Optimal design of a series of cstr's performing reversible reactions catalyzed by soluble enzymes: a theoretical study

The condition for the minimum overall reactor volume of a given number of CSTR's in series is theoretically determined for a reversible, single reactant-single product (Uni-Uni) enzyme catalyzed reaction. The reactor network is assumed to operate in steady-state, isothermal conditions with a single phase and a constant activity of biocatalyst. The method is based on a mathematical analysis of the discrete substrate concentration profile along the CSTR's assuming complete micromixing. The algebraic equations describing the critical loci are obtained for the general case, the mathematical proof that these equations define a minimum is presented, and an exact solution arising from an asymptotic situation is found. An approximate analytical method of optimization based on the aforementioned critical behavior is reported and its validity and usefulness discussed. The formula introduced can be used in more general situations as tools for getting the approximate range where the optimal overall volume of the series of CSTR's lies. Hence, the reasoning developed is important for the preliminary CSTR design and relevant in the initial steps of the more involved methods of numerical optimization. Finally, the enzymatic conversion of fumarate to L-malate is examined as a model system in order to assess the usefulness and applicability of the analysis developed

Therapeutic Electromagnetic Field Effects on Angiogenesis and Tumor Growth

Background: A new approach to cancer therapy based on the application of therapeutic electromagnetic fields (TEMF) has been developed by EMF Therapeutics, Inc., Chattanooga, TN, USA. This study was designed to assess the effect of TEMF on tumor vascularization and growth of murine 16/C mammmary adenocarcinoma cells in C3H/HeJ mice. Materials and Methods: Implanted tumors were allowed to grow for seven days until the tumor volume reached 100 mm3 before treatment was started. Mice (20 per control, 10 per EMF exposed group) received treatment (10 minutes per day with 0, 10 mT, 15 mT or 20 mT) with a 120 pulses per second pulsating magnetic field. Tumor growth was assessed throughout the treatment period. The extent of tumor vascularization was evaluated by immrmohistochemical staining for CD31. Results: Exposure to TEMF significantly reduced tumor growth, significantly reduced the percentage of area stained for CD31 indicating a reduction in the extent of vascularization and there was a concomitant increase in the extent of tumor necrosis. Conclusion: A novel TEMF treatment safely reduced growth and vasculadzalion of implanted breast cancers in mice. Implication: TEMF may prove a useful adjuvant to increase the therapeutic index of conventional cancer therapy

Postpneumonectomy syndrome: Surgical management and long-term results

ObjectivePostpneumonectomy syndrome is a rare syndrome of dynamic airway obstruction caused by extreme rotation and shift of the mediastinum after pneumonectomy, resulting in symptomatic central airway compression. We have treated this syndrome by mediastinal repositioning and placement of saline-filled prostheses into the pneumonectomy space. There is a paucity of outcome data for patients treated surgically, with only a single series of 11 patients previously reported. We analyzed our recent experience with treatment of this syndrome and report on the short and long-term outcomes and quality of life assessment of the largest series ever reported of patients treated by mediastinal repositioning.MethodsRecords were reviewed of all patients who underwent mediastinal repositioning for postpneumonectomy syndrome between January of 1992 and June of 2006. Long-term health-related quality of life was assessed by administration of the Saint George's Respiratory Questionnaire.ResultsThere were 18 patients (15 women and 3 men) with a median age of 44 years (range 14–67 years). Thirteen patients had undergone right pneumonectomy, and 5 patients had undergone left pneumonectomy. None of the patients in whom postpneumonectomy syndrome developed after left pneumonectomy had a right-sided aortic arch. Five patients had undergone pneumonectomy in childhood (age < 13 years). The median interval between pneumonectomy and mediastinal repositioning was 7.5 years (range 1.1–54.8 years). The median follow-up was 32 months (range 4–143 months). The operative mortality was 5.6% (1/18). Complications occurred in 5 patients (27.8%): pneumonia in 3 patients and acute respiratory distress syndrome in 2 patients. The median hospitalization was 6 days (range 3–155 days). Some 77% (10/13) of patients reported significant improvement in their breathing and overall state of health after surgery; 15.4% of patients (2/13) were somewhat better, and 7.7% of patients (1/13) had no improvement. No patients' condition was worse after surgery. All patients who reported improvement in their symptoms after surgery remained symptomatically improved at the time of the quality of life assessment. Some 92.3% (12/13) were not at all or only slightly limited in their social activities because of breathing problems, and 84.6% (11/13) were not at all or only slightly limited in their ability to work as a result of their physical health.ConclusionRepositioning of the mediastinum with placement of prostheses for postpneumonectomy syndrome can be performed with low mortality and morbidity. Surgical repositioning provides immediate and lasting symptomatic relief to patients in whom postpneumonectomy syndrome develops

