There is a need for a real-time, non-invasive method to monitor blood pH in a patient line during cardiopulmonary bypass, as today’s methods are both invasive and time consuming. Blood pH is an indicator of physiological and biochemical activity in the body and needs to be kept within a relatively narrow range, typically between 7.35-7.45. A pH value outside this range can be critical for the patient and therefore needs to be carefully monitored throughout the course of cardiopulmonary bypass. In this study the feasibility of using spectroscopic methods for indirect measurement of pH was investigated, and both transmission and reflectance spectroscopy were tested. The results showed that NIR reflectance spectroscopy is a feasible technique for blood pH monitoring during cardiopulmonary bypass. A strong correlation was found between measured pH values and spectral output in the wavelength range 800-930 nm. It was suggested that by means of the statistical partial least square regression method, a model could be created with three regression factors with a cross-validated R2 of 0.906 and a prediction error RMSEP of 0.089 pH units. The results presented here form a foundation for further analysis and experiments with larger sample set and more controlled experimental environment.

Eosinophilia is not an uncommon finding on a routine complete blood count (CBC) during a primary care visit. The differential diagnosis is varied including allergic/atopic disease, drug reaction, infection, inflammatory conditions, and malignancy. An 80-year-old male was incidentally found to have leukocytosis on routine labs. White blood cell (WBC) was 27.5 K/ul with eosinophilia 4.3 K/ul (normal range 0-0.6 Kul) and Hemoglobin/Platelet counts were normal. Patient was asymptomatic. Denied history of medication change or allergy. Chest X-Ray (CXR) followed by Computed tomography (CT) showed 5 cm pulmonary mass with mediastinal lymphadenopathy. Patient developed progressively enlarging left neck mass, hoarseness, weight loss and decreased appetite in the next 3 weeks. WBC increased steeply to 65 K/ul with eosinophil count - 18.5 K/ul. CT neck revealed a large heterogeneous mass of the thyroid extending to the trachea, esophagus, and mediastinum. Patient decided not to proceed with further diagnostic workup and management given his age and comorbidities. Eosinophilia can be asymptomatic or present with nonspecific symptoms like cough, fatigue, skin rash or neuropathy. Eosinophilia work up starts with a comprehensive history detailing travel history, exposure to well water/spring water, analysis of past medical history to include asthma, atopy and especially medication history. Physical exam with attention to atopy/eczema and skin rash is vital. Work up may include a CBC, peripheral blood smear, stool test (for ova and parasite), IgE/tryptase levels and evaluation for occult malignancy (CXR is an ideal first step). Further testing with Bone marrow biopsy and CT scans is a consideration if a clear diagnosis is not achieved. Life-threatening complications of untreated hyper-eosinophilia include thromboembolism, endomyocardial fibrosis, cognitive disturbances, and respiratory failure. Incidence of eosinophilia is 1% in malignant tumors. Malignancy encompasses hematological cancers (acute leukemia, chronic myeloid leukemia, systemic mastocytosis, lymphoid neoplasms) and solid tumors (lung, thyroid, breast and gastrointestinal tract cancers). Eosinophilia suggests advanced disease in solid tumors and portends poor prognosis. Paraneoplastic eosinophilia has been reported in thyroid cancer (sclerosing muco-epidermoid) and lung cancer (squamous and adenocarcinoma). Pathophysiology of eosinophilia in solid tumors is related to bone marrow stimulation through cytokines (interleukin-5, granulocyte-macrophage colony-stimulating factor, and interleukin-2). Primary eosinophilia responds to steroids and hydroxyurea. Treating the underlying malignancy is the cornerstone of paraneoplastic eosinophilia management. We present a case of extreme progressive eosinophilia secondary to a malignancy which would be of interest to the primary care clinician.

Acute lower respiratory tract infections are a leading cause of morbidity and mortality world-wide. Streptococcus pneumoniae (pneumococcus) is the most common bacterial cause of community-acquired pneumonia. Recovery from pneumococcal pneumonia results in the formation of resident memory CD4+ T cells, which act on lung epithelial cells to accelerate immune responses. Alveolar macrophages (AMs) are tissue-resident macrophages localized in the air spaces, where they orchestrate the lung anti-microbial responses. We hypothesized that recovery from pneumococcal pneumonia results in remodeling of the pool of alveolar macrophages, which act in concordance with other immune cells to protect the lungs from future infections. Although AM numbers were unchanged in experienced lungs, their surface phenotype showed significant changes, most prominently an increased MHC-II and a decreased SiglecF. This experienced AM phenotype was regionally-localized and long-lasting. Experienced AMs also exhibited extensive remodeling on the metabolomics and transcriptional level. Experienced AMs demonstrated significant increases in phosphocreatine and its metabolite precursors. The transcriptional analyses also revealed extensive changes. At baseline, experienced AMs exhibited a significant reduction in cell cycle activity and mRNA processing compared to naïve mice. During acute pneumonia, experienced AMs exhibited significant increases in immune signaling and energy metabolism. Moreover, transcriptional data also revealed strong but imperfect enrichment of a signature previously associated with IFN𝛾 signaling and marrow-derived AMs. IFN𝛾 gain and loss of functions experiments corroborated transcriptional data and revealed an essential role for IFN𝛾 in directly driving the AM MHC-II remodeling. Several immune cells produced IFN𝛾, with neutrophils being the most prominent source after the 1st pneumococcal challenge but other cells predominating after the 2nd pneumococcal challenge. CD4+ T cell depletion studies demonstrated that AMs' experienced phenotype was independent of CD4+ T cells. In contrast to naïve mice, lineage-tracing studies demonstrated that marrow-derived AMs predominately constitute the experienced AM pool. Upon experience, both embryonic AMs and marrow-derived AMs demonstrated similar remodeling for both SiglecF and MHC-II on their surfaces. While all AM similarly remodeled independent of their origin, marrow-derived AMs in experienced lungs displayed some differences from their embryonic counterparts, being less phagocytic. In conclusion, recovery from pneumococcal pneumonia remodels the pool of alveolar macrophages to acquire adaptive characteristics. This remodeling involves a combination of recruitment of new cells and trained immunity via IFN𝛾 signaling.

Die vorliegende Arbeit beschäftigte sich mit der Frage, inwieweit zytologische Untersuchungsmaterialien von Patienten mit nichtkleinzelligen Lungenkarzinomen geeignet sind, zur molekularbiologischen Analyse möglicher Mutationen des k-ras-Genes verwendet zu werden. Dafür wurden vier spezifische Polymerasekettenreaktionen mit anschließenden Restriktionsfragmentlängenpolymorphismus-Analysen kreiert und optimiert. In der Folge wurden die k-ras-Mutationen in den verschiedenen Codons nach einer Agarose-Gelelektrophorese unter der UV-Kamera detektiert. Es wurden vergleichende Untersuchungen mit Materialien tumorfreien Gewebes durchgeführt. Ebenso wurden, um die Eignung des zytologischen Materiales zur k-ras-Mutationsdiagnostik nachzuweisen, Mutationsanalysen in histologischem Material durchgeführt und dieses mit den zytologischen Proben derselben Patienten verglichen. Weiterhin wurden bestimmte Korrelationen des k-ras-Mutationsstatus der Patienten mit individuellen und klinischen Parametern analysiert und mit aus der Literatur bekannten Aussagen verglichen. Es ist bekannt, dass k-ras-Mutationen im Tumor bei Patienten mit fortgeschrittenen nichtkleinzelligen Lungenkarzinomen negative Prädiktoren für einen möglichen Erfolg einer Rezeptortyrosinkinaseinhibitor-Therapie darstellen und die Prognose der Erkrankung verschlechtern. Neuartige Therapiekonzepte scheinen aber auch eine Möglichkeit zu bieten, Patienten mit nachgewiesener k-ras-Mutation eine Therapiealternative ermöglichen zu können. Die vorliegende Arbeit liefert einen wichtigen Beitrag um eine einfache Methode zur Analyse von k-ras-Mutationen bei Patienten mit nichtkleinzelligen Lungenkarzinomen zu finden und damit eine Entscheidung über etwaige weitere Therapieoptionen zu erleichtern.

Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wildtype littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors. Interestingly, a significantly enhanced upregulation of Cox-2 was detected in Tg tumors than in WT tumors. Also, Tg tumors demonstrated upregulation of VEGF and angiopoietin-1, downregulation of AKAP12, and increased eNOS phosphorylation compared with WT tumors. Celecoxib, a selective Cox-2 inhibitor, suppressed the HSPA12B-induced increase in lung tumor burden. Moreover, celecoxib decreased angiogenesis and proliferation whereas increased apoptosis in Tg tumors. Additionally, celecoxib reduced angiopoietin-1 expression and eNOS phosphorylation but increased AKAP12 levels in Tg tumors. Our results indicate that HSPA12B stimulates lung tumor growth via a Cox-2-dependent mechanism. The present study identified HSPA12B as a novel facilitator of lung tumor growth and a potential therapeutic target for the treatment of lung cancer.

Non-small-cell lung carcinoma (NSCLC) is the major type of lung cancer, which is among the leading causes of cancer-related deaths worldwide. LIMD1 was previously identified as a tumor suppressor in lung cancer, but their detailed interaction in this setting remains unclear. In this study, we have carried out multiple genome-wide bioinformatic analyses for a comprehensive understanding of LIMD1 in NSCLC, using various online algorithm platforms that have been built for mega databases derived from both clinical and cell line samples. Our results indicate that LIMD1 expression level is significantly downregulated at both mRNA and protein levels in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), with a considerable contribution from its promoter methylation rather than its gene mutations. The Limd1 gene undergoes mutation only at a low rate in NSCLC (0.712%). We have further identified LIMD1-associated molecular signatures in NSCLC, including its natural antisense long non-coding RNA LIMD1-AS1 and a pool of membrane trafficking regulators. We have also identified a subgroup of tumor-infiltrating lymphocytes, especially neutrophils, whose tumor infiltration levels significantly correlate with LIMD1 level in both LUAD and LUSC. However, a significant correlation of LIMD1 with a subset of immune regulatory molecules, such as IL6R and TAP1, was only found in LUAD. Regarding the clinical outcomes, LIMD1 expression level only significantly correlates with the survival of LUAD (p0.1) patients. These findings indicate that LIMD1 plays a survival role in LUAD patients at least by acting as an immune regulatory protein. To further understand the mechanisms underlying the tumor-suppressing function of LIMD1 in NSCLC, we show that LIMD1 downregulation remarkably correlates with the deregulation of multiple pathways that play decisive roles in the oncogenesis of NSCLC, especially those mediated by EGFR, KRAS, PIK3CA, Keap1, and p63, in both LUAD and LUSC, and those mediated by p53 and CDKN2A only in LUAD. This study has disclosed that LIMD1 can serve as a survival prognostic marker for LUAD patients and provides mechanistic insights into the interaction of LIMD1 with NSCLC, which provide valuable information for clinical applications.

