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Impact Of Unconventional Gas Extraction On Tributaries Of Tenmile Creek, Greene County, Pennsylvania: A 12-Year Perspective, Christian L. Beall

Electronic Theses and Dissertations

Much of southwestern Pennsylvania has been central to a rapid increase in development for unconventional natural gas extraction in the past two decades. The continued monitoring of streams over their lifetime as extraction sites is pivotal to understanding the effects of fracking on local waterways and their ability to provide for wildlife and human use. Here, using multiple indices of biotic integrity (IBI), I perform analyses of fish and macroinvertebrate communities as well as water chemistry on two streams, Bates Fork (with shale wells) and Fonner Run (without), as part of a follow-up to work performed there from 2010-2012. Fish …

Earthworms, Slugs, And Salamanders: Community Interactions In A Massachusetts Forest, Emmalee Bent

Honors Program Theses and Projects

Earthworms (Order: Opisthopora) have several important ecological interactions with eastern red-backed salamanders (Plethodon cinereus). For the salamanders, earthworms can be nutrient-rich, easy-to-digest prey, or ecosystem engineers of burrows. Indirectly, earthworms can be competition for other microinvertebrate prey species that salamanders prefer to eat. Red-backed salamanders are thought to be a critical player in forest food-webs and possible ecosystem indicator, as they are highly abundant, mid-level consumers that are very sensitive to their abiotic environment. These factors make understanding the interactions between earthworms and salamanders valuable for broader understanding of forest communities. To better understand the earthworm community present at a …

Student Perceptions Of Supports And Barriers For Transferring Quantitative Reasoning In Introductory Biology Lab Courses, Joelle Prate, Jeremy L. Hsu

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Quantitative reasoning is a critical skill in biology and has been highlighted as a core competency by Vision and Change. Despite its importance, students often struggle to apply mathematical skills in new contexts in biology, a process called transfer of knowledge. However, the supports and barriers that students perceive for this process remain unclear. To explore this further, we interviewed undergraduate students in an introductory biology lab course about how they understand and report the transfer of quantitative skills in these courses. We then applied these themes to the Step Back, Translate, and Extend (SBTE) framework to examine student …

Sustainable Process Valorization For Bioactives From Invasive Plants Environmental Burden And Their Efficacy As Antimicrobial Agents, Shamprasad Br

Theses and Dissertations

Agri-food industries produce large quantities of fruit waste which are usually discarded and one such major beverage juice waste is Citrus waste. Likewise, invasive plants like Prosopis juliflora, which is richly distributed across Tamil Nadu, are underutilized for secondary metabolites/bioactives isolation. Halophytes are another rich source of bioactives present around mangrove forests and distributed in the salt rich marshy land.

1. Separation of phenylpropanoids from the Citrus waste through solvent extraction and pH-assisted precipitation was developed. The PPCM precipitated (phenylpropanoids form Citrus medica) were analysed by HPTLC and were found to contain Rutin, Naringin, Quercetin-3-beta-glycoside, Chlorogenic acid, Ferulic acid and optimization …

Developing Novel Radical Protein Footprinting Methods For Application In Living Systems, Lyle Tobin

Honors Theses

Radical protein footprinting (RPF) is a family of structural biology techniques that generate radicals in situ to label solvent-accessible amino acid residues. Coupled with liquid chromatography/mass spectrometry, RPF enables the characterization of protein higher order structure and sites of protein-protein and protein-ligand interactions. While traditionally performed in vitro, recent advancements have extended RPF to ex vivo and in vivo applications, including intact cells, nematodes, and 3D cell cultures. RPF in living systems allows the structural analysis of proteins and protein complexes in their native environment, preserving physiological interactions, dynamic conformational changes, and structural contexts that might otherwise be lost …

Ligand-Activated Egfr/Mapk Signaling But Not Pi3k, Are Key Resistance Mechanisms To Egfr-Therapy In Colorectal Cancer, Xueping Qu, Habib Hamidi, Radia M Johnson, Ethan S Sokol, Eva Lin, Cathy Eng, Tae Won Kim, Johanna Bendell, Smruthy Sivakumar, Benjamin Kaplan, Felipe De Sousa E Melo, Andrew Mancini, Matthew Wongchenko, Yi Shi, David Shames, Yibing Yan, Fortunato Ciardiello, Carlos Bais

