Better resolving of anti-CD38 antibody interference with blood compatibility testing by using manual polybrene method compared with dithiothreitol-pretreatment indirect antiglobulin test.

BACKGROUND: It is advised to pretreat the reagent erythrocytes with Dithiothreitol (DTT) to denature the surface CD38 to prevent anti-CD38 monoclonal antibodies (MoAb) from interfering with the blood compatibility test. Anti-CD38 has little impact on the Polybrene test, but it is still unknown how sensitive it is to detect irregular antibodies and how effective it is when compared to the standard DTT-based method. METHODS: Twenty-one patients receiving daratumumab (N = 13) and isatuximab (N = 8) had their serum collected. Standard anti-sera (anti-c, D, E, Fyb , Jka , M, Mia ) with serial dilution were added to patients' serum. Antibody screening tests were performed simultaneously using the manual polybrene method (MP) and DTT-pretreated, automatic indirect antiglobulin test (DTT-IAT) to compare the detection sensitivity. These two methods' operating times and costs were also analyzed. RESULTS: Both MP and DTT-IAT can overcome the interference caused by anti-CD38 MoAb. However, MP is more sensitive in detecting anti-M and anti-Mia and is comparable to DTT-IAT in detecting other antibodies. In terms of cost and operating time, MP is also far superior to DTT-IAT. CONCLUSION: MP is a cost-effective alternative to DTT-IAT in resolving anti-CD38 interference and is especially suitable for populations with a high prevalence of anti-M and anti-Mia . However, both methods have a well-known drawback of low detection sensitivity for anti-K, and K-units should be provided to patients to prevent hemolytic transfusion reactions.

A Smart "Sense-and-Treat" Nanoplatform Based on Semiconducting Polymer Nanoparticles for Precise Photothermal-Photodynamic Combined Therapy.

Integrated theranostic nanoplatforms with biomarker recognition and photothermal- and photodynamic (PTT/PDT) therapy is in high demand but remains challenging. Herein, a "sense-and-treat" nanoplatform based on semiconducting polymer nanoparticles (SPNs) for ratiometric bioimaging of phospholipase D (PLD) activity and PTT/PDT combined therapy was proposed. Semiconducting polymer nanoparticles (PSBTBT NPs) serve not only as photothermal agents but also as fluorescent quenchers of Rhodamine B (Rhod B) through a PLD-cleavable linker. Chlorin e6 (Ce6) was used as a photodynamic agent and fluorescence reference. The obtained nanoplatform (PSBTBT-Ce6@Rhod NPs) showed high PDT efficiency and photothermal performance upon single laser irradiation. The PTT/PDT combined therapy achieved more efficient tumor inhibition results as compared with single treatments. In addition, the overexpressed biomarker PLD in tumor tissue will cleave Rhod, leading to the fluorescence recovery of Rhod B and thus allowing the activatable fluorescence imaging of tumor and targeted phototherapy.

A novel protein upstream stimulatory factor 2 identified in lamprey, Lethenteron reissneri.

Upstream stimulatory factors are kinds of multi-functional transcription factors, which are expressed in eukaryotes widely, including Upstream stimulatory factor 1 (USFl) and upstream stimulatory factor 2 (USF2). USF protein has a typical basic helix-loop-helix leucine zipper (b-HLH-LZ) structure, which is involved in cell cycle, cell proliferations, glucose and lipid metabolism, and other biochemical processes. Although the USF family is an important regulator of cellular processes, little is known about the USF genes of lampreys, especially their evolutionary relationships, expression profiles, and biological functions. Here, an upstream stimulatory factor 2 (USF2) homolog from lamprey (Lethenteron reissneri) was identified and characterized (designated as L-USF2) because it is closer to USF2 subfamily than to USF1 subfamily. The cDNA fragment of L-USF2 has an open reading frame (ORF) of 765-bp length, encodes 254 amino acids, and contains an HLH domain at the c-terminal of amino acids. Meanwhile, motifs and genetic structure analysis reveal that USF2 gene exons are conserved. Moreover, the 3D structure analysis indicates that L-USF2 adopts the general USF2 folding and has a high structural similarity with H-USF2. The synteny results showed that the L-USF2 adjacent gene changed greatly compared with the jaw vertebrates. By real-time quantitative experiment and Western blot analysis, we found that L-USF2 gene played a significant role in the immune responses. This study not only provides us with a further understanding of the evolution and function of the USF gene family but also provides a basis for exploring its immune responses and immune defenses in lampreys.

Ag+-Adsorbing Semiconducting Polymer Nanosponge for Smart Local Treatment of Wound Infection.

