Doses Of Inhibitors Research Articles

EVOLVE-Lung02: A phase 3 study of first-line (1L) volrustomig plus chemotherapy (CT) versus pembrolizumab plus CT in metastatic non-small-cell lung cancer (mNSCLC) with PD-L1 tumor cell (TC) expression <50%.

TPS8652 Background: Immunotherapies targetingprogrammed cell death-1 (PD-1) and its ligand PD-L1 have transformed 1L mNSCLC. However, in a subset of patients (pts) with PD-L1-low or PD-L1-negative disease (i.e. PD-L1 TC expression <50% or <1%, respectively), anti-PD-(L)1 therapies, with or without CT, are associated with shorter overall survival (OS) than in pts with PD-L1-high disease. Dual inhibition of PD-1 and CTLA-4 is often undertaken in PD-L1-low, and especially PD-L1-negative, mNSCLC to address the poorer prognosis in these pts. Although combination therapy using lower doses of CTLA-4 inhibitors has shown benefit in this setting, toxicity at higher doses has limited the clinical utility of this approach. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. This mode of action may facilitate enhanced CTLA-4 inhibition at tolerable doses beyond those achievable with current PD-1/CTLA-4 combinations. Data from the first-in-human phase 1/2 study (NCT03530397) showed encouraging antitumor activity and acceptable tolerability with 1L volrustomig plus carboplatin/pemetrexed (CP) in NSCLC, particularly in pts with PD-L1 TC <1%. The phase 3, two-arm, parallel-group, randomized, multicenter, open-label eVOLVE-Lung02 study (NCT05984277) is designed to evaluate the efficacy of 1L volrustomig plus CT versus pembrolizumab plus CT in mNSCLC pts with PD-L1 TC <50%. Methods: Eligibility criteria include age ≥18 years; ECOG performance status 0 or 1; histologically or cytologically documented squamous (sq) or non-squamous (non-sq) stage IV NSCLC with PD-L1 TC expression <50%; wild-type EGFR, ALK, or ROS1; and no prior systemic therapy for mNSCLC. Approximately 900 pts will be randomized 1:1 to receive histology-specific CT (sq, paclitaxel plus carboplatin; non-sq, CP with pemetrexed maintenance at investigator discretion) in combination with either volrustomig or pembrolizumab (200 mg) every 3 weeks (Q3W) for 4 cycles; after this volrustomig or pembrolizumab will be administered Q3W until completion of 24 months of treatment or disease progression, or other discontinuation criteria are met. Randomization will be stratified according to histology (sq vs non-sq), PD-L1 (<1% vs 1–49%), smoking (never vs former/current), and region (Asia vs rest of world). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 and OS in the PD-L1 TC <1% population. Secondary endpoints include PFS and OS in all randomized pts (PD-L1 TC <50%), overall response rate, duration of response, PFS2, safety and tolerability, patient-reported outcomes, pharmacokinetics, and immunogenicity. Enrollment is ongoing. Clinical trial information: NCT05984277 .

Safety and feasibility of esophagectomy following neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Analysis of two phase 2 clinical trials.

4070 Background: Despite the survival benefit of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), the prognosis remains dismal. With the potential benefit of combining immune checkpoint inhibitors (ICIs) neoadjuvantly, we initiated two phase II single-armed clinical trials to explore the efficacy, feasibility, and safety of esophagectomy following the combination of preoperative PD-1 inhibitor with CT or CRT in ESCC. Methods: A total of 55 patients with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase 2, single-arm trials underwent neoadjuvant ICIs combined with chemotherapy (nICT) (n=38) (NCT04506138) or chemoradiotherapy (nICRT) (n=17) (NCT03940001) between May 2019 and June 2022 were enrolled. Patients received 2 doses of intravenous PD-1 inhibitor every 3 weeks, combined with 2 cycles of CT or CRT. Data on the pathological complete response (pCR) rates, operative time, blood loss volume, 30-day complications, hospital stay, and 30-day mortality were collected and assessed between these two groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. The primary endpoints of the studies were the safety and feasibility of esophagectomy after the combination of preoperative CT or CRT and PD-1 inhibitor. We also evaluated pCR, primary tumor pCR, operation time, postoperative stay, and 30-day mortality. Results: All the included patients successfully completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group, respectively (p=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group, respectively (p=0.19). Minimally invasive surgery was performed in 89.2% (33/37) of the nICT group and 94.1% (16/17) of the nICRT group. The risk of developing pulmonary, anastomotic, or other complications was similar in the two groups. Conclusions: Esophagectomy was safe after the addition of PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and exploratory endpoints, including biomarker analyses are ongoing. Clinical trial information: NCT03940001 ; NCT04506138 .

