Gradient conducting polymer surfaces with netrin-1-conjugation promote axon guidance and neuron transmission of human iPSC-derived retinal ganglion cells.

Major advances have been made in utilizing human-induced pluripotent stem cells (hiPSCs) for regenerative medicine. Nevertheless, the delivery and integration of hiPSCs into target tissues remain significant challenges, particularly in the context of retinal ganglion cell (RGC) restoration. In this study, we introduce a promising avenue for providing directional guidance to regenerated cells in the retina. First, we developed a technique for construction of gradient interfaces based on functionalized conductive polymers, which could be applied with various functionalized ehthylenedioxythiophene (EDOT) monomers. Using a tree-shaped channel encapsulated with a thin PDMS and a specially designed electrochemical chamber, gradient flow generation could be converted into a functionalized-PEDOT gradient film by cyclic voltammetry. The characteristics of the successfully fabricated gradient flow and surface were analyzed using fluorescent labels, time of flight secondary ion mass spectrometry (TOF-SIMS), and X-ray photoelectron spectroscopy (XPS). Remarkably, hiPSC-RGCs seeded on PEDOT exhibited improvements in neurite outgrowth, axon guidance and neuronal electrophysiology measurements. These results suggest that our novel gradient PEDOT may be used with hiPSC-based technologies as a potential biomedical engineering scaffold for functional restoration of RGCs in retinal degenerative diseases and optic neuropathies.

[The clinical safety and efficacy of selinexor combined with venetoclax and azactitidine induction therapy in relapsed and refractory acute myeloid leukemia].

To determine the efficacy and safety of selinexor combined with venetoclax (VEN) and azactitidine (AZA) for patients with relapsed and/or refractory acute myeloid leukemia (R/R AML) . Twelve patients with R/R AML treated with selinexor plus VEN and AZA in the Affiliated Cancer Hospital of Zhengzhou University from May 2022 to May 2023 were included. Their clinical data were retrospectively analyzed. Among the 12 R/R AML patients, 5 (41.7%) achieved complete remission (CR) , 1 (8.3%) achieved CR with incomplete hematological recovery, and 5 (41.7%) achieved partial remission. The median time to reach CR was 28 (16-59) days. The median PFS was 61 (15-300) days. The main adverse event of the regimen was hematological toxicity. No chemotherapy-related deaths were observed. The combination of selinexor plus VEN and AZA is an effective treatment for R/R AML patients.

Successfully treatment of PLZF-RARα positive acute promyelocytic leukemia by Venetoclax combining with decitabine: a case report and literature review.

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Flexible Microfluidic Strain Sensor Made with Poly(3,4-ethylenedioxythiophene):polystyrenesulfonate-MXene-Au Nanocomposites for Monitoring Physiological Signals.

Flexible strain sensors have been widely used in wearable electronics. However, the fabrication of flexible strain sensors with a large strain detection range, high sensitivity, and negligible hysteresis remains a formidable challenge, even after enormous advancements in the field. Herein, a flexible microfluidic strain sensor was fabricated by filling poly(3,4-ethylenedioxythiophene):polystyrenesulfonate-MXene-gold (PEDOT:PSS-MXene-Au) nanocomposites into microchannels in an elastic matrix. Owing to the unique properties of the nanofiller and Ecoflex elastomer microchannel, the microfluidic strain sensor detected a strain of 0%-500% with low hysteresis (2.4%), high sensitivity (guage factor = 25.4), short response times (∼86 ms), and good durability. Moreover, the flexible microfluidic sensor was used to detect various physiological signals and human activities, control a mechanical hand, and capture hand motions in real time. As demonstrated by its good performance, the proposed flexible microfluidic sensor holds great potential in applications such as wearable electronics, physiological signal monitoring and human-machine interactions.

Topical Therapy for Atopic Dermatitis: What is New and the New Paradigm.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that requires a complex management strategy, which often involves multiple and diverse topicals and systemic treatment regimens. While topical steroids and more recently calcineurin inhibitors have been the mainstay therapy for mild-to-moderate disease, recent advances in the understanding of AD pathogenesis have led to the development of different new targets, rapidly widening our therapeutic armamentarium. This review summarizes their efficacy and safety data. We also review topical optimization strategies, including the recently published topical volume calculator, to maximize long-term disease control, especially when using multiple agents at the same time.

MoS2_CNTs_aerogel-based PEDOT nanocomposite electrochemical sensor for simultaneous detection of chloramphenicol and furazolidone in food samples.

