Mature MUC5AC Expression in Resected Pancreatic Ductal Adenocarcinoma Predicts Treatment Response and Outcomes.

Neoadjuvant therapy (NAT) for early-stage pancreatic ductal adenocarcinoma (PDA) has recently gained prominence. We investigated the clinical significance of mucin 5 AC (MUC5AC), which exists in two major glycoforms, a less-glycosylated immature isoform (IM) and a heavily glycosylated mature isoform (MM), as a biomarker in resected PDA. Immunohistochemistry was performed on 100 resected PDAs to evaluate the expression of the IM and MM of MUC5AC using their respective monoclonal antibodies, CLH2 (NBP2-44455) and 45M1 (ab3649).

Solid tumor growth depends on an intricate equilibrium of malignant cell states.

Control of cell identity and number is central to tissue function, yet principles governing organization of malignant cells in tumor tissues remain poorly understood. Using mathematical modeling and candidate-based analysis, we discover primary and metastatic pancreatic ductal adenocarcinoma (PDAC) organize in a stereotypic pattern whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Leveraging lineage-tracing, we reveal the WNT-R state is transient and gives rise to the WNT-S state that is highly stable and committed to organizing malignant tissue.

Disparities in outcomes and access to therapy options in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) disproportionately impacts racial and ethnic minorities and patients with lower socioeconomic status. These social determinants of health (SDH) lead to disparities in access to care and outcomes. We aim to understand the relationship between SDH and survival and locoregional treatment options in HCC.

Treatment Patterns and Outcomes for Patients with Ampullary Carcinoma Who Do Not Undergo Surgery.

Surgical resection is the standard of care for ampullary adenocarcinoma (AC). Many patients are ineligible due to comorbidities/advanced disease. Evidence for the optimal non-operative management of localized AC is lacking.

Systematic Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State.

Unlabelled: Intratumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including pancreatic ductal adenocarcinoma (PDAC). As PDAC portends a dire prognosis, a better understanding of the mechanisms underpinning cellular diversity in PDAC is crucial. Here, we investigated the cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics.

TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma.

Background: p53 plays a key role in the DNA repair process and response to ionising radiation. We sought to determine the clinical phenotype of TP53 mutations and p53 pathway alterations in patients with rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) treated with radiation.

Methods: Of patients with available genomic sequencing, we identified 109 patients with RMS and ES treated to a total of 286 radiation sites.

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice.

Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure.

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice.

Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma.

Purpose: Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS).

Experimental Design: Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive.

High-dose radiation therapy is needed for intracranial control and long-term survival in patients with non-seminomatous germ cell tumor brain metastases.

Purpose: The presence of brain metastases (BM) in patients with non-seminomatous germ cell tumor (NSGCT) is associated with poor prognosis. While radiation therapy (RT) is an important treatment for patients with NSGCT BM, there is a paucity of data on the optimal regimen. We sought to investigate the impact of RT on clinical outcomes in patients with NSGCT BM.

Endoluminal high-dose-rate brachytherapy for locally recurrent or persistent esophageal cancer.

Purpose: Management of locally recurrent or persistent esophageal cancer (EC) after standard chemoradiation is challenging. This study updates our experience of treating medically inoperable EC patients with endoluminal high-dose-rate brachytherapy (EHDRBT) including the patients treated with a novel multiballoon channel centering esophageal applicator.

Methods And Materials: Thirty-three consecutive patients with early-stage primary (n = 7), posttreatment persistent (n = 7), and recurrent (n = 19) EC treated with EHDRBT at our institution were included.

High Precision Imaging of Microscopic Spread of Glioblastoma with a Targeted Ultrasensitive SERRS Molecular Imaging Probe.

The dismal prognosis of patients with malignant brain tumors such as glioblastoma multiforme (GBM) is attributed mostly to their diffuse growth pattern and early microscopic tumor spread to distant regions of the brain. Because the microscopic tumor foci cannot be visualized with current imaging modalities, it remains impossible to direct treatments optimally. Here we explored the ability of integrin-targeted surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles to depict the true tumor extent in a GBM mouse model that closely mimics the pathology in humans.

Corticosteroids compromise survival in glioblastoma.

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects.

Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo.

Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain.

Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging.

The inability to visualize the true extent of cancers represents a significant challenge in many areas of oncology. The margins of most cancer types are not well demarcated because the cancer diffusely infiltrates the surrounding tissues. Furthermore, cancers may be multifocal and characterized by the presence of microscopic satellite lesions.

The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.

In response to neurodegeneration, the adult mammalian brain activates a cellular cascade that results in reactive astrogliosis and microgliosis. The mechanism through which astrocytes become reactive and the physiological consequences of their activation in response to neurodegeneration is complex. While the activation and proliferation of astrocytes has been shown to occur during massive neuronal cell death, the functional relationship between these two events has not been clearly elucidated.

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis.

PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear.

Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth.

Stem-like glioma cells reside within a perivascular niche and display hallmark radiation resistance. An understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. Here, we show that the stem cell marker CD44 promotes cancer stem cell phenotypes and radiation resistance.

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers.

Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades.

Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma.

Background: Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition.

BAX activation is initiated at a novel interaction site.

BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown.

Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains.

The BCL-2 family of apoptotic proteins regulates the critical balance between cellular life and death and, thus, has become the focus of intensive basic science inquiry and a fundamental target for therapeutic development in oncology and other diseases. Classified based on the presence of conserved alpha-helical motifs and pro- and anti-apoptotic functionalities, BCL-2 proteins participate in a complex interaction network that determines cellular fate. The identification of BCL-2 homology domain 3 (BH3) as a critical death helix that engages and regulates BCL-2 family proteins has inspired the development of molecular tools to decode and drug the interaction network.