Evaluation of intramural hematoma: a novel use of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging.

BACKGROUND: Aortic intramural hematoma (IMH) is one of the typical entities of acute aortic syndrome and probably accounts for 5-25% of all cases. The ulcer-like projections (ULP), which are described as a focal, blood-filled pouch protruding into the hematoma of the aortic wall, are regarded as one of the high-risk imaging features of IMH and may cause initial medical treatment failure and death. CASE PRESENTATION: We present a case report of an acute type B IMH patient with impaired renal function and newly developed ULP in the acute phase. The 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MR) was performed to evaluate the condition of aortic hematoma. The 18F-FDG focal uptake along the aortic wall of the hematoma was normal compared to the background (SUVmax 2.17; SUVSVC 1.6; TBR 1.35). We considered the IMH stable in such cases and opted for medical treatment and watchful observation. Six months after discharge, the patient's recovery was satisfactory, and aortic remodeling was ideal. CONCLUSIONS: The 18F-FDG PET/MR is a novel tool to evaluate the risk of IMH patients and thus provides information for therapy selection.

Development of a novel patient-reported outcome measure for orthognathic surgery.

OBJECTIVES: This study aimed to develop a new patient-reported outcome measure (PROM) to systematically and scientifically evaluate patients' subjective feelings after orthognathic surgery. METHODS: A literature review and semi-structured interviews were conducted to construct a conceptual framework and an item pool, followed by expert and patient surveys for measure construction. We conducted a clinical investigation to test the feasibility, reliability, and content validity of this measure. RESULTS: The conceptual framework included four domains: psychological health, physiological health, social function, and satisfaction, and 33 items were included in the survey. Following the expert analysis, 31 items remained in the draft. The clinical investigation showed a 100% recovery and completion rate and good reliability, with Cronman-Brown formula coefficients of 0.893 and 0.944, respectively. CONCLUSIONS: A new outcome measure to evaluate patients' subjective feelings after orthognathic surgery was successfully developed, and the clinical investigation demonstrated that the PROM had satisfactory feasibility, reliability, and validity. Further studies are possible based on our PROM, and data on a larger scale may reveal more information on patients' subjective feelings about orthognathic surgery. CLINICAL SIGNIFICANCE: The novel PROM provides a systematic and scientific way to evaluate the patient's subjective feelings to help surgeons obtain complete patient-reported information after orthognathic surgery. Additionally, standardised multicentre research on patients' subjective feelings using our PROM is possible and could improve the effectiveness of the evaluation and help maintain treatment quality.

Cutting time & height improve carbon and energy use efficiency of the forage-food dual-purpose ratoon rice cropping.

Forage-food dual-purpose ratoon rice cropping (FFRR) is used to balance forage demands with ratoon rice grain yields, that is whole plant (stem and sheath, panicles) cuttings in the main season are used as forage, and rice in the regeneration season is used as food. In this study, the local ratoon rice production system as the control, we were carried out the field experiment of cultivation practices (cutting time and cutting height), and investigated the system productivity, economic benefits, carbon footprints and energy use efficiency. The energy use efficiency, energy productivity and energy profitability increased with cutting time delay, and cutting height decreased. Significant differences of these index were observed among the treatments for cutting time and cutting height (p < 0.05). Carbon efficiency and carbon sustainability index was increase with cutting time delay, and there was significant difference among the treatment of cutting time in 2018 (p < 0.05), the minimum carbon footprint of FFRR was 78.6 kgCO2 t-1 averagely at the cutting time of 30 days after the flowering stage. In 2018, the maximum net income of FFRR was 30,577 CNY hm-2 at a cutting time of 30 days after the flowering stage while the stubble height was 10 cm, and dependent on the forage yield of the main crop; in 2019, the maximum net income of FFRR was 27,326 CNY hm-2 at a cutting time of 10 days after the flowering stage while the stubble height was 10 cm, and dependent on the grain yield of the ratoon crop. Therefore, the optimal cultivation practice of the FFRR (cutting at 30 days after the flowering stage and with a stubble height of 10 cm) showed higher carbon and energy use efficiency, economic benefits of the FFRR were fluctuated with the price of forage of the main crop and rice grain of the ratoon crop.

