ACS Omega. 2023 Jul 7;8(28):25487-25495. doi: 10.1021/acsomega.3c03064. eCollection 2023 Jul 18.

ABSTRACT

Photoaffinity labeling followed by tandem mass spectrometry is an often used strategy to identify protein targets of small-molecule drugs or drug candidates, which, under ideal conditions, enables the identification of the actual drug binding site. In the case of bioactive peptides, however, identifying the distinct binding site is hampered because of complex fragmentation patterns during tandem mass spectrometry. We here report the development and use of small cleavable photoaffinity reagents that allow functionalization of bioactive peptides for light-induced covalent binding to their protein targets. Upon cleavage of the covalently linked peptide drug, a chemical remnant of a defined mass remains on the bound amino acid, which is then used to unambiguously identify the drug binding site. Applying our approach to known peptide-drug/protein pairs with reported crystal structures, such as the calmodulin-melittin interaction, we were able to validate the identified binding sites based on structural models. Overall, our cleavable photoaffinity labeling strategy represents a powerful tool to enable the identification of protein targets and specific binding sites of a wide variety of bioactive peptides in the future.

PMID:37483247 | PMC:PMC10357517 | DOI:10.1021/acsomega.3c03064

Analyst. 2023 Jul 24. doi: 10.1039/d3an00888f. Online ahead of print.

ABSTRACT

Electronic cigarettes are a popular nicotine consumption product that have risen in popularity as an alternative to cigarettes. However, their recent meteoric rise in market size and various controversies have resulted in the analyses of e-liquid ingredients to be focused on powerful laboratory-based slow methods such as chromatography and mass spectrometry. Here we present a complementary technology based on Raman spectroscopy combined with chemometrics as a fast, inexpensive, and highly portable screening tool to detect and quantify the propylene glycol : glycerol (PG : VG) ratio and nicotine content of e-cigarette liquids. Through this, the PG : VG ratio of 20 out of 23 commercial samples was quantified to within 3% of their stated value, while nicotine was successfully quantified to within 1 mg g-1 for 16 out of 23 samples without the need for accurate knowledge of flavonoid composition. High linearity was also achieved when flavours were kept constant. Finally, the limitations of Raman spectroscopy are discussed, and potential solutions are suggested.

PMID:37482759 | DOI:10.1039/d3an00888f

Toxicol In Vitro. 2023 Jul 21:105651. doi: 10.1016/j.tiv.2023.105651. Online ahead of print.

ABSTRACT

Targeting cell surface receptors with immunotoxins provides a novel, unique and highly potent treatment against cancers. A high expression of interleukin-13 (IL13) receptor α2 (IL13Rα2) has been reported in different types of cancers including glioblastoma multiforme (GBM). In this paper, to target IL13Rα2 on GBM cells, a fusion protein was generated comprising human IL13 and staphylococcal enterotoxin B (SEB), termed IL13-linker-SEB. The fusion protein was cloned into pET28a(+) and expressed in Escherichia coli strain BL21 (DE3); U251 (IL13Rα2-positive) and T98G (IL13Rα2-negative) GBM cell lines were employed and the functional activity of IL13-linker-SEB was evaluated by cell ELISA, cytotoxicity (MTT and LDH), apoptosis (flow cytometry and caspase-3 activity), adhesion, scratch and RT-PCR tests. SEB and chemotherapeutic drugs were employed to be compared to IL13-linker-SEB function. The IL13-linker-SEB exhibited higher binding affinity and cytotoxicity compared to SEB on U251 cells, although both recombinant proteins had shown similar behavior regarding T98G cells. Furthermore, the highest induction of apoptosis was observed in U251 cells treated with IL13-linker-SEB which was confirmed by Bax/Bcl-2 ratio. The expression of MMP2, MMP9 and VEGFR2 in U251 cells experienced a significant reduction after treatment with IL13-linker-SEB compared to SEB and T98G treated cells. The data showed that IL13-linker-SEB can be considered as a novel potential agent for GBM treatment; however, further research is needed to investigate the efficacy.

PMID:37482138 | DOI:10.1016/j.tiv.2023.105651

Biomed Pharmacother. 2023 Jul 20;165:114972. doi: 10.1016/j.biopha.2023.114972. Online ahead of print.

