WITHDRAWN: Oncogenic KRAS G12D extrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.

Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-to-mesenchymal transition (EMT), and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis lung carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, preexisting fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of EMT. IMPLICATIONS: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.

Clinical Features and Outcomes of Patients with Pancreaticobiliary Malignancies in Los Angeles County and Their Association with CA 19-9 Levels.

Although CA 19-9 is a commonly used tumor marker in the management of PBMs, the literature describing outcomes in patients with PBMs who have undetectable or low (hereinafter "low") CA 19-9 levels remains scarce. In this study, we sought to compare clinical features and outcomes in patients with PBMs and low CA 19-9 levels to those with normal and elevated CA 19-9 levels. METHODS: We retrospectively collected data on patients with biopsy-confirmed PBMs and stratified patients into categories based on their CA 19-9 level at diagnosis. Survival curves were estimated for patients in each of the three aforementioned CA 19-9 groups using the Kaplan-Meier method and compared using a Cox proportional hazards regression model. RESULTS: Of the 283 patients identified, 23 (8.1%) had low, 70 (24.7%) had normal, and 190 (67.1%) had elevated CA 19-9 levels. After controlling for sex, age, BMI, the presence of metastases at the time of diagnosis, and treatment with curative intent, the hazard ratio for death in the elevated CA 19-9 group compared to the low CA 19-9 group was 1.993 (95% CI 1.089-3.648; p = 0.025). CONCLUSION: The elevated CA 19-9 level compared to the low CA 19-9 level and the presence of metastases were associated with an increased hazard of death, while treatment with curative intent was associated with a decreased hazard of death.

Applying Lean Kaizen to Improve Timely Computed Tomography Scan Appointments for Oncology Patients in a Safety Net Hospital.

PURPOSE: Timely radiographic studies are essential to oncology care. At our institution, a safety net hospital in a large metropolitan area, baseline assessment determined that the overwhelming majority of outpatient computed tomographic (CT) scans for oncology patients were overdue and not scheduled within 2 weeks of their first requested date. METHODS: We conducted a series of structured, interdisciplinary meetings including staff from radiology, oncology, scheduling, and administration to critically review the scheduling process utilizing Lean Kaizen quality improvement methods. A new workflow was developed in which clinic staff scheduled CT scans before clinic discharge. Three months after our initial meeting, the new workflow was launched. We set a target of decreasing the percentage of overdue scans to below 20%. RESULTS: At baseline, 87% (65 of 75) of CT scans awaiting scheduling were overdue. Data were gathered at 5 and 10 weeks after implementation of our workflow. The percentage of CT scans overdue for scheduling was 17% (9 of 53) at 5 weeks and 0.97% (1 of 103) at 10 weeks after implementation. Clinic visit durations were not affected. CONCLUSION: The Lean Kaizen QI model was successful in decreasing the rate of oncology patients overdue for CT scan scheduling with minimal effects on clinic visit durations. This study demonstrated the importance of interdepartmental collaboration and continuous monitoring for improvement. Given the success of this project, this workflow will be expanded to other outpatient clinics within our institution.

Immune Thrombocytopenic Purpura (ITP) as an Uncommon Extraintestinal Complication of Crohn's Disease: Case Vignette and Systematic Literature Review.

While the association of immune thrombocytopenic purpura (ITP) and inflammatory bowel disease (IBD) has been described in a few case reports, management of ITP as an extraintestinal manifestation of Crohn's disease (CD) is less studied. There are approximately a dozen cases describing the management of patients dually diagnosed with CD/ITP. Previous reports postulated that the mechanism of ITP in CD was through the presence of circulating immune complexes in the serum and antigenic mimicry due to increased mucosal permeability in active colitis, versus increased mucosal production of TH1-type proinflammatory cytokines during CD flares, which may account for remission of ITP with surgery for CD. We present a case of a 27-year-old man who presented with medically refractory CD and ITP who responded to surgical management with colectomy and splenectomy, along with a systematic review of the literature. These cases suggest that colectomy should be considered in the treatment of medically refractory ITP among patients with concomitant CD.

p53 regulates hematopoietic stem cell quiescence.

The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild-type and p53 null mice identified Gfi-1 and Necdin as p53 target genes, and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell-cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells.

Use of PLGA 90:10 scaffolds enriched with in vitro-differentiated neural cells for repairing rat sciatic nerve defects.

Poly(lactic-co-glycolic acid) (PLGA) nerve tube guides, made of a novel proportion (90:10) of the two polymers, poly(L-lactide): poly(glycolide) and covered with a neural cell line differentiated in vitro, were tested in vivo for promoting nerve regeneration across a 10-mm gap of the rat sciatic nerve. Before in vivo testing, the PLGA 90:10 tubes were tested in vitro for water uptake and mass loss and compared with collagen sheets. The water uptake of the PLGA tubes was lower, and the mass loss was more rapid and higher than those of the collagen sheets when immersed in phosphate-buffered saline (PBS) solution. The pH values of immersing PBS did not change after soaking the collagen sheets and showed to be around 7.4. On the other hand, the pH values of PBS after soaking PLGA tubes decreased gradually during 10 days reaching values around 3.5. For the in vivo testing, 22 Sasco Sprague adult rats were divided into four groups--group 1: gap not reconstructed; group 2: gap reconstructed using an autologous nerve graft; group 3: gap reconstructed with PLGA 90:10 tube guides; group 4: gap reconstructed with PLGA 90:10 tube guides covered with neural cells differentiated in vitro. Motor and sensory functional recovery was evaluated throughout a healing period of 20 weeks using sciatic functional index, static sciatic index, extensor postural thrust, withdrawal reflex latency, and ankle kinematics. Stereological analysis was carried out on regenerated nerve fibers. Both motor and sensory functions improved significantly in the three experimental nerve repair groups, although the rate and extent of recovery was significantly higher in the group where the gap was reconstructed using the autologous graft. The presence of neural cells covering the inside of the PLGA tube guides did not make any difference in the functional recovery. By contrast, morphometric analysis showed that the introduction of N1E-115 cells inside PLGA 90:10 tube guides led to a significant lower number and size of regenerated nerve fibers, suggesting thus that this approach is not adequate for promoting peripheral nerve repair. Further studies are warranted to assess the role of other cellular systems as a foreseeable therapeutic strategy in peripheral nerve regeneration.