Nanoplatform combined with photothermal therapy (PTT) and silver nanoparticles have been widely used to combat bacterial infections. However, the development of environmentally benign antibacterial nanoplatforms with controllable and long-term antibacterial activity is still challenging. Herein, we synthesized an Ag+-adsorbing organic semiconducting polymeric nanosponge (PDPP3T NPe@Ag+) to realize Ag+ enhanced photothermal anti-infective therapy. Furthermore, the PDPP3T NPe@Ag+ sponge can also spatiotemporally release silver ions in a pH/NIR light-responsive manner for controllable and long-term antimicrobial therapy. Owing to good biocompatibility and controlled release of silver ions, PDPP3T NPe@Ag+ can effectively kill bacteria in vitro and promote wound healing in vivo. We expect that this antimicrobial platform could be utilized as a robust antibacterial agent for infective therapy.

Percutaneous Kyphoplasty to Relieve the Rib Region Pain in Osteoporotic Thoracic Vertebral Fracture Patients Without Local Pain of Fractured Vertebra.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) are common. A few patients with thoracic vertebral fracture show pain in the bilateral rib region but not at the fracture site. The point of specific tenderness in the rib region cannot be located. It is not clear whether percutaneous kyphoplasty (PKP) can relieve the pain in the bilateral rib region in these patients. OBJECTIVE: To check whether PKP can alleviate the rib region pain in thoracic vertebral fracture patients without local pain at the fractured vertebra. STUDY DESIGN: Retrospective study. SETTING: The study was carried out at a university hospital. METHODS: We performed a retrospective analysis of thoracic vertebral fracture patients admitted to our hospital for PKP surgery between January 2018 and June 2022. The main clinical manifestations of these patients were pain in the bilateral rib region but no local tenderness and percussion pain at the fractured vertebra. CT and MRI examinations of the thoracic vertebrae were performed after admission. PKP was performed under general anesthesia after no surgical contraindication. Visual analog scale (VAS) scores and heights of the anterior, middle, and posterior edges of the fractured vertebra before the surgery, one day after surgery, and one month after surgery were compared. Also, the Cobb angles formed by the upper and lower endplate of the fractured vertebra before the surgery, one day after surgery, and one month after surgery were compared. RESULTS: A total of 50 patients were included in this study (3 men and 47 women, with an average age of 72.46 ± 8.15 years), of which 7 patients had 2 segmental fractures, so a total of 57 vertebrae were included. The VAS scores on day one and one month after the surgery were significantly lower than that before the surgery. The heights of the anterior, middle, and posterior edges of the fractured vertebra on day one after the surgery were significantly higher than those before the surgery. The Cobb angle of the fractured vertebra on day one after the surgery was lower than that before the surgery. The vertebrae of 23 patients were examined using x-ray one month after the surgery. The heights of the anterior, middle, and posterior edges of the fractured vertebra one month after the surgery were also significantly higher than those before the surgery but significantly lower than those one day after the surgery. Also, the Cobb angle of the fractured vertebra one month after the surgery was significantly lower than that before the surgery. LIMITATIONS: This was a retrospective study, which may be prone to selection and recall bias. Single-center non-controlled studies may also introduce bias. CONCLUSION: The exact location of the pain in the rib region caused by thoracic fracture cannot be identified usually. PKP can alleviate the rib region pain caused by the thoracic fracture.

PDA-Based Drug Delivery Nanosystems: A Potential Approach for Glioma Treatment.

Glioma is characterized by high mortality and low postoperative survival. Despite the availability of various therapeutic approaches and molecular typing, the treatment failure rate and the recurrence rate of glioma remain high. Given the limitations of existing therapeutic tools, nanotechnology has emerged as an alternative treatment option. Nanoparticles, such as polydopamine (PDA)-based nanoparticles, are embodied with reliable biodegradability, efficient drug loading rate, relatively low toxicity, considerable biocompatibility, excellent adhesion properties, precisely targeted delivery, and strong photothermal conversion properties. Therefore, they can further enhance the therapeutic effects in patients with glioma. Moreover, polydopamine contains pyrocatechol, amino and carboxyl groups, active double bonds, catechol, and other reactive groups that can react with biofunctional molecules containing amino, aldehyde, or sulfhydryl groups (main including, self-polymerization, non-covalent self-assembly, π-π stacking, electrostatic attraction interaction, chelation, coating and covalent co-assembly), which form a reversible dynamic covalent Schiff base bond that is extremely sensitive to pH values. Meanwhile, PDA has excellent adhesion capability that can be further functionally modified. Consequently, the aim of this review is to summarize the application of PDA-based NPs in glioma and to acquire insight into the therapeutic effect of the drug-loaded PDA-based nanocarriers (PDA NPs). A wealthy understanding and argument of these sides is anticipated to afford a better approach to develop more reasonable and valid PDA-based cancer nano-drug delivery systems. Finally, we discuss the expectation for the prospective application of PDA in this sphere and some individual viewpoints.

Highly stable semiconducting polymer nanoparticles for multi-responsive chemo/photothermal combined cancer therapy.