A real-world study of anlotinib in combination with PD-L1 inhibitors plus chemotherapy as first-line therapy for extensive-stage small cell lung cancer.

e20135 Background: Current first-line treatment options for extensive stage small cell lung cancer (ES-SCLC) are the PD-L1 inhibitor in combination with chemotherapy. Although these regimens have improved outcomes, most patients experience disease progression (PD), and median survival remains approximately 12 months. Anlotinib represents a tyrosine kinase inhibitor targeting multiple receptor tyrosine kinases, achieved good efficacy in third-line therapy in ES-SCLC. We conducted a real-world study to explore the safety and efficacy of adding anlotinib to the current first-line therapy in ES-SCLC. Methods: This real-world study included 16 patients with ES-SCLC treated with antirotinib in combination with the PD-L1 inhibitor and etoposide and cisplatin chemotherapy at our hospital between Oct 2020 and Nov 2023. Patients received six cycles of a standard dose of the PD-L1 inhibitor (Atezolizumab; Adebrelimab; Envafolimab; Nivolumab; Pembrolizumab; Tirelizumab or Sugemalimab) in combination with cisplatin (25 mg/m2, day 1-3 of each cycle) and etoposide (100 mg/m2, day 1-3 of each cycle), and anlotinib was taken orally (4-6mg, day 1-14 of each cycle). Maintenance PD-L1 inhibitor plus anlotinib was followed in a 21-day cycle until disease progression, intolerant toxicity, or longer than 2 years of treatment. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were disease control rate (DCR), objective response rate (ORR), and adverse reactions. Treatment response and adverse events (AEs) were assessed using the RECIST 1.1 and CTCAE 5.0, respectively. Results: A total of 16 patients were recruited. The median age was 72 years (66-76). Four patients (25%) had brain metastases at baseline, and seven patients (43.8%) had liver metastases. Median PFS was 10.8 months (95% CI, 8.3-13.3 months) and the median OS was 16.4 months (95% CI, 9.6-23.2 months). Totally 15 and 1 participants showed PR and SD, respectively. ORR and DCR were 93.8% and 100%. All patients had treatment-related AEs, of which grade 3-4 AE occurred in 50% (8/16). No serious infection or treatment-related death occurred. Myelosuppression was the most common AE, such as anemia (100%), leukocytopenia (100%), lymphocytopenia (100%), neutropenia (87.5%), and thrombocytopenia (50%). Other common AEs included hypoproteinemia (68.8%); hyponatremia (62.5%); creatinine elevation (56.3%), proteinuria (43.8%); hypertension (37.5%) and hypertriglyceridemia (37.5%). No unexpected AEs were found in this study. No patient stopped treatment due to intolerable toxicity. Conclusions: The addition of anlotinib to first-line immunotherapy in combination with chemotherapy results in extended PFS and OS in patients with ES-SCLC without additional AEs. The preliminary results warrant further investigation of this treatment modality in ES-SCLC.

Routine documentation of pre-treatment functional variables to predict survival in patients on immunotherapy.

e14701 Background: Medical providers often describe concerns about a patient’s functional status in routine clinical documentation (e.g., hard of hearing, recent falls, difficulty with home medication). These clinician-documented pretreatment functional variables (PFVs) may be predictive of outcomes among patients receiving immunotherapy. The goal of this retrospective study is to check for an association between the documentation of PFVs with overall survival (OS), progression-free survival (PFS), and the incidence of immune-related adverse events (irAEs). Methods: We created a retrospective registry of all patients who received at least one dose of an immune checkpoint inhibitor for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center. The investigators created a validated REDCap registry; clinical research specialist at Vasta Global captured most data. PFVs were collected by review of routine clinical documentation 30 days before or after the first dose. Patients were stratified by their number of PFVs (0,1, or 2+) and by their age (≥ or <65 years). PFVs assessed function, nutritional status and social support and were dichotomized to indicate impaired vs not with ten total categories. We used Cox proportional hazard modeling for survival analyses between the three PFV groups, calculated from the first dose of immunotherapy to disease progression, death, and last known follow-up controlling for age, BMI, smoking, and disease type with a two-sided alpha of 0.05. Results: From the overall cohort (n = 3,101), 35% had no PFVs, 32% had one PFV, and 32% had two or more PFVs; 52.5% were considered younger, and 47.5% geriatric-aged (≥65yo). PFVs were more common among the geriatric-aged population (mean 1.43 vs 0.89). The most common cancer types were lung cancer (45%), melanoma (14%), and kidney (6%). The most noted PFVs were visual impairment (26%), unintentional weight loss (22%), inability to walk a quarter block (17%), living alone (16%), and falls (14%). In the overall population, an increasing number of PFVs was associated with shorter OS. When stratified by age, the number of PFVs was associated with shorter progression-free survival (p <0.01) and overall survival (p <0.01) among the geriatric and non-geriatric populations (Table). There was no association between increasing PFVs and incidence of irAEs. Conclusions: Although often considered to be signs of aging, documentation of multiple PFVs was associated with worse OS and PFS among geriatric-aged and non-geriatric-aged populations. This study highlights the utility of routine clinical documentation on health status, including function, nutrition, and social support, to estimate survival regardless of chronologic age. [Table: see text]

FLAG-IDA + venetoclax in newly diagnosed (ND) or relapsed/refractory (RR) AML.

