Investigation of river eutrophication as part of a low dissolved oxygen TMDL implementation

In the United States, environmentally impaired rivers are subject to regulation under total maximum daily load (TMDL) regulations that specify watershed wide water quality standards. In California, the setting of TMDL standards is accompanied by the development of scientific and management plans directed at achieving specific water quality objectives. The San Joaquin River (SJR) in the Central Valley of California now has a TMDL for dissolved oxygen (DO). Low DO conditions in the SJR are caused in part by excessive phytoplankton growth (eutrophication) in the shallow, upstream portion of the river that create oxygen demand in the deeper estuary. This paper reports on scientific studies that were conducted to develop a mass balance on nutrients and phytoplankton in the SJR. A mass balance model was developed using WARMF, a model specifically designed for use in TMDL management applications. It was demonstrated that phytoplankton biomass accumulates rapidly in a 88 km reach where plankton from small, slow moving tributaries are diluted and combined with fresh nutrient inputs in faster moving water. The SJR-WARMF model was demonstrated to accurately predict phytoplankton growth in the SJR. Model results suggest that modest reductions in nutrients alone will not limit algal biomass accumulation, but that combined strategies of nutrient reduction and algal control in tributaries may have benefit. The SJR-WARMF model provides stakeholders a practical, scientific tool for setting remediation priorities on a watershed scale

The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens

To target T-cells to the tumour area we created a recombinant protein of the bacterial superantigen (SAg) Staphylococcal enterotoxin A (SEA) and the Fab-fragment of a tumour-reactive antibody. This antibody-targeted SAg immunotherapy therapy has been shown to be highly efficient, eliminating > 95% of the pulmonary metastasis in mice carrying established melanoma micrometastases. Earlier studies demonstrated that elimination of the C215-expressing B16-melanoma lung metastasis was dependent on interferon (IFN)-γ release and expression of perforin. In the present study, therapeutic effector functions were analysed both locally at the tumour site and systemically in the spleen. In order to elucidate the role of each T-cell subset during Fab–SEA therapy, CD4 knock-out (KO) and CD8 KO mice were used. Tumour size reduction was statistically significant in Fab–SEA-based tumour therapy in both types of T-cell-deficient mice compared to wild-type mice. CD4 KO mice displayed a drastic reduction in the number of tumour-infiltrating macrophages and CD8+ T-cells. Therapy-induced accumulation of perforin-containing cells at the tumour site was significantly impaired in CD8 KO mice, and marginally in CD4 KO mice. Moreover, CD4 KO mice failed to produce substantial amounts of the tumour suppressive cytokine IFN-γ. This is in sharp contrast to normal mice where a massive local release was recorded. CD8 KO mice displayed a spontaneous production of interleukin (IL)-4 and IL-10 locally in the tumour. Neither normal nor CD4 KO mice produced detectable levels of these Th-2-associated cytokines. The high level of IL-10 was demonstrated to inhibit Fab–SEA tumour therapy, since the therapeutic efficacy was significantly higher in IL-10 KO mice. These results illustrate the importance of a finely tuned cellular collaboration to regulate the various phases of an efficient anti-tumour immune response. © 1999 Cancer Research Campaig

Highly selective photoenhanced wet etching of GaN for defect investigation and device fabrication

ABSTRACTPhotoenhanced electro-chemical (PEC) wet etching has been shown to be suitable for dislocation-density estimation in n-GaN films as well as for GaN-based device fabrication. We report on PEC etching of n-GaN samples grown by MBE and HVPE methods in unstirred aqueous KOH solution under He-Cd laser illumination. Characterization of the etched samples was carried out using atomic force microscopy (AFM) in both cross-sectional and plan-view configurations and scanning electron microscopy (SEM). At moderate illumination densities, the SEM and AFM analyses reveal sub-100 nm scale threading vertical wires on the etched surfaces. The calculated density (∼1×10 9cm−2) is in agreement with dislocation density found by transmission electron microscopy. Using cross-sectional AFM, we find that these vertical wires are ∼1[.proportional]m high and are perpendicular to the sapphire surface. Applying a higher illumination density or an external voltage, we obtain a higher etch rate with a smooth free-feature etched surface. Some highly resistive samples that cannot be etched under normal conditions because the band bending is too small to confine the holes to the surface for them to participate in the PEC process, can be etched with the application of a voltage to the sample. In this case, the etch rate depends on both the polarity and the magnitude of the voltage applied. In an MBE-grown sample with an AlN/GaN superstructure inside, we report on high selectivity between AlN and GaN (AlN is an etch stop); the selectivity is due to the etching mechanism of the PEC process

