Selective Targeting Research Articles

Surufatinib combined with locoregional therapies and immune checkpoint inhibitor (ICI) for treating unresectable or metastatic intrahepatic cholangiocarcinoma.

593 Background: Advanced metastatic ICC, characterized by poor survival and limited therapeutic options, may benefit from the combined use of surufatinib—a selective tyrosine kinase inhibitor targeting VEGFR 1, 2, and 3, FGFR1, and CSF-1R—and ICIs, alongside locoregional treatments like TACE, DEB-TACE, and HAIC. Methods: Eligible pts who were 18 -75 years old with histologically confirmed unresectable or metastatic intrahepatic cholangiocarcinoma were enrolled. Pts received surufatinib (250mg, orally daily), ICI, and locoregional therapies until surgery, disease progression, death, intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), conversion to surgical resection rate and safety. Results: By July 31, 2024, 20 pts were enrolled and 10 pts were evaluated. Median age was 56.4 years (range: 36-69), with a majority being male (70%). 9 pts were pathologically confirmed as adenocarcinoma, 1patient was small bile tract type. Treatment included DEB-TACE (20%), TACE (30%), and HAIC (50%). 50% (5/10) pts achieved partial response (PR), 20% (2/10) pts accepted conversion surgery, 30% (3/10) pts achieved stable disease (SD), and the confirmed ORR was 50%, DCR was 80%. The median PFS (95%Cl: 6.9-NA months) had not yet matured, with no significant differences in survival benefits based on age or gender, though TACE showed potential benefits. The most common AEs of all grades were nausea (30%), dizziness (30%), and headache (10%), No grade ≥ 3 TEAEs or new safety signals occurred. Conclusions: Surufatinib plus immune checkpoint inhibitor, along with locoregional therapies showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of ICC, providing an additional treatment option for pts with ICC. Clinical trial information: NCT05236699 .

Immunotherapy engagement in pancreatic adenocarcinoma: Provisional results of iLSTA study— Durvalumab, LSTA1 (certepetide), gemcitabine, and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma.

746 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dense, extracellular matrix-rich stroma, which creates a physical barrier against drug penetration. Evidence suggests that the iRGD peptide, LSTA-1, can increase the penetration of anti-cancer drugs to tumours through selective targeting of tumour endothelial cell receptors. Additionally, LSTA-1 administration promotes CD8+ immune cell tumour infiltration, potentially enabling immunotherapy as a treatment modality. iLSTA examined safety, tolerability and effect of the combination. Methods: Participants diagnosed with locally advanced PDAC were divided into 3 cohorts in a 1:1:4 ratio. Cohort 1 (n=5) received gemcitabine (1000mg/m 2 ), nab-paclitaxel (125mg/m 2 ), placebo LSTA-1 (3.2mg/kg) and placebo durvalumab (750mg). Cohort 2 (n=5) received gemcitabine, nab-paclitaxel, active and placebo LSTA-1, and placebo durvalumab. Cohort 3 (n=20) received gemcitabine, nab-paclitaxel, LSTA-1 and durvalumab. Tissue biopsies via endoscopic ultrasound were obtained pre-treatment and between weeks 12 and 16 for analysis of tumour infiltrating lymphocytes (TILs). Patient tumour sizes were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Results: 6/17 patients showed significant RECIST partial response after 2 cycles of treatment (5 patients in cohort 3), with the remaining 11 patients exhibiting stable disease. After 4 cycles of treatment, 10/17 patients demonstrated partial response (9 patients in cohort 3). Of the remaining 7 patients, 6 demonstrated stable disease, and 1 patient (cohort 2) exhibited a RECIST complete response. 13/17 patients who completed 4 treatment cycles showed a decrease in CA19-9 levels. 6 patients demonstrated >90% reduction in CA19-9 (5 in cohort 3), with the remaining 7 patients showing a >50% reduction in CA19-9 levels (5 in cohort 3). 12 patients underwent repeat biopsies 12-16 weeks post-treatment to assess TILs. 10 patients showed immune cell infiltration (5% to 50% stroma infiltration), 2 had no tumour found (Cohort 3). The combination was safe with no unexpected toxicities. Conclusions: The preliminary results of this study suggest that the combination of gemcitabine and nab-paclitaxel with LSTA-1 and durvalumab is safe and potentially induces tumour infiltrating lymphocytes and RECIST response in locally advanced pancreatic adenocarcinomas. Clinical trial information: ACTRN12623000223639 .