Toxic intermediates in food caused by chloramphenicol (CP) and furazolidone (FZ) have gained interest in research toward their detection. Hence, fast, reliable, and accurate detection of CP and FZ in food products is of utmost importance. Here, a novel molybdenum disulfide-connected carbon nanotube aerogel/poly (3,4-ethylenedioxythiophene) [MoS2/CNTs aerogel/PEDOT] nanocomposite materials are constructed and deposited on the pretreated carbon paste electrode (PCPE) by a facile eletropolymerization method. The characterization of MoS2/CNTs aerogel/PEDOT nanocomposite was analyzed by scanning electron microscopy (SEM), cyclic voltammetry, and differential pulse voltammetry. The modified MoS2/CNTs aerogel/PEDOT nanocomposite has improved sensing characteristics for detecting CP and FZ in PBS solution. For this work, we have studied various parameters like electrocatalytic activity, the effect of scan rates, pH variation studies, and concentration variation studies. Under optimum conditions, the modified electrode exhibited superior sensing ability compared to the bare and pretreated CPE. This improvement in electrocatalytic activity can be the higher conductivity, larger surface area, increased heterogeneous rate constant, and presence of more active sites in the MoS2/CNTs aerogel/PEDOT nanocomposite. The modified electrode demonstrated distinct electrochemical sensing toward the individual and simultaneous analysis of CP and FZ with a high sensitivity of 0.701 µA. µM-1 .cm-2 for CP and 0.787 µA. µM-1 .cm-2 for FZ and a low detection limit of 3.74 nM for CP and 3.83 nM for FZ with good reproducibility, repeatability, and interferences. Additionally, the prepared sensor effectively detects CP and FZ in food samples (honey and milk) with an acceptable recovery range and a relative standard deviation below 4%.

Advances in pathogenesis research and challenges in treatment development for acute myeloid leukemia.

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.

Relapse and resistance in acute myeloid leukemia post venetoclax: improving second lines therapy and combinations.

INTRODUCTION: The combined use of the BCL-2 inhibitor venetoclax with azacitidine now is the standard of care for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy with outcomes exceeding those achieved with hypomethylating agents alone. Venetoclax in combination with intensive chemotherapy is also increasingly used both as frontline as well as salvage therapy. However, resistance to and relapse after venetoclax-based therapies are of major concern and outcomes after treatment failure remain poor. AREAS COVERED: A comprehensive search was performed using PubMed database (up to April 2024). Studies evaluating venetoclax-based combination treatments in AML and studies assessing markers of response and resistance to venetoclax were investigated. We summarize the status of venetoclax-based therapies in the frontline and relapsed/refractory setting with focus on the main mechanisms of resistance to BCL-2 inhibition. Further, strategies to overcome resistance including combinatorial regimens of hypomethylating agent (HMA) + venetoclax + inhibitors targeting actionable mutations like IDH1/2 or FLT3-ITD and the introduction of novel agents like menin-inhibitors are addressed. EXPERT OPINION: Although venetoclax is reshaping the treatment of unfit and fit AML patients, prognosis of patients after HMA/VEN failure remains dismal, and strategies to abrogate primary and secondary resistance are an unmet clinical need.

NL101 synergizes with the BCL-2 inhibitor venetoclax through PI3K-dependent suppression of c-Myc in acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) comprises a group of heterogeneous and aggressive haematological malignancies with unsatisfactory prognoses and limited treatment options. Treatments targeting B-cell lymphoma-2 (BCL-2) with venetoclax have been approved for patients with AML, and venetoclax-based drug combinations are becoming the standard of care for older patients unfit for intensive chemotherapy. However, the therapeutic duration of either single or combination strategies is limited, and the development of resistance seems inevitable. Therefore, more effective combination regimens are urgently needed. METHODS: The efficacy of combination therapy with NL101, a SAHA-bendamustine hybrid, and venetoclax was evaluated in preclinical models of AML including established cell lines, primary blasts from patients, and animal models. RNA-sequencing and immunoblotting were used to explore the underlying mechanism. RESULTS: NL101 significantly potentiated the activity of venetoclax in AML cell lines, as evidenced by the enhanced decrease in viability and induction of apoptosis. Mechanistically, the addition of NL101 to venetoclax decreased the stability of the antiapoptotic protein myeloid cell leukaemia-1 (MCL-1) by inhibiting ERK, thereby facilitating the release of BIM and triggering mitochondrial apoptosis. Moreover, the strong synergy between NL101 and venetoclax also relied on the downregulation of c-Myc via PI3K/Akt/GSK3ß signalling. The combination of NL101 and venetoclax synergistically eliminated primary blasts from 10 AML patients and reduced the leukaemia burden in an MV4-11 cell-derived xenograft model. CONCLUSIONS: Our results encourage the pursuit of clinical trials of combined treatment with NL101 and venetoclax and provide a novel venetoclax-incorporating therapeutic strategy for AML.