An overview of PROTACs: a promising drug discovery paradigm.

Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin-proteasome system. Currently, about 20-25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.

Visibility, wind speed, and dew point temperature are important factors in SARS-CoV-2 transmissibility.

The aim of this study is to provide evidence for the influencing factors of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus mutation by determining the impact of geographical and meteorological factors on SARS-CoV-2 transmission, and the different impacts of SARS-CoV-2 variant strains. From January 20 to March 10, 2020, we collected a number of daily confirmed new cases and meteorological factors in all cities and regions in China and Italy affected by the Alpha "variants of concern" (VOC). We also collected the daily confirmed cases of the Delta VOC infection in China and Italy from May 21 to November 30, 2021. The relationships between daily meteorological data and daily verified new cases of SARS-CoV-2 transmission were then investigated using a general additive model (GAM) with a log link function and Poisson family. The results revealed that latitude was substantially connected with daily confirmed new instances of the Alpha VOC, while there was no such correlation with Delta VOC transmission. When visibility is greater than 7 m, the propagation of the Alpha and Delta VOCs in Italy and China can be controlled. Furthermore, greater temperatures and increased wind speed reduce the transmission of the Alpha and Delta VOCs. In conclusion, geographical and meteorological factors play an important role in SARS-CoV-2 transmissibility and should be considered in virus mitigation strategies.

Safety, Efficacy, and Pharmacokinetics of HP501 in Healthy Volunteers and Hyperuricemic Patients: A Phase I/IIa Study.

CONTEXT: Uricosuric agents are the typical approach to the control of hyperuricemia; however, their use has been eclipsed by adverse reactions, and a safer uricosuric drug is badly needed. OBJECTIVE: HP501 is a novel renal urate transporter 1 inhibitor for the treatment of hyperuricemia. In this first-in-human study, we investigated the safety, efficacy, and pharmacokinetics of HP501 in healthy volunteers and hyperuricemic patients. METHODS: The placebo-controlled, double-blind, randomized, 3-part, phase I/IIa study consists of a single ascending dose (SAD) part with 32 participants, a multiple ascending dose part with 48 participants, and a drug-drug interaction part with 20 participants. Effects of food in healthy volunteers administered 45 mg HP501 in the fed state were also assessed in the SAD part. RESULTS: A total of 68 healthy volunteers and 32 hyperuricemic patients were enrolled. HP501 appeared to be safe and well tolerated in both groups. In hyperuricemic patients dosed with 45 mg HP501 over 10 days, 2/10 and 3/10 patients had elevated AST (< 2 times upper limit of normal [ULN]) and ALT (< 2.5 times ULN), respectively. No dose-limiting adverse events were observed. Across doses of HP501 from 5 to 60 mg, the concentrations of serum uric acid (sUA) are reduced by a maximum of about 50%. HP501 exhibited predictable pharmacokinetics across different dose levels in healthy volunteers or hyperuricemic patients. HP501 and febuxostat have obvious synergistic sUA-lowering effects with no apparent pharmacokinetics interaction. CONCLUSION: HP501 was effective at reducing sUA in healthy volunteers and hyperuricemic patients with a tolerable safety profile, warranting further development.

Evaluation of efficacy of rituximab for membranous nephropathy: A systematic review and meta-analysis of 11 studies.