Little strokes fell big oaks: The use of weak magnetic fields and reactive oxygen species to fight cancer.

The increase in early-stage cancers, particularly gastrointestinal, breast and kidney cancers, has been linked to lifestyle changes such as consumption of processed foods and physical inactivity, which contribute to obesity and diabetes - major cancer risk factors. Conventional treatments such as chemotherapy and radiation often lead to severe long-term side effects, including secondary cancers and tissue damage, highlighting the need for new, safer and more effective therapies, especially for young patients. Weak electromagnetic fields (WEMF) offer a promising non-invasive approach to cancer treatment. While WEMF have been used therapeutically for musculoskeletal disorders for decades, their role in oncology is still emerging. WEMFs affect multiple cellular processes through mechanisms such as the radical pair mechanism (RPM), which alters reactive oxygen species (ROS) levels, mitochondrial function, and glycolysis, among others. This review explores the potential of WEMF in conjunction with reactive oxygen species as a cancer therapy, highlighting WEMFs selective targeting of cancer cells and its non-ionizing nature, which could reduce collateral damage compared to conventional treatments. In addition, synchronization of WEMF with circadian rhythms may further enhance its therapeutic efficacy, as has been demonstrated in other cancer therapies.

Melanoma extracellular vesicles membrane coated nanoparticles as targeted delivery carriers for tumor and lungs.

Targeting is the most challenging problem to solve for drug delivery systems. Despite the use of targeting units such as antibodies, peptides and proteins to increase their penetration in tumors the amount of therapeutics that reach the target is very small, even with the use of nanoparticles (NPs). Nature has solved the selectivity problem using a combination of proteins and lipids that are exposed on the cell membranes and are able to recognize specific tissues as demonstrated by cancer metastasis. Extracellular vesicles (EVs) have a similar ability in target only certain organs or to return to their original cells, showing home behavior. Here we report a strategy inspired by nature, using a combination of NPs and the targeting cell membranes of EVs. We implement the EV membranes, extracted by the EVs produced by melanoma B16-BL6 cells, as a coating of organosilica porous particles with the aim of targeting tumors and lung metastasis, while avoiding systemic effects and accumulation of the NPs in undesired organs. The tissue-specific fingerprint provided by the EVs-derived membranes from melanoma cells provides preferential uptake into the tumor and selective targeting of lungs. The ability of the EVs hybrid systems to behave as the natural EVs was demonstrated in vitro and in vivo in two different tumor models. As a proof of concept, the loading and release of doxorubicin, was investigated and its accumulation demonstrated in the expected tissues.

Small Molecule Modulators of AMP-Activated Protein Kinase (AMPK) Activity and Their Potential in Cancer Therapy.

AMP-activated protein kinase (AMPK) is a central mediator of cellular metabolism and is activated in direct response to low ATP levels. Activated AMPK inhibits anabolic pathways and promotes catabolic activities that generate ATP through the phosphorylation of multiple target substrates. AMPK is a therapeutic target for activation in several chronic metabolic diseases, and there is increasing interest in targeting AMPK activity in cancer where it can act as a tumor suppressor or conversely it can support cancer cell survival. Small molecule AMPK activators and inhibitors have demonstrated some success in suppressing cancer growth, survival, and drug resistance in preclinical cancer models. In this perspective, we summarize the role of AMPK in cancer and drug resistance, the influence of the tumor microenvironment on AMPK activity, and AMPK activator and inhibitor development. In addition, we discuss the potential importance of isoform-selective targeting of AMPK and approaches for selective AMPK targeting in cancer.

Deciphering the Selective Targeting of Noncovalent, Wild Type-sparing, and ATP-competitive Tyrosine Kinase Inhibitors to EGFR T790M Gatekeeper Mutant

