A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Conserved LBL1-ta-siRNA and miR165/166-RLD1/2 modules regulate root development in maize.

Root system architecture and anatomy of monocotyledonous maize is significantly different from dicotyledonous model Arabidopsis The molecular role of non-coding RNA (ncRNA) is poorly understood in maize root development. Here, we address the role of LEAFBLADELESS1 (LBL1), a component of maize trans-acting short-interfering RNA (ta-siRNA), in maize root development. We report that root growth, anatomical patterning, and the number of lateral roots (LRs), monocot-specific crown roots (CRs) and seminal roots (SRs) are significantly affected in lbl1-rgd1 mutant, which is defective in production of ta-siRNA, including tasiR-ARF that targets AUXIN RESPONSE FACTOR3 (ARF3) in maize. Altered accumulation and distribution of auxin, due to differential expression of auxin biosynthesis and transporter genes, created an imbalance in auxin signalling. Altered expression of microRNA165/166 (miR165/166) and its targets, ROLLED1 and ROLLED2 (RLD1/2), contributed to the changes in lbl1-rgd1 root growth and vascular patterning, as was evident by the altered root phenotype of Rld1-O semi-dominant mutant. Thus, LBL1/ta-siRNA module regulates root development, possibly by affecting auxin distribution and signalling, in crosstalk with miR165/166-RLD1/2 module. We further show that ZmLBL1 and its Arabidopsis homologue AtSGS3 proteins are functionally conserved.

Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: Single-arm, open-label, phase I study.

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for adolescent and adult Tlymphoblastic leukemia /lymphoma: a large cohort multicenter study in China.

T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6%) patients achieved overall response (ORR) with 138 complete response (CR) patients (70.8%) and 29 partial response (PR) patients (14.8%). Until October 1, 2023, no difference was found in 5-year overall survival (5-OS) and 5-year progression free survival(5-PFS) between allo-HSCT and auto-HSCT (5-OS 57.9% vs. 36.7%, P = 0.139, 5-year PFS 49.4% vs. 28.6%, P = 0.078) for patients who achieved CR, for patients who achieved PR, allo-HSCT recipients had higher 5-OS compared with chemo alone recipients (5-OS 23.8% vs. 0, P = 0.042). For patients undergoing allo-HSCT, minimal residual disease (MRD) negative population showed better 5-OS survival compared with MRD positive patients (67.8% vs. 19.6%, p = 0.000). There were no significant differences between early T-cell precursor (ETP), NON-ETP patients with or without expression of one or more myeloid-associated or stem cell-associated (M/S+) markers (NON-ETP with M/S+, NON-ETP without M/S+) groups in allo-HSCT population for 5-OS. (62.9% vs. 54.5% vs.48.4%, P > 0.05). Notch mutations were more common in patients with non-relapsed/refractory disease than relapsed/refractory disease (χ² =4.293, P = 0.038). In conclusion, Allo-HSCT could be an effective consolidation therapy not just for patients with CR, but also for those who achieved PR. The prognosis is significantly improved by obtaining MRD negative prior to allogeneic transplantation.

The mop1 mutation affects the recombination landscape in maize.

Meiotic recombination is a fundamental process that generates genetic diversity and ensures the accurate segregation of homologous chromosomes. While a great deal is known about genetic factors that regulate recombination, relatively little is known about epigenetic factors, such as DNA methylation. In maize, we examined the effects on meiotic recombination of a mutation in a component of the RNA-directed DNA methylation pathway, Mop1 (Mediator of paramutation1), as well as a mutation in a component of the trans-acting small interference RNA biogenesis pathway, Lbl1 (Leafbladeless1). MOP1 is of particular interest with respect to recombination because it is responsible for methylation of transposable elements that are immediately adjacent to transcriptionally active genes. In the mop1 mutant, we found that meiotic recombination is uniformly decreased in pericentromeric regions but is generally increased in gene rich chromosomal arms. This observation was further confirmed by cytogenetic analysis showing that although overall crossover numbers are unchanged, they occur more frequently in chromosomal arms in mop1 mutants. Using whole genome bisulfite sequencing, our data show that crossover redistribution is driven by loss of CHH (where H = A, T, or C) methylation within regions near genes. In contrast to what we observed in mop1 mutants, no significant changes were observed in the frequency of meiotic recombination in lbl1 mutants. Our data demonstrate that CHH methylation has a significant impact on the overall recombination landscape in maize despite its low frequency relative to CG and CHG methylation.

Advancements in Polymer-Assisted Layer-by-Layer Fabrication of Wearable Sensors for Health Monitoring.

