High Clearance Research Articles

Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT

AbstractTransplant-associated thrombotic microangiopathy (TA-TMA) is a fatal posttransplant complication of hematopoietic stem cell transplantation. We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal bleeding showed poor survival, even when treated with more frequent doses. Our objective was to develop separate models in bleeding and nonbleeding patients with TA-TMA and to propose precision dosing algorithms. Eculizumab PK/PD was analyzed in 19 bleeding and 38 nonbleeding patients (0.5-29.9 years of age). A complement activation biomarker (sC5b-9) and body weight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding than in nonbleeding patients (83.8 vs 61.3 mL/h per 70 kg; P = .07). The high clearance was maintained over treatment doses in bleeding patients, whereas nonbleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time, regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for atypical hemolytic uremic syndrome had <15% probability of attaining the target concentration of >100 μg/mL eculizumab in nonbleeding patients. We identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision guideline for precision dosing to improve outcomes in children and young adults with TA-TMA.

Insulin Clearance in Obesity and Type 2 Diabetes.

Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

Development and Stability Analysis of a Self-propelled High Clearance Multi-utility Vehicle

A self-propelled hydraulically actuated vehicle was developed for field crops of up to 2.0 m in height to carry out different operations like spraying, weeding, harvesting. The vehicle has provision for variable/adjustable ground clearance and track width to suit different spacing and heights of horticultural crops. Gradability, torque, and power required for the vehicle were calculated based on the dimensions of the selected bias ply traction tyre. The centre of gravity of the vehicle was calculated by the weight moment method. Microsoft Excel add-in was used to create a point manipulation programme, and the positions of the standard components were determined through an iterative process. The static load over the rear wheel and front wheel was kept at 60% and 40%, respectively, for design purposes. Analysis of chassis mechanics was done to find out weight transfer and impending stability on level ground as well as longitudinal and lateral slope. In longitudinal slope, the developed vehicle was found to be stable up to 45.19° and 20.68° under static and dynamic conditions, respectively; whereas in lateral slope, the vehicle was stable up to 39.08° and 22.10° under static and dynamic conditions, respectively. The developed vehicle was tested for weeding and spraying of okra and maize crops with an average height of 1.1 m to 1.5 m. The field capacity for the spraying and weeding operations was 1.9 ha.h-1 and 0.16 ha.h-1, respectively. The cost of operation for spraying and weeding was 400 ?.ha-1 and 1,500 ?.ha-1, respectively. Weeding efficiency and plant damage of the weeder were 92.58% and 1.55%, respectively.

Differential clearance rates of microbial phylotypes by four appendicularian species

Appendicularians are abundant planktonic filter feeders that play a significant role in the pelagic food web due to their high clearance rates. Their diet and feeding rates have typically been measured as bulk chlorophyll or cell removal, with some attention given to prey size but no differentiation between the microbial phylotypes. Using a combination ofin situand laboratory incubations with flow cytometry and next-generation sequencing, we found species-specific differences in clearance rates and diet compositions of 4 common species:Oikopleura albicans,O. fusiformis,O. longicauda, andO. dioica. WhileO. albicansmost efficiently removed nano-eukaryotic algae, the other smaller species preferentially removed micron-sized pico-eukaryotic algae. Pico- and nano-eukaryotic cells constituted the major food source of the studied appendicularians despite their occurrence in oligotrophic water dominated by prokaryotic cells. Across species, pico- and nano-planktonic microalgae biomass comprised 45 to 75% of the appendicularian diets. Although non-photosynthetic bacteria were removed at lower rates than all other prey groups, their total contribution to the appendicularian diet was not trivial, representing 5 to 19% of the planktonic carbon in the appendicularian diet; pico-cyanobacteria contributed an additional 9 to 18%. Removal rates and efficiencies of pico-eukaryotes were higher than those of prokaryotes of similar size. Strikingly different clearance rates were observed for different prokaryotic phylotypes, indicating that factors other than size are involved in determining the capturability of the cells. Collectively, our findings provide additional evidence for differential retention of microbial prey among mucous-mesh grazers and its substantial effect on the upper-ocean microbial community.