6519 Background: We report the outcomes of a phase 2 study of FLAG-IDA+VEN in AML. Methods: Pts ≥18 with ND or RR AML / MDS-EB2 fit for intensive chemotherapy were eligible. Induction comprised fludarabine 30mg/m2 D2–6, cytarabine 1.5g/m2 D2–6, idarubicin 8 (6 if RR) mg/m2 D4–6 & filgrastim 5mcg/kg D1–7. VEN 400mg was administered D1–14 with CYP3A inhibitor dose adjustment until Jul 2023; following a protocol modification, VEN is now administered D1–7. The primary outcome was ORR (CR + CRh + CRi + MLFS + PR). Secondary outcomes were CRc (CR + CRh + CRi), overall survival (OS), event-free survival (EFS) & duration of response (DOR). Measurable residual disease (MRD) was assessed by flow cytometry. Results: As of Jan 2024, 134 pts have enrolled, 127 (68 ND & 59 RR) evaluable at data cut. Median age was 45 (18 – 73); 19 (15%) age ≥60. 13 (19%), 22 (32%) & 33 (49%) ND pts were ELN22 favorable, intermediate & adverse respectively. There were 7 (10%) secondary (s), including 4 hypomethylating agent failure, & 7 (10%) therapy-related (t) AML. In RR pts, 40 (68%) were in salvage 1 (S1), of whom 32 (54%) were TP53WT. 20 (34%) had prior stem cell transplant (SCT). Median of 2 cycles were given. In ND pts, ORR was 99%, (96% CRc, of whom 89% MRD negative [Table]). Similar responses were seen across ELN groups & s/tAML. At median follow-up (mFU) of 30 months (mo), the mOS, mEFS & mDOR were not reached. The 2yr OS, EFS & DOR were 75% (64 – 88), 68% (56 – 81) & 71% (59 – 85) respectively, with no differences among ELN groups. 57% went to SCT in CR1. 4/4 pts with TP53mut became CRc MRD–, but mDOR was only 8.2 mo (95% CI, 2.2 – NE), resulting in poor mOS (13.5 mo, 95% CI, 8.6 – NE). In RR pts, ORR was 70% (66% CRc, of whom 79% MRD negative [Table]). At mFU 27 mo, the mOS, mEFS & mDOR were 12 (7 – 33), 7 (4 – 23) & 21 (8 – NE) mo respectively. The 2yr OS, EFS & DOR were 40% (28 – 55), 34% (23 – 49) & 49% (35 – 68) respectively. 58% went to SCT. S1+ TP53WT pts had mOS of 34 mo (12 – NE), with 72% going to SCT. 30d & 60d mortality were 0% & 3%. Of the 4 deaths within 60d, 1 was sepsis-related in CR in a ND pt while 3 were disease-related in NR RR pts. The most frequent adverse event was infection. Grade ≥3 infections, gastrointestinal toxicities & bleeding occurred in 102 (80%), 20 (16%) & 9 (7%) pts respectively. The median time to neutrophil >1x109/L & platelet >50x109/L were 27d & 28d for C1, 39d & 67d for C2 & 35d & 50d for C3 respectively. Conclusions: FLAG-IDA+VEN results in high MRD negative response rates, leading to impressive survival outcomes across ELN risk groups in ND AML. It is an effective salvage regimen for RR AML, especially for S1+ TP53WT pts. Clinical trial information: NCT03214562 . [Table: see text]

Assessing the effect of sodium nitrite as corrosion inhibitor against the corrosion of steel rebar in alkali-activated concrete

The aim of this study is to investigate the effectiveness of corrosion inhibitor against chloride-induced corrosion of steel rebar in fly-ash (FA) and GGBS (ground granulated blast furnace slag) and Nanofine-based alkali-activated concrete. The Alkali-Activated Concrete (AAC) was prepared from FA, ground granulated blast furnace slag (GGBS), and Nanofine with Sodium hydroxide (NaOH) and Sodium Silicate (Na2SiO3) solutions. The concentration of NaOH varies to 10 M, 12 M, and 14 M, and all the specimens were subjected to accelerated corrosion, to perform the non-destructive test after the corrosion of the steel rebars. Fourier Transform Infrared (FTIR), scanning electron microscope (SEM), Energy dispersive X-ray spectroscopy (EDS), and Electron Backscatter Diffraction (EBSD) were used to examine the microstructure of AAC in the presence of Nano-Fine GGBS (NF), Sodium Chloride (NaCl), and NaNO2 and to compare the strength and corrosion properties with AAC and OPC. The ratio of sodium silicate to sodium hydroxide was taken as 2.5 and the solution-to-binder ratio was taken as 0.5. The compressive strength and ultrasonic pulse velocity (UPV) test of the Nano-fine based alkali-activated concrete increases as compared to the control concrete. The increase in the dosages of corrosion inhibitor and nano-fine increases the compressive strength of the control concrete and alkali-activated concrete. The half-cell potential of the control concrete and nano fine admixed with alkali-activated concrete mixes with different molarities is uncertain. The increases in the dosages of corrosion inhibitors reduce the occurrence of corrosion in the steel reinforcement rebars.