Various tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for cancer therapy. However, many patients treated with first-line TKIs are clinically observed to eventually establish a gatekeeper T790M mutation in the ATP-binding site of the EGFR kinase domain, which is primarily responsible for acquired drug resistance to cancers. Over the past decades, a number of noncovalent, wild-type-sparing and ATP-competitive inhibitors (NWAIs) were reported to selectively target the T790M mutant over wild-type kinase, which are independent of the traditional inhibitor classification system that categorizes EGFR TKIs into four generations. Here, we systematically investigated the intermolecular interaction of wild-type EGFR (EGFR[Formula: see text] and its T790M mutant (EGFR[Formula: see text] with 15 existing NWAI inhibitors, paying attention to the structural and energetic responses of inhibitor ligands to the gatekeeper mutation. It was revealed that the NWAIs can be typed into three classes I, II and III, which can form S[Formula: see text] interactions, hydrophobic (van der Waals) contacts and weak hydrogen (halogen) bonding with the side-chain thioether moiety of the mutant Met790 residue, respectively, thus conferring additional affinity and specificity to inhibitor ligands upon the T790M mutation. In addition, we further performed 2D-chemical similarity search to identify new class I NWAIs, from which two Staurosporine analogs (i.e. UCN01 and ZHD0501) were identified to have a good selectivity for EGFR[Formula: see text] over EGFR[Formula: see text]. They can be exploited as promising leading chemical scaffolds to further develop potent, selective, wild-type-sparing NWAI inhibitors of EGFR[Formula: see text] gatekeeper mutant.

Phosphodiesterase 4 Inhibition in Neuropsychiatric Disorders Associated with Alzheimer’s Disease

Cognitive disorders and psychiatric pathologies, particularly Alzheimer’s disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer’s disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition—specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.

Selective expression and significance of ACKR2 in lung aerocytes

BackgroundACKR2 is an atypical chemokine receptor that plays a significant role in regulating inflammation by binding to inflammatory CC chemokines and facilitating their degradation. Previous findings suggest that the genetic...

The Target-Defining Attributes Can Determine the Effects of Attentional Control Settings in Singleton Search Mode.

The attentional control settings (ACSs) can help us efficiently select targets in complex real-world environments. Previous research has shown that category-specific ACS demands more attentional resources than feature-specific ACS. However, comparing natural or alphanumeric categories with color features does not distinguish the effects of processing hierarchy and target-defining properties. The present study employed a spatial cueing paradigm to better understand the effects of target-defining properties and search mode on attentional resources in visual search. The target was defined as a combination of shape feature (shape "X") and color category (green in different shades), which generated shape-specific ACS (sACS) and color-specific ACS (cACS). The degrees of shape matching (SM), color matching (CM), and spatial validity between the cue and target were manipulated. Search modes were manipulated by changing the homogeneity of distractors in either shape or color dimensions. Results show a main effect of CM across all four experiments, indicating that category can tune on attentional capture consistently. Importantly, the analysis between four experiments found different interactions across experiments, suggesting that the singleton search mode can reduce the effects of ACS and increase the interactions with other factors. In conclusion, this study suggests that the effects of ACS on attentional capture are determined by both target-defining properties and search mode, rather than processing hierarchy. The results indicate that attentional processes are highly dynamic and context-dependent, requiring a flexible allocation of resources to effectively prioritize relevant information.

Exploration of an adaptive proton therapy strategy using CBCT with the concept of digital twins

Objective.This study aims to develop a digital twin (DT) framework to achieve adaptive proton prostate stereotactic body radiation therapy (SBRT) with fast treatment plan selection and patient-specific clinical target volume (CTV) setup uncertainty. Prostate SBRT has emerged as a leading option for external beam radiotherapy due to its effectiveness and reduced treatment duration. However, interfractional anatomy variations can impact treatment outcomes. This study seeks to address these uncertainties using DT concept to improve treatment quality.Approach. A retrospective study on two-fraction prostate proton SBRT was conducted, involving a cohort of 10 randomly selected patient cases from an institutional database (n= 43). DT-based treatment plans were developed using patient-specific CTV setup uncertainty, determined through machine learning predictions. Plans were optimized using pre-treatment CT and corrected cone-beam CT (cCBCT). The cCBCT was corrected for CT numbers and artifacts, and plan evaluation was performed using cCBCT to account for actual patient anatomy. The ProKnow scoring system was adapted to determine the optimal treatment plans.Main Results.Average CTV D98 values for original clinical and DT-based plans across 10 patients were 99.0% and 98.8%, with hot spots measuring 106.0% and 105.1%. Regarding bladder, clinical plans yielded average bladder neck V100 values of 29.6% and bladder V20.8 Gy values of 12.0cc, whereas DT-based plans showed better sparing of bladder neck with values of 14.0% and 9.5cc. Clinical and DT-based plans resulted in comparable rectum dose statistics due to SpaceOAR. Compared to clinical plans, the proposed DT-based plans improved dosimetry quality, improving plan scores ranging from 2.0 to 15.5.Significance.Our study presented a pioneering approach that leverages DT technology to enhance adaptive proton SBRT, potentially revolutionizing prostate radiotherapy to offer personalized treatment solutions using fast adaptive treatment plan selections and patient-specific setup uncertainty. This research contributes to the ongoing efforts to achieve personalized prostate radiotherapy.