Hybrid Reynolds-Averaged/Large Eddy Simulation of the Flow in a Model SCRamjet Cavity Flameholder

Steady-state and scale-resolving simulations have been performed for flow in and around a model scramjet combustor flameholder. Experimental data available for this configuration include velocity statistics obtained from particle image velocimetry. Several turbulence models were used for the steady-state Reynolds-averaged simulations which included both linear and non-linear eddy viscosity models. The scale-resolving simulations used a hybrid Reynolds-averaged/large eddy simulation strategy that is designed to be a large eddy simulation everywhere except in the inner portion (log layer and below) of the boundary layer. Hence, this formulation can be regarded as a wall-modeled large eddy simulation. This e ort was undertaken to not only assess the performance of the hybrid Reynolds-averaged / large eddy simulation modeling approach in a flowfield of interest to the scramjet research community, but to also begin to understand how this capability can best be used to augment standard Reynolds-averaged simulations. The numerical errors were quantified for the steady-state simulations, and at least qualitatively assessed for the scale-resolving simulations prior to making any claims of predictive accuracy relative to the measurements. The steady-state Reynolds-averaged results displayed a high degree of variability when comparing the flameholder fuel distributions obtained from each turbulence model. This prompted the consideration of applying the higher-fidelity scale-resolving simulations as a surrogate "truth" model to calibrate the Reynolds-averaged closures in a non-reacting setting prior to their use for the combusting simulations. In general, the Reynolds-averaged velocity profile predictions at the lowest fueling level matched the particle imaging measurements almost as well as was observed for the non-reacting condition. However, the velocity field predictions proved to be more sensitive to the flameholder fueling rate than was indicated in the measurements

Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention

OBJECTIVE: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. MATERIALS AND METHODS: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. RESULTS: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. CONCLUSION: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention

Study protocol for the safety and efficacy of probiotic therapy on days alive and out of hospital in adult ICU patients: The multicentre, randomised, placebo-controlled Restoration Of gut microflora in Critical Illness Trial (ROCIT)

Introduction The effect of early and sustained administration of daily probiotic therapy on patients admitted to the intensive care unit (ICU) remains uncertain. Methods and analysis The Restoration Of gut microflora in Critical Illness Trial (ROCIT) study is a multicentre, randomised, placebo-controlled, parallel-group, two-sided superiority trial that will enrol 220 patients in five ICUs. Adult patients who are within 48 hours of admission to an ICU and are expected to require intensive care beyond the next calendar day will be randomised in a 1:1 ratio to receive early and sustained Lactobacillus plantarum 299v probiotic therapy in addition to usual care or placebo in addition to usual care. The primary endpoint is days alive and out of hospital to day 60. Ethics and dissemination ROCIT has been approved by the South Metropolitan Health Service Human Research Ethics Committee (ref: RGS00000004) and the St John of God Health Care Human Research Ethics Committee (ref: 1183). The trial results will be submitted for publication in a peer-reviewed journal. Trial registration number Australian and New Zealand Clinical Trials Registry (ANZCTR12617000783325); Pre-results

Handlebar hernia: a case report and literature review on traumatic abdominal wall hernia in children

A rare case of abdominal trauma, a handlebar hernia, is described, as well as a review of the pertinent literature. A 7-year-old boy presented to our emergency room after sustaining blunt force to the abdomen; he fell on the handlebar of his bicycle. Immediately after the accident, a bulge was noticeable at the point of impact. Handlebar hernia is a diagnosis that is easily missed, which can lead to strangulation and incarceration of the bowel. With this case report, we hope to augment the knowledge on traumatic abdominal wall hernia, hopefully leading to early diagnosis and treatment

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study

BACKGROUND: The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. PATIENTS AND METHODS: Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. RESULTS: Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (\u3e400 days after first dose). CONCLUSIONS: Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. CLINICALTRIALS.GOV IDENTIFIER: NCT03499353

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Exploration of Tumor BRCA Mutational Status

BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. CONCLUSION: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC