Search Results (20)

To achieve obstacle-avoiding puncture in breast interventional surgery, a robotics system based on three-fingered breast target-point manipulation is proposed and designed. Firstly, based on the minimum number of control points required for three-dimensional breast deformation control and the bionic structure of the human hand, the structure and control scheme of the robotics system based on breast target-point manipulation are proposed. Additionally, the workspace of the robotics system is analyzed. Then, an optimal control point selection method based on the minimum resultant force principle is proposed to achieve precise manipulation of the breast target point. Concurrently, a breast soft tissue manipulation framework incorporating a Model Reference Adaptive Control (MRAC) system is developed to enhance operational accuracy. A dynamic model of breast soft tissue is developed by using the manipulative force–displacement data obtained during the process of manipulating breast soft tissue with mechanical fingers to realize the manipulative force control of breast tissue. Finally, through simulation and experiments on breast target-point manipulation tasks, the results show that this robotic system can achieve spatial control of breast positioning at arbitrary points. Meanwhile, the robotic system proposed in this study demonstrates high-precision control with an accuracy of approximately 1.158 mm (standard deviation: 0.119 mm), fulfilling the requirements for clinical interventional surgery in target point manipulation. Full article

For a long time, D-amino acids remained unexplored in mammalian physiology. The technological advances in enantioseparation over the past 50 years have revealed that D-amino acids not only exist in human tissues and fluids but also play important roles in neurotransmission, immune regulation, and cellular proliferation. The present review provides a comprehensive assessment of the role of D-amino acids in cancer, including their endogenous and exogenous production pathways, along with the analytical methodologies used for detection and quantification, from liquid chromatography to biosensors. These methods have underlined how altered levels of D-amino acids can be helpful in early detection, progression, or response to treatment in several malignancies, including gastric, hepatic, colorectal, or breast cancer. The present review also explores how manipulation of D-amino acids can regulate cell proliferation, their mechanisms in cancer regulation, including the modulation of N-methyl-D-aspartate (NMDA) receptors and the production of hydrogen sulphide (H₂S), and the role of specific D-amino acids in cancer onset, immune defence, and protection against chemotherapy-induced toxicity. Finally, several underexplored research directions are outlined, such as potential correlations with gut microbiota composition, the impact of processed food consumption, and the integration of multiomics strategies. Full article

Minimally invasive interventional surgery is commonly used for diagnosing and treating breast cancer, but the high fluidity and deformability of breast tissue reduce intervention accuracy. This study proposes a bionic breast interventional robot that mimics the scorpion’s predation process, actively manipulating tissue deformation to control target displacement and enhance accuracy. The robot’s structure is designed using a modular method, and its kinematics and workspace are analyzed and solved. To address the nonlinear breast tissue deformation problem, a hierarchical tissue method is proposed to simplify the three-dimensional problem into a two-dimensional one. A two-dimensional tissue deformation solver is established based on the minimum energy method for quick resolution. The problem is treated as quasi-static, deriving the displacement relationship between external manipulation points and internal tissue targets. The method of active manipulation of tissue deformation is simulated using MATLAB (2019-b) software to verify the feasibility of the method. Results show maximum errors of 1.7 mm for prostheses and 2.5 mm for in vitro tissues in the X and Y directions. This method improves intervention accuracy in breast surgery and offers a new solution for breast cancer diagnosis and treatment. Full article

For triple-negative breast cancer (TNBC), the most aggressive subset of breast cancer, immune cell infiltrates have prognostic implications. The presence of myeloid-derived suppressor cells supports tumor progression, while tumor-infiltrating lymphocytes (TILs) correlate with improved survival and responsiveness to immunotherapy. Manipulating the abundance of these populations may enhance tumor immunity. Gemcitabine (GEM), a clinically employed chemotherapeutic, is reported to be systemically myeloablative, and thus it is a potentially useful adjunct therapy for promoting anti-tumor immunity. However, knowledge about the immunological effects of GEM intratumorally is limited. Thus, we directly compared the impact of systemic GEM on immune cell presence and functionality in the tumor microenvironment (TME) to its effects in the periphery. We found that GEM is not myeloablative in the TME; rather, we observed sustained, significant reductions in TILs and dendritic cells—crucial components in initiating an adaptive immune response. We also performed bulk-RNA sequencing to identify immunological alterations transcriptionally induced by GEM. While we found evidence of upregulation in the interferon-gamma (IFN-γ) response pathway, we determined that GEM-mediated growth control is not dependent on IFN-γ. Overall, our findings yield new insights into the tissue- and temporal-dependent immune ablative effects of GEM, contrasting the paradigm that this therapy is specifically myeloablative. Full article

Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients. Full article

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer management. Recent findings highlight the significance of microbial alterations in tissue, such as the gut and the breast, and their role in influencing the breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe–cancer interplay. As the field advances, the strategic manipulation of the microbiome and its metabolites presents innovative prospects for the enhancement of cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management. Full article