Point-of-care diagnosis of cervical cancer: potential protein biomarkers in cervicovaginal fluid.

Cervical cancer (CxCa) is preventable and treatable via vaccination and screening. Cervicovaginal fluid (CVF) represents the physiological components of the female genital tract. These components are suitable to be utilized for clinical purposes, therefore, making CVF a suitable material for disease screening approaches. Due to high false-negative result rates and low attendance of current expensive routine CxCa screening methods, it has become more important to develop a point-of-care (POC) screening method that every single woman could reach worldwide. For this purpose, various self-usage apparatus have been developed for screening of the human papilloma virus (HPV) infection. Furthermore, due to the low specificity of HPV tests and the high clearance rate of HPV infections, many patients undergo overtreatment. Since proteins play an important role in cellular process and carcinogenesis, it is appropriate to use proteins in a simple screening test for the detection of carcinogenesis. In this article, POC screening tests and the studies of discovery of CVF protein biomarkers will be overviewed to consider the development of a method that can be used for the rapid and conceivable screening method of CxCa.

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease.

Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up. This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. ATI were detected in 68% (53/78) patients with a median concentration of 76ng/mL (range 23-1828). Maximum ATI concentration was <200ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no-ATI patients (P<0.001). Neutrophil CD64 ratio >6 and starting dose <7.5mg/kg independently predicted ATI in multivariable regression, while HLA-DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 [95% CI 0.64-0.96]). In this real-world cohort, ATI as low as 23ng/mL impacted drug clearance. Our data suggest that dose optimisation for low-level ATI can improve infliximab clearance and prevent loss of response.

Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab

We present a novel approach for first-in-human (FIH) dose selection of the CD20xCD3 bispecific antibody, glofitamab, based on pharmacokinetic/pharmacodynamic (PKPD) assessment in cynomolgus monkeys to select a high, safe starting dose, with cytokine release (CR) as the PD endpoint. Glofitamab pharmacokinetics were studied in mice and cynomolgus monkeys; PKPD of IL-6, TNF-α and interferon-γ release following glofitamab, with/without obinutuzumab pretreatment (Gpt) was studied in cynomolgus monkeys. Potency differences for CR between cynomolgus monkeys and humans were determined by glofitamab incubation in whole blood of both species. The PKPD model for CR was translated to humans to project a starting dose that did not induce CR exceeding a clinically-predefined threshold. In cynomolgus monkeys, glofitamab showed a species-specific atypical high clearance, with and without B-cell debulking by Gpt. CR was related to glofitamab serum levels and B-cell counts. B-cell reduction by Gpt led to a marked decrease in CR. FIH starting dose (5 µg) was selected based on IL-6 release considering the markedly higher glofitamab in vitro potency in human vs monkey blood. This is a novel PKPD-based approach for selection of FIH starting dose for a CD20xCD3 bispecific antibody in B-cell lymphoma, evidenced in the glofitamab study, NP30179 (NCT03075696).

Furosemide clearance in very preterm neonates early in life: A pilot study using scavenged samples

Furosemide is an off-label drug frequently used as a diuretic in neonates with oliguria and/or edema. Its clearance in preterm neonates is lower than in term neonates or children. We aimed herein to clarify furosemide clearance (CL) in very preterm (VP) neonates (< 28 weeks gestation) within the first two weeks of life and identify the factors predictive of the PK parameters, such as CL. Furosemide was administered at 0.5 or 1 mg/kg in a 0.5-h infusion via a syringe pump, and blood samples were drawn from an artery or vein after the intravenous injection. The serum furosemide concentration was measured using high-performance liquid chromatography. The PK parameters were then analyzed using Bayesian estimation. Thirteen blood samples were obtained from ten VP neonates after intravenous injection. The mean postconceptional age and mean postnatal days at exposure to furosemide was 26.9 weeks and 7.1 days, respectively. The estimated mean CL was 16.5 mL/kg/h. The mean distribution volume (Vd) and elimination half-life (t1/2) was 0.37 L/kg and 15.3 h, respectively. Furosemide CL was negatively associated with serum creatinine (SCr) [CL = 84.2 - 67.1 × SCr (mg/dL)]. VP neonates within the first two weeks of life had a higher CL than subjects in other preterm neonatal studies. The SCr level was the sole parameter influencing furosemide CL and might serve as a good index for furosemide dosing in VP neonates.

