Search Results (1,718)

Triple-negative breast cancer (TNBC) has historically been challenging to treat due to limited therapeutic options. Since 2018, the treatment landscape has evolved substantially with the approval of precision therapies, including immune checkpoint inhibitors, poly (ADP-ribose) polymerase inhibitors, and antibody–drug conjugates. Despite these advancements, the therapeutic benefit remains limited due to various clinical challenges, largely driven by TNBC heterogeneity and an incomplete understanding of drug–tumor crosstalk mechanisms—both contributing to a restricted pool of eligible patients and variable treatment responses. Concurrently, emerging drugs tested in recent pivotal TNBC trials have demonstrated variable outcomes. Additionally, the associated economic burden has become a pressing global concern, as several approved drugs provide insufficient clinical benefit in relation to high expenditures, often driven by drug pricing. The situation is particularly critical in low- and middle-income countries, where TNBC is highly prevalent, yet access to even chemotherapeutic treatment remains limited. These factors collectively hinder real-world patient outcomes. This review provides a comprehensive analysis of TNBC management, integrating clinical advancements with economic perspectives and raising awareness of underdiscussed topics. The overview presented herein highlights the necessity for a global, interdisciplinary approach and patient centered care in TNBC drug development. Full article

We investigate the thermoelectric response of single-molecule junctions composed of acyclic cross-conjugated molecules, including dendralene analogues and related iso-poly(diacetylene) (iso-PDA) motifs, in which node-possessing repeat units are connected in series. Using many-body quantum transport theory, we show that increasing the number of repeat units leaves the fundamental gap essentially unchanged while giving rise to a split-node spectrum whose cumulative broadening dramatically enhances the thermopower. This form of quantum enhancement can exceed other interference-based mechanisms, such as the coalescence of nodes into a supernode, suggesting new opportunities for scalable quantum-interference–based materials. Although illustrated here with cross-conjugated systems, the underlying principles apply broadly to series-connected architectures hosting multiple interference nodes. Finally, we evaluate the scaling of the electronic figure of merit ZT and the maximum thermodynamic efficiency. Together, these results highlight the potential for split-node-based materials to realize quantum-enhanced thermoelectric response. Full article

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

Since the first paper published by Susan Cole in 1990 detailing multidrug resistance mediated by ABCC1/MRP1, research into the C-subfamily of ATP-binding cassette transporters has continued to uncover a wide range of functionally divergent proteins. However, several orphan transporters remain in the C-subfamily, and the physiological function and substrates of ABCC5, ABCC11, and ABCC12 remain elusive. This review explores the emerging understanding of human ABCC5. Unlike other ABC transporters with well-defined drug export functions, ABCC5’s physiological roles remain only partially understood. While it is known for its involvement in multidrug resistance in cancers, recent studies suggest broader implications in development, metabolism, neurobiology, and male fertility. ABCC5 exports various endogenous substrates, including cyclic nucleotides (cAMP and cGMP), glutamate conjugates like NAAG, and possibly haem. Knockout models in mice, zebrafish, and sea urchins reveal ABCC5’s role in gut formation, brain function, eye development, and iron metabolism. In mice, its deletion results in lower adipose tissue mass, enhanced insulin sensitivity, and neurobehavioral changes resembling schizophrenia, highlighting its role in glutamatergic signalling and circadian regulation. Functionally, ABCC5 appears to impact adipocyte differentiation and GLP-1 release, implicating it in type 2 diabetes susceptibility in humans. Structural studies using human ABCC5 revealed a novel autoinhibitory mechanism involving a peptide segment (C46–S64) that blocks substrate binding, offering new potential for selective inhibitor development. However, this review emphasises caution in targeting ABCC5 for cancer therapy due to its underappreciated physiological function(s), particularly in the brain and male reproductive system. Understanding ABCC5’s substrate specificity, regulatory mechanisms, and functional redundancy with its paralog ABCC12 remains critical for successful therapeutic strategies in humans. Full article