INTRODUCTION: The use of traditional immunosuppressive medicines for the treatment of membranous nephropathy is being challenged, owing to its limited efficacy and tolerability. Research on M-type phospholipase A2 receptor antibodies has provided a new way for evaluating the efficiency and prognosis of treatment of membranous nephropathy. However, the relationship between rituximab, a monoclonal antibody against CD20, and antiphospholipase A2 receptor antibodies and the drug regimen of rituximab for membranous nephropathy is uncertain. We conducted a meta-analysis to evaluate the efficacy of rituximab treatments in membranous nephropathy and compared the clinical effects of first-line and second-line rituximab therapies. METHODS: PubMed, Embase, Web of Science, Scopus, the Cochrane Central Register ofControlled Trials, and ClinicalTrials.gov were searched to find articles about rituximab treatment of patients with membranous nephropathy between January 2000 and August 2020. The outcomes included remission, antiphospholipase A2 receptor antibodies, relapse, and adverse events. The Grading of Recommendations Assessment Development and Evaluation criteria were used to evaluate the strength of evidence. RESULTS: A total of 723 participants from 11 trials were included in this meta-analysis. The other treatments included cyclosporine, cyclophosphamide, steroids, and non-immunosuppressive antiproteinuric treatment. Rituximab significantly improved cumulative remission (P=0.007; Odds Ratio [OR]=3.06; 95% confidence interval [CI]=1.35-6.94) compared with other treatments. It significantly reduced relapse (P<0.00001; OR=0.06; 95% CI=0.02-0.19), antiphospholipase A2 receptor antibody levels (P=0.0009; SMD=-0.52; 95% CI=-0.83 to -0.21), and the proportion of patients positive for anti-PLA2R antibodies (P=0.003; OR=6.11; 95% CI=1.85-20.24) compared with other treatments. Compared with the second-line, first-line rituximab therapy achieved a higher rate of cumulative remission (P=0.03; OR=0.32, 95% CI=0.11-0.91). CONCLUSIONS: Rituximab can improve the rate of clinical remission in patients with membranous nephropathy. Rituximab was more effective than other treatments in reducing relapse, antiphospholipase A2 receptor antibody levels, and the proportion of patients positive for antiphospholipase A2 receptor antibodies. The clinical remission rate following first-line rituximab therapy was better than that of second-line rituximab therapy for membranous nephropathy.

[A photothermal/chemotherapy injectable paclitaxel gel with irradiation stability].

The aim of this study is to construct an injectable gel with stable phototherapy and chemotherapy. Res-PTX@IR780 gel with phototherapy and chemotherapy property was prepared by introduction of photosensitizer IR780 and antioxidant resveratrol (Res) into the polyethylene glycol (PEG) solution of paclitaxel (PTX). The results showed that PTX, PTX@IR780 and Res-PTX@IR780 could form gels and the gels were injectable. ATR-FTIR results indicated not only components of the gels but also the formation of hydrogen bonding during the gelation. The results of UV showed instability of IR780 solution and stability improvement of Res-IR780 solution under infrared radiation (IR) irradiation. Photothermal tests showed that Res-PTX@IR780 displayed better photothermal conversion and photothermal stability under multiple irradiations than PTX@IR780. The results of in vivo exploration in mice showed that the skin site injected with Res-PTX@IR780 gel heated up from 35 ℃ to 64 ℃, and the temperature difference was up to 30 ℃. Res-PTX@IR780 gel is very promising as a combination agent of photothermal therapy and chemotherapy for the in situ treatment of tumors due to good photothermal conversion and photothermal stability under multiple irradiations.

Toward a Mobile Platform for Real-world Digital Measurement of Depression: User-Centered Design, Data Quality, and Behavioral and Clinical Modeling.