ABSTRACT

The rising incidence of breast cancer has been a significant source of concern in the medical community. Regarding the adverse effects and consequences of current treatments, cancers' health, and socio-economical aspects have become more complicated, leaving research aimed at improved or new treatments on top priority. Medicinal herbs contain multitarget compounds that can control cancer development and advancement. Owing to Nigella Sativa's elements, it can treat many disorders. Thymoquinone (TQ) is a natural chemical derived from the black seeds of Nigella sativa Linn proved to have anti-cancer and anti-inflammatory properties. TQ interferes in a broad spectrum of tumorigenic procedures and inhibits carcinogenesis, malignant development, invasion, migration, and angiogenesis owing to its multitargeting ability. It effectively facilitates miR-34a up-regulation, regulates the p53-dependent pathway, and suppresses Rac1 expression. TQ promotes apoptosis and controls the expression of pro- and anti-apoptotic genes. It has also been shown to diminish the phosphorylation of NF-B and IKK and decrease the metastasis and ERK1/2 and PI3K activity. We discuss TQ's cytotoxic effects for breast cancer treatment with a deep look at the relevant stimulatory or inhibitory signaling pathways. This review discusses the various forms of polymeric and non-polymeric nanocarriers (NC) and the encapsulation of TQ for increasing oral bioavailability and enhanced in vitro and in vivo efficacy of TQ-combined treatment with different chemotherapeutic agents against various breast cancer cell lines. This study can be useful to a broad scientific community, comprising pharmaceutical and biological scientists, as well as clinical investigators.

PMID:37481931 | DOI:10.1016/j.biopha.2023.114972

BMC Gastroenterol. 2023 Jul 24;23(1):248. doi: 10.1186/s12876-023-02891-4.

ABSTRACT

BACKGROUND: Gastric cancer (GC) ranks among the most common malignancies worldwide. This study aimed to find critical genes/pathways in GC pathogenesis.

METHODS: Gene interactions were analyzed, and the protein-protein interaction network was drawn. Then enrichment analysis of the hub genes was performed and network cluster analysis and promoter analysis of the hub genes were done. Age/sex analysis was done on the identified genes.

RESULTS: Eleven hub genes in GC were identified in the current study (ATP5A1, ATP5B, ATP5D, MT-ATP8, COX7A2, COX6C, ND4, ND6, NDUFS3, RPL8, and RPS16), mostly involved in mitochondrial functions. There was no report on the ATP5D, ND6, NDUFS3, RPL8, and RPS16 in GC. Our results showed that the most affected processes in GC are the metabolic processes, and the oxidative phosphorylation pathway was considerably enriched which showed the significance of mitochondria in GC pathogenesis. Most of the affected pathways in GC were also involved in neurodegenerative diseases. Promoter analysis showed that negative regulation of signal transduction might play an important role in GC pathogenesis. In the analysis of the basal expression pattern of the selected genes whose basal expression presented a change during the age, we found that a change in age may be an indicator of changes in disease insurgence and/or progression at different ages.

CONCLUSIONS: These results might open up new insights into GC pathogenesis. The identified genes might be novel diagnostic/prognostic biomarkers or potential therapeutic targets for GC. This work, being based on bioinformatics analysis act as a hypothesis generator that requires further clinical validation.

PMID:37482618 | DOI:10.1186/s12876-023-02891-4

Commun Biol. 2023 Jul 22;6(1):768. doi: 10.1038/s42003-023-05128-y.

ABSTRACT

Aging manifests as progressive deteriorations in homeostasis, requiring systems-level perspectives to investigate the gradual molecular dysregulation of underlying biological processes. Here, we report systemic changes in the molecular regulation of biological processes under multiple lifespan-extending interventions. Differential Rank Conservation (DIRAC) analyses of mouse liver proteomics and transcriptomics data show that mechanistically distinct lifespan-extending interventions (acarbose, 17α-estradiol, rapamycin, and calorie restriction) generally tighten the regulation of biological modules. These tightening patterns are similar across the interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response. Differences in DIRAC patterns between proteins and transcripts highlight specific modules which may be tightened via augmented cap-independent translation. Moreover, the systemic shifts in fatty acid metabolism are supported through integrated analysis of liver transcriptomics data with a mouse genome-scale metabolic model. Our findings highlight the power of systems-level approaches for identifying and characterizing the biological processes involved in aging and longevity.

PMID:37481675 | DOI:10.1038/s42003-023-05128-y

BioData Min. 2023 Jul 22;16(1):23. doi: 10.1186/s13040-023-00338-w.

ABSTRACT

BACKGROUND: Deep learning models can infer cancer patient prognosis from molecular and anatomic pathology information. Recent studies that leveraged information from complementary multimodal data improved prognostication, further illustrating the potential utility of such methods. However, current approaches: 1) do not comprehensively leverage biological and histomorphological relationships and 2) make use of emerging strategies to "pretrain" models (i.e., train models on a slightly orthogonal dataset/modeling objective) which may aid prognostication by reducing the amount of information required for achieving optimal performance. In addition, model interpretation is crucial for facilitating the clinical adoption of deep learning methods by fostering practitioner understanding and trust in the technology.

