bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities
Authors: Yin Nanhao , Li Xintong , Zhang Xuanwei , Xue Shaolong , Cao Yu , Niedermann Gabriele , Lu You , Xue Jianxin 
Published: May 2024

AbstractImmunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
TRIM65 promotes renal cell carcinoma through ubiquitination and degradation of BTG3
Authors: Zhang Qi , Li Yong , Zhu Qing , Xie Tao , Xiao Yue , Zhang Feng , Li Na , Deng Keyu , Xin Hongbo , Huang Xuan 
Published: May 2024

AbstractAs a typical E3 ligase, TRIM65 (tripartite motif containing 65) is involved in the regulation of antiviral innate immunity and the pathogenesis of certain tumors. However, the role of TRIM65 in renal cell carcinoma (RCC) and the underlying mechanism has not been determined yet. In this study, we identified TRIM65 as a novel oncogene in RCC, which enhanced the tumor cell proliferation and anchorage-independent growth abilities both in vitro and in vivo. Moreover, we found that TRIM65-regulated RCC proliferation mainly via direct interaction with BTG3 (BTG anti-proliferation factor 3), which in turn induced the K48-linked ubiquitination and subsequent degradation through K41 amino acid. Furthermore, TRIM65 relieved G2/M phase cell cycle arrest via degradation of BTG3 and regulated downstream factors. Further studies revealed that TRIM65 acts through TRIM65-BTG3-CyclinD1 axis and clinical sample IHC chip data indicated a negative correction between TRIM65 and BTG3. Taken together, our findings demonstrated that TRIM65 promotes RCC cell proliferation via regulation of the cell cycle through degradation of BTG3, suggesting that TRIM65 may be a promising target for RCC therapy.
IL-33/NF-κB/ST2L/Rab37 positive-feedback loop promotes M2 macrophage to limit chemotherapeutic efficacy in lung cancer
Authors: Yang You-En , Hu Meng-Hsuan , Zeng Yen-Chen , Tseng Yau-Lin , Chen Ying-Yuan , Su Wu-Chou , Chang Chih-Peng , Wang Yi-Ching 
Published: May 2024

AbstractIL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.
Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in lamin A/C-deficient mice
Authors: Kirby Tyler J. , Zahr Hind C. , Fong Ern Hwei Hannah , Lammerding Jan 
Published: May 2024

AbstractLamins A and C, encoded by the LMNA gene, are nuclear intermediate filaments that provide structural support to the nucleus and contribute to chromatin organization and transcriptional regulation. LMNA mutations cause muscular dystrophies, dilated cardiomyopathy, and other diseases. The mechanisms by which many LMNA mutations result in muscle-specific diseases have remained elusive, presenting a major hurdle in the development of effective treatments. Previous studies using striated muscle laminopathy mouse models found that cytoskeletal forces acting on mechanically fragile Lmna-mutant nuclei led to transient nuclear envelope rupture, extensive DNA damage, and activation of DNA damage response (DDR) pathways in skeletal muscle cells in vitro and in vivo. Furthermore, hearts of Lmna mutant mice have elevated activation of the tumor suppressor protein p53, a central regulator of DDR signaling. We hypothesized that elevated p53 activation could present a pathogenic mechanism in striated muscle laminopathies, and that eliminating p53 activation could improve muscle function and survival in laminopathy mouse models. Supporting a pathogenic function of p53 activation in muscle, stabilization of p53 was sufficient to reduce contractility and viability in wild-type muscle cells in vitro. Using three laminopathy models, we found that increased p53 activity in Lmna-mutant muscle cells primarily resulted from mechanically induced damage to the myonuclei, and not from altered transcriptional regulation due to loss of lamin A/C expression. However, global deletion of p53 in a severe muscle laminopathy model did not reduce the disease phenotype or increase survival, indicating that additional drivers of disease must contribute to the disease pathogenesis.
Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST
Authors: Zheng Dayong , Zhang Yan , Yang Sukjin , Su Ning , Bakhoum Michael , Zhang Guoliang , Naderinezhad Samira , Mao Zhengmei , Wang Zheng , Zhou Ting , Li Wenliang 
Published: May 2024