BACKGROUND: Although effective mental health treatments exist, the ability to match individuals to optimal treatments is poor, and timely assessment of response is difficult. One reason for these challenges is the lack of objective measurement of psychiatric symptoms. Sensors and active tasks recorded by smartphones provide a low-burden, low-cost, and scalable way to capture real-world data from patients that could augment clinical decision-making and move the field of mental health closer to measurement-based care. OBJECTIVE: This study tests the feasibility of a fully remote study on individuals with self-reported depression using an Android-based smartphone app to collect subjective and objective measures associated with depression severity. The goals of this pilot study are to develop an engaging user interface for high task adherence through user-centered design; test the quality of collected data from passive sensors; start building clinically relevant behavioral measures (features) from passive sensors and active inputs; and preliminarily explore connections between these features and depression severity. METHODS: A total of 600 participants were asked to download the study app to join this fully remote, observational 12-week study. The app passively collected 20 sensor data streams (eg, ambient audio level, location, and inertial measurement units), and participants were asked to complete daily survey tasks, weekly voice diaries, and the clinically validated Patient Health Questionnaire (PHQ-9) self-survey. Pairwise correlations between derived behavioral features (eg, weekly minutes spent at home) and PHQ-9 were computed. Using these behavioral features, we also constructed an elastic net penalized multivariate logistic regression model predicting depressed versus nondepressed PHQ-9 scores (ie, dichotomized PHQ-9). RESULTS: A total of 415 individuals logged into the app. Over the course of the 12-week study, these participants completed 83.35% (4151/4980) of the PHQ-9s. Applying data sufficiency rules for minimally necessary daily and weekly data resulted in 3779 participant-weeks of data across 384 participants. Using a subset of 34 behavioral features, we found that 11 features showed a significant (P<.001 Benjamini-Hochberg adjusted) Spearman correlation with weekly PHQ-9, including voice diary-derived word sentiment and ambient audio levels. Restricting the data to those cases in which all 34 behavioral features were present, we had available 1013 participant-weeks from 186 participants. The logistic regression model predicting depression status resulted in a 10-fold cross-validated mean area under the curve of 0.656 (SD 0.079). CONCLUSIONS: This study finds a strong proof of concept for the use of a smartphone-based assessment of depression outcomes. Behavioral features derived from passive sensors and active tasks show promising correlations with a validated clinical measure of depression (PHQ-9). Future work is needed to increase scale that may permit the construction of more complex (eg, nonlinear) predictive models and better handle data missingness.

Phase I clinical trial of HC-1119: A deuterated form of enzalutamide.

The purpose of our study was to investigate the safety, pharmacokinetics (PK), and initial antitumor efficacy of HC-1119 in patients with metastatic castration-resistant prostate cancer (mCRPC). Eligible mCRPC patients were included in our study (NCT03774056) with two parts. Part A was a dose escalation study in which patients received a dose escalation of HC-1119 (40, 80, 160 and 200 mg/day). Part B was a dose expansion study in which patients received HC-1119 at the dose of 80 and 160 mg. Safety assessment and pharmacokinetic samplings were performed for all patients at the given time points; preliminary tumor response was also assessed. Twenty-four patients were enrolled in part A and 19 patients in part B, respectively. HC-1119 was safe, well tolerated and no dose-limiting toxicity was observed. Fatigue was the most common treatment-related adverse event and no seizures were observed. At the dose levels of 40, 80 and 160 mg, the AUC and Cmax of HC-1119 in plasma increased almost dose-proportionally at the steady state in mCRPC patients. Maximum prostate-specific antigen (PSA) response rates (≥50% reduction from the baseline) in dose escalation and dose expansion cohorts were 77% and 75%, respectively; the overall disease control rate (22 patients available for imaging analysis) was 72.7%, with PR in 4 patients, SD in 12 patients and PD in 6 patients; the 2-year overall survival rate in patients from Part B was 56.8%. HC-1119 was safe, well tolerated and efficacious and HC-1119 at 80 mg/day is recommended for further studies.

Injectable Self-Healing Hydrogels Containing CuS Nanoparticles with Abilities of Hemostasis, Antibacterial activity, and Promoting Wound Healing.