METHODS: Here, we develop an interpretable multimodal modeling framework that combines DNA methylation, gene expression, and histopathology (i.e., tissue slides) data, and we compare performance of crossmodal pretraining, contrastive learning, and transfer learning versus the standard procedure.

RESULTS: Our models outperform the existing state-of-the-art method (average 11.54% C-index increase), and baseline clinically driven models (average 11.7% C-index increase). Model interpretations elucidate consideration of biologically meaningful factors in making prognosis predictions.

DISCUSSION: Our results demonstrate that the selection of pretraining strategies is crucial for obtaining highly accurate prognostication models, even more so than devising an innovative model architecture, and further emphasize the all-important role of the tumor microenvironment on disease progression.

PMID:37481666 | DOI:10.1186/s13040-023-00338-w

J Hematol Oncol. 2023 Jul 22;16(1):79. doi: 10.1186/s13045-023-01470-0.

ABSTRACT

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).

METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house.

RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.

CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.

CLINICALTRIALS: gov as NCT03676504.

PMID:37481608 | DOI:10.1186/s13045-023-01470-0

J Exp Bot. 2023 Jul 22:erad290. doi: 10.1093/jxb/erad290. Online ahead of print.

ABSTRACT

Diel regulation of protein levels and protein modification had been less studied than transcript rhythms. Here, we compare transcriptome data under light-dark cycles to partial proteome and phosphoproteome data, assayed using shotgun mass-spectrometry, from the alga Ostreococcus tauri, the smallest free-living eukaryote. 10% of quantified proteins but two-thirds of phosphoproteins were rhythmic. Mathematical modelling showed that light-stimulated protein synthesis can account for the observed clustering of protein peaks in the daytime. Prompted by night-peaking and apparently dark-stable proteins, we also tested cultures under prolonged darkness, where the proteome changed less than under the diel cycle. Among the dark-stable proteins were prasinophyte-specific sequences that were also reported to accumulate when O. tauri formed lipid droplets. In the phosphoproteome, 39% of rhythmic phospho-sites reached peak levels just before dawn. This anticipatory phosphorylation suggests that a clock-regulated phospho-dawn prepares green cells for daytime functions. Acid-directed and proline-directed protein phosphorylation sites were regulated in antiphase, implicating the clock-related, casein kinases 1 and 2 in phase-specific regulation, alternating with the CMGC protein kinase family. Understanding the dynamic phosphoprotein network should be facilitated by the minimal kinome and proteome of O. tauri. The data are available from ProteomeXchange, with identifiers PXD001734, PXD001735 and PXD002909.

PMID:37481465 | DOI:10.1093/jxb/erad290

J Biol Chem. 2023 Jul 20:105075. doi: 10.1016/j.jbc.2023.105075. Online ahead of print.

ABSTRACT

Iron sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC containing proteins are the ferredoxin family of electron carriers. Humans have two ferredoxins, FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but ferredoxins were not included in that study. Here we report that FDX1, but not FDX2, is dispensable under 1% O2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC containing enzyme lipoyl synthase (LIAS). While hypoxia can rescue the growth phenotype of either FDX1 or LIAS knockout cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.

PMID:37481209 | DOI:10.1016/j.jbc.2023.105075

Bone. 2023 Jul 20:116855. doi: 10.1016/j.bone.2023.116855. Online ahead of print.

ABSTRACT

Bone development is a highly orchestrated process that establishes the structural basis of bone strength during growth and functionality across the lifespan. This developmental process is generally robust in establishing mechanical function, being adaptable to many genetic and environmental factors. However, not all factors can be fully accommodated, leading to abnormal bone development and lower bone strength. This can give rise to early-onset bone fragility that negatively impacts bone strength across the lifespan. Current guidelines for assessing bone strength include measuring bone mineral density, but this does not capture the structural details responsible for whole bone strength in abnormally developing bones that would be needed to inform clinicians on how and when to treat to improve bone strength. The clinical consequence of not operationalizing how altered bone development informs decision making includes under-detection and missed opportunities for early intervention, as well as a false positive diagnosis of fragility with possible resultant clinical actions that may actually harm the growing skeleton. In this Perspective, we emphasize the need for a multi-trait, integrative approach to better understand the structural basis of bone growth for pediatric conditions with abnormal bone development. We provide evidence to showcase how this approach might reveal multiple, unique ways in which bone fragility develops across and within an array of pediatric conditions that are associated with abnormal bone development. This Perspective advocates for the development of new translational research aimed at informing better ways to optimize bone growth, prevent fragility fractures, and monitor and treat bone fragility based on the child's skeletal needs.