Autophagy is a conserved catabolic pathway that degrades intracellular cargo through the lysosomal system. Canonically, this process is orchestrated by the autophagy-related (Atg)5-Atg7 conjugation system, which facilitates the formation of microtubule-associated protein 1 light chain 3 (LC3)-decorated double-membrane vesicles known as autophagosomes. However, accumulating evidence has revealed the existence of an Atg5-Atg7-independent, alternative autophagy pathway that still relies on upstream regulators such as the unc-51 like autophagy activating kinase 1 (Ulk1) kinase and the Beclin1 complex. In this review, we provide a comprehensive overview of the role of the Beclin1 complex in canonical autophagy and highlight its emerging importance in alternative autophagy. Notably, the recent identification of transmembrane protein 9 (TMEM9) as a lysosomal protein that interacts with Beclin1 to promote member RAS oncogene family 9 (Rab9)-dependent autophagosome formation has significantly advanced our understanding of alternative autophagy regulation. Furthermore, this Ulk1-Rab9-Beclin1-dependent mitophagy has been shown to mediate to mitochondrial quality control in the heart, thereby contributing to cardioprotection under ischemic and metabolic stress conditions. We further examine how the Beclin1 complex functions as a central scaffold in both canonical and alternative autophagy, with a focus on its modulation by novel factors such as TMEM9 and the potential therapeutic implications of these regulatory mechanisms. Full article

Under the complex geological structural stress of the Western Himalayan syntaxis, the widespread distribution of hard and brittle rocks (such as sandstone and limestone) makes them prone to the formation of conjugate joints, also known as X-joints. These joints create weak structural planes in the slope rock mass, and when combined with weak interlayers within the slope, they result in a complex dynamic response and hazard situation in this region, which is further exacerbated by frequent seismic activity. This poses a serious threat to the planning, construction, and safe operation of the Belt and Road Initiative. To study the slope vibration response and instability mechanisms under these conditions, we conducted a shaking table test using the Iymek avalanche as a case study and performed Hilbert–Huang Transform (HHT) analysis. We also compared the results of the shaking table test on slope models without X-joints but containing weak interlayers. The findings show that the presence of X-joints leads to an earlier onset of plastic failure in the slope. During the failure development, X-joints cause stress concentration and the diversification of stress redistribution paths, delaying energy release. Ultimately, the avalanche failure mode in the X-joint slopes is more dispersed compared to the landslide failure mode in the model without X-joints. At the toe of the slope beneath the weak interlayer, low-frequency seismic waves can cause a significant amplification of acceleration, and the weak interlayer is often the shear outlets of the slope. These findings provide new insights into the seismic failure evolution of jointed slopes with weak interlayers and offer practical references for seismic hazard mitigation in mountainous infrastructure. Full article

The proposed physiological roles of bile acids have expanded beyond the digestion of fats to encompass cell signaling via the activation of a variety of nuclear and plasma membrane receptors in multiple organ systems. The current in silico study was inspired by previous observations from our group and others that bile acids interact functionally with cardiac, pulmonary, and gastrointestinal muscarinic receptors and more recent work demonstrating allosteric binding of cholesterol, the parent molecule for bile acid synthesis, to M₁ muscarinic receptors (M₁R). Here, we computationally tested the hypothesis that bile acids can allosterically bind to M₁R and thereby modulate receptor activation. Utilizing de novo site identification by the ligand competitive saturation (SILCS) method, putative novel allosteric binding sites of bile acid targeting M₁R were identified. Molecular dynamics simulations were used to uncover the molecular details of the activation mechanism of M₁R due to agonist binding along with allosteric modulation of bile acids on M₁R activation. Allosteric binding of bile acids and their glycine and taurine conjugates to M₁R negatively impacts the activation process, findings consistent with recent reports that M₁R expression and activation inhibit colon cancer cell proliferation. Thus, bile acids may augment colon cancer risk by inhibiting the tumor suppressor actions of M₁R. When validated experimentally, these findings are anticipated to shed light on our understanding of how bile acids in the membrane microenvironment can allosterically modulate the function of M₁R and possibly other G protein-coupled receptors. Full article

