Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.

Salt stress is a primary abiotic constraint that adversely affects the growth and development of tomato plants. Silicon, a beneficial element, has shown potential in mitigating various abiotic stresses. However, although numerous studies have been conducted in this field, the precise mechanism by which exogenous silicon mitigates salt stress in tomato seedlings remains to be fully elucidated. In this study, we analyzed the physiological responses and underlying molecular mechanisms in tomato seedlings under NaCl stress with or without silicon application. The results showed that salt stress severely inhibited seedling growth, as indicated by reductions in shoot and root fresh weight and plant height, while this damage was markedly alleviated by the application of exogenous silicon. Compared to the treatment with NaCl alone (Na), salt stress plus silicon treatment (Na + Si) improved plant growth, the leaf chlorophyll a content, the net photosynthetic rate (Pn), and the proline content and decreased the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) in tomato seedlings. Transcriptomic analysis showed that there were 435 differentially expressed genes (DEGs) (397 upregulated and 38 downregulated) between Na + Si and Na treatments. Further enrichment analysis showed that the upregulated DEGs in Na + Si treatment were enriched in response to salt stress, ethylene and abscisic acid biosynthesis process, lignin catabolic process, cell wall biogenesis and the MAPK signaling pathway. Additionally, exogenous silicon application (Na + Si) upregulated the expression of key families of transcription factors, notably the AP2/ERF, WRKY and NAC families. Taken together, our study preliminarily revealed candidate genes and metabolic pathways affected by exogenous silicon treatment, which may provide a strategy for improving the adaptation of tomato to salt stress.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the immunohistochemical images shown in Fig. 1A on p. 1377, the 'DNMT3A' and 'DNMT3B' images for the 'BN' row of data contained an overlapping section, such that date which were intended to show the results from differently performed experiments had apparently been derived from the same original source. In addition, upon performing an independent analysis of the data in this paper in the Editorial Office, it came to light that the same data had been included for the Petri dish images in Fig. 3B on p. 1382 for the DMSO experiments with the T24 and EJ cell lines, albeit the EJ image had been rotated through 90°. The authors were contacted by the Editorial Office to offer an explanation for this apparent duplication of data within these figures; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 35: 1375‑1384, 2016; DOI: 10.3892/or.2015.4492].

Progesterone (P4) is believed to inhibit breast cancer growth, but its role in counteracting estrogen (E2)-driven progression remains unclear. This study aimed to investigate the inhibitory effect of P4 on E2-induced cell proliferation, migration, and invasion in Estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer cells by examining its regulatory role in the epithelial-mesenchymal transition (EMT).

MicroRNAs (miRNAs) are small, non-coding RNAs that play a key role in the development of chemoresistance in various cancer types, including colorectal cancer (CRC). In this study, we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.

Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.

Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST2-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

Jasmonic acid (JA) is directly involved in a transcriptional activation loop where the JA signaling transcription factor, FmMYC2 (a bHLH protein), activates the biosynthesis gene FmLOX6 to promote pollen adhesion, germination, and subsequent pollen tube growth. Jasmonic acid (JA) plays a critical role in plant reproduction; yet, its functions during pollen-stigma interaction remain largely unexplored. Transcriptomic analysis of pollinated stigmas in Manchurian ash (Fraxinus mandshurica) revealed that differentially expressed genes (DEGs) were significantly enriched in the JA biosynthesis pathway. Exogenous JA application to stigmas promoted pollen adhesion, germination, and tube growth, whereas inhibition of JA biosynthesis or JA transport in stigmas suppressed these processes. Similarly, in in vitro pollen germination assays, exogenous JA treatment enhanced pollen germination and tube elongation, while inhibition of endogenous JA biosynthesis in pollen reduced both parameters. Combined treatments with JA and transport inhibitors confirmed that functional JA transport is required for pollen germination. Further transcriptomic analysis showed that both FmMYC2 a basic helix-loop-helix (bHLH) transcription factor in the JA signaling network and FmLOX6 a lipoxygenase involved in JA biosynthesis were significantly upregulated during pollen germination. Antisense oligodeoxynucleotide-mediated repression of either FmMYC2 or FmLOX6 inhibited pollen tube growth. Yeast one-hybrid and dual-luciferase reporter assays demonstrated that FmMYC2 directly activates FmLOX6 expression by binding to a G-box motif in its promoter. Our findings reveal a positive feedback loop in which JA signaling via FmMYC2 promotes JA biosynthesis through FmLOX6, thereby enhancing pollen germination and tube growth in F. mandshurica. This study offers new insights into JA-mediated pollination mechanisms in tree species and provides fundamental information for breeding improved varieties.