AbstractAlthough effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2’s repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity
Authors: Langguth Miriam , Maranou Eleftheria , Koskela Saara A. , Elenius Oskar , Kallionpää Roosa E. , Birkman Eva-Maria , Pulkkinen Otto I. , Sundvall Maria , Salmi Marko , Figueiredo Carlos R. 
Published: May 2024

AbstractImmune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.
Trends and outcomes of hospitalized patients with priapism in Germany: results from the GRAND study
Authors: Pyrgidis Nikolaos , Schulz Gerald B. , Chaloupka Michael , Volz Yannic , Pfitzinger Paulo L. , Berg Elena , Weinhold Philipp , Jokisch Friedrich , Stief Christian G. , Becker Armin J. , Marcon Julian 
Published: May 2024

AbstractWe aimed to provide evidence on the trends and in-hospital outcomes of patients with low- and high-flow priapism through the largest study in the field. We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2008-2021), and performed multiple patient-level analyses. We included 6,588 men with low-flow and 729 with high-flow priapism. Among patients with low-flow priapism, 156 (2.4%) suffered from sickle cell disease, and 1,477 (22.4%) patients required shunt surgery. Of them, only 37 (2.5%) received a concomitant penile prosthesis implantation (30 inflatable and 7 semi-rigid prosthesis). In Germany, the total number of patients with low-flow priapism requiring hospital stay has steadily increased, while the number of patients with high-flow priapism requiring hospital stay has decreased in the last years. Among patients with high-flow priapism, 136 (18.7%) required selective artery embolization. In men with low-flow priapism, sickle cell disease was associated with high rates of exchange transfusion (OR: 21, 95% CI: 14–31, p < 0.001). The length of hospital stay (p = 0.06) and the intensive care unit admissions (p = 0.9) did not differ between patients with low-flow priapism due to sickle cell disease versus other causes of low-flow priapism. Accordingly, in men with high-flow priapism, embolization was not associated with worse outcomes in terms of length of hospital stay (p > 0.9), transfusion (p = 0.8), and intensive care unit admission (p = 0.5). Low-flow priapism is an absolute emergency that requires shunt surgery in more than one-fifth of all patients requiring hospital stay. On the contrary, high-flow priapism is still managed, in most cases, conservatively.
Far-East Asian Toxoplasma isolates share ancestry with North and South/Central American recombinant lineages
Authors: Ihara Fumiaki , Kyan Hisako , Takashima Yasuhiro , Ono Fumiko , Hayashi Kei , Matsuo Tomohide , Igarashi Makoto , Nishikawa Yoshifumi , Hikosaka Kenji , Sakamoto Hirokazu , Nakamura Shota , Motooka Daisuke , Yamauchi Kiyoshi , Ichikawa-Seki Madoka , Fukumoto Shinya , Sasaki Motoki , Ikadai Hiromi , Kusakisako Kodai , Ohari Yuma , Yoshida Ayako , Sasai Miwa , Grigg Michael E. , Yamamoto Masahiro 
Published: May 2024

AbstractToxoplasma gondii is a global protozoan pathogen. Clonal lineages predominate in Europe, North America, Africa, and China, whereas highly recombinant parasites are endemic in South/Central America. Far East Asian T. gondii isolates are not included in current global population genetic structure analyses at WGS resolution. Here we report a genome-wide population study that compared eight Japanese and two Chinese isolates against representative worldwide T. gondii genomes using POPSICLE, a novel population structure analyzing software. Also included were 7 genomes resurrected from non-viable isolates by target enrichment sequencing. Visualization of the genome structure by POPSICLE shows a mixture of Chinese haplogroup (HG) 13 haploblocks introgressed within the genomes of Japanese HG2 and North American HG12. Furthermore, two ancestral lineages were identified in the Japanese strains; one lineage shares a common ancestor with HG11 found in both Japanese strains and North American HG12. The other ancestral lineage, found in T. gondii isolates from a small island in Japan, is admixed with genetically diversified South/Central American strains. Taken together, this study suggests multiple ancestral links between Far East Asian and American T. gondii strains and provides insight into the transmission history of this cosmopolitan organism.
Localized and global representation of prior value, sensory evidence, and choice in male mouse cerebral cortex
Authors: Ishizu Kotaro , Nishimoto Shosuke , Ueoka Yutaro , Funamizu Akihiro 
Published: May 2024