Neuron-specific Hu proteins sub-cellular localization in primary sensory neurons.

The Hu family of RNA-binding proteins is involved in many post-transcriptional mechanisms for the development and maintenance of the nervous system. Three members of the Hu family (HuB, HuC and HuD) are neuron-specific proteins. In this study, we present data using light and electron microscopy to show the sub-cellular localization of neuron-specific Hu proteins in rat primary sensory neurons taken from dorsal root ganglia (DRG). Using these techniques we morphologically revealed the presence of neuron-specific-Hu proteins in the nucleus and in the cytoplasm and discriminated the presence of Hu proteins within different cellular organelles, specifically mitochondria and Golgi apparatus, thus supporting previous ideas that NS-Hu proteins enable RNA interactions with sub-cellular organelles and may be involved in mRNA cellular localization.

Lesions to the nucleus basalis magnocellularis lower performance but do not block the retention of a previously acquired learning set.

Rats were first trained to acquire an olfactory discrimination learning set (ODLS) on 40 olfactory-unique discrimination problems. Following acquisition of ODLS, animals were lesioned bilaterally in the nucleus basalis magnocellularis (nBM) using either quisqualic acid (QUIS) or 192 IgG-saporin (SAP). QUIS animals performed significantly worse than control animals following surgery and SAP animals performed transiently worse than control animals. Despite lowered performances, both QUIS and SAP animals performed significantly better than expected by chance on trial 2 indicating retention of the ODLS previously acquired. Implications for the role of the nBM in aspects of cognitive flexibility and its role in acquisition versus retention are discussed.

The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development.

Prolactin and leukemia inhibitory factor (LIF) have different roles in the adult mammary gland, which are mediated in part by the signal transducers and activators of transcription (STAT)5 and STAT3. In vivo studies have shown that STAT5 contributes to prolactin-dependent lobuloalveolar development and lactation whereas STAT3 mediates LIF-dependent epithelial apoptosis during postlactational involution. To understand the molecular basis of these STAT-dependent pathways, we demonstrate the ligand-independent effects of STAT5 and STAT3 in mammary epithelial cells in vitro and also identify the genes regulated by these related transcription factors. Thus, using conditionally active STAT3- or STAT5a-GyraseB fusion proteins, we observed that enforced and specific dimerization of STAT3 induced apoptosis whereas STAT5 induced differentiation of mammary epithelial cells. Furthermore, STAT5 attenuated apoptosis mediated by LIF, the physiological inducer of STAT3. Microarray analysis of STAT3- and STAT5-induced genes using this system demonstrated a marked specificity, which reflected their different physiological effects in vitro and in vivo. STAT5-specific gene targets included the milk protein genes alpha-casein and kallikrein-8 and the survival factors prosaposin and Grb10. STAT3-specific genes included the apoptosis regulators CCAAT enhancer binding protein-delta, phosphatidylinositol 3-kinase-regulatory subunits, purine nucleoside phosphorylase, and c-fos. These data illustrate that specific activation of STAT3 and STAT5 alone is sufficient to induce and suppress apoptosis, respectively, and that these transcription factors elicit their actions by inducing distinct subsets of target genes in mammary epithelial cells.

Economic burden of head and neck cancer. A literature review.

This literature review presents the economics of head and neck cancer (HNC), the world's sixth most common neoplasm. HNC economics is complicated by the involvement of multiple body sites, multiple medical specialties, and multiple treatment modalities. Economic analyses of HNC published in English between 1990 and 2002 were identified from electronic data sources. Additional studies were identified manually from bibliographies of retrieved articles. Study characteristics and findings were analyzed. We identified 51 studies that reported original cost data. Most were cost-identification or cost-comparison studies; only one evaluated cost-effectiveness. Few assessed the overall economic burden of HNC or cost effectiveness of current treatments, thus making appropriate comparisons impossible. Systematic measurement of the cost of HNC and its treatment in existing practice settings would be valuable. Inclusion of economic components in clinical trials and the conduct of retrospective or prospective observational studies, such as patient registries, would yield important new information.

Epidemiology and clinical burden of acute myeloid leukemia.

Acute myeloid leukemia is the most common type of leukemia in adults, yet it continues to have the lowest survival rate of all leukemias. Prognosis for the elderly in particular continues to be dismal. This review examines the currently available literature on the epidemiology, etiology, diagnosis and management of acute myeloid leukemia. New therapies and therapeutic strategies must be found to improve survival, especially as the worldwide population ages. Gemtuzumab ozogamicin (Mylotarg) for the treatment of patients with CD33-positive acute myeloid leukemia, selective FLT3 inhibitors currently in advanced development (e.g., SU11248, PKC412, CT53518 and CEP-710) and other targeted compounds (e.g., farnesyl transferase inhibitors, BCL-2 inhibitors and interleukin-2) may present initial opportunities to achieve improved outcomes.