Corrigendum: Targeting thymidylate synthase enhances the chemosensitivity of triple-negative breast cancer towards 5-FU-based combinatorial therapy.

[This corrects the article DOI: 10.3389/fonc.2021.

TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background.

We previously showed that elevated TYMS exhibits oncogenic properties and promotes tumorigenesis after a long latency, suggesting cooperation with sequential somatic mutations. Here we report the cooperation of ectopic expression of human TYMS with loss of Ink4a/Arf, one of the most commonly mutated somatic events in human cancer. Using an hTS/Ink4a/Arf genetically engineered mouse model we showed that deregulated TYMS expression in Ink4a/Arf null background accelerates tumorigenesis and metastasis.

First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival.

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase.

Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival.

Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1-/-).

Targeting Thymidylate Synthase Enhances the Chemosensitivity of Triple-Negative Breast Cancer Towards 5-FU-Based Combinatorial Therapy.

Background: The ongoing treatment modalities for breast cancer (BC) primarily rely on the expression status of ER, PR and HER-2 receptors in BC tissues. Our strategy of chemosensitization provides new insights to counter chemoresistance, a major obstacle that limits the benefits of chemotherapy of mammary cancers.

Methods: By utilizing a murine breast cancer model employing NSG mice bearing orthotopic triple-negative breast cancer (TNBC) xenografts, we have evaluated the ability of phytochemical curcumin in chemosensitizing BC to 5-Fluorouracil (5-FU) chemotherapy and the differential modulations of cellular events in response to this strategy, independent of their receptor status.

Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells.

TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells (MSCs) are unknown.

Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.

Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration.

NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations.

The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects.

Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors.

Background: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.

Green tea polyphenols induce p53-dependent and p53-independent apoptosis in prostate cancer cells through two distinct mechanisms.

Inactivation of the tumor suppressor gene p53 is commonly observed in human prostate cancer and is associated with therapeutic resistance. We have previously demonstrated that green tea polyphenols (GTP) induce apoptosis in prostate cancer cells irrespective of p53 status. However, the molecular mechanisms underlying these observations remain elusive.

Intratunnel versus extratunnel fixation of hamstring autograft for anterior cruciate ligament reconstruction.

Purpose: To determine which is more effective: intratunnel or extratunnel anterior cruciate ligament soft-tissue graft fixation. A secondary purpose was to determine whether groups displayed differing relations between objective International Knee Documentation Committee (IKDC) grade and the timing of full weight bearing (FWB), jogging/running, and return to sports. The study hypotheses were that intratunnel fixation would display a greater percentage of normal or nearly normal objective IKDC grades and enable earlier FWB, return to jogging/running, and return to sports.

DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer.

Zebularine is a novel potent inhibitor of both cytidine deaminase and DNA methylation. We examined the effect of zebularine on mammary tumor growth in genetically engineered MMTV-PyMT transgenic mice that develop mammary tumors at 60 days of age with 100% penetrance. The MMTV-PyMT transgenic mice were randomized at 46 days of age into control (n = 25) and zebularine (n = 25) treatment groups and monitored for parameters of tumor growth.

Selective cell cycle arrest and induction of apoptosis in human prostate cancer cells by a polyphenol-rich extract of Solanum nigrum.

Progression of prostate cancer is associated with escape of tumor cells from cell cycle arrest and apoptosis. Agents capable of selectively eliminating cancer cells by cell cycle arrest and/or induction of apoptosis offer a highly desirable approach. Here we demonstrate that a polyphenolic extract derived from ripe berries of Solanum nigrum (SN) differentially causes cell cycle arrest and apoptosis in various human prostate cancer cells without affecting normal prostate epithelial cells.

Supplemental bio-tenodesis improves tibialis anterior allograft yield load in extremely low density tibiae.

Introduction: Improved soft tissue tendon graft mechanical properties have led to their increased use for anterior cruciate ligament (ACL) reconstruction. Because they do not have an osseous component; however, there are greater concerns regarding tibial graft slippage during early postoperative rehabilitation and activities of daily living, particularly in patients with poor bone mineral density (BMD), such as older patients, women, smokers, and patients undergoing revision ACL reconstruction surgery.

Methods: This in vitro biomechanical study attempted to determine the effectiveness of supplemental ACL graft fixation in low BMD tibiae.

Biomechanical comparison of screw-in suture anchor-suture combinations used for Bankart repair.

Introduction: Bankart repair laxity may contribute to pathologic joint instability. This biomechanical study compared two screw-in suture anchor-suture combinations under tensile loads.

Methods: Twelve pairs of scapulae were implanted with either a 3 mm diameter, 14 mm long poly-L/D-lactide suture anchor with a suture eyelet (Group 1) or a 3.

Influence of age on aluminum induced lipid peroxidation and neurolipofuscin in frontal cortex of rat brain: a behavioral, biochemical and ultrastructural study.

