Calls to action on lung cancer management and research.

Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action.

International Association for the Study of Lung Cancer Study of the Impact of Coronavirus Disease 2019 on International Lung Cancer Clinical Trials.

Introduction: To evaluate the effects of the global coronavirus disease 2019 (COVID-19) pandemic on lung cancer trials, we surveyed investigators and collected aggregate enrollment data for lung cancer trials across the world before and during the pandemic.

Methods: A Data Collection Survey collected aggregate monthly enrollment numbers from 294 global lung cancer trials for 2019 to 2020. A 64-question Action Survey evaluated the impact of COVID-19 on clinical trials and identified mitigation strategies implemented.

From clinical specimens to human cancer preclinical models-a journey the NCI-cell line database-25 years later.

The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi-disciplinary team that collaborated to generated large, comprehensively annotated, cell-line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient-donated specimens that have been remarkably valuable for other types of cancer and disease research.

Long Noncoding RNA SBF2-AS1 Is Critical for Tumorigenesis of Early-Stage Lung Adenocarcinoma.

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA).

Doxorubicin induces specific immune functions and cytokine expression in peritoneal cells.

To examine the basis of the immune modulation induced by the anticancer agent doxorubicin (DOX), the immunophenotype, tumoricidal activity, cytokine protein and mRNA expression were determined using peritoneal exudate cells (PEC) from saline-treated (untreated) and DOX-treated mice. A greater percentage of PEC from DOX-treated mice than from untreated mice were adherent to plastic, had characteristics of granulocytes, and were positive for the NK1.1, CD11b/Mac-1, and CD3 markers.

Analysis of the effect of intestinal resection on rat ileal bile Acid transporter expression and on bile Acid and cholesterol homeostasis.

Ileal reclamation of bile salts is mediated in large part by an apical sodium-dependent bile acid transporter (ASBT) located in the terminal ileum. The following studies were performed to elucidate the adaptive response of ASBT to intestinal resection. Two separate series of intestinal resections were performed: 1) limited (25%) ileal and 2) massive (70%) intestinal resection.

Familial intrahepatic cholestasis 1: studies of localization and function.

Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy-dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain.

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.

Measurement of low-abundance cytokine mRNA in cells of murine lymphoid organs: a new quantitative reverse transcription/polymerase chain reaction method.

To investigate cytokine regulation in cells of freshly excised lymphoid tissues, rigorous quantitative reverse transcription/polymerase chain reaction (QRT-PCR) assays were developed to measure attomole (10(-18) mol) amounts of the mRNA for seven cytokines: interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), transforming growth factor beta (TGFbeta), IL-2 and IL-6. RNA was purified from single-cell suspensions of immune tissues (spleen, thymus and resident peritoneal cells). Data are presented demonstrating the utility of these assays for quantifying basal levels of all seven cytokine mRNAs in the freshly isolated splenocytes and thymocytes.

Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles.

Bile acid transport and secretion in hepatocytes require phosphatidylinositol (PI) 3-kinase-dependent recruitment of ATP-dependent transporters to the bile canalicular membrane and are accompanied by increased canalicular PI 3-kinase activity. We report here that the lipid products of PI 3-kinase also regulate ATP-dependent transport of taurocholate and dinitrophenyl-glutathione directly in canalicular membranes. ATP-dependent transport of taurocholate and dinitrophenyl-glutathione in isolated canalicular vesicles from rat liver was reduced 50-70% by PI 3-kinase inhibitors, wortmannin, and LY294002, at concentrations that are specific for Type I PI 3-kinase.

The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver.

Recent studies indicate that wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3-kinase, interferes with bile acid secretion in rat liver; taurocholate induces recruitment of ATP-dependent transporters to the bile canalicular membrane, and PI 3-kinase products are important in intracellular trafficking. We investigated the role of PI 3-kinase in bile acid secretion by studying the in vivo effect of taurocholate, colchicine, and wortmannin on bile acid secretion, kinase activity, and protein levels in canalicular membrane vesicle (CMV) and sinusoidal membrane vesicle (SMV) fractions from rat liver. Treatment of rats or perfusion of isolated liver with taurocholate significantly increased PI 3-kinase activity in both membrane fractions.