Injectable self-healing hydrogels containing functional nanoparticles (NPs) have attracted much attention in many fields of biomedicine. A series of injectable self-healing hydrogels containing PEGylation CuS NPs based on N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OA) were developed by taking advantages of the unique functions of CuS NPs and chitosan, referred to as CuS NP hydrogels or CEC-OAm-CuSn, where "m" stands for the concentration percentage of the added OA solution (w/v) and "n" represents the molar concentration of CuS NPs in the hydrogels. The physical properties of CuS NP hydrogels, syringeability, rapid self-repair ability, and photothermal performance were systematically investigated. The multiple functions for CuS NP hydrogels requested in the skin healing process were explored. The results showed that CuS NP hydrogels had not only adjustable physical properties and good injectable self-healing characteristics but also excellent functionalities, concurrently including hemostatic ability, bacteria killing capability, and cell migration and proliferation promotion. In vivo wound healing and histomorphological examinations of immunofluorescence staining in a mouse full-thickness wound model demonstrated good acceleration effects of these hydrogels for infected wound healing. Therefore, these injectable self-healing CuS NP hydrogels which possess the abilities of hemostasis, antibacterial activity, and infected-wound healing promotion exhibit great potential as in situ wound dressings.

Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.

Elastic sowing dates with low seeding rate for grain yield maintenance in mechanized large-scale double-cropped rice production.

Elastic sowing dates (ESDs) are correlated with rice grain yield. ESD is the easiest factor for farmers to manipulate in mechanized large-scale farming. In this study, field experiments were conducted over a 2-year period to determine the effects of different sowing dates on growth duration, effective accumulated temperature, and yield attributes in two early- and late-season machine-transplanted rice cultivars. In early rice (ER), a delay in the sowing date led to decreased grain yield and shorter growth duration. In late rice (LR), delayed sowing led to significantly lower grain yield and prolonged growth duration. In LR, significantly positive correlations were detected between effective accumulated temperature in the post-heading stage and both filling ratio and yield. Reproductive redundancy increased markedly in LR, by 7.72% over a 5-day interval. We determined that the ESDs for LR were 10 days later than the control, and that of ER was recommend early sowing rather than late sowing. These findings suggest a new strategy to meet the demands of mechanized large-scale rice farming: the development of thermal sensitive high-yield long-duration ER cultivars and high-yield short-duration LR cultivars.

The novel long noncoding RNA lncRNA-Adi regulates adipogenesis.

Adipogenesis participates in many physiological and pathological processes, such as obesity and diabetes, and is regulated by a series of precise molecular events. However, the molecules involved in this regulation have not been fully characterized. In this study, we identified a long noncoding (lnc)RNA, lncRNA-Adi, which is highly expressed in adipose tissue-derived stromal cells (ADSCs) that are differentiating into adipocytes. Knockdown of lncRNA-Adi impaired the adipogenic differentiation ability of ADSCs. Moreover, lncRNA-Adi was found to interact with microRNA (miR)-449a to enhance the expression of cyclin-dependent kinase (CDK)6 during adipogenesis. The mechanism by which lncRNA-Adi regulates adipogenesis was determined to involve an lncRNA-Adi-miR-449a interaction that competes with the CDK6 3' untranslated region to increase CDK6 translation and activate the pRb-E2F1 pathway to promote adipogenesis. These findings provide valuable information and a new study angle to search for therapeutic targets against metabolic disorders such as obesity and diabetes.

Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer.

Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.

Triclosan-loaded pH-responsive copolymer to target bacteria and to have long bacteriostatic efficacy.

