Experimental Studies of Low-Load Limit in a Stoichiometric Micro-Pilot Diesel Natural Gas Engine

While operating at light loads, diesel pilot-ignited natural gas engines with lean pre-mixed natural gas suffer from poor combustion efficiency and high methane emissions. This work investigates the limits of low-load operation for a micro-pilot diesel natural gas engine that uses a stoichiometric mixture to enable methane and nitrogen oxide emission control. By optimizing engine hardware, operating conditions, and injection strategies, this study focused on defining the lowest achievable load while maintaining a stoichiometric equivalence ratio and with acceptable combustion stability. A multi-cylinder diesel 6.7 L engine was converted to run natural gas premix with a maximum diesel micro-pilot contribution of 10%. With a base diesel compression ratio of 17.3:1, the intake manifold pressure limit was 80 kPa (absolute). At a reduced compression ratio of 15:1, this limit increased to 85 kPa, raising the minimum stable load. Retarding the combustion phasing, typically used in spark-ignition engines to achieve lower loads, was also tested but found to be limited by degraded diesel ignition at later timings. Reducing the pilot injection pressure improved combustion stability, as did increasing pilot quantity at the cost of lower substitution ratios. The lean operation further reduced load but increased NOx and hydrocarbon emissions. At loads below the practical dual-fuel limit, a transition to lean diesel operation will likely be required with corresponding implications for the aftertreatment system

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy

Diagnostic pathways and direct medical costs incurred by new adult pulmonary tuberculosis patients prior to anti-tuberculosis treatment - Tamil Nadu, India.

BACKGROUND: Tuberculosis (TB) patients face substantial delays prior to treatment initiation, and out of pocket (OOP) expenditures often surpass the economic productivity of the household. We evaluated the pre-diagnostic cost and health seeking behaviour of new adult pulmonary TB patients registered at Primary Health Centres (PHCs) in Vellore district, Tamil Nadu, India. METHODS: This descriptive study, part of a randomised controlled trial conducted in three rural Tuberculosis Units from Dec 2012 to Dec 2015, collected data on number of health facilities, dates of visits prior to the initiation of anti-tuberculosis treatment, and direct OOP medical costs associated with TB diagnosis. Logistic regression analysis examined the factors associated with delays in treatment initiation and OOP expenditures. RESULTS: Of 880 TB patients interviewed, 34.7% presented to public health facilities and 65% patients sought private health facilities as their first point of care. The average monthly individual income was $77.79 (SD 57.14). About 69$39.74. Overall, patients experienced a median of 6 days (3-11 IQR) of time to treatment initiation and 21 days (10-30 IQR) of health systems delay. Age ≤ 40 years (aOR: 1.73; CI: 1.22-2.44), diabetes (aOR: 1.63; CI: 1.08-2.44) and first visit to a private health facility (aOR: 17.2; CI: 11.1-26.4) were associated with higher direct OOP medical costs, while age ≤ 40 years (aOR: 0.64; CI: 0.48-0.85) and first visit to private health facility (aOR: 1.79, CI: 1.34-2.39) were associated with health systems delay. CONCLUSION: The majority of rural TB patients registering at PHCs visited private health facilities first and incurred substantial direct OOP medical costs and delays prior to diagnosis and anti-tuberculosis treatment initiation. This study highlights the need for PHCs to be made as the preferred choice for first point of contact, to combat TB more efficiently.Eunice Kennedy Shriver National Institute of Child Health and Human Developmen

Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gemcitabine on the tumor microenvironment in order to identify potential therapeutic options for chemo-refractory PDAC. Using a combination of mouse models, primary cell line-derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, Gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring Gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined Gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, Gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that Gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of Gemcitabine-refractory PDAC

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

Aerodynamics and dynamics of bluff bodies in presence of the moving surface boundary-layer control