Recent advances in PEDOT/PProDOT-derived nano biosensors: engineering nano assemblies for fostering advanced detection platforms for biomolecule detection.

With the recent unprecedented emergence of a global pandemic, unknown diseases and new metabolic patterns expressing serious health issues, the requirement to develop new diagnostic tools, therapeutic solutions, and healthcare and environmental monitoring systems are significantly higher in the present situation. Considering that high sensitivity, selectivity, stability and a low limit of detection (LOD) are inevitable requirements for an ideal biosensor, the class of conducting polymers of poly(3,4-ethylenedioxythiophene) (PEDOT) and recently poly(3,4-propylenedioxythiophene) (PProDOT) materials have been demonstrated to be promising candidates for designing sensor devices. Nanostructure engineering of these polymeric materials with tunable surface properties and side chain functionalization to enable sensor probe conjugation combined with signal amplification devices such as OECTs and OFETs can fulfil the requirements of next-generation smart nano-biosensors. In this review, we analyze recent reports on PEDOT/PProDOT nanostructures and nanocomposites for developing nano-biosensors and their application in the detection of different biomarkers, environmental, toxicology, marine and aquatic monitoring, forensic and illicit drug detection, etc. In addition, we discuss the challenges associated with the design of PEDOT/PProDOT nano-biosensors and future perspectives on the exploration of novel sensor platforms, particularly PProDOT derivatives for bioelectronics and novel design strategies for next-generation smart nano-biosensors.

Mechanical confinement prevents ectopic platelet release.

Blood platelets are produced by megakaryocytes (MKs), their parent cells, which are in the bone marrow. Once mature, MK pierces through the sinusoid vessel, and the initial protrusion further elongates as proplatelet or buds to release platelets. The mechanisms controlling the decision to initiate proplatelet and platelet formation are unknown. Here, we show that the mechanical properties of the microenvironment prevent proplatelet and platelet release in the marrow stroma while allowing this process in the bloodstream. Loss of marrow confinement following myelosuppression led to inappropriate proplatelet and platelet release into the extravascular space. We further used an inert viscoelastic hydrogel to evaluate the impact of compressive stress. Transcriptional analysis showed that culture in three-dimensional gel induced upregulation of genes related to the Rho-GTPase pathway. We found higher Rho-GTPase activation, myosin light chain phosphorylation and F-actin under mechanical constraints while proplatelet formation was inhibited. The use of latrunculin-A to decrease F-actin promoted microtubule-dependent budding and proplatelet extension inside the gel. Additionally, ex vivo exposure of intact bone marrow to latrunculin-A triggered proplatelet extensions in the interstitial space. In vivo, this confinement-mediated high intracellular tension is responsible for the formation of the peripheral zone, a unique actin-rich structure. Cytoskeleton reorganization induces the disappearance of the peripheral zone upon reaching a liquid milieu to facilitate proplatelet and platelet formation. Hence, our data provide insight into the mechanisms preventing ectopic platelet release in the marrow stroma. Identifying such pathways is especially important for understanding pathologies altering marrow mechanics such as chemotherapy or myelofibrosis.

Efficacy and Effectiveness Outcomes of Treatments for Double-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double-exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double-exposed CLL patients. METHODS: PubMed, Embase, and Web of Science databases were searched until December 2023. RESULTS: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T-cell therapy. CONCLUSION: This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

Core-Shell PEDOT-PVDF Nanofiber-Based Ammonia Gas Sensor with Robust Humidity Resistance.

Current ammonia sensors exhibit cross-sensitivity to water vapor, leading to false alarms. We developed a core-shell nanofiber (CSNF) structure to address these issues, using conductive poly(3,4-ethylenedioxythiophene) (PEDOT) as the core and hydrophobic polyvinylidene fluoride-tetrafluoroethylene (PVDF-TrFE) as the shell. The PEDOT-PVDF CSNF, with a diameter of ~500 nm and a 300 nm thick PVDF layer, showed a superior sensitivity and humidity resistance compared to conventional PEDOT membranes for ammonia concentrations of 10-100 ppm. In humid environments, CSNF sensors outperformed membrane sensors, exhibiting a tenfold increase in performance at 51% relative humidity (RH). This study highlights the potential of CSNF sensors for practical ammonia detection, maintaining a high performance under varying humidity levels.