#388 IONIS-FB-LRx, an antisense oligonucleotide to complement factor B for treatment of IgA nephropathy

Abstract Background and Aims Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgAN, it has been hypothesized that a reduction of AP activity would improve proteinuria. IONIS-FB-LRx, (ISIS696844, RO7434656), is an investigational antisense oligonucleotide targeting complement factor B (CFB) mRNA and reduces CFB production in the liver. We have previously demonstrated that administration of IONIS-FB-LRx lowered the production of CFB, a required component of the AP, and led to reduction of AP and reduction in proteinuria in IgAN patients (2023 ASN Abstract#SA-PO926, N = 13 patients). Current abstract provides an update to our previous report extending results to 19 patients treated with IONIS-FB-LRx. Method An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria >1.5 g/d, eGFR >40 mL/min/1.73 m2, and hematuria despite maximum tolerated RAAS blockade and/or stable dose of SGLT-2 inhibitor for a minimum of 6 months. Study drug was administered at Weeks 1, 3, and 5, and then every 4 weeks through Week 25 (Cohort A) and at Week 1 and then every 4 weeks through Week 25 (Cohort B). Primary outcome was change in 24-hr proteinuria at Week 29 (4 weeks after last dose) compared to baseline (BL). Results 19 patients have completed study to date (13Nov2023), 25-62 yr, 42% Female, 11 Asian, and 8 White. Median 24-hr UPCR at BL was 1.56 g/g (IQR 1.23, 2.33 g/g). At Week 29, a 45% geometric mean ratio reduction was observed. There was little change in eGFR at Week 29 compared to BL (mean ± SD; BL 72 ± 22; Week 29 74.6 ± 20 mL/min/1.73 m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAEs; the only clinically meaningful laboratory finding was reversible and transient ALT elevation without a change in bilirubin. All patients completed the study and one patient discontinued study drug after 4 months to initiate SGLT-2 inhibitors. That patient experienced a 38% reduction in 24-hr UPCR collected 3 weeks (Week 27) after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors. Conclusion This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN.

#1418 Phase II dose-selection, randomised, controlled trial of ASi BI 690517 with and without EMPA in CKD: subgroup analysis by T2D status

Abstract Background and Aims High aldosterone levels accelerate chronic kidney disease (CKD) progression. BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. ASi may reduce deleterious haemodynamic, inflammatory, and fibrotic actions of aldosterone. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may also mitigate the risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given either alone or in combination with empagliflozin (EMPA), in people who had CKD with or without type 2 diabetes (T2D) [1, 2]. Here, we present an analysis by T2D status (pooled for background randomizedon to EMPA or placebo [PBOEMPA]). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to an 8-week run-in to receive background EMPA 10 mg or PBOEMPA, then randomized again (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBOASI for 14 weeks. The primary endpoint was the change from R2 baseline in urine albumin:creatinine ratio (UACR) in the first morning void of urine at Week 14. A secondary endpoint was UACR response (≥30% reduction from R2 baseline in UACR at Week 14). Changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14 were also assessed, as were safety outcomes. Results Of 586 people randomized at R2, 414 (70.6%) were reported to have T2D and 172 (29.4%) did not have T2D. Baseline demographics and clinical characteristics were mostly similar between these two groups [1]; however, those with T2D had higher mean BMI (30.6 vs 28.3 kg/m2), SBP (135.3 vs 130.2 mmHg) and eGFR (53.0 vs 49.4 mL/min/1.73 m2), and higher median UACR (444.7 vs 409.2 mg/g) than those without T2D. BI 690517 consistently reduced UACR versus PBOASI in people with and without T2D (p = 0.38, indicating no difference in treatment effect between these groups), with the largest reductions observed in the 10 mg and 20 mg dose groups; however, for the 3 mg dose group, UACR reduction was only observed in people with T2D (Figure). UACR response rates (≥30% reduction) were achieved in more than half of people with and without T2D in the BI 690517 10 mg and 20 mg dose groups, with the highest response rates in those also receiving EMPA (10 mg dose group: with T2D, 74.3%; without T2D, 64.0%). Decreases in SBP and small decreases in eGFR were also observed in people with and without T2D in response to BI 690517 10 mg and 20 mg, and were consistent with the observed changes in the overall population; however, for the 3 mg dose group, eGFR reduction was only observed in people with T2D. Adverse events leading to discontinuation in BI 690517 10 mg and 20 mg dose groups were more common among people with T2D than those without T2D who were receiving the same dose of BI 690517. Conclusion In people who had CKD, with or without T2D, BI 690517 dose-dependently reduced UACR, with high rates of UACR response suggestive of additive beneficial effects when given with EMPA.