Fatty-acid amide hydrolase inhibition mitigates Alzheimer's disease progression in mouse models ofamyloidosis.

The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer's disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis (APP/PS1 and Tg2576). Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inhibition robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis and provide proof of concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.

Targeting EBV Episome for Anti-Cancer Therapy: Emerging Strategies and Challenges.

As a ubiquitous human pathogen, the Epstein-Barr virus (EBV) has established lifelong persistent infection in about 95% of the adult population. The EBV infection is associated with approximately 200,000 human cancer cases and 140,000 deaths per year. The presence of EBV in tumor cells provides a unique advantage in targeting the viral genome (also known as episome), to develop anti-cancer therapeutics. In this review, we summarize current strategies targeting the viral episome in cancer cells. We also highlight emerging technologies, such as clustered regularly interspersed short palindromic repeat (CRISPR)-based gene editing or activation, which offer promising avenues for selective targeting of the EBV episome for anti-cancer therapy. We discuss the challenges, limitations, and future perspectives associated with these strategies, including potential off-target effects, anti-cancer efficacy and safety.

CFTR dictates monocyte adhesion by facilitating integrin clustering but not activation

Monocytes are critical in controlling tissue infections and inflammation. Monocyte dysfunction contributes to the inflammatory pathogenesis of cystic fibrosis (CF) caused by CF transmembrane conductance regulator (CFTR) mutations, making CF a clinically relevant disease model for studying the contribution of monocytes to inflammation. Although CF monocytes exhibited adhesion defects, the precise mechanism is unclear. Herein, superresolution microscopy showed that an integrin clustering but not an integrin activation defect determines the adhesion defect in CFTR-deficient monocytes, challenging the existing paradigm emphasizing an integrin activation defect in CF patient monocytes. We further found that the clustering defect is accompanied by defects in CORO1A membrane recruitment, actin cortex formation, and CORO1A engagement with integrins. Complementing canonical studies of leukocyte adhesion focusing on integrin activation, we highlight the importance of integrin clustering in cell adhesion and report that integrin clustering and activation are distinctly regulated, warranting further investigation for selective targeting in therapeutic strategy design involving leukocyte-dependent inflammation.

Directed Evolution of Multicyclic Peptides Using Yeast Display for Sensitive and Selective Fluorescent Analysis of CD28 on the Cell Surface.

CD28 is a costimulatory receptor that provides the second signal necessary for T-cell activation and is associated with diseases, including rheumatoid arthritis, asthma, and cancer. Targeting CD28 is crucial for both functional bioanalysis and therapeutic development. Molecular probes, particularly fluorescent probes, can enhance our understanding of CD28's cellular roles. However, existing antibody-based probes face challenges such as high production costs, low stability, and large size, which limit their bioanalytical applications. Thus, there is a need for smaller, robust probes that enable the sensitive and selective targeting of CD28. Multicyclic peptides have emerged as promising candidates for novel therapeutics and molecular probes. Recently, we identified disulfide-directed multicyclic peptides (DDMPs) that bind CD28 with submicromolar affinity; however, their relatively low affinity limits further applications. In this study, we develop a DDMP evolving system based on yeast display and error-prone PCR to identify high-affinity peptide binders. We obtained DDMPs with a picomolar affinity for CD28, exceptional binding specificity, and remarkable oxidative folding efficiency. Furthermore, we developed fluorescent probes and labeling strategies for detecting and visualizing CD28 expression in human T cells. This advancement opens new avenues for studying T-cell dynamics and activation states, which are essential for understanding immune responses and developing targeted therapies. Our study not only produces potent CD28 binders and probes but also establishes a robust platform for optimizing other multicyclic peptide-based probes and therapeutics.

Ionizable Cholesterol Analogs as the Fifth Component of Lipid Nanoparticles for Selective Targeting Delivery of mRNA.

Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential for precise therapeutic outcomes and minimized side effects in various disease models. However, achieving targeted delivery beyond the liver is a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto the head of a cholesterol-like structure and incorporated them as a fifth component into conventional commercial LNPs based on ALC-0315 or SM-102. Selective targeting delivery of mRNA is achieved by adjusting the proportion of the fifth component in the LNP. Specifically, a spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% delivery efficiency, while a lung-targeted 102-Sito-40% formulation achieved up to 78%. Moreover, when this strategy is applied to a self-developed ionizable lipid named U-101 instead of ALC-0315 or SM-102, the targeting delivery efficiencies to the spleen and lungs reach 96 and 71%, respectively. Multiple assessments suggest that inclusion of the fifth component does not compromise LNP stability, as indicated by consistent particle size, polydispersity index (PDI), and encapsulation efficiency. Furthermore, the test results of liver and kidney function and immunogenicity reveal no increase of toxicity in vivo following the introduction of the fifth component. Additional studies on in vitro cytotoxicity, lysosomal escape, and cellular transfection efficiency confirm that the fifth component does not diminish delivery performance. Taken together, the incorporation of ionizable cholesterol analogs leads to targeting of LNP delivery, which features strong organ selectivity, high safety, and suitability for further evaluation.

Targeted NIR Fluorescent Mechanically Interlocked Molecules-Peptide Bioconjugate for Live Cancer Cells Submitochondrial Stimulated Emission Depletion Super-Resolution Microscopy.

Herein, a water-soluble, ultrabright, near-infrared (NIR) fluorescent, mechanically interlocked molecules (MIMs)-peptide bioconjugate is designed with dual targeting capabilities. Cancer cell surface overexpressed αVβ3 integrin targeting two RGDS tetrapeptide residues is tethered at the macrocycle of MIMs-peptide bioconjugate via Cu(I)-catalyzed click chemistry on the Wang resin, and mitochondria targeting lipophilic cationic TPP+ functionality is conjugated at the axle dye. Living carcinoma cell selective active targeting, subsequently cell penetration, mitochondrial imaging, including the ultrastructure of cristae, and real-time tracking of malignant mitochondria by MIMs-peptide bioconjugate (RGDS)2-Mito-MIMs-TPP+ are established by stimulated emission depletion (STED) super-resolved fluorescence microscopy. Water-soluble NIR (RGDS)2-Mito-MIMs-TPP+ is an effective class of MIMs-peptide bioconjugate with promising photophysics; for instance, remarkable photostability and thermal stability, strong and narrow NIR abs/em bands with high quantum yield, ultrabrightness, decent fluorescence lifetime, reasonable stability against cellular nucleophiles, biocompatibility, noncytotoxicity, and dual-targeted living cancer cell submitochondrial imaging ability are all indispensable criteria for targeted super-resolved STED microscopy.

DNA Aptamer-Polymer Conjugates for Selective Targeting of Integrin α4β1+ T-Lineage Cancers.

Selective therapeutic targeting of T-cell malignancies is difficult due to the shared lineage between healthy and malignant T cells. Current front-line chemotherapy for these cancers is largely nonspecific, resulting in frequent cases of relapsed/refractory disease. The development of targeting approaches for effectively treating T-cell leukemia and lymphoma thus remains a critical goal for the oncology field. Here, we report the discovery of a DNA aptamer, named HR7A1, that displays low nanomolar affinity for the integrin α4β1 (VLA-4), a marker associated with chemoresistance and relapse in leukemia patients. After truncation of HR7A1 to a minimal binding motif, we demonstrate elevated binding of the aptamer to T-lineage cancer cells over healthy immune cells. Using cryo-EM and competition studies, we find that HR7A1 shares an overlapping binding site on α4β1 with fibronectin and VCAM-1, which has implications for sensitizing blood cancers to chemotherapy. We last characterize barriers to in vivo aptamer translation, including serum stability, temperature-sensitive binding, and short circulation half-life, and synthesize an aptamer-polymer conjugate that addresses these challenges. Future work will seek to validate in vivo targeting of α4β1+ tumors with the conjugate, establishing an aptamer-based biomaterial that can be readily adapted for targeted treatment of T-cell malignancies.

Y2O3NPs induce selective cytotoxicity, genomic instability, oxidative stress and ROS mediated mitochondrial apoptosis in human epidermoid skin A-431 Cancer cells