Light- and laser-based treatments for granuloma annulare: A systematic review.

Granuloma annulare (GA) is challenging to treat, especially when generalized. A systematic review to support the use of light- and laser-based treatments for GA is lacking. We performed a systematic review by searching Cochrane, MEDLINE, and Embase. Title, abstract, full-text screening, and data extraction were done in duplicate. Quality appraisal was performed using the Joanna Briggs Institute critical appraisal tool for case series. Thirty-one case series met the inclusion criteria, representing a total of 336 patients. Overall, psoralen ultraviolet light A (PUVA) showed the greatest frequency of cases with complete response (59%, n=77/131), followed by photodynamic therapy (PDT) (52%, n=13/25), ultraviolet light B (UVB)/narrowband UVB (nbUVB)/excimer laser (40%, n=19/47), UVA1 (31%, n=27/86), and lasers (29%, n=8/28). Overall across treatment modalities, higher response rates were seen in localized GA compared to generalized GA. The body of evidence for light- and laser-based treatment of GA is sparse. Our results suggest that PUVA has a high clearance rate for GA but its use may be limited by concerns of carcinogenesis. Although PDT has the second highest clearance rate, adverse effects, small sample sizes, impractical treatment delivery (especially with generalized disease), and long-term concerns of carcinogenesis may limit its use. Although UVB/nbUVB/excimer laser appeared slightly less effective than other light therapies, we recommend UVB/nbUVB/excimer laser therapy as a first-line treatment for patients with generalized GA given wider availability and a favorable long-term safety profile.

A Bright, Renal‐Clearable NIR‐II Brush Macromolecular Probe with Long Blood Circulation Time for Kidney Disease Bioimaging

AbstractEarly detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near‐infrared window (NIR‐II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR‐II organic renal‐clearable probes are hampered by their low brightness (ϵmaxΦf&gt;1000 nm&lt;10 M−1 cm−1) and limited blood circulation time (t1/2&lt;2 h), which impede the targeted imaging performance. Herein, we develop the aza‐boron‐dipyrromethene (aza‐BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmaxΦf&gt;1000 nm≈60 M−1 cm−1), which is about 10‐fold higher than that of previously reported NIR‐II renal‐clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non‐invasively diagnosis of renal ischemia‐reperfusion injury (RIR) earlier than clinical serum‐based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2≈6.1 h) and higher brightness than traditional PEGylated renal‐clearable control fluorophores (t1/2&lt;2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.

A Bright, Renal-Clearable NIR-II Brush Macromolecular Probe with Long Blood Circulation Time for Kidney Disease Bioimaging.

Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near-infrared window (NIR-II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR-II organic renal-clearable probes are hampered by their low brightness (ϵmax Φf>1000 nm <10 M-1 cm-1 ) and limited blood circulation time (t1/2 <2 h), which impede the targeted imaging performance. Herein, we develop the aza-boron-dipyrromethene (aza-BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmax Φf>1000 nm ≈60 M-1 cm-1 ), which is about 10-fold higher than that of previously reported NIR-II renal-clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non-invasively diagnosis of renal ischemia-reperfusion injury (RIR) earlier than clinical serum-based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2 ≈6.1 h) and higher brightness than traditional PEGylated renal-clearable control fluorophores (t1/2 <2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal-to-noise ratio and extended retention time.

Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100mL/min.

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose‐reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti–factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti–factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60‐75 mg) resulted in ≈25% exposure increase in the 75‐mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

Driver Behavior When Overtaking Cyclists Riding in Different Group Configurations on Two-Lane Rural Roads.