PMID:37481149 | DOI:10.1016/j.bone.2023.116855

Antiviral Res. 2023 Jul 20:105675. doi: 10.1016/j.antiviral.2023.105675. Online ahead of print.

ABSTRACT

Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well-characterized and linked to the encoded Tax-1 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analyzed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.

PMID:37481039 | DOI:10.1016/j.antiviral.2023.105675

Cell. 2023 Jul 16:S0092-8674(23)00695-5. doi: 10.1016/j.cell.2023.06.019. Online ahead of print.

ABSTRACT

Injury induces systemic responses, but their functions remain elusive. Mechanisms that can rapidly synchronize wound responses through long distances are also mostly unknown. Using planarian flatworms capable of whole-body regeneration, we report that injury induces extracellular signal-regulated kinase (Erk) activity waves to travel at a speed 10-100 times faster than those in other multicellular tissues. This ultrafast propagation requires longitudinal body-wall muscles, elongated cells forming dense parallel tracks running the length of the organism. The morphological properties of muscles allow them to act as superhighways for propagating and disseminating wound signals. Inhibiting Erk propagation prevents tissues distant to the wound from responding and blocks regeneration, which can be rescued by a second injury to distal tissues shortly after the first injury. Our findings provide a mechanism for long-range signal propagation in large, complex tissues to coordinate responses across cell types and highlight the function of feedback between spatially separated tissues during whole-body regeneration.

PMID:37480850 | DOI:10.1016/j.cell.2023.06.019

Res Vet Sci. 2023 Jul 17;162:104959. doi: 10.1016/j.rvsc.2023.104959. Online ahead of print.

ABSTRACT

Canine degenerative myelopathy (CDM) is a late-onset fatal disorder associated with a point mutation of the superoxide dismutase 1 (SOD1) gene (c.118G > A). The purpose of this study was to determine the genotype and allele frequencies of this mutation in 108 dogs, mainly in Belgian Malinois and German Shepherd dogs with (CDM-affected group) and without CDM clinical symptoms (control group) in Greece. Genotyping of the c.118G > A mutation was possible by Sanger sequencing and PCR-RFLP. The observed genotype frequencies for the control group were 89.4% for the homozygous (G/G), 9.6% for the heterozygous (A/G), and 0.96% for the homozygous mutant (A/A) allele. The mutant allele was not common in the Belgian Malinois dogs (allele frequency = 0.029), but quite common in the German Shepherd dogs (allele frequency = 0.138). In the CDM affected group, all 4 dogs were homozygous for the mutant allele. These frequencies were close to those expected, indicating no significant departure from Hardy-Weinberg equilibrium. A strong but not statistically significant association between the mutant allele and CDM was observed. A previously identified deletion upstream of the mutation of interest was found at a high frequency (0.361) in the population.

PMID:37480717 | DOI:10.1016/j.rvsc.2023.104959

Plant Mol Biol. 2023 Jul 21. doi: 10.1007/s11103-023-01368-y. Online ahead of print.

ABSTRACT

AtAIRP5 RING E3 ubiquitin ligase was recently identified as a positive regulator of the abscisic acid (ABA)-mediated drought stress response by stimulating the degradation of serine carboxypeptidase-like 1. Here, we identified GDSL-type esterase/lipase 22 (AtGELP22) and AtGELP23 as additional interacting partners of AtAIRP5. Yeast two-hybrid, pull-down, co-immunoprecipitation, and ubiquitination analyses verified that AtGELP22 and AtGELP23 are ubiquitinated target proteins of AtAIRP5. AtGELP22 and AtGELP23 were colocalized with AtAIRP5 to punctate-like structures in the cytosolic fraction, in which PYK10 and NAI2, two ER body marker proteins, are localized. T-DNA insertion atgelp22 and atgelp23 single knockout mutant plants showed phenotypes indistinguishable from those of wild-type plants under ABA treatment. In contrast, RNAi-mediated cosuppression of AtGELP22 and AtGELP23 resulted in hypersensitive ABA-mediated stomatal movements and higher tolerance to drought stress than that of the single mutant and wild-type plants. Taken together, our results suggest that the putative GDSL-type esterases/lipases AtGELP22 and AtGELP23 act as redundant negative regulators of the ABA-mediated drought stress response in Arabidopsis.