Faculty, Staff and Student Publications

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for …

Biomarkers That Could Explain Parasite-Induced Behavioral Alterations In The Golden Shiner (Notemigonus Crysoleucas) – Posthodiplostomum System, Laura D. Nicolas

All HCAS Student Capstones, Theses, and Dissertations

Trophically transmitted parasites require an intermediate host to be consumed and often manipulate host phenotype (i.e., morphology, physiology, and/or behavior) to increase predation risk by definitive hosts. Posthodiplostomum is a trematode with a complex life cycle involving snails as first hosts, fish as second intermediate hosts, and piscivorous birds as definitive hosts. In fish hosts, Posthodiplostomum infection has been linked to increased predation, suggesting suppression of antipredator behaviors. However, the specific physiological pathways remained unexplored and changes in the host’s neural, endocrine, and immune systems could be involved. Thus, I examined whether Posthodiplostomum infection intensity was associated with brain serotonin …

Mesoderm-Specific Transcript Has A Role In The Systemic Regulation Of Obesity, Maria J. Orellana Rosales

Thinking Matters Symposium

Mesoderm specific transcript (Mest) expression in white adipose tissue (WAT) is variable in genetically identical mice. Previous studies have shown a connection between Mest high expression and propensity for fat mass expansion. WAT and liver crosstalk has been well documented with hormone-like peptides signaling and regulating important metabolic pathways. The aim of this study is to investigate the correlation between these circulating factors and Mest expression in mice after exposure to a high fat diet (HFD). A group of 120 C57B6/J mice, males and females, were exposed to a HFD (Western Diet, 40 kcal% fat) for 4 weeks (8-12 weeks …

Application Of Bioactive Materials Primary Cilia As A Novel Delivery Vehicle, Ayan K. Barui, Farideh Amirrad, Vansh Goel, Sharareh Ohadi, Rajasekharreddy Pala, Ashraf M. Mohieldin, Andromeda M. Nauli, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are hair-like structured cell organelles functioning as cellular antennae with chemosensory and mechanosensory roles. Dysfunction of cilia results in ciliopathies, including renovascular diseases (polycystic kidneys, hypertension, aneurysm), mental impedances (Alzheimer's disease, Parkinson's disease, dementia), metabolic diseases (obesity, developmental skeleton defects), blindness, and so on. With a diameter of 150 nm, cilia can be cleaved, released and circulated in the body as injury biomarkers. We here assessed the potential use of isolated cilia as a novel delivery vehicle. Cilia were isolated from renal epithelial cells, and a specific-targeting chemotherapeutic was designed on the cilia. The data show a remarkable …

Comparative Three-Barcode Phylogenetics And Soil Microbiomes Of Planted And Wild Strawberry Trees., Flannery Mclamb, Armando Vazquez, Natalie Olander, Miguel F. Vasquez, Zuying Feng, Niharika Malhotra, Liisa Bozinovic, Karen Najera Ruiz, Katherine O'Connell, Joseph Stagg, Goran Bozinovic

Center for Life in Extreme Environments Publications

Taxonomic identification of closely related plants can be challenging due to convergent evolution, hybridization, and overlapping geographic distribution. To derive taxonomic relationships among planted and wild plants across a large geographic range, we complemented three standard plastid barcodes , , and with soil and fruit chemistry, soil microbiome, and plant morphology analyses. Soil and plant sampling included planted from manicured sites in Southern California, USA, wild plants from Southern and Northern California, and wild populations from Mediterranean island of Hvar, Croatia. We hypothesized that phenotypic variation within and between sites correlates with plants' genotype and geographic distribution. Similar fruit chemistry …

Associations Of Muscular And Cardiovascular Fitness Variables With Cardiovascular Disease In Older Adult Athlete Populations, Lauren T. Zick

Honors Thesis

This data analysis examined associations between cardiovascular and muscular fitness indicators and the presence of cardiovascular disease (CVD) in older adult athletes. Using cross-sectional data from 1,110 participants aged 50 and older who completed the Sustained Athlete Fitness Exam (SAFE) at state-level Senior Games events, we evaluated both objective performance metrics and self-reported exercise behaviors. Cardiovascular measures included systolic blood pressure (SBP), waist circumference (WC), waist-to-hip ratio (WHR), and body mass index (BMI). Muscular fitness was assessed through grip strength, maximum walking speed, and chair stand time. CVD status was defined as the presence of two or more self-reported cardiovascular …