Rationale: Structural stability and size controllability are critical issues to semiconducting polymer nanoparticles (SPNs), which currently show great potential for theranostic applications. Methods: Herein, multi-responsive semiconducting polymer semi-interpenetrating nanoparticles (PDPP3T@PNIPAMAA IPNs) with highly stable structure and uniform size have been successfully designed by semi-interpenetrating technique. Results: It is proposed for the first time that PDPP3T@PNIPAMAA IPNs were prepared with "reinforced concrete" particle structure, which is even resistant to organic solvent such as ethanol and THF. By adjusting the polymerization time, the obtained PDPP3T@PNIPAMAA IPNs exhibit uniform and controllable particle size with extremely low polydispersity index (~0.037) at 1 h of reaction time. The presence of pH/light/GSH multi-responsive semi-interpenetrating network in PDPP3T@PNIPAMAA IPNs dramatically increase their drug loading efficiency (92.64%), which is significantly higher than previously reported comparable SPNs-based drug delivery systems. Additionally, PDPP3T@PNIPAMAA-DOX IPNs further provide improved therapeutic efficacy by the combination of chemotherapy and photothermal therapy with controllably regulated release of doxorubicin (DOX). In vitro and in vivo results indicate that PDPP3T@PNIPAMAA-DOX IPNs are able to release drugs at controlled rate by pH/light/GSH regulation and offer PAI-guided chemo/photothermal combined therapy with excellent therapeutic efficacy. Conclusions: The semi-interpenetrating network method may be generally extended for the preparation of a wide range of organic polymer nanoparticles to achieve ultrahigh structural stability, precise particle size controllability and excellent drug loading capacity.

pH/NIR-responsive semiconducting polymer nanoparticles for highly effective photoacoustic image guided chemo-photothermal synergistic therapy.

Multifunctional drug delivery nanoplatform (PDPP3T@PSNiAA NPs) based on NIR absorbing semiconducting polymer nanoparticles for pH/NIR light-controllably regulated drug release has been successfully prepared. In this strategy, pH/thermal-sensitive multifunctional polymer polystyrene-b-poly(N-isopropylacrylamide-co-acrylic acid) (PSNiAA) was meticulously designed and synthesized using the reversible addition fragmentation chain transfer (RAFT) polymerization method. Furthermore, PSNiAA was used to functionalize diketopyrrolopyrrole-based semiconducting polymer (PDPP3T) to combine photothermal capacity and pH/thermo-responsive drug release in one entity. The prepared PDPP3T@PSNiAA NPs exhibited high photothermal conversion efficiency (η = 34.1%) and excellent photoacoustic (PA) brightness. Meanwhile, benefiting from the photothermal effect of PDPP3T and the pH/thermal-responsive properties of PSNiAA, Dox-loaded PDPP3T@PSNiAA NPs (PDPP3T@PSNiAA-Dox NPs) were able to controllably regulate the release of Dox by pH/NIR light, in which the enhanced drug release at acidic condition upon NIR irradiation phenomenon would minimize unnecessary drug release in normal tissues and was highly beneficial for precise synergistic chemo- and photothermal therapy.

Two-photon semiconducting polymer nanoparticles as a new platform for imaging of intracellular pH variation.

Intracellular pH (pHi) plays a crucial role in cell physiological and pathological processes. We herein report an efficient pH-sensitive sensor based on two-photon excitable semiconducting polymer nanoparticles (PFV/PSMA-DA NPs) for pHi sensing. PFV/PSMA NPs were functionalized with redox-active dopamine (DA) and the obtained PFV/PSMA-DA NPs showed sensitive and reversible pH response over the pH range of 5.0-9.0. Owning to the high biocompatibility and pH-responsive DA, PFV/PSMA-DA NPs show low cytotoxicity and the quantification and imaging of intracellular pH changes of HeLa cells were successfully realized. Moreover, the detection of intracellular pH fluctuation induced by redox species such as NAC (N-acetylcysteine) and H2O2 was also achieved by both one- and two-photon excitation of the PFV/PSMA-DA NPs probe. This work clearly shows that nanoprobe based on two-photon PFV/PSMA-DA NPs could serve as a promising platform for quantitatively monitoring the intracellular pH fluctuations.

Highly Stable Core-Shell Structured Semiconducting Polymer Nanoparticles for FRET-Based Intracellular pH Imaging.