#2170 BET inhibitor nanotherapy reduces chronic kidney disease progression after ischemia-reperfusion injury

Abstract Background and Aims Targeting epigenetic mechanisms offer a potential breakthrough in addressing kidney diseases. Thus, inhibition of the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1, has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, clinical translation faces hurdles like poor pharmacokinetics and side effects. To tackle this, we engineered liposomes loaded with JQ1 to enhance kidney drug delivery and minimize side effects. By optimizing the encapsulation of JQ1, our aim was to improve its efficacy compared to freely delivered JQ1 and reduce its cytotoxicity. Moreover, the therapeutic potential of this new nanoformulation to halt the acute renal ischemic injury and its transition to CKD will be explored. Method JQ1 was encapsulated in different types of lipid nanoparticles (NPs), and its effect was analyzed in vitro on the HK2 tubular epithelial line. Additionally, in vivo administration was carried out 1 hour after the induction of 45 minutes bilateral renal ischemia, and its effect was further analyzed at 24 h in the AKI setting or at 21 days for CKD. Non-encapsulated JQ1 was used as a control, and in vivo biodistribution studies were conducted using IVIS and fluorescent Cy5.5-labelled NPs. Damage markers, inflammatory burden and fibrosis development were analyzed through conventional techniques (Western blot, RT-PCR, IHC, flow cytometry), and functional parameters (BUN, Creatinine) were assessed through colorimetric assays. Results Three types of liposomal NPs were assayed to optimize JQ1 encapsulation, being the combined encapsulation of JQ1 in both the core and lipid layer the ones proving the best effectiveness. With an average hydrodynamic diameter of 78 nm, these NPs effectively reached the kidneys as assayed by in vivo biodistribution assays. In vitro assays performed on the HK2 cell line reveal their potential to inhibit TNF-α-induced inflammation. Importantly, in vivo dose-dependent studies determined that a 40 mg/kg dose was effective in post-ischemic acute kidney injury, showing a reduction in inflammatory (Il6, Csf2, Ccl2, Ccl5) and renal damage markers (Ngal), as well as reduced immune cell infiltration into the renal tissue of monocytes (CD45+CD11b+Ly6G−Ly6ChiF4/80low) and neutrophils (CD45+CD11b+Ly6GhiLy6Clow) quantified by flow cytometry. In accordance, decreased levels of serum BUN and Creatinine were detected in the group of mice treated with NPs-JQ1, indicating a better renal function. Of note, none of these effects were observed when the same dose of the unencapsulated inhibitor was used, demonstrating no effectiveness whatsoever. In the long term, by establishing an AKI to CKD transition model analysing fibrosis at 21 days post-ischemia induction, mice receiving a single dose of NPs-JQ1 early after damage displayed reduced fibrosis markers expression (α-SMA and Fibronectin), decreased collagen deposits quantified by Masson's Trichrome tissue staining and a partial recovery of the renal function. Conclusion The encapsulation of JQ1 in lipid nanoparticles is an effective strategy that allows for a decrease in the minimum effective dose of the drug. Due to its higher concentration and stability in the kidney, this therapy could be relevant in the treatment of renal pathologies and represents a significant step forward in the development of an innovative therapy for AKI-to-CKD transition. Our pioneering liposomal formulation not only expands the therapeutic potential of JQ1 but also addresses a significant barrier to its clinical translation in the nephrology field.

#2770 Evaluation of the effect of IV iron therapy on eGFR and Pro-BNP in patients with chronic kidney disease and heart failure with preserved EF