The presence of cyclists on Spanish rural roads is ever increasing and currently frequent, and thus becoming a serious safety concern. In rural environments, the risk of a crash is higher than in rural areas. The main cause is the higher speed of motor vehicles during overtaking manoeuvres. This manoeuvre is especially challenging when cyclists ride in groups as they may change size, length, shape, and speed along their route. These variables and those related to road cross-section can influence driver behaviour when overtaking a group of cyclists. To study this, instrumented bicycles were used to ride along five road segments with different geometric and traffic characteristics. Cyclists rode individually and in groups. Overtaking was evaluated by analysing the lateral distance, the speed, and other characteristics of the manoeuvre. Wider roads presented higher lateral clearances and overtaking speeds. Narrower roads had a high opposing lane invasion but a high level of compliance with the minimum lateral clearance. A higher clearance and lower speed of overtaking vehicles was registered when cyclists rode in line. Compliance with the 1.5 m clearance depended on the group configuration, being higher when cyclists rode in line. However, overtaking cyclists riding two abreast presented more accelerative manoeuvres, especially on narrow roads.

162P Population pharmacokinetic modeling of tremelimumab in patients (pts) with advanced solid tumors

Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) human monoclonal antibody of the immunoglobulin G2 kappa isotype, has been studied in oncology clinical trials as both monotherapy (MONO) and in combination with durvalumab (COMBO). Previous pharmacokinetic (PK) analyses showed that tremelimumab as monotherapy exhibits linear PK and that higher clearance (CL) may be associated with higher disease burden or poorer efficacy outcomes. Here we used updated/newly available data to build and validate an up-to-date population PK model for tremelimumab.

Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects.

This open-label, single-period study describes the human absorption, distribution, metabolism, excretion, and pharmacokinetics of velsecorat (AZD7594). Healthy subjects received inhaled velsecorat (non-radiolabeled; 720 µg) followed by intravenous infusion of carbon 14 (14C)-velsecorat (30 µg). Plasma, urine, and feces were collected up to 168 hours post-dose. Objectives included identification and quantification of velsecorat and its metabolites (i.e., drug-related material) in plasma and excreta, and determining the elimination pathways of velsecorat by measuring the rate and route of excretion, plasma half-life (t1/2), clearance, volume of distribution and mean recovery of radioactivity. On average, 76.0% of administered 14C dose was recovered by the end of the sampling period (urine = 24.4%; feces = 51.6%), with no unchanged compound recovered in excreta, suggesting that biliary excretion is the main elimination route. Compared with intravenous 14C-velsecorat, inhaled velsecorat had a longer t1/2 (27 versus 2 hours), confirming that plasma elimination is absorption-rate-limited from the lungs. Following intravenous administration, t1/2 of 14C-drug-related material was longer than for unchanged velsecorat, and 20% of the 14C plasma content was related to unchanged velsecorat. The geometric mean plasma clearance of velsecorat was high (70.7 l/h) and the geometric mean volume of distribution at steady state was 113 l. Velsecorat was substantially metabolized via O-dealkylation of the indazole ether followed by sulfate conjugation, forming the M1 metabolite, the major metabolite in plasma. There were 15 minor metabolites. Velsecorat was well tolerated, and these results support the progression of velsecorat to phase 3 studies. SIGNIFICANCE STATEMENT: This study describes the human pharmacokinetics and metabolism of velsecorat, a selective glucocorticoid receptor modulator, evaluated via co-administration of a radiolabeled intravenous microtracer dose and a non-radiolabeled inhaled dose. This study provides a comprehensive assessment of the disposition of velsecorat in humans. It also highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion for velsecorat, related to the inhaled route, the high metabolic clearance, sequential metabolite formation and the low intravenous dose.