Depalmitoylation Regulates Metabolism And Mitochondrial Function, Sarah Lilly Speck

Arts & Sciences Graduate Student Theses and Dissertations

Tens of millions of Americans suffer from metabolic disorders, predisposing patients to cardiovascular disease, kidney disease, liver disease, infertility, and cancer. Unfortunately, the etiology of many of these diseases remains a mystery, limiting our ability to identify targets for pharmacologic therapies. Due to the relationship between altered lipid dynamics and metabolic dysfunction, we decided to study the effect of the posttranslational lipid modification, S-palmitoylation, on metabolism. S-palmitoylation is the only known reversible lipid modification for proteins, and this depalmitoylation process is catalyzed by acyl-protein thioesterases including APT1 and APT2. We hypothesized that APT deficiency in various tissues would predispose mammals …

Expanding The Druggable Proteome By Integrating Deep Learning With Molecular Simulations To Predict Cryptic Pockets, Artur Meller

Arts & Sciences Graduate Student Theses and Dissertations

Of the protein structures deposited in the Protein Data Bank, less than half have pockets suitable for the binding of drugs. Even when proteins contain pockets in their ground state structures (e.g., the nucleotide-binding active site in myosin motors), achieving specificity remains a central challenge in drug design as many protein families share common structural motifs. Cryptic pockets are cavities absent in ligand-free experimental structures that form due to protein fluctuations in solution. They provide a means to specifically target proteins currently considered undruggable. While cryptic pockets are alluring drug targets, it remains difficult to predict which proteins will form …

Pan-Cancer Universal Targets For Immunotherapy Resulted From Transposable Elements Activation, Yonghao Liang

Arts & Sciences Graduate Student Theses and Dissertations

Transposable elements (TEs) contribute to nearly half of the human genome yet have been overlooked in genomic medicines due to the stereotypic impression as “junk DNA” and technical challenges. However, studies in the last two decades demonstrated that dysregulation of the epigenome in cancer cells resurrects the cis-regulatory functions of TEs, including the promoter activities. The tumor-specific TE activation events along with the resulting tumor-specific RNA and protein molecules, provide a potential “gold mine” for identifying tumor-specific therapeutic targets for cancer treatments, including immunotherapy. Here, I present a series of works to investigate the potential of providing actionable, pan-cancer, and …

Mechanisms Of Mll-Rearranged Infant Leukemogenesis, Jonny Mendoza-Castrejon

Arts & Sciences Graduate Student Theses and Dissertations

Infant leukemias arise as either B cell acute lymphoblastic leukemia (B-ALL) or acute myeloid leukemia (AML) and are primarily driven by MLL/KMT2A-rearrangements (MLLr). Prior work has shown that MLLr transform fetal/neonatal hematopoietic progenitors more efficiently than adult progenitors. However, the genetics and epidemiology of MLLr leukemias present an important paradox. MLLr arise during late gestation under conditions that would seemingly favor leukemic transformation (i.e., fetal/neonatal progenitors have high proliferation rates and self-renewal). Furthermore, MLLr infant leukemias require very few cooperating mutations for transformation. Yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias …

Oxycodone Self-Administration Modulates Ventral Pallidal Neuron Activity And Plasticity, Jessica Tooley

Arts & Sciences Graduate Student Theses and Dissertations

Opioid use disorder is an urgent public health crisis in the United States. Over 800,000 Americans have died from opioid-related overdoses since 2000. Nearly 30% of people who misuse opioids begin with prescription oral opioids, such as oxycodone, and continue misusing to avoid the immediate aversive state of withdrawal and the persistent dysphoria associated with protracted abstinence from opioids. The persistency of these dysphoric symptoms increases the risk of relapse even after long periods of abstinence. Treatment for opioid use disorder currently consists of pharmacological opioid treatment to reduce withdrawal symptoms and behavioral counseling. However, these strategies have significant real-world …

Parental Guidance Suggested: Genetic, Epigenetic, And Environmental Factors Shape Allele-Specific Gene Regulation In Metabolic Traits, Celine Louise St. Pierre

Arts & Sciences Graduate Student Theses and Dissertations

Deciphering the “genotype to phenotype” map is a crucial goal of biology. We will not improve our ability to predict phenotypes from DNA sequences until we better incorporate epigenetic and environmental variation into our models of human health and disease. Genes are typically presumed to express both parental alleles equally, but genetic and epigenetic factors can cause one allele to function differently than the other (e.g. expressed or silenced more). These allele-specific imbalances can alter the final composition of a gene’s transcriptional product and ultimately shape phenotypes. Allele-specific effects have widespread impacts on complex traits, but how environmental signals contribute …