Abstract Background and Aims Iron replacement in treating heart failure (HF) is an issue whose importance has been better understood in recent years. Although controversies exist, randomized controlled studies have shown that IV iron treatment reduces mortality and improves symptomatology in heart failure with low EF (HFrEF). IV iron has not dramatically affected survival in heart failure with preserved EF (HFpEF). However, there is data that it might reduce symptoms and hospitalizations. For patients with chronic kidney disease (CKD) and HF, around 60% of them have HFpEF. Major heart failure and iron studies have often been performed on patients with low EF. Furthermore, in some of these studies, GFR values were not reported, and in the others, GFR was often > 60 ml/minute. We planned this study to evaluate the effects of IV iron therapy on eGFR and Pro-BNP levels in non-dialysis CKD patients with HFpEF. Method This study was conducted between January 2022 and December 2023. Patients with iron deficiency anemia, stage 2-5ND chronic kidney disease, and those with Pro-BNP values of 1000 and above were selected. Two independent cardiologists evaluated them, and the diagnosis of heart failure was confirmed. Patients were given one dose of 500 or 1000 mg of FCM. Control values were obtained at the 1-month follow-up. Hospitalized or transfused patients, cases with primary hematological disease, and cases with conditions affecting ferritin levels were excluded. Patients whose RAAS blockade, SGLT-2 inhibitor, and diuretic doses were changed, were excluded from the analysis. No patients received ESA or HIF stabilizers. Demographic and clinical data of the patients were recorded. The patients' creatinine, eGFR, hemoglobin, ferritin, and pro-BNP levels were evaluated before and after iron treatment Results Seventy-four patients were recruited. Forty-seven patients were women. The average age was 68 ± 11 years. Forty-eight of the patients had diabetes (64.9%) and 47 (63.5%) had coronary artery disease. The etiology of HFpEF was diastolic heart failure in 45 patients (60%). Other patients had valve disease, HFmEF, HFimpEF, isolated right-sided HF, and mixed types of HFpEF. After IV iron treatment, an increase of 3 ± 1 ml/min in GFR and 1.1 ± 0.1 g/dL in hemoglobin was detected. ProBNP levels decreased by 46%. All findings were statistically significant. The findings are summarized in Table 1. Conclusion The decrease in ProBNP levels was similar to the HFrEF literature. No positive or negative effects of iron on GFR were observed in the REVOKE and FIND-CKD studies, which compared oral and IV iron in CKD patients. The small but significant increase in GFR in our study could be attributed to the improvement of cardiac function. However, the small number of patients and the short follow-up period make it difficult to reach a definitive conclusion on this issue. We have shown that IV iron treatment significantly reduces Pro-BNP levels in CKD patients with HFpEF. IV iron has no adverse effects on renal function in the short term, and there is little signal of potential positive effects. Longer-term studies, preferably randomized with oral iron, with appropriate sample size, are needed to evaluate how IV iron affects end-points such as HF symptom score, hospitalization, eGFR slope, need for renal replacement, and mortality in this patient group. Strengths Well-selected patient group, a high Pro-BNP cut-off point, re-evaluation of each patient by the cardiologists Limitations Relatively small cohort, short follow-up period

Development and application of wellbore flow assurance monitoring system for combustible ice production in deepwater

The commercial development of combustible ice, as the most promising strategy energy, requires not only efficient gas production technology but also a safe flow assurance system. For the depressurization development of combustible ice in the sea area, the issues of wellbore fluid carrying sand, hydrate re-formation in the wellbore, and instability of wellbore flow, are the key problems leading to flow obstacles in the wellbore and affecting the normal production. Therefore, some measures must be taken to effectively monitor and analyze the flow situation in the wellbore during the development of combustible ice in the sea. In this paper, a Wellbore Flow Assurance Monitoring System (WFAMS) is developed to display the fluid flow conditions in the wellbore in real-time during the gas hydrate production, including temperature, pressure, flow rate, the carrying sand amount, etc. Furthermore, the system is capable of online monitoring for potential plug risks, including sand plugs and hydrate blockages caused by gas hydrate formation, as well as assessing flow stability. Additionally, it can provide valuable information, such as production adjustment data and the required injection dosage of thermodynamic inhibitors to prevent hydrate formation. In the 2020 South China Sea production test, this system was used for depressurization production and successfully predicted wellbore flow conditions. This enabled field engineers to monitor flow risks and adjust production plans in a timely manner, ensuring smooth test progress.

Longitudinal NT-proBNP: Associations With Echocardiographic Changes and Outcomes in Heart Failure.

The relationship of serial NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements with changes in cardiac features and outcomes in heart failure (HF) remains incompletely understood. We determined whether common clinical covariates impact these relationships. In 2 nationwide observational populations with HF, the relationship of serial NT-proBNP measurements with serial echocardiographic parameters and outcomes was analyzed, further stratified by HF with reduced versus preserved left ventricular ejection fraction, inpatient versus outpatient enrollment, age, obesity, chronic kidney disease, atrial fibrillation, and attainment of ≥50% guideline-recommended doses of renin-angiotensin system inhibitors and β-blockers. Among 1911 patients (mean±SD age, 65.1±13.4 years; 26.6% women; 62% inpatient and 38% outpatient), NT-proBNP declined overall, with more rapid declines among inpatients, those with obesity, those with atrial fibrillation, and those attaining ≥50% guideline-recommended doses. Each doubling of NT-proBNP was associated with increases in left ventricular volume (by 6.1 mL), E/e' (transmitral to mitral annular early diastolic velocity ratio) (by 1.4 points), left atrial volume (by 3.6 mL), and reduced left ventricular ejection fraction (by -2.1%). The effect sizes of these associations were lower among patients with HF with preserved ejection fraction, atrial fibrillation, or advanced age (Pinteraction<0.001). A landmark analysis identified that an SD increase in NT-proBNP over 6 months was associated with a 27% increase in the risk of the composite event of HF hospitalization or all-cause death between 6 months and 2 years (adjusted hazard ratio, 1.27 [95% CI, 1.15-1.40]; P<0.001). The relationships between NT-proBNP and structural/functional remodeling differed by age, presence of atrial fibrillation, and HF phenotypes. The association of increased NT-proBNP with increased risk of adverse outcomes was consistent in all subgroups.