Moving Surface Boundary-layer Control (MSBC) was applied to several two dimensional bluff bodies using a high speed rotating cylinder as a momentum injecting device. Flow past a symmetric airfoil; a D-section; as well as square and rectangular prisms, representing a family of shapes with progressively increasing bluffness were studied in presence of the MSBC. In the case of the airfoil, the leading edge was replaced by a rotating cylinder; while the cylindrical element formed the top and bottom upstream corners of the D-section, square and rectangular prisms. Extensive wind tunnel investigation gave data about the effect of system parameters like rate of the momentum injection, angle of attack and the surface condition of the cylinder on steady and fluctuating components of the pressure distribution around the body, vortex shedding frequency (Strouhal number), and the lift and drag coefficients. A gain in the Strouhal number with increasing momentum injection suggest a decrease in the effective bluffness of the body. A significant reduction in the drag (up to 80%) was observed for the prisms at a maximum rate of momentum injection, Uc/U = 4 (Uc = cylinder surface speed, U = freestream wind speed). In the case of the airfoil, the lift coefficient increased by 160% and the stall angle was delayed from 110° to 48°. A rough criterion in terms of the location of the stagnation point was established to help decide the reversal in the direction of momentum injection as a function of angle of attack to ensure continued benefit. Effect of momentum injection in suppressing the vortex resonance and galloping type of instabilities were studied by mounting the bluff prism models on a dynamic-test rig inside the wind tunnel test section. The measurement of amplitude and frequency of the transverse oscillations over a range of wind speeds showed complete vibration suppression for momentum injection rates Uc/U < 2. Asymmetric momentum injection (e.g. top cylinder rotating, bottom cylinder stationary), was also found to be effective in disrupting the vortex shedding process and thereby inhibiting vibrations. The suppression of galloping instability in presence of the MSBC was also predicted by the quasisteady analysis. A numerical panel method was developed to simulate bluff body fluid dynamnics in presence of the MSBC. The body is descretized into a large number of panels (100 - 150) with each panel comprising of a continuous distribution of linearly varying vorticity and a constant source strength. A set of linear algebraic equations approximates the Fredholm type integral equation derived from ideal fluid flow assumption. The wake is modelled by upper and lower 'free vortex layers' emanating from the separation points on the body. Vorticity is allowed to be shed and dissipated as it is convected downstream along the panels on the 'free vortex layers'. An analytical expression relates the point vortex modelling a.rotating cylinder to the rate of momentum injection. The panel method is capable of treating multielement configurations (e.g. a rotating cylinder and the truncated airfoil). An iterative scheme based on the convergence of the wake shape is used to obtain the final solution. The numerically obtained pressure distribution, the lift and drag coefficients agree well with the experimental results. Flow visualization studies in a water channel were performed to obtain better physical insight into the MSBC process. Plexiglas models with rotating cylinders in conjunction with a fine suspension of polyvinyl chloride particles and slit lighting were used to visualize the streaklines. The still photographs and video movie recorded, rather dramatically, the effectiveness of the MSBC in suppressing separation and vortex shedding, making the flow approach the potential character. Overall, the present research firmly establishes potential of the MSBC as a versatile tool for lift augmentation, drag reduction and vibration suppression of several bluff bodies encountered in industrial engineering practice.Applied Science, Faculty ofMechanical Engineering, Department ofGraduat

Radiotherapy-induced depigmentation in a patient with breast cancer

Vitiligo is a common dermatological disorder. A middle-aged woman with preexisting vitiligo was diagnosed with breast carcinoma. After surgery and chemotherapy she received regional radiotherapy. Six months after the completion of radiotherapy she developed depigmentation in the irradiated area. This article discusses the etiology for this phenomenon and the literature in this regard

Radiotherapy-induced depigmentation in a patient with breast cancer

Vitiligo is a common dermatological disorder. A middle-aged woman with preexisting vitiligo was diagnosed with breast carcinoma. After surgery and chemotherapy she received regional radiotherapy. Six months after the completion of radiotherapy she developed depigmentation in the irradiated area. This article discusses the etiology for this phenomenon and the literature in this regard

Radiotherapy-induced depigmentation in a patient with breast cancer

Vitiligo is a common dermatological disorder. A middle-aged woman with preexisting vitiligo was diagnosed with breast carcinoma. After surgery and chemotherapy she received regional radiotherapy. Six months after the completion of radiotherapy she developed depigmentation in the irradiated area. This article discusses the etiology for this phenomenon and the literature in this regard