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Articles 1 - 30 of 181
Full-Text Articles in Biomedical Engineering and Bioengineering
Friend Or Foe? The Role Of Transforming Growth Factor-Β (Tgfβ) Signaling In Calcineurin Inhibitor-Induced Renal Damage, Adaku Uwe
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With its incorporation into clinical practice in the early 1980s, the class of pharmacological agents known as calcineurin inhibitors (CNIs) quickly became the cornerstone of immunosuppressive therapy post-organ transplantation. However, its use is limited by irreversible kidney damage in the form of renal fibrosis. The molecular mechanism by which CNIs induce renal fibrosis remains to be better understood, and to date, there are no specific therapeutic strategies to mitigate this damage. This dilemma presents a critical need to explain mechanisms by which CNIs cause renal damage. Kidneys of patients on chronic CNI therapy show increased expression of the proinflammatory cytokine …
Development Of Gene Regulatory Elements For Biosensing Applications, Mallory N. Bates
Development Of Gene Regulatory Elements For Biosensing Applications, Mallory N. Bates
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21% of U.S adults experienced mental illnesses in 2020. Nearly 1 in 4 active- duty military personnel showed signs of mental health conditions in 2014 [89]. Mental health can be identified in the body by different biomarkers. These biomarkers potentially could be controlled by riboswitches, which could help mental illnesses and regulate diseases. Riboswitches are desirable in these cases due to responding without affecting vital functions. Riboswitches are located in mRNA and switch “ON” or “OFF” depending on the concentration of a biomarker [13]. In this research, riboswitches were re-engineered to take a known riboswitch and control its response in …
Erk3 And Dgkζ Interact To Modulate Cell Motility In Lung Cancer Cells, Amanda Myers
Erk3 And Dgkζ Interact To Modulate Cell Motility In Lung Cancer Cells, Amanda Myers
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Extracellular-regulated kinase 3 (ERK3) is overexpressed in a variety of cancers, including lung cancer. This atypical mitogen-activated protein kinase (MAPK) has a unique structure which includes a C34 domain and C-terminus and about which relatively little is known. ERK3 has been demonstrated to promote cell migration and metastasis in multiple cancer types. A yeast two-hybrid assay using ERK3 as bait indicated Diacylglycerol kinase ζ (DGKζ) is a binding partner. DGKζ is an isoform in the DGK family, all the members of which phosphorylate the lipid diacylglycerol (DAG) to generate phosphatidic acid (PA). DGKζ was shown to promote migration in mouse …
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
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G protein-coupled receptors (GPCRs) initiate intracellular signaling pathways via interaction with external stimuli. [1-5] Despite sharing similar structure and cellular mechanism, GPCRs participate in a uniquely broad range of physiological functions. [6] Due to the size and functional diversity of the GPCR family, these receptors are a major focus for pharmacological applications. [1,7] Current state-of-the-art pharmacology and toxicology research strategies rely on computational methods to efficiently design highly selective, low toxicity compounds. [9], [10] GPCR-targeting therapeutics are associated with low selectivity resulting in increased risk of adverse effects and toxicity. Psychoactive drugs that are active at Class A GPCRs used …
Acute Oxygen-Sensing By The Carotid Bodies : The Thermal Microdomain Model, Ryan Joseph Rakoczy
Acute Oxygen-Sensing By The Carotid Bodies : The Thermal Microdomain Model, Ryan Joseph Rakoczy
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The carotid bodies (CB) are peripheral chemoreceptors that detect changes in arterial oxygenation and, via afferent inputs to the brainstem, correct the pattern of breathing to restore blood gas homeostasis. Elucidating the “signal” that couples carotid body sensory type I cell (CBSC) hypoxic mitochondrial inhibition with potassium channel closure has proven to be an arduous task; to date, a multitude of oxygen-sensing chemotransduction mechanisms have been described and altercated (Varas, Wyatt & Buckler, 2007; Gao et al, 2017; Rakoczy & Wyatt, 2018). Herein, we provide preliminary evidence supporting a novel oxygen-sensing hypothesis suggesting CBSC hypoxic chemotransductive signaling may in part …
Silk Hydrogels Incorporated With Melanin, Anne Lutz
Silk Hydrogels Incorporated With Melanin, Anne Lutz
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Melanin is a naturally produced pigment found within the human body. Melanin is known for its ability to protect against Ultra Violet light, but also its ability to allow for mechanical protection. Making melanin a good addition to biomedical devices such as hydrogels. Silk hydrogels are weak in their load bearing capabilities but are known for their biocompatibility, biodegradability, and porosity. This makes the silk hydrogel a good material to incorporate melanin into in order to improve the mechanical properties. For the silk solution to form a solid, there must be a presence of both a catalyst and an oxidizer …