Intraoperative haemoadsorption for antithrombotic drug removal during cardiac surgery: initial report of the international safe and timely antithrombotic removal (STAR) registry

Intraoperative antithrombotic drug removal by haemoadsorption is a novel strategy to reduce perioperative bleeding in patients on antithrombotic drugs undergoing cardiac surgery. The international STAR registry reports real-world clinical outcomes associated with this application. All patients underwent cardiac surgery before completing the recommended washout period. The haemoadsorption device was incorporated into the cardiopulmonary bypass (CPB) circuit. Patients on P2Y12 inhibitors comprised group 1, and patients on direct-acting oral anticoagulants (DOAC) group 2. Outcome measurements included bleeding events according to standardised definitions and 24-hour chest-tube-drainage (CTD). 165 patients were included from 8 institutions in Austria, Germany, Sweden, and the UK. Group 1 included 114 patients (62.9 ± 11.6years, 81% male) operated at a mean time of 33.2 h from the last P2Y12 inhibitor dose with a mean CPB duration of 117.1 ± 62.0 min. Group 2 included 51 patients (68.4 ± 9.4years, 53% male), operated at a mean time of 44.6 h after the last DOAC dose, with a CPB duration of 128.6 ± 48.4 min. In Group 1, 15 patients experienced a BARC-4 bleeding event (13%), including 3 reoperations (2.6%). The mean 24-hour CTD was 651 ± 407mL. In Group 2, 8 patients experienced a BARC-4 bleeding event (16%) including 4 reoperations (7.8%). The mean CTD was 675 ± 363mL. This initial report of the ongoing STAR registry shows that the intraoperative use of a haemoadsorption device is simple and safe, and may potentially mitigate the expected high bleeding risk of patients on antithrombotic drugs undergoing cardiac surgery before completion of the recommended washout period.Clinical registration number: ClinicalTrials.gov identifier: NCT05077124.Graphical

Grape Leaves and Ziziphus Spina-Christi, Extracts as a Green Inhibitors Corrosion for The Carbon Steel and Oil Pipelines in 1M H2SO4

Metals suffer from corrosion by the surrounding fluids, which causes great economic losses and bad environmental effects, especially in oil pipelines or reservoirs. The extract of grape leaves (GL) and Sidr leaves, (Ziziphus spina-christi), (Zizi) were used as green corrosion inhibitors (CI) for carbon steel (CS), and Oil Pipelines in 1M H2SO4, these extracts showed varying capabilities in resisting corrosion. Corrosion rate was decreased with increase in inhibitor dose which could be due to enhanced surface coverage, as well as the effect of increasing the temperature on the percentage of the efficiency of inhibition, are decrease, and drawing the curves for that, as well as studying some physical properties related to the process of adsorption of extracts on the surface of (CS), such as the activation energy and entropy of the process of adsorption of the extracts on the surface of (CS), and calculating those values, and the extracts showed an efficiency that exceeded 90% at concentrations up to 400 ppm and a temperature of 313-343K. The activation energy associated with this process indicated surface interaction as the main mechanism and positive values of enthalpy change confirmed the endothermic nature. The potentiometric method showed the extent of voltage change with time for each concentration of extract of grape leaves for immersion time (2–24 h), and that the voltage increases with increasing concentration, which indicates a high ability of the inhibitor to adsorb to the metal..

Cardioprotective Effects of Sodium-Glucose Cotransporter Subtype Inhibition on Ischemic and Pharmacological Preconditioning.

Sodium-glucose cotransporter (SGLT) 2 inhibitors partially inhibit SGLT1 expression; however, whether a clinical dose of SGLT2 inhibitor abrogates ischemic preconditioning (IPC) is unknown, and the pharmacological cardioprotective effect under SGLT1 inhibition has not been examined. In this study, we investigated whether a clinical dose of tofogliflozin abrogates IPC and whether pharmacological preconditioning with olprinone has cardioprotective effects under SGLT1 inhibition. Male Wistar rats were divided into seven groups (seven rats per group) and subjected to the following treatments before inducing ischemia/reperfusion (I/R; 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion): saline infusion control treatment (Con); ischemic preconditioning(IPC); IPC after phlorizin infusion (IPC+Phl); IPC after low-dose tofogliflozin infusion (IPC+L-Tof); IPC after high-dose tofogliflozin infusion (IPC+H-Tof); olprinone infusion (Olp); and Olp infusion after phlorizin infusion (Olp+Phl). The infarct size was significantly decreased in the IPC group, but not in the IPC+Phl group. In contrast, the infarct size decreased in the IPC+L-Tof and IPC+H-Tof groups. Additionally, Olp reduced the infarct size, and the effect was preserved in Olp+Phl groups. Phosphorylated AMP-activated protein kinase (AMPK) expression was lower in the IPC+Phl group compared to that in the IPC group. The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition.

Optimizing BTK Inhibition in Waldenström Macroglobulinemia.