The relative reactivity of the nitrovinyl molecular segment characterized by the “cis” orientation of nitro group and the aryl ring was evaluated based on the experimental and Density Functional Theory quantum chemical data. It was found that, on the contrary to E-R-nitroethenes, the Z-2-Ar-1-EWG-1-nitroethene molecular segment is not planar. This fact reduces the possibility of the conjugation of π-electron systems, and as a consequence, decreases the global reactivity. Due to these conditions, the reaction of the model ethyl 4,β-dinitrocinnamate and 2-methylenecyclopentane is realized as a very difficult process; however, with full regioselectivity, it leads to the expected (4 + 2) hetero Diels–Alder cycloadduct. Bonding Evolution Theory studies show that the first new C4-C5 single bond is formed in Phase VIII by merging two pseudoradical centers. In turn, the second C6-O1 single bond is formed in last phase of the reaction, by the depopulation of V(C6), V(O1) and V’(O1) monosynaptic basins. According to this, the title reaction was classified as a process carried out according to a “one-step two-stage” mechanism. Full article

Ultrafast laser processing can produce micro/nanostructures, which is of great interest in advanced manufacturing. Ultrafast laser-induced events include non-equilibrium dynamic phenomena, occurring on the femtosecond to picosecond time scale and nanometer to micron space scale. Single-shot ultrafast imaging can provide multiple time-correlated evolution frames in one non-repeatable event with a temporal resolution of sub-picoseconds. However, previous approaches suffer from degraded spatial resolution, which is a bottleneck in microscopic imaging. For the spatial-frequency multiplexing methods based on structured illumination, a reconstruction strategy was proposed utilizing the frames’ conjugate symmetry in the Fourier domain. The spatial resolution is double that of the traditional algorithm by evaluating with synthetic data, revealing that the reconstruction resolution can reach the diffraction limitation. A two-frame microscopic system was constructed with a frame interval of 300 fs and a maximum spatial resolution of 1.4 μm. The interaction between a femtosecond laser and a fused silica glass plate was captured in a single shot and the dynamic evolution of the induced plasma was observed, verifying the application feasibility in ultrafast laser processing, providing experimental observations for interaction mechanism research and theoretical model optimization. Full article

We report the exceptional observations of amplified eastward subauroral polarization streams (SAPS) made by the F15 spacecraft at ~840 km altitude near magnetic midnight during 2015–2016 in 17 events. The results show the dawn-cell-associated amplified eastward SAPS flows streaming alongside the duskward-extending dawn cell. The amplified eastward SAPS flows maximized at ~3200 m/s within their respective deep plasma density troughs, mimicking the SAPS flows and thus implying positive feedback mechanisms in action, where the electron temperature reached ~7000 K. One set of correlated magnetosphere–ionosphere conjugate observations is also presented. This illustrates the magnetotail-reconnection-related inward-directed cross-tail convection electric field (E_C) reaching the near-earth plasmasheet’s tailward end, while the inward-directed SAPS E field was absent on the inner-magnetosphere plasmapause, and the emerging eastward SAPS flow in the conjugate ionosphere. These results provide observational evidence that the earthward-propagating inward-directed dawn–dusk cross-tail E field (1) mapped down to auroral latitudes with an equatorward direction, (2) propagated to subauroral latitudes, and (3) played a key role in the development of the emerging eastward SAPS flow and in the amplification of the fully-developed eastward SAPS flows near magnetic midnight, while positive feedback mechanisms supported further SAPS growth. Full article