AbstractAdaptive behavior requires integrating prior knowledge of action outcomes and sensory evidence for making decisions while maintaining prior knowledge for future actions. As outcome- and sensory-based decisions are often tested separately, it is unclear how these processes are integrated in the brain. In a tone frequency discrimination task with two sound durations and asymmetric reward blocks, we found that neurons in the medial prefrontal cortex of male mice represented the additive combination of prior reward expectations and choices. The sensory inputs and choices were selectively decoded from the auditory cortex irrespective of reward priors and the secondary motor cortex, respectively, suggesting localized computations of task variables are required within single trials. In contrast, all the recorded regions represented prior values that needed to be maintained across trials. We propose localized and global computations of task variables in different time scales in the cerebral cortex.
Dual-mode harvest solar energy for photothermal Cu2-xSe biomineralization and seawater desalination by biotic-abiotic hybrid
Authors: Gong Sheng-Lan , Tian YangChao , Sheng Guo-Ping , Tian Li-Jiao 
Published: May 2024

AbstractBiotic-abiotic hybrid photocatalytic system is an innovative strategy to capture solar energy. Diversifying solar energy conversion products and balancing photoelectron generation and transduction are critical to unravel the potential of hybrid photocatalysis. Here, we harvest solar energy in a dual mode for Cu2-xSe nanoparticles biomineralization and seawater desalination by integrating the merits of Shewanella oneidensis MR-1 and biogenic nanoparticles. Photoelectrons generated by extracellular Se0 nanoparticles power Cu2-xSe synthesis through two pathways that either cross the outer membrane to activate periplasmic Cu(II) reduction or are directly delivered into the extracellular space for Cu(I) evolution. Meanwhile, photoelectrons drive periplasmic Cu(II) reduction by reversing MtrABC complexes in S. oneidensis. Moreover, the unique photothermal feature of the as-prepared Cu2-xSe nanoparticles, the natural hydrophilicity, and the linking properties of bacterium offer a convenient way to tailor photothermal membranes for solar water production. This study provides a paradigm for balancing the source and sink of photoelectrons and diversifying solar energy conversion products in biotic-abiotic hybrid platforms.
DNA methylation-based high-resolution mapping of long-distance chromosomal interactions in nucleosome-depleted regions
Authors: Li Yi , Lee James , Bai Lu 
Published: May 2024

Abstract3C-based methods have significantly advanced our understanding of 3D genome organization. However, it remains a formidable task to precisely capture long-range chromosomal interactions between individual loci, such as those between promoters and distal enhancers. Here, we present Methyltransferase Targeting-based chromosome Architecture Capture (MTAC), a method that maps the contacts between a target site (viewpoint) and the rest of the genome in budding yeast with high resolution and sensitivity. MTAC detects hundreds of intra- and inter-chromosomal interactions within nucleosome-depleted regions (NDRs) that cannot be captured by 4C, Hi-C, or Micro-C. By applying MTAC to various viewpoints, we find that (1) most long-distance chromosomal interactions detected by MTAC reflect tethering by the nuclear pore complexes (NPCs), (2) genes co-regulated by methionine assemble into inter-chromosomal clusters near NPCs upon activation, (3) mediated by condensin, the mating locus forms a highly specific interaction with the recombination enhancer (RE) in a mating-type specific manner, and (4) correlation of MTAC signals among NDRs reveal spatial mixing and segregation of the genome. Overall, these results demonstrate MTAC as a powerful tool to resolve fine-scale long-distance chromosomal interactions and provide insights into the 3D genome organization.
Controlled oxygen delivery to power tissue regeneration
Authors: Zoneff Elizabeth , Wang Yi , Jackson Colin , Smith Oliver , Duchi Serena , Onofrillo Carmine , Farrugia Brooke , Moulton Simon E. , Williams Richard , Parish Clare , Nisbet David R. , Caballero-Aguilar Lilith M. 
Published: May 2024