Multi-Label Classification On Locally-Linear Data: Application To Chemical Toxicity Prediction, Xiu Huan Yap
Multi-Label Classification On Locally-Linear Data: Application To Chemical Toxicity Prediction, Xiu Huan Yap
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Computational models may assist in identification and prioritization of large chemical libraries. Recent experimental and data curation efforts, such as from the Tox21 consortium, have contributed towards toxicological datasets of increasing numbers of chemicals and toxicity endpoints, creating a golden opportunity for the exploration of multi-label learning and deep learning approaches in this thesis. Multi-label classification (MLC) methods may improve model predictivity by accounting for label dependence. However, current measures of label dependence, such as correlation coefficient, are inappropriate for datasets with extreme class imbalance, often seen in toxicological datasets. In this thesis, we propose a novel label dependence measure …
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
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Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. …
Nmr Metabolomics For Optimizing Cell-Free Protein Synthesis, Angela M. Campo
Nmr Metabolomics For Optimizing Cell-Free Protein Synthesis, Angela M. Campo
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Cell-Free Protein Synthesis (CFPS) has been utilized by biochemists to produce a variety of chemicals and therapeutics. While CFPS has spawned research in the biochemistry and medical communities, there are still unknown issues with interlaboratory variability with the technique. This work explored the black box nature of CFPS reactions by analyzing the CFPS reactions in situ with Nuclear Magnetic Resonance (NMR) spectroscopy. Aim 1 developed the protocol for conducting NMR experiments on E. coli cell-free reactions as well as a data analysis pipeline. This was accomplished with 1H NMR, capturing metabolite changes over time. The 1D NOESY experiment proved to …
Low Frequency Oscillations Of Hemodynamic Parameters As A Novel Diagnostic Measure For Traumatic Brain Injury, Andrea Gomez Carrillo
Low Frequency Oscillations Of Hemodynamic Parameters As A Novel Diagnostic Measure For Traumatic Brain Injury, Andrea Gomez Carrillo
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There is a need to improve methods of monitoring patients with traumatic brain injury (TBI) in hospital settings. Current monitoring techniques and diagnosis methods are expensive, invasive, do not provide continuous measures, expose the patient to radiation, are ambiguous in the information they provide, and/or cannot be implemented at the bedside. These techniques measure imperative markers of brain function including intracranial pressure (ICP), cerebral blood flow (CBF), and oxygenation in the brain, among others. Hospitals not only require a practical method for real-time monitoring of patients at the bedside, but also meaningful metrics that characterize TBIs, since the variety of …
Modeling Of Excitation In Skeletal Muscle, Sabrina Kinzie Metzger
Modeling Of Excitation In Skeletal Muscle, Sabrina Kinzie Metzger
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Recent experimental findings in the Rich lab suggest there are important gaps in our understanding of muscle excitability in various disease states. To generate and test hypotheses as well as to determine whether our current understanding of various aspects of muscle excitation can fully explain experimental findings, an accurate model of muscle excitation was needed. Previous studies have modeled excitation of muscle, but in each case, important aspects were omitted. One reason for this is that little effort has been made to accurately simulate muscle action potentials. In this thesis I present progress made towards generation of a model of …
Alterations In Cardiac Motions Of The Failing Heart During Direct Mechanical Ventricular Actuation, Benjamin Allyn Schmitt
Alterations In Cardiac Motions Of The Failing Heart During Direct Mechanical Ventricular Actuation, Benjamin Allyn Schmitt
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Objectives: Heart failure (HF) refractory to medical management can be effectively treated with mechanical support. However, available devices are frequently associated with complications due to blood contact. Direct cardiac compression (DCC) devices augment LV systolic pump function by externally compressing the heart surface. Direct Mechanical Ventricular Actuation (DMVA) is a unique DCC method providing not only systolic but, importantly, diastolic support. However, DCC in general remains a relatively poorly understood modality. The purpose of this study was to examine DMVA’s effect on restoration of physiologic function in the failing heart. Methods: Global ischemic HF was induced with 5 mins of …
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