PYL receptor proteins are essential for enhancing plant resilience to extreme environments; however, their functions in woody plants-particularly in response to osmotic stress-remain poorly understood. In this study, we identified and comprehensively characterized 14 PYL genes in Populus trichocarpa. PtrPYL11, a core member, showed up-regulation following both ABA and dehydration treatments, suggesting that it may act as a positive regulator of osmotic stress responses by mediating the expression of ABA-related genes. Specifically, PtrPYL11-overexpressing poplar lines exhibited stronger osmotic stress tolerance than the wild type. Transcriptome analysis revealed that PtrPYL11 may indirectly regulate the expression of core transcription factors such as DOF1 and TCP9, mediating the ABA-signaling pathway in poplar. This study systematically characterizes the molecular features of the PtrPYL gene family and clarifies the role of PtrPYL11 in poplar osmotic stress responses. These findings not only lay a foundation for further exploration of its biological functions but also provide valuable genetic resources for breeding drought-tolerant forest tree varieties through genetic engineering.

Rice genotypes differ in aluminium tolerance, with resistant landraces sustaining root growth OsSTAR1 / OsSTAR2 mediated exclusion, organic acid efflux, and antioxidant defense, whereas sensitive varieties accumulate Al³⁺ via OsNRAT1-OsALS1 mediated internal sequestration, leading to oxidative damage. This study reveals two contrasting molecular strategies of aluminium (Al) tolerance root-based exclusion and internal detoxification among indigenous rice landraces of Northeast India, a region severely affected by acidic soil-related Al toxicity. Fifty-three rice genotypes were evaluated under hydroponic Al stress (200 μM AlCl₃) through integrated morphophysiological, biochemical, and gene expression analyses. Tolerant genotypes such as Ahom Sali and Disang sustained root growth, biomass, and relative water content, whereas sensitive types such as Ranjit Sub-1 and Jolkonwari showed severe root inhibition and oxidative damage. SSR marker analysis of 33 polymorphic loci (mean PIC = 0.48) confirmed high genetic diversity, but weak correlation with phenotypic performance, indicating complex inheritance of tolerance. Biochemical profiling revealed that tolerant landraces maintained higher chlorophyll and antioxidant enzyme activities and secreted greater quantities of organic acids (citrate and malate), facilitating Al exclusion through rhizosphere chelation. Gene expression analysis revealed the upregulation of OsSTAR1, OsSTAR2, and OsFRDL4 in tolerant genotypes, promoting Al exclusion, whereas sensitive lines showed increased OsNRAT1 and OsALS1 expression, indicating a reliance on less effective internal detoxification pathways. These findings demonstrate that aluminium tolerance in traditional rice landraces from Northeast India is driven primarily by exclusion mechanisms. The identified tolerant genotype represents a valuable genetic resource for the breeding of acid soil-resilient rice cultivars, offering promising prospects for sustainable rice production and food security in Al-affected regions.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA).

Neurodegenerative diseases are complex disorders characterized by the progressive loss of neuronal structure and function, involving pathological mechanisms such as oxidative stress, chronic inflammation, protein misfolding, and impaired synaptic plasticity. Recent studies have revealed that epigenetic regulation plays a critical role in the onset and progression of these diseases, including mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation. Natural polyphenolic compounds, known for their safety and multi-target properties, have emerged as promising candidates for neuroprotection and therapeutic intervention.

Plant hormones regulate a wide array of developmental and stress-response pathways by modulating gene expression through specific transcription factors (TFs). Understanding how these TFs interact with their genomic targets is essential for dissecting hormone signaling networks. Chromatin immunoprecipitation (ChIP), coupled with quantitative PCR (ChIP-qPCR) or next-generation sequencing (ChIP-seq), offers a powerful approach to study in vivo protein-DNA interactions. However, ChIP in plants poses unique technical challenges due to the presence of rigid cell walls, abundant secondary metabolites, and chromatin accessibility constraints. Here, we present a detailed and optimized protocol for performing ChIP-qPCR and ChIP-seq in Arabidopsis thaliana to investigate hormone-responsive gene regulation. The protocol includes steps for hormone treatment, tissue fixation, chromatin extraction, immunoprecipitation using specific antibodies, reverse crosslinking, DNA purification, and downstream quantification. This method enables high-resolution mapping of transcription factor occupancy at target loci and can be adapted for different hormones and plant species. Compared to indirect transcriptomic approaches, ChIP-based assays provide direct evidence of TF-DNA binding and allow identification of primary targets in signaling cascades. The protocol supports mechanistic studies of hormone action in plants and facilitates the construction of gene regulatory networks.