It is important to reduce side effects and to explore novel usage for hydrophobic broad-spectrum antibacterial agent triclosan (TCS). In this study, a new amphiphilic copolymer with tertiary amine groups, monomethyl ether poly(ethylene glycol)-b-poly{α-[4-(diethylamino)methyl-1,2,3-triazol]-caprolactone-co-caprolactone} (mPEG-PDCL) was designed and synthesized, and its micelles were applied as carries of TCS to enhance antimicrobial and bacteriostatic action. mPEG-PDCL and its contrastive copolymer mPEG-PCL could form uniform spherical micelles with sizes 50-110 nm. The zeta potential of mPEG-PDCL micelles was positive and changed from 7.00 ± 0.67 mV at pH 7.5 to 24.67 ± 1.23 mV at pH 5.5. Both TCS-loaded micelles displayed quite high drug loading content (approx. 15%) and drug loading efficiency (more than 85%). In comparison with pH 7.4, TCS released faster in acidic environment which was induced by bacteria metabolism. MIC values of both TCS-loaded micelles against S. aureus and E. coli were as low as free TCS. TCS-loaded micelles showed much better antibacterial activity than free TCS, especially, mPEG-PDCL/TCS micelles displayed long bacteriostatic efficacy in 60 h against S. aureus and in 54 h against E. coli. mPEG-PDCL micelles preferred targeting to both S. aureus and E. coli due to positive zeta potential. In in vivo experiment, the purulence of the infected wound almost disappeared for SD rats treated with mPEG-PDCL/TCS micelles. Therefore, mPEG-PDCL micelles may be used as good carriers for antimicrobial agents, and the TCS-loaded micelles possess long antimicrobial/bacteriostatic efficacy.

Synergistic action of doxorubicin and 7-Ethyl-10-hydroxycamptothecin polyphosphorylcholine polymer prodrug.

There are opportunities for improvements to the efficiency and toxicity of widely used cancer chemotherapy agents such as doxorubicin (DOX·HCl) and 7-Ethyl-10-hydroxycamptothecin (SN38). We developed a safe and effective combination therapy by encapsulating DOX into micelles of a zwitterionic polymer prodrug, SN38 conjugate of poly (α-azide caprolactone-co-caprolactone)-b-poly (2-methacryloyloxyethyl phosphorylcholine [P(CL/CL-g-SN38)-b-PMPC)] which was described in our previous work. The polymer prodrug micelles displayed a higher loading capacity of DOX due to the π-π stacking effect between DOX and SN38 in comparison with the micelles self-assembled by prodrug's precursor, poly(α-azide caprolactone-co-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine (P(ACL/CL)-b-PMPC). The DOX loaded prodrug micelles decelerated the release of DOX, and also prolonged its circulation. The micelles showed favorable cellular internalization by 4T1 cells. DOX loaded SN38 prodrug micelles displayed good in vitro anticancer effects owing to the synergistic action of doxorubicin and SN38 and were as effective as DOX·HCl, but with lower toxicity than DOX·HCl. Given the synergetic effects of free drug and polymer prodrug, this nanomedicine may offer a safe and effective drug delivery methodology for conventional drug formations.

Biocompatible Polyphosphorylcholine Hydrogels with Inherent Antibacterial and Nonfouling Behavior Effectively Promote Skin Wound Healing.

Hydrogels with inherent antibacterial activity and nonfouling behavior can not only provide better environment for skin wounds to avoid infection but also accelerate wound healing. Herein, 2-(methacryloyloxy) ethyl 2-(trimethylammonio) ethyl phosphate (MPC) copolymers with epoxy groups, referred to as P(MPC-co-GMA), are designed and synthesized for preparing hydrogel wound dressing with inherent antibacterial and nonfouling properties. The P(MPC-co-GMA) hydrogel network is fabricated by a ring-opening reaction of the epoxy group with nontoxic and antibacterial cystamine under mild conditions. The hydrogel shows an appropriate swelling ratio, elastic behavior, and good cytocompatibility on L929 and RBCs. Bacteria scarcely adhered on the hydrogel surfaces, and the adhered bacteria could be killed by the hydrogels. Furthermore, curcumin (Cur) could be loaded into and released from the three-dimensional network structure of the hydrogels. P(MPC-co-GMA) hydrogel and its Cur-loaded hydrogel can accelerate wound healing of full-thickness skin injury compared to control groups. Conclusively, this polyphosphorylcholine hydrogel displays a potential application for skin wound healing on account of inherent antibacterial activity, antibacterial adhesion behavior, and drug release ability.

Development of selective mono or dual PROTAC degrader probe of CDK isoforms.

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM). In human prostate cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.