Fluvial Geomorphology and Bank Stabilization: White River at Stotts Creek Confluence

Fluvial geomorphology is the study of how rivers and streams move or change their cross section and adjacent land form over time under the influence of water flow. This presentation focuses on the fluvial geomorphology of the White River in the vicinity of the Stotts Creek confluence and proposed actions to protect I-69 (currently SR 37) from lateral migration of the river and subsequent erosion and scour

INDOT DM Chapter 204: “Post- Construction Stormwater BMPs”

INDOT has developed Chapter 204, “Post-Construction Stormwater Best Management Practices” (BMPs), in the Indiana Design Manual (IDM) to help the agency comply with IDEM stormwater and MS4 permit requirements. The BMPs are designed to prevent or reduce non-point source pollution to help achieve water quality goals. This presentation will provide the industry with a project update and an implementation plan for this new chapter

Protection of Karst Features During Project Development and Construction

INDOT released a new procedure in July 2021 to protect karst features during project development and construction. Three key components of the new procedure are: (1) an expanded Indiana Karst Region, (2) integration with other INDOT environmental procedures and federal and state environmental laws, and (3) an educational component that includes best management practices and karst geology and biology. This presentation will provide an overview of the procedure, implementation guidance, and key concepts

Effect of Municipal Waste Incinerator Bottom Ash on Nutrient Removal Efficiency in a Bioretention Column Study

Nitrogen and phosphorus pollution in hydrologic ecosystems is a costly environmental problem. Low Impact Development measures, such as bioretention, can help prevent nutrient pollution. Bioretention is a type of green stormwater infrastructure and landscaping feature that collects, stores and treats stormwater runoff. Bioretention media is composed of sand, soil and an organic material such as compost or wood fines. While bioretention in itself is a sustainable practice, there is an ever growing demand for more sustainable solutions to the world's environmental problems. The St. Louis Metropolitan Sewer District's Lemay Waste Water Treatment (WWTP) incinerates biosolids, which creates a non-hazardous byproduct referred to as bottom ash. Incinerator bottom ash from the Lemay WWTP is mostly composed of silica and is very similar to sand. So, if incinerator bottom ash from the Lemay WWTP can be used in bioretention media as a substitute for sand, it will make a sustainable stormwater management technique even more sustainable. However, bioretention media with incinerator bottom ash will have to behave as a typical media to be an acceptable substitution. Nitrogen and phosphorus concentrations in the effluent from bioretention cells are of particular interest due to the drastic environmental issues associated with nutrient pollution. Therefore, a bioretention column study was performed to observe nutrient pollutant removal efficiency and plant compatibility of bioretention media containing municipal waste incinerator bottom ash. The results of the column study indicate that municipal waste incinerator bottom ash from the Lemay WWTP could be an acceptable substitution for sand in bioretention media

Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma : interim analysis of a randomized phase III trial

PurposeZanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities.Patients and methodsALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled.ResultsBetween November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib.ConclusionZanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

BACKGROUND In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P=0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, .

Scaff10 derivatives.

<p>(A) Overview of the synthesis of Scaff10 derivatives. By addition of iodine in methanol (a), acetophenone derivatives (1) reacted with the corresponding α-iodoketones (2a), removal of excessive iodine by addition of Na₂SO₃-solution (b). Resorcinol (3) and diethyl-2-acetylglutarat (4) were transformed into the 7-hydroxycoumarin derivative ethyl 3-(7-hydroxy-4-methyl-2-oxo-chromen-3-yl)propanoate (5a) in ethanolic HCl (c). In the presence of excess potash, 5 reacted with α-haloketone derivatives (2) in a Williamson ether synthesis at 55°C in acetone (d) to 6. Saponification to 7 was carried out in 1 M NaOH at 55–95°C and from 0.3–16 h (e). Final cyclization of ketones to furocoumarin derivatives (8) was carried out upon further heating in NaOH solution (60–110°C) for various times (0.75–10 h) (f). R is indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191423#pone.0191423.t001" target="_blank">Table 1</a> and (C). (B) Compounds of the generalized structures 6–8 from (A) were allocated into classes 6–8, respectively. (C) Structures of Scaff10 derivatives, which inhibit the AKAP-Lbc/DHPH-RhoA interaction in the homogenous time-resolved fluorescence (HTRF) assay depicted in Fig 3A and B. IC₅₀ values (μM ± SEM) were obtained from n = 3–15 independent HTRF experiments carried out in duplicate (S3 Table). Structural differences compared to Scaff10-8 are shown in grey. R² indicates the coefficient of determination.</p