Systemically administered chemotherapy reduces the efficiency of the anticancer agent at the target tumor tissue and results in distributed drug to non-target organs, inducing negative side effects commonly associated with chemotherapy and necessitating repeated administration. Injectable hydrogels present themselves as a potential platform for non-invasive local delivery vehicles that can serve as a slow-releasing drug depot that fills tumor vasculature, tissue, or resection cavities. Herein, we have systematically formulated and tested an injectable shear-thinning hydrogel (STH) with a highly manipulable release profile for delivering doxorubicin, a common chemotherapeutic. By detailed characterization of the STH physical properties and degradation and release dynamics, we selected top candidates for testing in cancer models of increasing biomimicry. Two-dimensional cell culture, tumor-on-a-chip, and small animal models were used to demonstrate the high anticancer potential and reduced systemic toxicity of the STH that exhibits long-term (up to 80 days) doxorubicin release profiles for treatment of breast cancer and glioblastoma. The drug-loaded STH injected into tumor tissue was shown to increase overall survival in breast tumor- and glioblastoma-bearing animal models by 50% for 22 days and 25% for 52 days, respectively, showing high potential for localized, less frequent treatment of oncologic disease with reduced dosage requirements. Full article

Gd- and Fe-based contrast agents reduce T₁ and T₂ relaxation times, respectively, are frequently used in MRI, providing improved cancer detection. Recently, contrast agents changing both T₁/T₂ times, based on core/shell nanoparticles, have been introduced. Although advantages of the T₁/T₂ agents were shown, MR image contrast of cancerous versus normal adjacent tissue induced by these agents has not yet been analyzed in detail as authors considered changes in cancer MR signal or signal-to-noise ratio after contrast injection rather than changes in signal differences between cancer and normal adjacent tissue. Furthermore, the potential advantages of T₁/T₂ contrast agents using image manipulation such as subtraction or addition have not been yet discussed in detail. Therefore, we performed theoretical calculations of MR signal in a tumor model using T₁-weighted, T₂-weighted, and combined images for T₁-, T₂-, and T₁/T₂-targeted contrast agents. The results from the tumor model are followed by in vivo experiments using core/shell NaDyF₄/NaGdF₄ nanoparticles as T₁/T₂ non-targeted contrast agent in the animal model of triple negative breast cancer. The results show that subtraction of T₂-weighted from T₁-weighted MR images provides additional increase in the tumor contrast: over two-fold in the tumor model and 12% in the in vivo experiment. Full article

MiR-150-5p is frequently deregulated in cancer, with expression and mode of action varying according to the tumor type. Here, we investigated the expression levels and role of miR-150-5p in the aggressive breast cancer subtype triple-negative breast cancer (TNBC). MiR-150-5p expression levels were analyzed in tissue samples from 113 patients with invasive breast cancer (56 TNBC and 57 non-TNBC) and 41 adjacent non-tumor tissues (ANT). Overexpression of miR-150-5p was observed in tumor tissues compared with ANT tissues and in TNBC compared with non-TNBC tissues. MiR-150-5p expression levels were significantly associated with high tumor grades and the Caucasian ethnicity. Interestingly, high miR-150-5p levels were associated with prolonged overall survival. Manipulation of miR-150-5p expression in TNBC cells modulated cell proliferation, clonogenicity, migration, and drug resistance. Manipulation of miR-150-5p expression also resulted in altered expression of its mRNA targets, including epithelial-to-mesenchymal transition markers, MYB, and members of the SRC pathway. These findings suggest that miR-150-5p is overexpressed in TNBC and contributes to the aggressiveness of TNBC cells in vitro. Full article

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. Here, we establish a murine model of HGSOC and utilize image-guided microinjections of retrograde neuro-tracer to label tumor-infiltrating peripheral neurons, mapping their source and circuitry. We show that regional sensory neurons innervate HGSOC tumors. Interestingly, the axons within the tumor trace back to local dorsal root ganglia as well as jugular–nodose ganglia. Further manipulations of these tumor projecting neurons may define the neuronal contributions in tumor growth, invasion, metastasis, and responses to therapeutics. Full article

Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies. Full article

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies. Full article

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer. Full article

The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb₃) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin–receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb₃ (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb₃ is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb₃ is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb₃ levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb₃ is upregulated in the neovasculature of many tumours, irrespective of tumour Gb₃ status. Gb₃ is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented. Full article

Even though the administration of chemotherapeutic agents such as erlotinib is clinically established for the treatment of breast cancer, its efficiency and the therapy outcome can be greatly improved using RNA interference (RNAi) mechanisms for a combinational therapy. However, the cellular uptake of bare small interfering RNA (siRNA) is insufficient and its fast degradation in the bloodstream leads to a lacking delivery and no suitable accumulation of siRNA inside the target tissues. To address these problems, non-ionic surfactant vesicles (niosomes) were used as a nanocarrier platform to encapsulate Lifeguard (LFG)-specific siRNA inside the hydrophilic core. A preceding entrapment of superparamagnetic iron-oxide nanoparticles (Fe_xO_y-NPs) inside the niosomal bilayer structure was achieved in order to enhance the cellular uptake via an external magnetic manipulation. After verifying a highly effective entrapment of the siRNA, the resulting hybrid niosomes were administered to BT-474 cells in a combinational therapy with either erlotinib or trastuzumab and monitored regarding the induced apoptosis. The obtained results demonstrated that the nanocarrier successfully caused a downregulation of the LFG gene in BT-474 cells, which led to an increased efficacy of the chemotherapeutics compared to plainly added siRNA. Especially the application of an external magnetic field enhanced the internalization of siRNA, therefore increasing the activation of apoptotic signaling pathways. Considering the improved therapy outcome as well as the high encapsulation efficiency, the formulated hybrid niosomes meet the requirements for a cost-effective commercialization and can be considered as a promising candidate for future siRNA delivery agents. Full article