Nodal disease burden and oncologic outcomes of 312 real-world patients with HR+HER2-breast cancer meeting SOUND eligibility criteria were similar to the SLNB arm of the SOUND trial, supporting careful implementation of omission of SLNB in this population ( https://doi.org/ https://doi.org/10.
View Article and Find Full Text PDFOver the past 2 decades, axillary surgical management for breast cancer patients has been reshaped after several practice-changing randomized clinical trials provided evidence to support the de-escalation of axillary surgery, specifically the omission of axillary lymph node dissection, for patients with positive axillary lymph nodes. One such practice-changing trial was the American College of Surgeons Oncology Group Z0011 trial, which showed that patients with clinical T1-2 breast tumors and limited nodal disease (1-2 positive sentinel lymph nodes) who underwent upfront breast-conserving therapy could be safely spared the morbidity of axillary lymph node dissection. American College of Surgeons Oncology Group Z0011 has been criticized as several important groups were excluded, such as patients who underwent a mastectomy, patients with >2 positive sentinel lymph nodes, or patients with imaging-detected lymph node metastases.
View Article and Find Full Text PDFBackground: Results of an earlier retrospective study from our institution suggested that patients with triple negative breast cancer (TNBC) who had preoperative MRI may have had an improved local recurrence rate (LRR) after breast conserving surgery (BCS). We aimed to clarify the impact of preoperative MRI on surgical outcomes in an expanded TNBC cohort treated by BCS in a contemporary era.
Methods: Our study cohort comprised 648 patients with TNBC who underwent BCS between 2009 and 2018.
Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways.
View Article and Find Full Text PDFPurpose: Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof of concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML, but have met with limited success.
View Article and Find Full Text PDFKnockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty.
View Article and Find Full Text PDFTumor-stroma interactions play a critical role in the development of lung squamous carcinoma (LUSC). However, understanding how these dynamic interactions contribute to tissue architectural changes observed during tumorigenesis remains challenging due to the lack of appropriate models. In this protocol, we describe the generation of a 3D coculture model using a LUSC primary cell culture known as TUM622.
View Article and Find Full Text PDFIodine deficiency in pregnancy is a common problem in the United States and parts of Europe, but whether iodine deficiency is associated with increased pregnancy loss has not been well studied. The LIFE study provided an excellent opportunity to examine the relationship between iodine status and pregnancy loss because women were monitored prospectively to ensure excellent ascertainment of conceptions. The LIFE study, a population-based prospective cohort study, monitored 501 women who had discontinued contraception within two months to become pregnant; 329 became pregnant, had urinary iodine concentrations measured on samples collected at enrollment, and were followed up to determine pregnancy outcomes.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2018
Tumorigenesis depends on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. While oncogenic drivers in lung squamous carcinoma (LUSC) have been described, the role of stroma in modulating tissue architecture, particularly cell polarity, remains unclear. Here, we report the establishment of a 3D coculture system of LUSC epithelial cells with cancer-associated fibroblasts (CAFs) and extracellular matrix that together capture key components of the tumor microenvironment (TME).
View Article and Find Full Text PDFBackground: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.
Methods: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.
Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases.
View Article and Find Full Text PDFBackground: Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.
Objective: We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.
Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA.
View Article and Find Full Text PDFPrune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare congenital disorder characterized by absence or hypoplasia of the abdominal wall musculature, urinary tract anomalies, and cryptorchidism in males. The etiology of PBS is largely unresolved, but genetic factors are implicated given its recurrence in families. We examined cases of PBS to identify novel pathogenic copy number variants (CNVs).
View Article and Find Full Text PDFPharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools.
View Article and Find Full Text PDFBackground: The Elipse Balloon is a swallowable gastric balloon for weight loss that can be deployed without the use of endoscopy or anesthesia. This study aims to report on 12-month safety and efficacy outcomes.
Setting: Private hospital, Athens, Greece.
Conventional gastric balloons for weight loss require endoscopy for placement and removal. The Elipse device is swallowed, resides in the stomach for 4 months, and is then expelled. The objectives of this study were to assess the safety of Elipse and to measure its effects on weight loss, metabolic parameters, and quality of life.
View Article and Find Full Text PDFBackground: Results from validated national databases suggest that a 1-day length of stay (LOS) is not only unattainable in more than 20% of primary laparoscopic Roux-en-Y gastric bypass (LRYGB) operations, but it is also associated with an increased 30-day mortality risk. There are no published data regarding the feasibility and safety of 1-day LOS after revisional LRYGB.
Study Design: We reviewed 1 surgeon's experience after implementation of a 1-day fast-track protocol (FTP) in 784 primary and 36 revisional consecutive LRYGB patients.
Unlabelled: Somatic mutations in the EGFR kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here, we demonstrate that MIG6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models.
View Article and Find Full Text PDFIn addition to genetic alterations, cancer cells are characterized by myriad epigenetic changes. EZH2 is a histone methyltransferase that is over-expressed and mutated in cancer. The EZH2 gain-of-function (GOF) mutations first identified in lymphomas have recently been reported in melanoma (~2%) but remain uncharacterized.
View Article and Find Full Text PDFAntibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker.
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