Antineoplastic Drug Synergy of Artesunate with Navitoclax in Models of High-Grade Serous Ovarian Cancer.

Artesunate belongs to a class of medications derived from the sweet wormwood plant () known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis.

Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells.

Artesunate is a derivative of artemisinin, an active compound isolated from Artemisia annua which has been used in Traditional Chinese Medicine and to treat malaria worldwide. Artemisinin derivatives have exhibited anti-cancer activity against both solid tumors and leukemia. The direct target(s) of artesunate are controversial; although, heme-bound proteins in the mitochondria have been implicated.

Creation of EGD-Derived Gastric Cancer Organoids to Predict Treatment Responses.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities.

Human macrophage-engineered vesicles for utilization in ovarian cancer treatment.

Background: Ovarian cancer is a deadly female malignancy with a high rate of recurrent and chemotherapy-resistant disease. Tumor-associated macrophages (TAMs) are a significant component of the tumor microenvironment and include high levels of M2-protumor macrophages that promote chemoresistance and metastatic spread. M2 macrophages can be converted to M1 anti-tumor macrophages, representing a novel therapeutic approach.

Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers.

DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin.

KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer.

Artesunate is the most common treatment for malaria throughout the world. Artesunate has anticancer activity likely through the induction of reactive oxygen species, the same mechanism of action utilized in infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular response to oxidative stress, are mutated in approximately 30% of non-small-cell lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required for artesunate sensitivity in NSCLC.

Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment.

Background: Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment.

Methods: Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects.

Determination of the protein quality of almonds ( L.) as assessed by in vitro and in vivo methodologies.

Almonds (), such as all nuts, are positioned within the protein foods grouping within the current U.S. Dietary Guidelines.

Plays Oncogenic Roles and Is a Therapeutic Target for Wild-Type Melanomas.

Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in , and . encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway.

Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation.

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform.

Effective number of breeders, effective population size and their relationship with census size in an iteroparous species, Salvelinus fontinalis.

The relationship between the effective number of breeders (Nb) and the generational effective size (Ne) has rarely been examined empirically in species with overlapping generations and iteroparity. Based on a suite of 11 microsatellite markers, we examine the relationship between Nb, Ne and census population size (Nc) in 14 brook trout (Salvelinus fontinalis) populations inhabiting 12 small streams in Nova Scotia and sampled at least twice between 2009 and 2015. Unbiased estimates of Nb obtained with individuals of a single cohort, adjusted on the basis of age at first maturation (α) and adult lifespan (AL), were from 1.

Quality of life outcomes in proton and photon treated pediatric brain tumor survivors.

Background: Radiotherapy can impair Health Related Quality of Life (HRQoL) in survivors of childhood brain tumors, but proton radiotherapy (PRT) may mitigate this effect. This study compares HRQoL in PRT and photon (XRT) pediatric brain tumor survivors.

Methods: HRQoL data were prospectively collected on PRT-treated patients aged 2-18 treated at Massachusetts General Hospital (MGH).

PKCι maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis.

Unlabelled: Protein kinase Cι (PKCι) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCι. However, whether PKCι is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, it is demonstrated that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis.

Regulation of HGF expression by ΔEGFR-mediated c-Met activation in glioblastoma cells.

The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival.

Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer.

Prospective study of health-related quality of life for children with brain tumors treated with proton radiotherapy.

Purpose: We describe the health-related quality of life (HRQoL) of a cohort of children with brain tumors treated with proton radiotherapy.

Patients And Methods: We recruited 142 pediatric patients with brain tumors (age 2 to 18 years) and parents of such patients treated with proton radiation at Massachusetts General Hospital from 2004 to 2010. HRQoL was assessed using the PedsQL core, brain tumor, and cancer modules (range, 0 to 100).

Altered down regulation of the receptor tyrosine kinase met in pancreatic adenocarcinoma cells.

Increased signaling from Met, the receptor for Hepatocyte Growth Factor, promotes pancreatic tumorigenesis and poor patient prognosis by enhancing tumor cell growth, survival and motility. Increased Met levels can result from gene amplification or increased transcription. However, receptor down regulation--a process that normally functions to attenuate Met signaling in vivo--could if impaired, amplify Met signaling in pancreatic tumor cells.

Analysis of receptor tyrosine kinase internalization using flow cytometry.

The internalization of activated receptor tyrosine kinases (RTKs) by endocytosis and their subsequent down regulation in lysosomes plays a critical role in regulating the duration and intensity of downstream signaling events. Uncoupling of the RTK cMet from ligand-induced degradation was recently shown to correlate with sustained receptor signaling and increased cell tumorigenicity, suggesting that the corruption of these endocytic mechanisms could contribute to increased cMet signaling in metastatic cancers. To understand how cMet signaling for normal cell growth is controlled by endocytosis and how these mechanisms are dysregulated in metastatic cancers, we developed flow cytometry-based assays to examine cMet internalization.

The well-being of parental caregivers of children with activity limitations.

This paper describes well-being (health status/quality of life, healthcare utilization, employment, and financial status) of parental caregivers of children with activity limitations and compares their well-being to parental caregivers with children without activity limitations. Using Medical Expenditure Panel Survey data from 1996 to 2001, we examined the well-being of parents of children with and without an activity limitation. Children were considered as having an activity limitation if they reported a limitation in school, play or social activities.

Met receptor tyrosine kinase degradation is altered in response to the leucine-rich repeat of the Listeria invasion protein internalin B.

Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry.

Medicaid managed care and the unmet need for mental health care among children with special health care needs.

Objective: To determine the association between Medicaid managed care pediatric behavioral health programs and unmet need for mental health care among children with special health care needs (CSHCN).

Data Source: The National Survey of CSHCN (2000-2002), using subsets of 4,400 CSHCN with Medicaid and 1,856 CSHCN with Medicaid and emotional problems. Additional state-level sources were used.

State policy environment and delayed or forgone care among children with special health care needs.

Objective: To evaluate if children with special health care needs (CSHCN) residing in states with more generous public insurance programs were less likely to report delayed or forgone care.

Methods: We used multilevel modeling to evaluate state policy characteristics after controlling for individual characteristics. We used the 2001 National Survey of CSHCN for individual-level data (N=33,317) merged with state-level data, which included measures of the state's public insurance programs (Medicaid eligibility and enrollment, spending on Medicaid, SCHIP and Title V, and income eligibility levels), state poverty level and provider supply (including pediatric primary care and specialty providers).

Correlates of therapy use and expenditures in children in the United States.

Introduction: This paper describes correlates of use and expenditures for therapies (physical, occupational, speech or home health services) among children in the US.

Methods: It is data from the Medical Expenditure Panel Survey, a nationally-representative US sample. The Characteristics of users and describe patterns of expenditures were examined.