Average motion of emerging solar active region polarities II: Joy's law

The tilt of solar active regions described by Joy's law is essential for converting a toroidal field to a poloidal field in Babcock-Leighton dynamo models. In thin flux tube models the Coriolis force causes Joy's law, acting on east-west flows as they rise towards the surface. Our goal is to measure the evolution of the average tilt angle of hundreds of active regions as they emerge, so that we can constrain the origins of Joy's law. We measured the tilt angle of the primary bipoles in 153 emerging active regions in the Solar Dynamics Observatory Helioseismic Emerging Active Region survey. We used line-of-sight magnetic field measurements averaged over 6 hours to define the polarities and measure the tilt angle up to four days after emergence. We find that at the time of emergence the polarities are on average aligned east-west, and that neither the separation nor the tilt depends on latitude. We do find, however, that ARs at higher latitudes have a faster north-south separation speed than those closer to the equator at the emergence time. After emergence, the tilt angle increases and Joy's law is evident about two days later. The scatter in the tilt angle is independent of flux until about one day after emergence, when higher-flux regions have a smaller scatter in tilt angle than lower-flux regions. Our finding that active regions emerge with an east-west alignment is surprising since thin flux tube models predict that tilt angles of rising flux tubes are generated below the surface. Previously reported tilt angle relaxation of deeply anchored flux tubes can be largely explained by the change in east-west separation. We conclude that Joy's law is caused by an inherent north-south separation speed present when the flux first reaches the surface, and that the scatter in the tilt angle is consistent with buffeting of the polarities by supergranulation.Comment: accepted in Astronomy and Astrophysic

Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis

BACKGROUND: The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1α (HIF). RESULTS: Most tumors <35 mm(3 )were white but tumors >35 mm(3 )were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at >100 microns from the capsule (subcortex). Tumors >35 mm(3 )treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. CONCLUSION: TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis

Assessment of preoperative accelerated radiotherapy and chemotherapy in stage IIIa (N2) non-small-cell lung cancer

AbstractForty patients with N2 non-small-cell lung cancer (stage IIIA), as determined by mediastinoscopy, were entered into a preoperative neoadjuvant study of chemotherapy (platinum, 5-fluorouracil, vinblastine) and accelerated radiotherapy (150 cGy twice per day for 7 days) for two cycles. Surgical resection was then performed and followed up with an additional cycle of chemotherapy and radiotherapy. All patients completed preoperative therapy. A major clinical response was seen in 87% of patients. Thirty-five patients underwent resection (one preoperative death, one refused operation, one had deterioration of pulmonary function, and two had pleural metastases). Operative mortality rate was 5.7% (2/35). Sixty percent of patients had no complications. Major complications included pulmonary emboli (three), pneumonia (two), and myocardial infarction (one). Downstaging was seen in 46% of patients, with two patients (5.7%) having no evidence of tumor in the specimen, five patients having sterilization of all lymph nodes, and nine patients having sterilization of mediastinal nodes but positive N1 nodes. Median survival of 40 patients was 28 months, with a projected 5-year survival of 43%. Patients with downstaged disease had statistically significant improved survival compared with patients whose disease was not downstaged. (J THORAC CARDIOVASC SURG 1996;111:123-33

Targeting dendritic cell dysfunction to circumvent anti-PD1 resistance in head and neck cancer

PURPOSE: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed. EXPERIMENTAL DESIGN: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model. RESULTS: An aPD1-resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen-specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1-resistant tumors compared with sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1-resistant model, intratumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T-cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1-resistant model, enhanced cDC1 tumor infiltration, restored antigen-specific responses, and recovered sensitivity to aPD1 treatment. CONCLUSIONS: These data highlight the contribution of tumor-infiltrating cDC1 in HNSCC aPD1 response and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in patients with HNSCC