Comparison of nephroscopy and cystoscopy used in the treatment of bladder stones: a systematic review and meta-analysis of randomized controlled trials

BackgroundA systematic review and meta-analysis was conducted to compare the safety and efficiency of nephroscopy and cystoscopy in transurethral cystolithotripsy (TUCL) for bladder stones (BS).MethodsThe PubMed, Web of Science, Embase, EBSCO, and Cochrane Library databases were searched up to January 2021 for studies assessing the effect of different types of endoscopes among patients who underwent TUCL. The search strategy and study selection process were in accordance with the PRISMA statement.Results Five randomized controlled trials were included in the meta-analysis. The results showed no difference in stone-free rate (RR = 1.00, CI = 0.98–1.02, p = 1.00) between the two groups and nonsignificant heterogeneity (I2 = 0%, p = 1.00), and all patients were rendered stone free. Use of the nephroscope significantly shortened the operative time compared with the cystoscope group (RR= − 26.26, CI = − 35.84 to − 16.68, p < 0.00001), and there was significant heterogeneity (I2= 87%, p < 0.00001). There was no significant difference in mean urethral entries (RR = 0.66, CI = − 0.71 to − 2.04, p = 0.35), hospitalization (MD = 0.08, 95% CI = − 0.07 to 0.23, p = 0.31) or total complication rate (RR=1.37, 95% CI = 0.47–4.00, p = 0.56) between the two groups.ConclusionsIn conclusion, this systematic review demonstrates that both nephroscopy and cystoscopy have high stone clearance efficiency, low rates of complications and short hospitalizations. The mean urethral entries depend on the treatment method for large stone fragments. However, the use of nephroscopy can significantly reduce the operative time.

Abstract P237: PRT2527 is a potent and selective CDK9 inhibitor that demonstrates anti-cancer activity in preclinical models of hematological malignancies and solid tumors with MYC amplification

Abstract Cyclin-dependent kinase 9 (CDK9) is a master regulator of transcription that controls paused RNA polymerase II (RNAP2) release through phosphorylation of its carboxy-terminal domain, resulting in productive transcription elongation. CDK9 has been extensively studied as a potential target for cancer therapy in “transcriptionally addicted” tumors as transient inhibition of CDK9 primarily depletes proteins with short half-lives, such as the oncogenes MCL1 and MYC, making CDK9 a promising target in cancer. Here we show that PRT2527 is a potent and highly selective CDK9 inhibitor with moderate to high clearance that achieves optimal temporal target engagement and exhibits potent in vitro and in vivo activities. PRT2527 inhibited CDK9 enzymatic activity with an IC50 of 0.98 nM in a biochemical assay and showed high selectivity in a panel of kinases when tested at physiologically relevant 1 mM ATP concentration. In vitro, PRT2527 inhibited phosphorylation of Ser2RNAP2 in NCI-H929 cells with an IC50 of 54 nM, and an IC50 of 198 nM in a plasma assay to adjust for human plasma protein binding. Transient treatment of cells with PRT2527 inhibited pSer2RNAP2, depleted MCL1 and MYC proteins, and activated cleaved caspase-3 (CC3) in a concentration-dependent manner. In a proteomic profiling study, MCL1 was identified as one of the major down-regulated proteins following PRT2527 treatment. In a panel of hematological cancer cell lines representing B- and T-ALL, AML, and non-Hodgkin’s lymphoma (NHL), as well as subsets of sarcoma, prostate, adenoid cystic carcinoma (ACC), and non-small cell lung cancer (NSCLC) cell lines, PRT2527 treatment consistently led to a potent, concentration-dependent inhibition of proliferation. In a pharmacokinetic/pharmacodynamic (PK/PD) study, intravenous (IV) administration of PRT2527 achieved transient target engagement, depletion of MCL1 and MYC proteins, and induction of apoptosis in tumor tissue. This PK/PD correlation was successfully translated into in vivo efficacy in multiple models. Once weekly dosing of PRT2527 was well-tolerated and significantly inhibited tumor growth in various AML CDX models and induced tumor regressions in double-hit and triple-hit diffuse large B-cell lymphoma (DLBCL) CDX and PDX models carrying the MYC translocation. Combining PRT2527 with venetoclax achieved complete tumor regressions in a venetoclax resistant OCI-AML3 model. PRT2527 demonstrated potent ex vivo activity in PDX models of B-ALL and T-ALL, as well as various solid tumor PDX models with high levels of MYC amplification and overexpression, including pancreatic carcinoma, gastric and gastroesophageal carcinomas, NSCLC, and sarcoma. In vivo efficacy studies with once weekly IV administration of PRT2527 confirmed significant tumor growth inhibition in select MYC-amplified solid tumor PDX models. Taken together, this preclinical characterization supports the advancement of PRT2527 into clinical studies for transcriptionally addicted hematological malignancies and solid tumors with MYC amplification and/or dysregulation. Citation Format: Yang W. Zhang, Liang Lu, Min Wang, Dave Rominger, Stefan Ruepp, Kirsten Gallagher, William Gowen-MacDonald, Chaofeng Dai, Miles Cowart, Andrew Combs, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. PRT2527 is a potent and selective CDK9 inhibitor that demonstrates anti-cancer activity in preclinical models of hematological malignancies and solid tumors with MYC amplification [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P237.