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G protein-coupled receptors (GPCRs) initiate intracellular signaling pathways via interaction with external stimuli. [1-5] Despite sharing similar structure and cellular mechanism, GPCRs participate in a uniquely broad range of physiological functions. [6] Due to the size and functional diversity of the GPCR family, these receptors are a major focus for pharmacological applications. [1,7] Current state-of-the-art pharmacology and toxicology research strategies rely on computational methods to efficiently design highly selective, low toxicity compounds. [9], [10] GPCR-targeting therapeutics are associated with low selectivity resulting in increased risk of adverse effects and toxicity. Psychoactive drugs that are active at Class A GPCRs used …
Als-Induced Excitability Changes In Individual Motorneurons And The Spinal Motorneuron Network In Sod1-G93a Mice At Symptom Onset, Christiana S.I. Draper
Als-Induced Excitability Changes In Individual Motorneurons And The Spinal Motorneuron Network In Sod1-G93a Mice At Symptom Onset, Christiana S.I. Draper
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Amyotrophic lateral sclerosis (ALS) is the most common motorneuron (MN) disease in adulthood. ALS is hallmarked by the progressive loss of MNs in the brain, brainstem, and spinal cord. Many hypotheses to explain the pathogenesis of ALS have been explored, but the exact mechanisms underlying the development of this disease remain unknown. However, abnormalities in MN excitability and glutamate excitotoxicity are the most widely studied. For decades, researchers have examined MN excitability in ALS, but the current literature is inconsistent, showing evidence of hyperexcitability, hypoexcitability, or no change in excitability of MNs in ALS. Many of these studies also focus …
Carbon Nanotube-Coated Scaffolds For Tissue Engineering Applications, Soham Dipakbhai Parikh
Carbon Nanotube-Coated Scaffolds For Tissue Engineering Applications, Soham Dipakbhai Parikh
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Carbon Nanotubes (CNTs) have beneficial properties for cell scaffolding, which has translated into effective growth of bone, muscle, and cardiac cells. However, loose carbon nanotubes can cause in vivo toxicity. To reduce this risk, our team has developed biomimetic scaffolds with multiscale hierarchy where carpet-like CNT arrays are covalently bonded to larger biocompatible substrates. In this study, we have tested such scaffolds in two distinct types of biomedical applications involving glioblastoma and keratinocyte cells. The growth of glioblastoma (GBM) cells on our CNT-coated biomimetic scaffolds was evaluated to check their suitability as a potential chemotherapy-loaded implant for GBM patient treatment. …
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
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Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. …
The Regulation Of Small Gtpase Rac1 Phosphorylation, Activation And Subcellular Localization By Δnp63Α, Amjad Ahmed Aljagthmi
The Regulation Of Small Gtpase Rac1 Phosphorylation, Activation And Subcellular Localization By Δnp63Α, Amjad Ahmed Aljagthmi
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ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in normal development and human disease. Loss of ΔNp63α expression is associated with increased cancer invasiveness and metastasis. The small GTPase Rac1 is a master regulator of cell motility, and increased Rac1 activity upregulates cell invasion in multiple human cancers. Increased cancer cell invasion associated with ΔNp63α knockdown and Rac1 activation suggests a novel mechanism by which ΔNp63α regulates tumor invasiveness through Rac1. Accordingly, we sought to delineate the effects of ΔNp63α on Rac1 phosphorylation, activation and subcellular localization. We identified a novel ΔNp63α/miR-320a/PKCᵧ signaling pathway …
Single-Pixel Camera Based Spatial Frequency Domain Imaging For Non-Contact Tissue Characterization, Alec M. Petrack
Single-Pixel Camera Based Spatial Frequency Domain Imaging For Non-Contact Tissue Characterization, Alec M. Petrack
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Optical imaging has demonstrated potential as a medical imaging modality for measuring tissue functionality. Recently, interest in fluorescence guided surgery has emerged from improvements in optical imaging that have allowed real-time feedback. Of the optical imaging modalities, spatial frequency domain imaging (SFDI) has gained a lot of interest. Unlike spectroscopic techniques, such as functional near infrared spectroscopy (fNIRS) and frequency domain spectroscopy that measure bulk tissue properties, SFDI quantifies tissue functionality locally and wide field making it practical for clinical applications. Unfortunately, traditional SFDI systems use multi-pixel detectors, which may not exhibit ideal spectral characteristics, have limited sensitivity, be expensive, …
Global Joint Registry: Analysis Of Revision Hip Arthroplasty Data, Alicia M. Runser
Global Joint Registry: Analysis Of Revision Hip Arthroplasty Data, Alicia M. Runser
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Total hip arthroplasty (THA) has become well-known as being one of the most successful procedures with much long-term positive clinical results. However, revision surgeries are still required. The four most common failure modes for THAs, “reasons for revision”, are loosening, dislocation or instability, fracture, and infection. The goal of a hip arthroplasty register is to gather information on patients that undergo a total hip arthroplasty and factors pertaining to their surgery which may affect their outcome for future years such as the reason for revision. Analysis of this data can help with the allocation of healthcare funds and the efficacy …