Thymic anti-tumor effectors in mice cured of lymphoma by cyclophosphamide plus TNF-alpha therapy: phenotypic and functional characterization up to 20 months after initial tumor inoculation.

As reported previously, cyclophosphamide plus tumor necrosis factor-alpha treatment of C57BL/6 mice bearing advanced EL4 lymphoma induced approx. 60% long-term (i.e.

Doxorubicin plus tumor necrosis factor alpha combination treatments in EL4-lymphoma-bearing C57BL/6 mice.

The therapeutic efficacy of a total of 42 single-agent or combination protocols involving doxorubicin (Adriamycin, ADM) and tumor necrosis factor alpha (TNFalpha) were evaluated in the syngeneic murine lymphoma model, C57BL/6-EL4. Combination treatments were the most effective and the therapeutic effects were schedule-dependent; e.g.

Expression of B cell markers on SR-4987 cells derived from murine bone marrow stroma.

The murine cell line SR-4987 was originated in our laboratory from adherent cells of a long term bone marrow culture. SR-4987 cells do not express p21-ras and c-fms products on membrane whereas secrete M-CSF, evidence a fibroblast-like morphology and are vimentine positive. This line shows a very poor "in vitro" agar clonogenicity which is not modulated by the addition of different cytokines and growth factors (M-CSF, GM-CSF, G-CSF, IL-3, IL-7, alpha-TNF, PDGF, and EGF).

Evidence for the involvement of ecto-5'-nucleotidase (CD73) in drug resistance.

Increased ecto-5'-nucleotidase (ecto-5'NT) protein expression in several multidrug-resistant (MDR) cell lines, documented previously by our group, suggests that this enzyme is involved in drug resistance. Here, Northern blot analysis of selected cell lines and their MDR variants positively correlated ecto-5'NT protein with its mRNA expression. An inhibitor of ecto-5'NT enzymatic activity, alpha,beta-methyleneadenosine 5'-diphosphate (AMP-CP), was used to determine if functionally active enzyme had a role in drug resistance.

Specific anti-EL4-lymphoma immunity in mice cured 2 years earlier with doxorubicin and interleukin-2.

This laboratory has reported the conditions for an effective, non-toxic, chemoimmunotherapy utilizing doxorubicin in combination with prolonged administration of interleukin-2 and the identification of the critical role of activated CD8+ T cells in the therapeutic effect. Mice (C57BL/6) cured in those studies have been followed for the remainder of their life spans. These mice, approximately 2 months of age when initially inoculated with syngeneic EL4 lymphoma, survived for more than 2 years, the normal life span of C57BL/6 mice.

Cyclophosphamide plus tumor necrosis factor-alpha chemoimmunotherapy cured mice: life-long immunity and rejection of re-implanted primary lymphoma.

Changes in functionally and phenotypically definable splenocyte subsets in aging mice which had been rendered tumor-free in early life by immunochemotherapy (cyclophosphamide plus tumor necrosis factor-alpha) were studied in the syngeneic EL4 lymphoma-C57BL/6 murine model. Treatment-induced long-term survivors (LTS) surviving rechallenge are termed "immune-LTS". On day 120 (day 0, initial tumor inoculation), splenocytes from day 60 rechallenged immune-LTS developed significantly greater specific anti-EL4 cytolytic activity in an ex vitro assay than those from non-rechallenged LTS.

Murine splenic macrophage tumoricidal activation by cytokines.

Interleukin-2 (IL-2), IL-1 beta, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha), each alone and in all possible combinations, were studied for their capacity to activate murine resident splenic macrophages to a tumoricidal state. Two approaches were used in these studies. The first approach was to add cytokine directly to the adherent macrophages that had been washed free of nonadherent spleen cells.

Protective specific immunity induced by cyclophosphamide plus tumor necrosis factor alpha combination treatment of EL4-lymphoma-bearing C57BL/6 mice.

A combination treatment protocol initiated 12 days after tumor injection, when the tumor was large, by administering cyclophosphamide (CY, 150 or 250 mg/kg) intraperitoneally followed by intravenous tumor necrosis factor alpha (TNF alpha, 1000 units injection) on days 13, 16, 18, 21, and 23, resulted in about 60% long-term survival (i.e., survival for at least 60 days) in the syngeneic C57BL/6 mouse/EL4 lymphoma model system.