In order to investigate the compression damage characteristics of the “interface section coal pillar–backfill body (ICPF)” composite structure formed after coal pillar excavation and gangue material backfill in the key technologies of coal pillar excavation and gangue material backfill replacement in the interface section of thick coal seams, an ICPF single-axis compression damage experiment under different internal dimensions of backfill was conducted using the PFC^2D numerical model, with the interface section coal pillar of a working face at a certain mine in northern Shaanxi Province as the research background. In addition, the stress–strain state, peak strength characteristics, damage mode, energy evolution, and damage characteristics of the ICPF composite were analyzed, and models for the evolution of the ICPF elastic modulus and compressive strength were established. The results showed that the stress–strain state of the ICPF changed from brittle to ductile as backfill strength decreased. The distribution of the elastic modulus is primarily influenced by backfill strength, and as the excavation–backfill width increases, the curve exhibits a distinct S-shaped distribution. The compressive strength decreases by up to 63.4% with an increase in excavation–backfill width and by up to 65.1% with a decrease in backfill strength. The sensitivity of compressive strength to backfill strength is greater than that to excavation–backfill width. Based on the established ICPF elastic modulus and compressive strength evolution model, the two mechanical properties were compared using model fitting, and the model fitting results were satisfactory. The ICPF exhibits three types of damage characteristics as the excavation and backfill width increases: oblique shear and tensile damage, edge coal stripping and X-shaped conjugate damage of the backfill body, and large-area plastic damage of the backfill body. By establishing a theoretical damage variable based on linear dissipation energy, damage factors can be quickly obtained from stress–strain curves. The damage curves all exhibit exponential growth, and their growth rates show certain dispersion as the excavation and backfill width increases and backfill strength decreases. Based on the brittleness index analysis of the ICPF composite, as the backfill strength decreases and excavation and backfill width increases, the brittleness index of the composite increases, and the tendency for impact increases. At an excavation and backfill width of 80 mm, rib damage tends to happen. Full article

Background/Objectives: Temporizin-1, a hybrid antimicrobial peptide derived from the combination of Temporin A, Gramicidin peptide, and a poly-leu sequence, has strong trypanocide activity against Trypanosoma cruzi and moderate cytotoxicity towards mammalian cells. In this study, we investigated the mode of action of the peptide upon interaction with protozoan and eukaryotic membranes. Methods: To this end, we conducted a series of biophysical assays using liposomes as biomimetic models, along with fluorescence-based experiments such as lipid mixing, membrane leakage, and assays involving Thioflavin and Laurdan. Results: Temporizin-1 displayed potent membranolytic activity on protozoan and eukaryotic membranes, causing significant membrane fusion and leakage with consequent pore formation. In addition, we also performed structural studies on liposome interaction, where we observed a helical structure that is conserved during membrane interaction. The NMR study confirms all the data obtained, providing both the structure of free Temporizin-1 in solution and the way it interacts with micelles. Moreover, Temporizin-1 demonstrated high selectivity against intracellular forms of T. cruzi and exhibited an additive effect when combined with benznidazole, highlighting its promising therapeutic activity. Conclusions: In conclusion, elucidating the mechanism of action of Temporizin-1 is essential for optimizing its structure and improving target selectivity, and driving the rational design of next-generation antimicrobial peptides by applying chemical strategies and delivery system’s conjugation. Full article

Antibiotics are widely used in modern medicine. However, as global antibiotic consumption rises, environmental contamination with antibiotics and antibiotic resistance genes (ARGs) is becoming a serious concern. The impact of antibiotic use on human health is now under scrutiny, particularly regarding the emergence of antibiotic-resistant bacteria (ARB) in the environment. This has heightened interest in technologies for treating ARGs, highlighting the need for effective solutions. This review traces the life cycle of ARB and ARGs driven by human activity, revealing pathways from antibiotic use to human infection. We address the mechanisms enabling resistance in ARB during this process. Beyond intrinsic resistance, the primary cause of ARB resistance is the horizontal gene transfer (HGT) of ARGs. These genes exploit mobile genetic elements (MGEs) to spread via conjugation, transformation, transduction, and outer membrane vesicles (OMVs). Currently, biological wastewater treatment is the primary pollution control method due to its cost-effectiveness. However, these biological processes can promote ARG propagation, significantly amplifying the environmental threat posed by antibiotics. This review also summarizes key mechanisms in the biological treatment of antibiotics and evaluates risks associated with major ARB/ARG removal processes. Our aim is to enhance understanding of ARB risks, their pathways and mechanisms in biotreatment, and potential biomedical applications for pollution control. Full article