Observing P300 Amplitudes In Multiple Sensory Channels Using Cognitive Probing, Cody Lee Wintermute
Observing P300 Amplitudes In Multiple Sensory Channels Using Cognitive Probing, Cody Lee Wintermute
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High cognitive workload occurs when excessive working memory resources have been deployed to resolve sensory and cognitive processing, resulting in decremented task performance. The P300 event-related potential (ERP) component has shown sensitivity to cognitive load, and it was hypothesized that an attenuated P300 amplitude could be indicative of high cognitive load. We tested this hypothesis by having eight participants complete two continual performance tasks at increasing workload levels while simultaneously performing an oddball task, evoking P300 ERPs in either the auditory or tactile sensory channel. In our experiment, electroencephalographic recordings were collected over the parietal region to observe the P300 …
Kv2.1 Channel Clustering In The Sod1-G93a Mouse Model Of Als, Joshua Christopher Harris
Kv2.1 Channel Clustering In The Sod1-G93a Mouse Model Of Als, Joshua Christopher Harris
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Kv2.1 channels mediate slow-activating K+ rectifier current within the membrane of spinal motoneurons (MNs), and they are known to co-localize with other synapses and ion channels. Although Kv2.1 channels are suggested to regulate MN excitability, little research has gone into investigating its potential contribution to MN-altered excitability in Amyotrophic Lateral Sclerosis (ALS). Using the male SOD1-G93A mouse model of ALS, we examined Kv2.1 cluster area and density in lumbar MNs at four key stages of disease progression. In our experiments, MNs were separated by type via SK3 immunoreactivity in order to isolate and compare the responses of disease-resistant (slow; SK3+) …
Renca Macrobeads Inhibit Tumor Cell Growth Via Egfr Activation And Regulation Of Mef2 Isoform Expression, Prithy Caroline Martis
Renca Macrobeads Inhibit Tumor Cell Growth Via Egfr Activation And Regulation Of Mef2 Isoform Expression, Prithy Caroline Martis
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Tumors are heterogeneous systems, whose growth is influenced by intrinsic properties of malignant cells, external systemic factors (i.e. immune, neural, endocrine, etc.), and the dynamic interactions between tumor cells and their microenvironment. Given the inherent complexity of cancers, combined with the continual evolution of tumors and the development of treatment resistance, a precision medicine approach may not provide an optimal clinical response. Exploring a new paradigm that focuses on regulating cancer as a system may not only control tumor progression but also address the extraordinary challenges of tumor heterogeneity and disease recurrence in order to improve clinical outcomes. As a …
Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider
Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider
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Alpha-synuclein is a small lipid binding protein abundantly expressed in the brain. Lewy body or Lewy-like pathology, primarily composed of misfolded alpha-synuclein, is a pathological feature shared by several neurodegenerative disorders, including Parkinson's disease (PD). Both missense mutations and increased copy numbers of the SNCA gene, encoding the alpha-synuclein protein, have been genetically linked to autosome dominant PD. Other genetic variations affecting the expression of the SNCA gene have been associated with sporadic PD. Although the physiological function of alpha-synuclein is not well understood, its localization to plasma and vesicular membranes at the presynaptic terminals suggests a role in neurotransmission. …
Visual Sampling With The Eeg Alpha Oscillation, Kevin Eugene Alexander
Visual Sampling With The Eeg Alpha Oscillation, Kevin Eugene Alexander
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The posterior alpha rhythm, seen in human electroencephalograms (EEG), is posited to originate from cycling inhibitory/excitatory states of visual relay cells in the thalamus, which could result in discrete sampling of visual information. Here, we tested this hypothesis by presenting light flashes at perceptual threshold intensity through closed eyelids to 20 participants during times of spontaneous alpha oscillations. Alpha phase and amplitude were calculated relative to each individual’s retina-to-V1 conduction delay, estimated by the individuals’ C1 visual-evoked potential latency. Our results show that an additional 20.96% of stimuli are observed when afferenting at V1 during an alpha wave trough (272.41°) …
Ultraviolet-B Radiation Induces Release Of Bioactive Microvesicle Particles In Keratinocytes Via Platelet-Activating Factor And Acid Sphingomyelinase, Langni Liu