Recent advancements in polymer-assisted layer-by-layer (LbL) fabrication have revolutionized the development of wearable sensors for health monitoring. LbL self-assembly has emerged as a powerful and versatile technique for creating conformal, flexible, and multi-functional films on various substrates, making it particularly suitable for fabricating wearable sensors. The incorporation of polymers, both natural and synthetic, has played a crucial role in enhancing the performance, stability, and biocompatibility of these sensors. This review provides a comprehensive overview of the principles of LbL self-assembly, the role of polymers in sensor fabrication, and the various types of LbL-fabricated wearable sensors for physical, chemical, and biological sensing. The applications of these sensors in continuous health monitoring, disease diagnosis, and management are discussed in detail, highlighting their potential to revolutionize personalized healthcare. Despite significant progress, challenges related to long-term stability, biocompatibility, data acquisition, and large-scale manufacturing are still to be addressed, providing insights into future research directions. With continued advancements in polymer-assisted LbL fabrication and related fields, wearable sensors are poised to improve the quality of life for individuals worldwide.

[CAR T-cell therapy for T cell malignancies: challenges and recent advances].

T cell malignancies pose several unique issues for CAR-T cell therapy that were not significant concerns with CAR-T cells for B-cell malignancies. A general problem to consider in the production of CAR-T cells is "on target-off tumor toxicity." This occurs when the antigen targeted by the CAR-T cells is also expressed on normal cells, not just tumor cells, which causes CAR-T cells to damage these normal cells. In CAR-T cell therapy for T cell tumors, antigens expressed on T cells (such as CD5, CD7, etc.) are the targets, which leads to a problem known as "fratricide," where CAR-T cells kill each other. Other issues include T cell aplasia and contamination of CAR-T cell products with tumor cells. However, several recent clinical trials have shown excellent outcomes for CAR-T cell therapy when genome editing technology is used to overcome these issues by knocking out target antigens or T cell receptors. This review article outlines these challenges and their solutions and discusses the results of recent clinical trials.

SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms.

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

Room-Temperature Synthesis of a COFs Membrane Via LBL Self-Assembly Strategy for Energy Harvesting.

The covalent organic frameworks (COFs) membrane with ordered and confined one-dimensional channel has been considered as a promising material to harvest the salinity gradient energy from the seawater and river water. However, the application of the COFs in the field of energy conversion still faces the challenges in membrane preparation. Herein, energy harvesting is achieved by taking advantage of a COFs membrane where TpDB-HPAN is synthesized via layer-by-layer self-assembly strategy at room temperature. The carboxy-rich TpDB COFs can be expediently assembled onto the substrate with an environmental-friendly method. The increased open-circuit voltage (Voc ) endows TpDB-HPAN membrane with a remarkable energy harvesting performance. More importantly, the application perspective is also illuminated by the cascade system. With the advantages of green synthesis, the TpDB-HPAN membrane can be considered as a low-cost and promising candidate for energy conversion.

Validation study for in vitro skin irritation test using reconstructed human skin equivalents constructed by layer-by-layer cell coating technology.

The aim of this study is to validate an in vitro skin irritation test (SIT) using three-dimensional reconstructed human epidermal (RhE) skin equivalents prepared by layer-by-layer (LbL) method (LbL-3D Skin) in a series of interlaboratory studies. The goal of these validation studies is to evaluate the ability of this in vitro test to reliably discriminate skin irritant from nonirritant chemicals, as defined by OECD and UN GHS. This me-too validation study is to assess the within- and between-laboratory reproducibility, as well as the predictive capacity, of the LbL-3D Skin SIT in accordance with performance standards for OECD TG 439. The developed skin model, LbL-3D Skin had a highly differentiated epidermis and dermis, similar to the validated reference methods (VRM) and native human skin. The quality parameters (cell survival in controls, tissue integrity, and barrier function) were similar to VRM and in accordance with OECD TG 439. The LbL-3D Skin SIT validation study was performed by three participating laboratories and consisted of three independent tests using 20 reference chemicals. The results obtained with the LbL-3D Skin demonstrated high within-laboratory and between-laboratory reproducibility, as well as high accuracy for use as a stand-alone assay to distinguish skin irritants from nonirritants. The predictive potency of LbL-3D Skin SIT using total 54 test chemicals were comparable to those in other RhE models in OECD TG 439. The validation study demonstrated that LbL-3D Skin has proven to be a robust and reliable method for predicting skin irritation.