Antiarthritic activity of OA-DHZ; a gastroprotective NF-κB/MAPK/COX inhibitor.

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1β by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration.

Podophyllotoxin-combined 5-aminolevulinic acid photodynamic therapy significantly promotes HR-HPV-infected cell death.

Human papillomavirus (HPV) infection and related diseases are difficult clinical challenges. The efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating condyloma acuminata is remarkable, with high virus clearance and low recurrence rates. Podophyllotoxin (POD) is the first-line drug with a significant therapeutic effect on condyloma acuminata. However, no studies have determined whether POD-combined ALA-PDT improves high-risk (HR)-HPV-infected cell killing. We aimed to investigate whether POD-combined ALA-PDT could promote HPV-infected cell death more effectively than the single treatment and explore the underlying mechanism. In HeLa and SiHa cells, flow cytometry, EdU assay and LDH release test were used to detect apoptosis, cell proliferation change and necrosis, respectively. To investigate whether the combined therapy might activate apoptosis and induce endoplasmic reticulum (ER) stress, flow cytometry was used to determine intracellular levels of ROS and calcium, and Western blotting was used to determine the expression of related proteins. Mitochondrial membrane depolarization was detected by JC-1 assay. Immunofluorescence staining and Western blotting were used to detect the activation of autophagy. Podophyllotoxin -combined ALA-PDT inhibited the proliferation and promoted apoptosis and necrosis more effectively than the single treatment at the same intensity and concentration. The activation of the caspase-dependent apoptosis pathway, ER stress and autophagy was more substantial in POD-combined ALA-PDT than with single treatments. Podophyllotoxin -combined ALA-PDT effectively promoted cell death through several pathways in HeLa and SiHa cells. This combination might be a promising therapeutic strategy for the HR-HPV infection.

Comparison in Growth, Feeding, and Metabolism Between a Fast-Growing Selective Strain and a Cultured Population of Pearl Oyster (Pinctada fucata martensii)

Pearl oyster (Pinctada fucata martensii) is the main species cultured for marine pearls in the world. A breeding program was carried out for desirable production traits, including high growth rate, and a fast-growing selective strain of pearl oysters was established. In the current study, we compared the growth characteristics between a selective strain and a cultured population of P. f. martensii in Beihai, Guangxi Province, China. Large size (SL) and small size (SS) individuals of the selective strain were selected, and the differences of physiological and metabolic indexes, such as feeding, respiration, excretion, and enzyme activities between SL and SS and cultured population (CL), were also compared. The results showed that at the age of 6 months, pearl oysters of the selective strain were 14.61% larger than CL, and the proportion of SL (30–40 mm) was 59%, which was two times higher than CL (28%). SL with a rapid growth rate had a high clearance rate (CR), and the CR of SL was about 1.8 times higher than that of CL and 5 times higher than that of SS. In addition, the activities of digestive enzymes (amylase, pepsin, and lipase) and growth-related carbonic anhydrase enzymes in SL were higher than those in the other two groups (p &amp;lt; 0.05). SS with a slow growth rate had higher oxygen consumption (OCR) and ammonia excretion (AER) rates than SL and CL (p &amp;lt; 0.05). Our results suggest that the rapid growth of the selective strain P. f. martensii can be attributed to increased energy intake and reduced energy consumption.