Highly stable semiconducting polymer nanoparticles (NPs) (poly(9,9-dioctylfluorenyl-2,7-diyl) (PFO)/ poly(fluorene-2,7-ylenevinylene-co-phenylene) (PFV)-dopamine (DA) NPs) with previously unreported core-shell structure are developed for ratiometric sensing of intracellular pH values. PFO/PFV-DA NPs comprise central polyfluorene (PFO) as donor and PFV as acceptor, in which the donor and acceptor are spatially separated into the central core and nanoparticle shell. Specifically, thick PFV shells can not only significantly minimize the quenching interference of dopamine on the emission of standard reference (PFO), but are also able to maximize its accessibility to pH-sensitive dopamine and lead to sensitive response to pH changes. The resulting core-shell PFO/PFV NPs are structurally and optically stable, which can avoid the photobleaching and leakage of materials issues compared to traditional semiconducting polymer nanoparticles (SPNs)-based fluorescence resonance energy transfer (FRET) systems containing small molecules. Additionally, the designed compact PFO/PFV-DA NPs show quantitative response to the pH values in aqueous media and are capable of mapping intracellular pH fluctuations by ratiometric imaging. This work may open up opportunities for the generalizability of the consistent ratiometric emission intensity strategy based on core-shell structured SPNs nanoprobes for highly sensitive biological sensing.

Mussel-inspired functionalization of semiconducting polymer nanoparticles for amplified photoacoustic imaging and photothermal therapy.

A versatile and straightforward strategy for the encapsulation of semiconducting polymer nanoparticles (SPNs) using biocompatible polydopamine (PDA) as both the protection and versatile bioconjugation layer is proposed. In addition to providing stable functionalized SPNs, this approach provides SPNs with a flexible surface for further modification with various functional ligands. In this study, three representative surface modifiers including a small molecule (folic acid, FA), a peptide (cRGD) and a stealth polymer (SH-PEG) were conjugated onto the surface of SPNs. Specifically, PDA encapsulation can reliably form SPNs that are uniform in size (∼65 nm) and facilitate the rapid purification of SPN bioconjugates by centrifugation which is difficult to achieve using traditional methods for preparing SPN bioconjugates. Compared to pristine PSBTBT NPs, the synthesized PSBTBT@PDA NPs simultaneously showed more excellent structural stability, significantly enhanced PA brightness and amplified PTT efficacy. Benefiting from the outstanding PA and PTT performances, it is possible for the PSBTBT@PDA NPs to ablate tumors more effectively compared to PSBTBT NPs. Our study thus demonstrates that the PDA encapsulated SPNs should be a promising theranostic agent for PA imaging and PTT.

A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients.

Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12 ). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 µM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

Understanding the influence of Tween 80 on pullulan fermentation by Aureobasidium pullulans CGMCC1234.

In this paper, several new perspectives concerned with the effect of Tween 80 promoting pullulan production were presented. With the presence of Tween 80, the maximum pullulan yield increased by 41% (53.04 g/L). Meanwhile, the carbon source was consumed faster and the broth viscosity was higher. The lower final pH suggested that Tween 80 could protect the integrity of the mycelia. The dispersed filaments were not easily entangled with each other and less pellets were formed in the Tween 80 culture broth. FT-IR spectrum analysis indicated that the evaluated sample structure was coincided with commercial pullulan. The molecular weight of sample significantly dropped comparing with the control. The above findings indicated that Tween 80 facilitated the uptake of nutrient from surroundings to the microorganism and the release of pullulan into the extracellular fluid. These results were useful in better understanding the regulation and optimization of efficient pullulan fermentation.

Safety and efficacy of pegylated liposomal doxorubicin-based adjuvant chemotherapy in patients with stage I-III triple-negative breast cancer.

BACKGROUND/AIM: Pegylated liposomal doxorubicin (PLD) has been proven to be an effective antitumor drug for metastatic breast cancer, with less toxicity than conventional anthracycline. Our objective was to evaluate the efficacy and safety of PLD-based adjuvant chemotherapy compared to conventional chemotherapy for patients with stages I-III Triple-negative breast cancer (TNBC). PATIENTS AND METHODS: A total of 162 patients, histologically proven to have TNBC at stages I-III between 2003 and 2010, were enrolled to evaluate the impact of PLD- and non-PLD-based adjuvant chemotherapy by using the end-pint of overall survival (OS) and relapse-free survival (RFS). RESULTS: Forty-nine (30.2%) patients received PLD-based adjuvant chemotherapy and 113 (69.8%) a non-PLD regimen, including 84 (52%) patients receiving non-PLD anthracycline. The Kaplan-Meier calculation indicated no differences in RFS and OS between the PLD and non-PLD groups. Multivariate analysis adjusted for tumor size and lymph node status also revealed similar RFS (HR=0.86, 95% CI=0.43-1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41-1.79, p=0.692) for PLD-based chemotherapy compared with non-PLD-based. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia (25% vs. 41.6%, respectively; p=0.054) and significantly higher incidence of hand-foot syndrome (16.3% vs. 4.4%, respectively; p=0.010). CONCLUSION: PLD-based adjuvant chemotherapy was as effective as conventional chemotherapy for patients with TNBC. PLD is an alternative for patients with TNBC when conventional anthracycline is inappropriate.