PMID:37479835 | DOI:10.1007/s11103-023-01368-y

Mol Cell Proteomics. 2023 Jul 19:100622. doi: 10.1016/j.mcpro.2023.100622. Online ahead of print.

ABSTRACT

Characterization of highly glycosylated biopharmaceuticals by mass spectrometry is challenging because of the huge chemical space of co-existent glycoforms, i.e. heterogenous glycoprotein variants. Here, we report the use of an array of HPLC-MS-based approaches at different structural levels of released glycan, glycopeptide, and hitherto unexplored intact glycoforms to scrutinize the biopharmaceutical Myozyme®, containing the highly complex lysosomal enzyme recombinant acid α-glucosidase. The intrinsic heterogeneity of recombinant acid α-glucosidase glycoforms was unraveled using a novel strong anion-exchange (SAX)-HPLC-MS approach involving a pH-gradient of volatile buffers to facilitate chromatographic separation of glycoforms based on their degree of sialylation followed by the acquisition of native mass spectra in an Orbitrap mass spectrometer. Upon considering the structures of 60 different glycans attached to seven glycosylation sites in the intact protein, the large set of interdependent data acquired at different structural levels was integrated using a set of bioinformatic tools and allowed the annotation of intact glycoforms unraveling more than 1,000,000 putative intact glycoforms. Detectable isoforms also included several mannose-6-phosphate variants, which are essential for directing the drug towards its target - the lysosomes. Finally, for the first time, we sought to validate the intact glycoform annotations by integrating experimental data on the enzymatically dissected proteoforms, which reduced the number of glycoforms supported by experimental evidence to 42,104. The latter verification clearly revealed the strengths but also intrinsic limitations of this approach for fully characterising such highly complex glycoproteins by mass spectrometry.

PMID:37478974 | DOI:10.1016/j.mcpro.2023.100622

Curr Biol. 2023 Jul 17:S0960-9822(23)00846-1. doi: 10.1016/j.cub.2023.06.061. Online ahead of print.

ABSTRACT

Controlling intracellular osmolarity is essential to all cellular life. Cells that live in hypo-osmotic environments, such as freshwater, must constantly battle water influx to avoid swelling until they burst. Many eukaryotic cells use contractile vacuoles to collect excess water from the cytosol and pump it out of the cell. Although contractile vacuoles are essential to many species, including important pathogens, the mechanisms that control their dynamics remain unclear. To identify the basic principles governing contractile vacuole function, we investigate here the molecular mechanisms of two species with distinct vacuolar morphologies from different eukaryotic lineages: the discoban Naegleria gruberi and the amoebozoan slime mold Dictyostelium discoideum. Using quantitative cell biology, we find that although these species respond differently to osmotic challenges, they both use vacuolar-type proton pumps for filling contractile vacuoles and actin for osmoregulation, but not to power water expulsion. We also use analytical modeling to show that cytoplasmic pressure is sufficient to drive water out of contractile vacuoles in these species, similar to findings from the alveolate Paramecium multimicronucleatum. These analyses show that cytoplasmic pressure is sufficient to drive contractile vacuole emptying for a wide range of cellular pressures and vacuolar geometries. Because vacuolar-type proton-pump-dependent contractile vacuole filling and pressure-dependent emptying have now been validated in three eukaryotic lineages that diverged well over a billion years ago, we propose that this represents an ancient eukaryotic mechanism of osmoregulation.

PMID:37478864 | DOI:10.1016/j.cub.2023.06.061

Immunity. 2023 Jul 11:S1074-7613(23)00279-0. doi: 10.1016/j.immuni.2023.06.022. Online ahead of print.

ABSTRACT

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.

PMID:37478853 | DOI:10.1016/j.immuni.2023.06.022

Cancer Cell. 2023 Jul 17:S1535-6108(23)00235-0. doi: 10.1016/j.ccell.2023.06.010. Online ahead of print.

ABSTRACT

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

PMID:37478850 | DOI:10.1016/j.ccell.2023.06.010

Cell Chem Biol. 2023 Jul 20;30(7):703-705. doi: 10.1016/j.chembiol.2023.06.024.

ABSTRACT

Immunosuppression contributes to tumor-radiotherapy failure, but the mechanism remains elusive. Wang et al.1 reported that ionizing radiation (IR) induces YTHDF2 expression in myeloid-derived suppressor cells (MDSCs) via an IR-YTHDF2-NF-κB circuit, which contributes to MDSC expansion/migration and treatment failure. Genetic depletion or pharmacological inhibition of YTHDF2 overcomes immunosuppression and improves radiotherapy.

PMID:37478827 | DOI:10.1016/j.chembiol.2023.06.024