Assessing the clinical advantage of opioid-reduced anesthesia in thoracoscopic sympathectomy: a prospective randomized controlled trial.

BACKGROUND: Opioid-reduced multimodal analgesia has been used clinically for many years to decrease the perioperative complications associated with opioid drugs. We aimed to assess the clinical effects of opioid-reduced anesthesia during thoracoscopic sympathectomy. METHODS: Surgical patients (n = 151) with palmar hyperhidrosis were randomly divided into control (Group C, 73 patients) and test (Group T, 78 patients) groups. All patients were administered general anesthesia using a laryngeal mask. In Group C, patients received propofol, fentanyl, and cisatracurium for anesthesia induction, and maintenance was achieved with propofol and remifentanil, along with mechanical ventilation during the operation. In Group T, anesthesia was induced with propofol, dezocine, and dexmedetomidine (DEX) and maintained with propofol, DEX, and an intercostal nerve block, along with spontaneous breathing throughout the operation. Perioperative complications related to opioid use include hypotension, bradycardia, hypertension, tachycardia, hypoxemia, nausea, vomiting, urine retention, itching, and dizziness were observed. To assess the impact of these complications, we recorded and compared vital signs, blood gas indices, visual analogue scale (VAS) scores, adverse events, and patient satisfaction between the two groups. RESULTS: Perioperative complications related to opioid use were similar between groups. There were no significant differences in the type of perioperative sedation, analgesia index, respiratory and circulatory indicators, blood gas analysis, postoperative VAS scores, adverse reactions, propofol dosage, postoperative recovery time, and patient satisfaction. CONCLUSIONS: In minimally invasive surgeries such as thoracoscopic sympathectomy, opioid-reduced anesthesia was found to be safe and effective; however, this method did not demonstrate clinical advantages. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2100055005, on December 30, 2021.

[Development of Lomentospora prolificans infection during induction therapy with venetoclax and azacitidine for acute myeloid leukemia].

Lomentospora prolificans is a rare filamentous fungus that causes invasive fungal disease (IFD) in immunocompromised patients with hematological malignancies, as well as hematopoietic cell or solid organ transplant recipients. A 75-year-old woman was diagnosed with acute myeloid leukemia, and started induction therapy with azacitidine and adjusted-dose venetoclax along with antifungal prophylaxis with fluconazole. On day 7, she became febrile and chest CT imaging showed multiple nodules in both lung fields, and the serum galactomannan antigen index became positive, indicating probable IFD. Anti-fungal therapy with liposomal amphotericin B was immediately initiated; however, the patient's condition rapidly deteriorated, and she died on day 15. L. prolificans was later identified in blood culture tests that had been repeatedly performed while she had been febrile. L. prolificans is generally resistant to most antifungal agents, which can make it fatal. As early definitive diagnosis is difficult, it may be appropriate to consider combination therapy when conventional anti-IFD therapy seems inadequate.

SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.

The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.

Effective Treatment with Venetoclax and Hypomethylating Agents for the Coexistence of Multiple Myeloma and Acute Myeloid Leukemia: A Case Report and Literature Review.

OBJECTIVE: Multiple myeloma (MM) and Acute myeloid leukemia (AML) are distinct hematologic malignancies originating from different cell lineages. Their coexistence is extremely rare, and current treatment approaches are even more so. Therefore, exploring the clinical features of their coexistence and the promising treatment strategy is worthwhile. CASE REPORT: We described three cases involving the coexistence of MM and DNMT3A-mutant AML, two of which presented simultaneous occurrences, while Case 3 had secondary AML about 70 months after the MM. DISCUSSION: All cases exhibited DNMT3A mutations, which characterized by one missense mutation and two frameshift mutations; all were likely loss of function mutations. Among them, two patients were treated with Venetoclax-based regimens and achieved favorable effects. The patients were alive for 62,38 and 103 months. CONCLUSIONS: Clonal hematopoiesis of DNMT3A may have a crucial role in the coexistence of MM and AML and Venetoclax-based regimens reveal favorable treatment responses. However, drug resistance still needs to be considered, and further research is required to elucidate the underlying mechanisms and treatment strategies.