Aluminum exposure is known to be associated with oxidative stress and cognitive decline in experimental animals but the precise mechanism of its neurotoxicity has not yet been delineated. The present study attempts to assess the learning and memory capacity of rats using Y-maze test for cognitive functioning. The markers of oxidative stress, e.

Cyclic loading comparison of Bio-SutureTak-#2 FiberWire and Bio Mini-Revo-#2 Hi-Fi suture anchor-sutures in cadaveric scapulae.

This study compared tap-in Bio-SutureTak suture anchor-#2 FiberWire suture (Group 1) and screw-in Bio Mini-Revo suture anchor-#2 Hi-Fi suture (Group 2) fixation in the glenoid region of interest for Bankart repair, in addition to evaluation of isolated suture loop biomechanical properties under progressive incremental cyclic loads. With knowledge of glenoid apparent bone mineral density (BMD), implant preparation and fit characteristics, and following application of a light manual tensile load, the primary investigator scored each specimen for perceived within group biomechanical test performance using a 0-10 point modified visual analog scale. After scoring, 12 paired constructs were placed in a servo hydraulic device clamp, preloaded to 25 N, and cycled between 25 and 50 Hz with a 25 N load increase every 25 cycles.

Anatomic double bundle ACL reconstruction: a literature review.

With the abundance of anatomic double bundle ACL reconstruction techniques that currently exist and limited patient outcome data, one has to ask whether or not they should be used and if so, which one, and what is the learning curve for the average knee surgeon to become competent with the technique that they select? The purpose of this literature review is to summarize existing anatomic double bundle ACL reconstruction surgical and rehabilitation techniques and the clinical and biomechanical study evidence that currently exists. In choosing to perform anatomic double bundle ACL reconstruction we suggest that the knee surgeon should look for evidence of: (1) control of the pivot shift phenomenon, (2) improved transverse plane rotatory knee control during the performance of sports type movements, (3) a decreased likelihood of revision procedures either for ACL reconstruction or for treatment of associated primary or recurrent meniscal injuries, (4) improved patient self-reports of perceived function, satisfaction, and quality of life, and (5) radiographic evidence of a lower incidence and/or magnitude of osteoarthritic changes compared to conventional single bundle ACL reconstruction.

Bioabsorbable screw divergence angle, not tunnel preparation method influences soft tissue tendon graft-bone tunnel fixation in healthy bone.

Bone tunnel fixation of a soft tissue tendon graft is the weak link immediately following ACL reconstruction. This biomechanical study evaluated the influence of extraction drilled or step dilated bone tunnels and bioabsorbable screw divergence on soft tissue tendon graft fixation. From an initial group of 50 available specimens, similar apparent bone mineral density porcine tibiae (1.

A biomechanical comparison of the FasT-Fix meniscal repair suture system and the RapidLoc device in cadaver meniscus.

Purpose: This biomechanical study compared the fixation characteristics of horizontally or vertically implanted FasT-Fix devices (Smith & Nephew, Endoscopy Division, Andover, MA) consisting of two 5-mm PLLA suture T-bar anchors with a pretied self-sliding knot (No. 0 nonabsorbable, USP, braided polyester suture material) and the RapidLoc device (Mitek Surgical Products, Westwood, MA) consisting of a PLLA T-bar anchor or "backstop," a connecting suture (No. 2 nonbiodegradable Ethibond; Ethicon, Somerville, NJ), and a PLLA grommet, for repairing posterior third lesions in human menisci.

Reconstruction of neglected Achilles' tendon defect with peroneus brevis tendon allograft: a case report.

This case report describes the use of a peroneus brevis allograft to reconstruct a neglected Achilles' tendon injury in a 75-year-old woman. She had difficulty walking, had stiffness, and was unable to perform a heel raise from a single-leg standing position. Magnetic resonance imaging confirmed a 6.

Comparison of volumetric bone mineral density in the tibial region of interest for ACL reconstruction.

Adequate tibial bone mineral density (BMD) is essential to soft tissue graft fixation during anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare volumetric bone plug density measurements at the tibial region of interest for ACL reconstruction using a standardized immersion technique and Archimedes' principle. Cancellous bone cores were harvested from the proximal, middle, and distal metaphyseal regions of the lateral tibia and from the standard tibial tunnel location used for ACL reconstruction of 18 cadaveric specimens.

Biomechanical comparison of the bioabsorbable RetroScrew system, BioScrew XtraLok with stress equalization tensioner, and 35-mm Delta Screws for tibialis anterior graft-tibial tunnel fixation in porcine tibiae.

Background: Achieving effective soft tissue graft-tibial tunnel fixation remains problematic.

Hypothesis: No differences would exist for tibialis anterior graft-tibial tunnel fixation when comparing the RetroScrew System (20-mm retrograde screw, 17-mm antegrade screw), the 35-mm tapered Delta Screw (manual tensioning), and the 35-mm BioScrew XtraLok (applied using an instrumented tensioner).

Study Design: Controlled laboratory study.