Spatially resolved transcriptomics captures gene expression in tissue context, enabling direct mapping of defense pathways across organs and cell layers. This chapter describes a complete Stereo-seq workflow for Arabidopsis leaves treated with salicylic acid (SA), from plant growth and hormone application through cryosectioning, fixation, bright-field imaging and optional histology, on-chip permeabilization, in situ reverse transcription and library construction on STOmics V1.3 1 × 1 cm chips, sequencing on DNBSEQ platforms, and analysis using STOmics Analysis Workflow (SAW) with downstream spatial statistics and pathway enrichment. Practical parameters are given for section thickness, fixation, imaging, permeabilization optimization, sequencing configuration, and quality control. The bioinformatics analyses include binning strategies, alignment to TAIR10, normalization, clustering, spatial differential expression, pathway testing, and integration with single-cell RNA-seq references for cell-type deconvolution.

Salicylic acid (SA) and jasmonic acid (JA) coordinate plant immunity through partially antagonistic signaling pathways that differ across cell types and over time. Single-cell and single-nucleus RNA sequencing now resolve these hormone responses at cellular resolution, allowing clear separation of early primary signaling waves from secondary and downstream transcriptional programs. In the context of plant-pathogen interactions, these approaches are particularly powerful for uncovering how distinct cell populations perceive SA and JA, reprogram defense networks, and balance growth-immunity trade-offs. This chapter provides end-to-end wet-lab protocols for nuclei-based snRNA-seq tailored to SA and JA treatments, including sample preparation, nuclei isolation, and library construction. In parallel, a bioinformatics analysis workflow is described, covering quality control, ambient RNA correction, doublet removal, dataset integration, cell type mapping, differential expression analysis, and pathway and module scoring. Together, these experimental and computational pipelines enable researchers to dissect hormone-driven immune responses at single-cell resolution and to generate cell-type-resolved hypotheses that can guide downstream genetic and physiological studies.

Salicylic acid (SA) functions as a key signaling molecule in plant defense, orchestrating responses to diverse biotic and abiotic stresses. A clear understanding of SA-mediated immunity requires systematic analysis of SA-responsive transcriptional programs at both targeted and genome-wide levels. This chapter describes methodological strategies for examining SA-responsive gene expression through quantitative polymerase chain reaction (qPCR) as well as bulk transcriptome profiling using the Bio-Rad SEQuoia Complete Stranded RNA Kit. The workflow covers experimental design, sample preparation, data acquisition, and result interpretation within the framework of plant immune responses. Integrating targeted qPCR assays with SEQuoia-enabled transcriptome analysis enables robust characterization of regulatory networks underlying SA-induced immunity and supports reproducible comparisons across experiments. This combined approach provides insights into the complexity of plant defense signaling and its transcriptional control.

Multidrug-resistant Staphylococcus aureus (MRSA). This study investigated the antimicrobial efficacy of zinc oxide (ZnO) nanoparticles synthesised through a blue laser-enhanced hydrothermal method combined with the flavonoid Naringenin (NAR) against multidrug-resistant S. aureus isolates. Sixty S. aureus strains were identified using a combination of morphological, biochemical and molecular analyses (VITEK-2 and 16 S rRNA). All strains showed total resistance (100%) to oxacillin and cefoxitin and high resistance levels (60-90%) for vancomycin, erythromycin and fluoroquinolones. Characterization confirmed hexagonal ZNPs with a crystallite size of 38.78 nm. Disk diffusion assays demonstrated enhanced efficacy of ZNPs-NAR combination, achieved a 16.67 mm inhibition zone (p ≤ 0.0001). Notably, while ZNPs singly suppressed leukocidin toxin genes lukD and lukE by 90.3% and 94.9%, inhibition, and NAR reduced expression by 62.4% and 61.9%, the ZNPs-NAR combination showed lower gene suppression (59.3% and 52.8%) yet superior bactericidal activity. This discrepancy reveals that the enhanced bactericidal effect stems not from amplified transcriptional inhibition, but from complementary mechanisms: ZNPs likely disrupt bacterial membranes to facilitate NAR uptake, while NAR concurrently interferes with intracellular targets like DNA replication. The findings demonstrate that nanoparticle-phytochemical combinations can achieve superior antimicrobial effects through synergistic mechanisms, offering a promising strategy to combat multidrug-resistant infections and reduce reliance on conventional antibiotics.

In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.