Vascular corrosion casts of normal and elastaseinduced emphysemic hamster lungs, prepared with a low viscosity resin mixture consisting of Mercox and Sevriton, were observed by scanning electron microscopy. Casts were quantitated by measuring vascular volume or determining nonalveolar air space using confocal laser scanning microscopy. Normal lung casts were characterized by wellorganized fields of alveoli (about 70m in diameter) connected by distinct alveolar ducts. Emphysemic lung casts exhibited numerous bullae (often as large as 0.5 mm in diameter). The vasculature of the bullae indicated that they were formed by destruction of alveolar walls and subsequent coalescence of numerous alveolae. Remnants of alveolar walls, consisting of shallow ridges of capillaries, lined the bases of the bullae. Vascular volumes expressed as cast volume/total tissue volume were calculated at 20% and 12% for uninflated and inflated lungs, respectively, for both control and emphysemic lungs. Four months after elastase instillation, nonalveolar air space of the emphysemic lungs was increased by 73% over controls. These observations indicate that elastase emphysema results, initially, in remodeling of the alveolar structure (bullae formation) and loss of surface area for gas exchange, rather than from extensive loss of vasculature. Vascular corrosion casting is a useful technique for monitoring emphysema both morphologically and quantitatively.

Methotrexate has proven to be effective in treating rheumatoid arthritis (RA), and is believed to be nononcogenic in the low weekly dose typically employed in the patients with RA. We report, however, a patient with RA in whom a rapidly enlarging diffuse large B-cell lymphoma developed in the left upper lung after weekly treatment with methotrexate for 5 years. The patient had a positive serum IgG for Epstein-Barr virus but a negative in situ hybridization of the resected specimen. Methotrexate therapy was discontinued, and the patient elected for clinical observation instead of chemotherapy or radiation therapy. There has been no clinically detectable recurrence of the lymphoproliferative disorder for 2 years. We believe that methotrexate has an oncogenic potential even in low weekly dosing in a subset of patients with RA and latent Epstein-Barr virus infection. The strongest causal link is demonstrated by the persistent tumor remission after stopping treatment with methotrexate.

Lung cancer is the deadliest cancer in women. In the last decade, the first measurable decline in disease-related mortality has occurred and in the last 5 years, the first decline in lung cancer incidence in women in the United States has been reported. Five-year survival rates are much higher in early-stage disease, making effective screening a priority. Data on screening with low-dose computed tomography are controversial; existing guidelines are not sex specific and recommend testing only for patients at high risk for the disease. Although cigarette smoking remains the predisposing factor that is most often associated with tumor development, the advent of molecularly targeted therapy and the growing evidence that susceptible targets are more prevalent in never-smoking women have brought more attention to this particular subpopulation. Studies of both surgery and systemic therapy suggest that not only never-smoking women but also women overall experience better outcomes than men. Identifying all of the factors contributing to these sex differences presents us with an opportunity to identify potentially a distinct tumor biology in women who would warrant a distinct personalized treatment approach.

Growing evidence supports the role of transcription factor activation in the pathophysiology of inflammatory disorders, sepsis, ARDS, SIRS, and shock. Kinase mediated phosphorylation of IκBα is a crucial step in the NFκB activation pathway. We investigated IκBα phosphorylation in murine liver and lung extracts after cecal ligation and puncture (CLP) in the presence and absence of a glucan ligand. ICR mice were subjected to CLP. Unoperated and sham-operated mice served as the controls. Glucan phosphate (50 mg/kg) was administered 1 h before or 15 min after CLP. CLP increased hepatic and pulmonary levels of phospho-IκBα by 48-192%. Pre-or post-treatment with glucan phosphate decreased (P < 0.05) tissue phospho-IκBα levels in CLP mice. Phospho-IκBα in the glucan-CLP group were not significantly different from the unoperated controls. To investigate mechanisms we examined IKKβ kinase activity, IκBα phosphorylation and degradation, and NFκB activity in a murine macrophage cell line, J774a.1, treated with LPS (1 μg/mL) and/or glucan phosphate (1 μg/mL) for up to 120 min. The glucan ligand blunted LPS-induced IKKβ kinase activity, phosphorylation and degradation of IκBα, and NFκB nuclear binding activity. The data indicate that one mechanism by which (1→3)-β-D-glucan may alter the response to endotoxin or polymicrobial sepsis involves modulation of IKKβ kinase activity with subsequent decreases in IκBα phosphorylation and NFκB activation.