Induced Cd8a Identifies Enhanced Human Nk Cell Il-15-Induced Proliferation And Metabolism And Modulates Nk Cell Activation, Celia Cubitt

Arts & Sciences Graduate Student Theses and Dissertations

Natural Killer (NK) cells are cytotoxic innate lymphoid cells that play an important role in the surveillance and elimination of virally-infected and malignantly-transformed cells. These primary effector functions are achieved by producing cytokines and chemokines which activate and recruit additional immune effectors, as well as direct cytotoxic killing via perforin and granzymes. NK cell function is tightly regulated by a balance of germ-line encoded activating, inhibitory, co-stimulatory, and cytokine receptors expressed at the cell surface. Through these activating and inhibitory receptors, NK cells recognize and kill targets without prior sensitization through the loss of self-identifying molecules such as major histocompatibility …

A Subset Of Senescent Myofibroblasts Orchestrates Immunosuppression In Pancreatic Cancer., Jad Belle

Arts & Sciences Graduate Student Theses and Dissertations

Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal solid malignancy with a 12% 5-year survival rate. Most tumors are detected at metastatic stages that are extremely resistant to therapy. PDAC recalcitrance is driven by a unique tumor microenvironment (TME) comprising dense collagenous fibrosis embedded with an abundance of cancer associated fibroblasts (CAFs) and infiltrating leukocytes. Preclinical studies have indicated that PDAC CAFs can have both pro- and anti-tumorigenic effects. This is likely owed to CAF phenotypic heterogeneity which was recently uncovered by single cell transcriptomics. Three major CAF subpopulations have been identified in mouse and human PDAC thus far: myofibroblastic …

Circuit-Specific Vulnerability In A Mouse Model Of Alzheimer's Disease, Samuel Brunwasser

Arts & Sciences Graduate Student Theses and Dissertations

The relationship between brainwide functional decline and accumulation of pathological protein aggregates in Alzheimer’s disease (AD) is complex and not well understood. A set of highly interconnected cortical regions known as the Default Mode Network (DMN) exhibits selective vulnerability to both functional decline and amyloid beta (Aβ) plaques in early AD. One possibility is that early Aβ accumulation in the DMN drives vulnerability. However, it is unknown whether there is something intrinsic to neuronal projections within the DMN that biases these circuits towards dysfunction. In this dissertation, I describe the development of a multisite in vivo electrophysiology pipeline for chronic …

Parapinopsin: A Photoswitchable Inhibitory Gpcr For Two-Photon Optogenetics, Bobbie J. Brown

Arts & Sciences Graduate Student Theses and Dissertations

The development of optogenetic tools has greatly advanced the capability of researchers to understand the connection between neuronal activity and behavior. Optogenetics makes use of opsins, which are light activated ion-channels, ion pumps, or G-Protein coupled receptor (GPCR-based) proteins used to regulate cellular activity. Coupled with technological advances in genetics and optical physics/microscopy, optogenetics can be used to control specific populations of cells in a time-locked, spatially specific manner. The experiments possible with optogenetics depend largely on the capabilities and limitations of the opsin used; thus, there have been continuous efforts to design and employ new opsins with a variety …

Genomic Characterization Of Novel Bacteriophage: Bellis, Emmanauel Z. Gibbs

Honors Theses

Phages are the most abundant life-forms on the planet. Due to their unique ability to infect and lyse specific bacterial strains, phages have been proposed as a potential therapeutic agent to fight antibiotic resistance bacterial infections. Consequently, more research is required to further our understanding of phages. We were provided with an isolated, novel Mycobacterium bacteriophage: Bellis. Utilizing a bioinformatic approach, we successfully annotated Bellis’ genome using a variety of computer programs like GeneMark, Glimmer, HHpred, and PECAAN. We discovered that Bellis has 122 genes, including a RecB-like endonuclease and an AAA-ATPase, as well as 10 tRNAs. Through the genomic …