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Ultraviolet-B (UV-B) radiation is one of the most common environmental factors and is known to induce the production of bioactive agents that cause several diseases including skin cancer. UVB exposure stimulates the production of a phospholipid activator, platelet-activating factor (PAF), and its analogs in keratinocytes that activate the PAF receptor (PAF-R) resulting in acute inflammatory and delayed systematic immunosuppressive effects. However, as UVB only penetrates into the skin epidermal layer, the detailed mechanisms of how UVB exerts systematic effects remains unclear. Previously we found that UVB induces keratinocytes to release large numbers of microvesicle particles (MVPs). These small membrane-bound particles …
Chondroitin Sulfate Hydrogels For Total Wound Care Devices, Tushar Goswami
Chondroitin Sulfate Hydrogels For Total Wound Care Devices, Tushar Goswami
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Chondroitin sulfate (CS) is a naturally occurring bio-polymer found in areas of high cartilage in mammals. In directed applications, such as hydrogels, CS can be used to impact keratinocyte growth cycles. In this work, CS based hydrogels were utilized to accelerate wound healing and, in conjunction with a graphene sensor, monitor wound fluid pH. The hydrogels were cast onto a graphene field effect transistor (GFET) to obtain the benefits of the hydrogel wound healing capabilities, while also utilizing the pH sensitivity of the graphene. Results showed that the hydrogel caused a fivefold increase in cell size over the course of …
Differential Microrna Expression In Barrett's Esophagus Correlates With Regulation Of Posterior Homeotic Genes, Reilly June Clark
Differential Microrna Expression In Barrett's Esophagus Correlates With Regulation Of Posterior Homeotic Genes, Reilly June Clark
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Barrett’s Esophagus (BE) is characterized by the appearance of an intestinal-like epithelium in the distal esophagus. The molecular mechanisms behind BE development are unknown. BE is often preceded by Gastroesophageal Reflux Disease (GERD) and predisposes patients to esophageal adenocarcinoma (EAC). Due to the high mortality rate associated with EAC, BE patients are continuously monitored through upper endoscopy with biopsy for progression to low grade dysplasia (LGD), high grade dysplasia, and EAC. This monitoring technique poses numerous risks, so alternative surveillance and diagnostic techniques for BE pathogenesis are continually studied. microRNA biomarkers in BE pathogenesis may provide alternative means of diagnosis …
Mitochondria-Dependent Cellular Toxicity Of Α-Synuclein Modeled In Yeast, Rajalakshmi Santhanakrishnan
Mitochondria-Dependent Cellular Toxicity Of Α-Synuclein Modeled In Yeast, Rajalakshmi Santhanakrishnan
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Parkinson’s disease is the second most common neurodegenerative disease. This disease is caused by the degeneration of dopaminergic neurons, leading to debilitating motor symptoms and early mortality. The protein α-synuclein (α-syn), encoded by SNCA, misfolds and forms inclusions in Parkinson’s disease brains. When α-syn is overexpressed in yeast, it causes cellular toxicity and an increased number of aggregates, recapitulating the toxic phenotypes observed in humans and animal models. Yeast models are a powerful tool to perform high-throughput overexpression screening to identify modifiers of α-syn toxicity. α-syn causes mitochondrial dysfunction by inhibiting complex I and inducing mitochondrial fragmentation. Prior screening of …
Mechanical Stresses On Nasal Mucosa Using Nose-On-Chip Model, Zachary Edward Brooks
Mechanical Stresses On Nasal Mucosa Using Nose-On-Chip Model, Zachary Edward Brooks
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The objective of this research was to design and fabricate a nose-on-chip device and bi-directional airflow system that models flow within the nasal cavity to investigate how airflow induced mechanical stresses impact nasal secretion rates and cytoskeletal remodeling. This research hypothesizes that the airflow induced shear stresses on the nasal mucosa will influence mucus production and the cytoskeleton of the cells. The RPMI 2650 cell line was used to model the nasal mucosa. The system was used to replicate the wall shear stresses (WSS) and wall shear forces (WSF) present in the anterior region of the nose. The WSS and …
Characterizing Basal-Like Triple Negative Breast Cancer Using Gene Expression Analysis: A Data Mining Approach, Qamar Alsabi
Characterizing Basal-Like Triple Negative Breast Cancer Using Gene Expression Analysis: A Data Mining Approach, Qamar Alsabi
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Triple-negative breast cancer (TNBC) is characterized by the absence of expression of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2). Therefore, TNBC is unresponsive to targeted hormonal therapies, which limits treatment options to nonselective chemotherapeutic agents. Basal-like breast cancers (BLBCs) represent a subset of about 70% of TNBCs, more frequently affecting younger patients, being more prevalent in African-American women and significantly more aggressive than tumors of other molecular subtypes, with high rates of proliferation and extremely poor clinical outcomes. Proper classification of BLBCs using current pathological tools has been a major challenge. Although TNBCs have …