Yttrium oxide nanoparticles (Y2O3NPs) have emerged as a promising avenue for cancer therapy, primarily due to their distinctive properties that facilitate selective targeting of cancer cells. Despite their potential, the therapeutic effects of Y2O3NPs on human epidermoid skin cancer remain largely unexplored. This study was thus conducted to investigate the impact of Y2O3NPs on both human skin normal and cancer cells, with an emphasis on assessing their cytotoxicity, genotoxicity, and the mechanisms underlying these effects. Cell viability and apoptosis induction were assessed using the Sulforhodamine B and chromatin diffusion assay, respectively. Reactive oxygen species (ROS) level, mitochondrial membrane potential integrity, oxidative stress markers and expression level of apoptotic and mitochondrial genes were also estimated. Our findings highlight the selective and significant cytotoxicity of Y2O3NPs against human epidermoid A-431 cancer cells. Notably, exposure to five Y2O3NPs concentrations (0.1, 1, 10, 100 and 1000 µg/ml) resulted in a high concentration-dependent reduction in cell viability and a corresponding increase in cell death observed 72 h post-treatment specifically in A-431 cancer cells, while normal skin fibroblast (HSF) cells exhibited minimal toxicity. When A-431 cancer cells were treated with the half-maximal inhibitory concentration (IC50) of Y2O3NPs for 72 h, a significant increase in ROS generation was noted. This led to oxidative stress, along with severe damage to genomic DNA and mitochondrial membrane potential, triggering substantial apoptosis. Furthermore, a concurrent significant upregulation of apoptotic p53 and mitochondrial ND3 genes was observed, coupled with a notable decrease in the anti-apoptotic Bcl2 gene expression.Overall, Y2O3NPs demonstrate considerable promise as a therapeutic agent for skin epidermoid cancer due to their ability to selectively target and induce cytotoxic effects in A-431 cancer cells, all while causing minimal harm to normal HSF cells. This selective cytotoxicity appears to be associated with Y2O3NPs’ ability to induce excessive ROS production and subsequent oxidative stress, leading to significant genomic DNA fragmentation, loss of mitochondrial permeability, and alterations in apoptotic and mitochondrial genes’ expression, ultimately promoting apoptosis in A-431 cancer cells. These findings establish a foundation for further research into the utilization of Y2O3NPs in targeted cancer therapies and underscore the necessity for ongoing investigation into their safety and efficacy in clinical applications.

A Conjugate of an EGFR-Binding Peptide and Doxorubicin Shows Selective Toxicity to Triple-Negative Breast Cancer Cells.

Selective targeting of cancer cells via overexpressed cell-surface receptors is a promising strategy to enhance chemotherapy efficacy and minimize off-target side effects. In this study, we designed peptide 31 (YHWYGYTPERVI) to target the overexpressed epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC) cells. Peptide 31 is internalized by TNBC cells through EGFR-mediated endocytosis and shares sequence and structural similarities with human EGF (hEGF), a natural EGFR ligand. Unlike hEGF, peptide 31 does not induce cell migration in TNBC cells. A novel conjugate of peptide 31 with doxorubicin (Dox) retains selectivity for TNBC cells and exhibits significant toxicity comparable to that of unconjugated Dox. Importantly, this conjugate shows no toxicity toward normal breast epithelial cells up to a high concentration (25 μM). Thus, peptide 31 serves as a versatile targeting ligand for developing novel conjugates with high selectivity for EGFR-positive cancers.

Analysis of quantitative trait loci and candidate gene exploration associated with cold tolerance in rice (Oryza sativa L.) during the seedling stage.

Cold stress during the seedling stage significantly threatens rice (Oryza sativa L.) production, specifically in temperate climates. This study aimed to identify quantitative trait loci (QTLs) associated with cold tolerance at the seedling stage. QTL analysis was conducted on a doubled haploid (DH) population derived from a cross between the cold-sensitive indica cultivar 93-11 and the cold-tolerant japonica cultivar Milyang352. Phenotypic analysis was conducted over 2 years (2022-2023) under cold water treatment (13°C) at the Chuncheon Substation, South Korea. Cold tolerance scores were used to classify the DH populations and parental lines. In 2022, three QTLs were identified on chromosomes 3, 10, and 11; in 2023, a single QTL was identified on chromosome 10. The QTL qCTS1022/23 on chromosome 10 was consistently observed across both years, explaining up to 16.06% and 40.55% of the phenotypic variance, respectively. Fine-mapping of qCTS1022/23 narrowed the candidate region to a 300-kb interval containing 44 polymorphic single-nucleotide polymorphisms. Among the candidate genes, Os10g0409400 was significantly expressed in the cold-tolerant japonica parent Milyang352 under cold stress, indicating its role in conferring cold tolerance. These findings offer valuable insights into the genetic mechanisms of cold tolerance and highlight qCTS1022/23 as a potential target for marker-assisted selection in rice breeding programs to enhance cold tolerance.