Genome Annotation Of Stargaze, Madison R. Murray

Honors Theses

Bacteriophages are viruses which solely infect bacteria. They are one of the most abundant and diverse biological entities, yet there is a limited amount of information on these viruses, including their gene functions. Several previously unknown phages have been discovered including Stargaze, whose bacterial host is Mycobacterium Smegmatis. Characterization of phage genes and their functions deepen our understanding of phages and potentially contribute to the broader biomedical effort associated with phages ability to combat bacterial infections. Stargaze is a G5 subcluster phage and it only has one other related phage in its cluster, that phage is from Madagascar. Using a …

Microplastics In Brachyurans: Comparing Contents Of The Atlantic Ghost Crab, Ocypode Quadrata, And Their Surrounding Sediments, Michael See

Honors Theses

The emergence of microplastics as a threat to physiological and environmental health has led to an increase in studies in recent years that aim to identify and quantify potential risks to marine ecosystems. Ocypode quadrata is a species that is a critical component of coastal ecology, leading this study to collect and analyze specimens regarding microplastics and their presence as a pollutant to the marine environment. Samples were collected from beaches along the Grand Strand of South Carolina. Microplastic density and diversity were recorded from investigating fecal pellets from the captive crab specimens to examine microplastic abundance. In addition to …

Monitoring Mangrove Dynamics And Evaluating Future Afforestation Potential In The Egyptian Red Sea, Rasha M. Abou Samra, Mansour Almazroui, Wenzhao Li, Hesham El-Askary

Mathematics, Physics, and Computer Science Faculty Articles and Research

Mangrove forests are vital for ecosystem services and coastal management but face stressors from anthropogenic activities and climate change. This study estimates the extent and afforestation potential of mangroves along the Egyptian Red Sea coast from 1984 to 2022 using NDVI derived from Landsat-5 and Sentinel-2 data in Google Earth Engine. Aboveground biomass (AGB), belowground biomass (BGB), carbon (C) stock, and CO₂ sequestration potential were evaluated using Sentinel-2 and elevation data. Future afforestation suitability (2020–2050) under SSP2-4.5 and SSP5-8.5 scenarios was assessed with the MaxEnt model. Mangrove area increased from 0.95 km² in 1984 to 1.46 km^{2 …}

A Search For Transcriptional Cofactors Of Gcm/Repo Involved In Determining Glia Cell Fate In Drosophila Melanogaster, Nivedha Kosalram

Honors Theses

In Drosophila melanogaster, the mechanism influencing the differentiation of glia and neurons is directed by a key transcription factor known as glial cells missing (gcm). gcm is a crucial regulator of cell fate decision, functioning as a binary switch to direct glial fate in gcm- positive cells and neuronal fate in gcm-negative cells (Jones, et.al, 1995; Hosoya, et.al, 1995; and Vincent, et.al, 1996). In addition to directing gliogenesis, gcm and its homolog gcm2 facilitate the determination of macrophages and tendon cells, highlighting that gcm acts with supplementary factors to induce various signaling pathways in different contexts (Jones, 2005; Johnson, et …

Metabolic Reprogramming Driven By Ant2 Deficiency Augments T Cell Function And Anti-Tumor Immunity In Mice, Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger

Faculty, Staff and Student Publications

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT …

Disrupting Nrf2-Driven Cancer Biology Through One-Carbon Metabolism Inhibition, Julius Chembo

Arts & Sciences Graduate Student Theses and Dissertations

Cancer remains a leading cause of mortality worldwide, with treatment resistance and recurrence posing major barriers to long-term survival. Despite advancements in targeted therapies, many cancers develop resistance to chemotherapy, radiation, and immunotherapy, significantly limiting their effectiveness. One key driver of therapeutic resistance is nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2), a transcription factor that regulates antioxidant responses and drug detoxification. While NRF2 protects normal cells from oxidative stress, its aberrant activation in cancer promotes tumor progression, metabolic reprogramming, and resistance to standard treatments. Alarmingly, NRF2 hyperactivation is implicated in some of the most aggressive and refractory malignancies, yet no …

Discovery Of Novel, Potent, And Orally Bioavailable Smarca2 Proteolysis-Targeting Chimeras With Synergistic Antitumor Activity In Combination With Kirsten Rat Sarcoma Viral Oncogene Homologue G12c Inhibitors, Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 …

Zanidatamab Monotherapy Or Combined With Chemotherapy In Her2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial, Funda Meric-Bernstam, Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L Hanna, Syma Iqbal, Keun-Wook Lee, Jeeyun Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A Goodwin, Jaffer A Ajani, Lin Yang, Rajen Oza, Elena Elimova

Faculty, Staff and Student Publications

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, …