethynylethylene (PTEE) derivatives by a stepwise process, which provides a flexible platform for the synthesis of complex π-bond enrichment frameworks that were difficult to synthesize by previous methods. The initial optical characterization revealed that the synthesized molecules exhibited aggregation-induced emission (AIE) properties, which further establishes the groundwork for future applications and enriches and advances the field of functional π-conjugated frameworks research.

17.
Acta Pharmacol Sin ; 2024 Mar 27.
Article En | MEDLINE | ID: mdl-38538718

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

18.
Maturitas ; 184: 107965, 2024 Jun.
Article En | MEDLINE | ID: mdl-38460416

BACKGROUND: Sexual and reproductive health (SRH) is critical to the overall health of older adults. We assessed the utilization of SRH services and its correlates among older adults in China. METHODS: We recruited community-dwelling adults aged 50 and above in five Chinese cities between June 2020 and December 2022. In this study SRH services included reproductive health examination, cervical cancer screening, and sexual life counselling. Logistic regression was used to assess correlates of SRH services utilization. RESULTS: A total of 3001 older adults (1819 men and 1182 women) were enrolled. Among them, 11.4 % (343/3001) of participants received a reproductive health examination, 35.4 % (418/1182) of female participants received cervical cancer screening, and 30.1 % (401/1332) of sexually active participants sought help for their sexual lives. Older men with an annual income of USD 7500 or more (aOR = 3.21, 95%CI: 1.39-7.44), two or more chronic conditions (2.38, 1.39-4.08), and reproductive health problems (2.01, 1.18-3.43) were more likely to receive a urological examination. For older women, individuals who were younger (aged 50-59 years: 5.18, 2.84-9.43; aged 60-69 years: 2.67, 1.49-4.79), lived in an urban area (1.88, 1.31-2.71), were employed (1.73, 1.21-2.47), had two or more chronic conditions (2.04, 1.37-3.05), were sexually active (1.72, 1.15-2.58) and talked about sex (1.69, 1.21-2.36) were more likely to receive a gynecological examination. CONCLUSION: SRH services utilization among older adults was low, with urological examination among older men particularly low. SRH messages and services tailored for older adults are needed to enhance their utilization of SRH services.


Reproductive Health Services , Humans , Male , Female , China , Middle Aged , Aged , Reproductive Health Services/statistics & numerical data , Sexual Health/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Reproductive Health/statistics & numerical data , Uterine Cervical Neoplasms , Early Detection of Cancer/statistics & numerical data , Sexual Behavior/statistics & numerical data
19.
Cell Genom ; 4(3): 100511, 2024 Mar 13.
Article En | MEDLINE | ID: mdl-38428419

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.


Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/genetics , Prostate/metabolism , Mutation , Genomics , Evolution, Molecular
20.
Cancer Cell ; 42(5): 780-796.e6, 2024 May 13.
Article En | MEDLINE | ID: mdl-38518774

Emerging as the most potent and durable combinational immunotherapy, dual anti-PD-1 and CTLA-4 immune checkpoint blockade (ICB) therapy notoriously increases grade 3-5 immune-related adverse events (irAEs) in patients. Accordingly, attempts to improve the antitumor potency of anti-PD-1+CTLA-4 ICB by including additional therapeutics have been largely discouraged due to concerns of further increasing fatal toxicity. Here, we screened ∼3,000 Food and Drug Administration (FDA)-approved drugs and identified clofazimine as a potential third agent to optimize anti-PD-1+CTLA-4 ICB. Remarkably, clofazimine outperforms ICB dose reduction or steroid treatment in reversing lethality of irAEs, but unlike the detrimental effect of steroids on antitumor efficacy, clofazimine potentiates curative responses in anti-PD-1+CTLA-4 ICB. Mechanistically, clofazimine promotes E2F1 activation in CD8+ T cells to overcome resistance and counteracts pathogenic Th17 cells to abolish irAEs. Collectively, clofazimine potentiates the antitumor efficacy of anti-PD-1+CTLA-4 ICB, curbs intractable irAEs, and may fill a desperate clinical need to improve patient survival.


CTLA-4 Antigen , Clofazimine , Immune Checkpoint Inhibitors , Programmed Cell Death 1 Receptor , Clofazimine/pharmacology , Clofazimine/therapeutic use , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Animals , Humans , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Female , Mice, Inbred C57BL , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Th17 Cells/drug effects , Th17 Cells/immunology
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