Bruton tyrosine kinase (BTK) inhibitors have become a standard of care in the treatment of patients with Waldenström macroglobulinemia (WM) and are the only medications approved by the FDA to treat these patients. As more patients with WM are treated with BTK inhibitors in the United States and worldwide, it is essential to optimize this therapy by selecting the patients who are more likely to benefit from it, and by managing the unique adverse effects associated with these agents. Herein, we propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results, making the horizon for BTK-targeting therapies in WM bright and hopeful.

Supra-Therapeutic Selective Serotonin Reuptake Inhibitor (Ssri) Dosesfor Refractory Obsessive-Compulsive Disorder: A Case Report

Supra-Therapeutic Selective Serotonin Reuptake Inhibitor (Ssri) Dosesfor Refractory Obsessive-Compulsive Disorder: A Case Report

Chemical Approach to Control Hydrate in Offshore Gas Production Facilities

- Hydrate formation presents a significant operational challenge in offshore oil and gas production, primarily due to the potential formation of hydrate plugs which obstruct fluid flow, thereby posing serious flow assurance risks. Additionally, these solid, crystalline, icelike structures, composed of low molecular weight gases (such as methane, ethane, and propane) encapsulated in hydrogen-bonded water cages, can aggregate into larger masses capable of damaging or rupturing pipelines. Such formations typically occur under the high-pressure and low-temperature conditions prevalent in subsea flowlines and cold-weather operations. This study employs the Prosper simulation software to model these complex thermodynamic and hydrodynamic conditions and to predict the effective dosages of chemical inhibitors required to prevent hydrate formation. Specifically, our simulations suggest optimal dosages of 35% wt. methanol (MeOH) and 45% wt. monoethylene glycol (MEG) for gas stream 1, and 22% wt. MeOH and 33% wt. MEG for gas stream 2. Based on these findings, we advocate the use of Prosper simulation software as a predictive tool for the strategic administration of hydrate inhibitors in offshore gas production facilities. This research contributes to the ongoing development of chemical strategies for hydrate management, providing a basis for improved safety and efficiency in hydrocarbon extraction processes.

Synthesis and evaluation of a new scale inhibitor: the modified epoxysuccinic acid copolymer

Polyepoxysuccinic acid (PESA) scale inhibitor is widely recognized as a green and environmentally friendly scale inhibitor. However, its functional group type is single and cannot be used for a variety of scales. Based on this, a modified epoxy succinic acid quaternary polymer scale inhibitor PEAPS was prepared by introducing a variety of functional groups. The effects of scale inhibitor dosage, temperature, and solution pH on the scale inhibition performance of CaCO3, CaSO4, BaSO4, and SrSO4 were studied. At the same time, it is compared with the commonly used oilfield scale inhibitors Polyacrylic acid (PAA), PESA, and Ethylenediaminetetramethylenephosphonic acid (EDTMP). The results show that under the optimal synthesis conditions, the scale inhibition efficiency of PEAPS scale inhibitor on CaCO3 scale and CaSO4 reaches 100%, and the scale inhibition efficiency of BaSO4 and SrSO4 can reach at least 60%. Its comprehensive scale inhibition efficiency is better than other commonly used scale inhibitors under the same test conditions, and it has certain corrosion inhibition performance through static corrosion evaluation. The crystal parameters and micro-morphology of the four scales before and after the addition of scale inhibitor were analyzed using SEM and XRD. The results showed that after adding the PEAPS scale inhibitor, the crystal structure parameters of the CaCO3 scale and CaSO4 scale changed, and the micro-morphology of the four scale crystals also changed, to achieve the purpose of scale inhibition.

Renin-angiotensin system inhibitor use and risk of Parkinson's disease: a meta-analysis.

Hypertension is a recognized risk factor for Parkinson's disease (PD). The renin-angiotensin system (RAS) inhibitors are widely used to treat hypertension. However, the association of RAS inhibitor use with PD has still been an area of controversy. Thus, we conducted a meta-analysis to investigate the relationship between RAS inhibitor use and PD. PUBMEDand EMBASE databases were searched for articles published up to Oct 2023. All studies that examined the relationship between RAS inhibitor use and the incidence of PD were included. Seven studies with total 3,495,218 individuals met our inclusion criteria for this meta-analysis. Overall, RAS inhibitor use was associated with a reduction in PD risk (OR = 0.88, 95%CI = 0.79-0.98) compared with the controls. When restricted the analysis to individuals with RAS inhibitor use indication, RAS inhibitor exposure was also associated with a decreased risk of PD (OR = 0.76, 95%CI = 0.62-0.92). Pooled results of cohort studies also did support a protective role of angiotensin converting enzyme inhibitors (ACEIs) (OR = 0.97, 95%CI = 0.89-1.07) users and angiotensin II receptor blockers (ARBs) (OR = 0.8, 95%CI = 0.63-1.02) in PD. Overall, RAS inhibitor use as a class is associated with a reduction in PD risk. However, the findings of ACEIs and ARBs may be limited by small sample size. Future well-designed studies considering the classification by inhibitor type, duration, dose, or property of BBB penetration of RAS inhibitors are needed to clarify the contribution of these exposure parameters on the risk of PD.