AbstractOxygen plays a crucial role in human embryogenesis, homeostasis, and tissue regeneration. Emerging engineered regenerative solutions call for novel oxygen delivery systems. To become a reality, these systems must consider physiological processes, oxygen release mechanisms and the target application. In this review, we explore the biological relevance of oxygen at both a cellular and tissue level, and the importance of its controlled delivery via engineered biomaterials and devices. Recent advances and upcoming trends in the field are also discussed with a focus on tissue-engineered constructs that could meet metabolic demands to facilitate regeneration.
Environmental conditions associated with initial northern expansion of anatomically modern humans
Authors: Saltré Frédérik , Chadœuf Joël , Higham Thomas , Ochocki Monty , Block Sebastián , Bunney Ellyse , Llamas Bastien , Bradshaw Corey J. A. 
Published: May 2024

AbstractThe ability of our ancestors to switch food sources and to migrate to more favourable environments enabled the rapid global expansion of anatomically modern humans beyond Africa as early as 120,000 years ago. Whether this versatility was largely the result of environmentally determined processes or was instead dominated by cultural drivers, social structures, and interactions among different groups, is unclear. We develop a statistical approach that combines both archaeological and genetic data to infer the more-likely initial expansion routes in northern Eurasia and the Americas. We then quantify the main differences in past environmental conditions between the more-likely routes and other potential (less-likely) routes of expansion. We establish that, even though cultural drivers remain plausible at finer scales, the emergent migration corridors were predominantly constrained by a combination of regional environmental conditions, including the presence of a forest-grassland ecotone, changes in temperature and precipitation, and proximity to rivers.
Diastereoselective dearomatization of indoles via photocatalytic hydroboration on hydramine-functionalized carbon nitride
Authors: Zhang Qiao , Xu Wengang , Liu Qiong , Xia Congjian , Shao Qi , Ma Lishuang , Wu Mingbo 
Published: May 2024

AbstractA protocol for trans-hydroboration of indole derivatives using heterogeneous photocatalysis with NHC-borane has been developed, addressing a persistent challenge in organic synthesis. The protocol, leveraging high crystalline vacancy-engineered polymeric carbon nitride as a catalyst, enables diastereoselective synthesis, expanding substrate scope and complementing existing methods. The approach emphasizes eco-friendliness, cost-effectiveness, and scalability, making it suitable for industrial applications, particularly in renewable energy contexts. The catalyst’s superior performance, attributed to its rich carbon-vacancies and well-ordered structure, surpasses more expensive homogeneous alternatives, enhancing viability for large-scale use. This innovation holds promise for synthesizing bioactive compounds and materials relevant to medicinal chemistry and beyond.
Central-Pacific El Niño-Southern Oscillation less predictable under greenhouse warming
Authors: Chen Hui , Jin Yishuai , Liu Zhengyu , Sun Daoxun , Chen Xianyao , McPhaden Michael J. , Capotondi Antonietta , Lin Xiaopei 
Published: May 2024

AbstractEl Niño-Southern Oscillation (ENSO) is the dominant mode of interannual climate variability in the tropical Pacific, whose nature nevertheless may change significantly in a warming climate. Here, we show that the predictability of ENSO may decrease in the future. Across the models in the Coupled Model Intercomparison Project Phase 6 (CMIP6), we find a robust decrease of the persistence and predictability for the Central Pacific (CP) ENSO under global warming, notably in passing through the boreal spring. The strength of spring predictability barrier will be increased by 25% in the future. The reduced predictability of CP ENSO is caused by the faster warming over surface ocean in tropical Pacific and, in turn, the enhanced thermodynamical damping rate on CP ENSO in response to global warming. In contrast, the predictability of Eastern Pacific ENSO will not change. Our results suggest that future greenhouse warming will make the prediction of CP ENSO more challenging, with far-reaching implications on future climate predictions.
Rediscovery of mononuclear phagocyte system blockade for nanoparticle drug delivery
Authors: Zelepukin Ivan V. , Shevchenko Konstantin G. , Deyev Sergey M. 
Published: May 2024

AbstractRapid uptake of nanoparticles by mononuclear phagocyte system (MPS) significantly hampers their therapeutic efficacy. Temporal MPS blockade is one of the few ways to overcome this barrier – the approach rediscovered many times under different names but never extensively used in clinic. Using meta-analysis of the published data we prove the efficacy of this technique for enhancing particle circulation in blood and their delivery to tumours, describe a century of its evolution and potential combined mechanism behind it. Finally, we discuss future directions of the research focusing on the features essential for successful clinical translation of the method.