The effectiveness of problem-based learning compared with lecture-based learning in surgical education: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis was conducted to systematically evaluate the impact of problem-based learning (PBL) and lecture-based learning (LBL) teaching models on students' learning in surgical education. METHODS: We systematically searched the publications related to the application of PBL and LBL in surgical courses in PubMed, Embase, Web of Science and Cochrane Library databases, the last retrieval time is September 20, 2022. After screening the literature according to the inclusion and exclusion criteria, extracting data and evaluating the methodological treatment of the included studies, Stata 17.0 software was used to perform meta-analysis. RESULTS: Nine studies were included totally. The results showed that compared with LBL, PBL was superior in clinical competence (SMD = 0.81, 95% CI: 0.12 ~ 1.49, P = 0.020) and student satisfaction (SMD = 2.13, 95% CI: 1.11 ~ 3.15, P < 0.0001) with significant differences. But the comprehensive scores (SMD = 0.26, 95% CI: -0.37 ~ 0.89, P = 0.421) and theoretical knowledge (SMD=-0.19, 95% CI: -0.71 ~ 0.33, P = 0.482) to PBL and LBL had no significant difference. CONCLUSION: This study showed that the PBL teaching model is more effective than the LBL teaching model in surgical education on the aspects of enhancing clinical competence and student satisfaction. However, further well-designed studies are needed to confirm our findings.

Mental health differences in medical students based on curriculum and gender.

BACKGROUND: The prevalence of mental health struggles among students in medical school is widely reported; however, little is known about how it is impacted by the medical school curriculum. This study aimed to evaluate differences in anxiety, depression, and emotional exhaustion in medical students based on gender, class year, and curriculum. METHODS: An anonymous online survey consisting of questions from established, validated questionnaires about demographics, anxiety, depression, emotional exhaustion, and personal health behaviors was sent to 817 medical students who attended Rowan-Virtua School of Osteopathic Medicine during the Spring of 2021. When applying to this school, each of these students had the option to choose either the problem-based learning (PBL) or lecture-based learning (LBL) curriculum track. RESULTS: The survey was completed by 222 students. Females experienced higher levels of anxiety, depression, and emotional exhaustion than males. Students in the PBL had lower levels of emotional exhaustion than their peers in the LBL. Increase in emotional exhaustion was most pronounced between 1st and 2nd year students. Emotional exhaustion was inversely correlated with sleep and exercise. CONCLUSIONS: On average, students who were either male or in the PBL curriculum experienced less mental distress in the form of anxiety, depression, and emotional exhaustion than their peers. While gender continues to be an established factor in how mental distress is experienced, the reduced levels of emotional exhaustion in PBL students is a novel finding that can potentially shed light on how to better optimize medical education. Despite the inherent selection bias and lower number of PBL students, to our knowledge, this is the first study comparing two different curricula within a single institution. This finding along with a focus on good sleep and exercise habits may provide a path for improving mental health in medical students.

Clinical and prognostic role of 2-[18F]FDG PET/CT and sarcopenia in treatment-naïve patients with T-cell lymphoblastic lymphoma.

T-cell lymphoblastic lymphoma (T-LBL) is a rare and highly aggressive non-Hodgkin lymphoma. This study aimed to explore the role of 2-[18F]FDG PET/CT, sarcopenia, clinical features, and treatment regimens in 49 treatment-naïve patients with T-LBL, and assess their predictive value in the prognosis. Sarcopenia was measured as skeletal muscle index (SMI) at L3 level from the CT component of PET/CT images. All 49 patients (35 males, 14 females; median age, 26 years [range, 3-66 years]) were enrolled in this study, including 36 adult patients and 13 pediatric patients. Lymph nodes, thymus, bone marrow, and pleura were the most common involved sites of T-LBL. The median SUVmax, MTV, and TLG of all lesions in these 49 patients were 12.4 (range, 4.2-40.5), 532.6 (17.4-3518.1), and 2112.2 (53.9-18,699.2), respectively. Eighteen out of 49 patients (36.7%) were diagnosed with sarcopenia. Sarcopenia patients had lower BMI and SUVmax of muscle at L3 level than non-sarcopenia patients (P < 0.05). Univariate Cox regression analysis indicated that higher MTV and TLG and intrathecal therapy (IT) were associated with longer progression-free survival (PFS) and overall survival (OS), while multivariate Cox regression analysis showed that TLG and IT were independent predictors for PFS, and only IT was an independent predictor for OS. In conclusion, low BMI and SUVmax of muscle at L3 level correlated with sarcopenia in T-LBL patients. Higher initial MTV and TLG and receiving IT were associated with better prognosis in T-LBL patients. TLG and IT, but not sarcopenia, were independent prognostic factors.

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

PBL teaching in ultrasonography resident standardization training in the COVID-19 pandemic.

OBJECTIVE: To study the effect of the problem-based learning (PBL) method in ultrasonography (US) resident standardization training during the COVID-19 pandemic. METHODS: Fifty residents were divided into two groups to participate in a 30-day US training program. The residents in the observation group underwent PBL combined with the lecture-based learning (LBL) method, while the residents in the control group experienced the LBL method alone, with 25 residents in each group. A basic theoretical test, practical examination, and questionnaire were used to evaluate the teaching effect of the PBL + LBL method and the LBL method alone. RESULTS: The basic theoretical pretest score of the observation group was not significantly different from that of the control group. However, the posttest theoretical score and practical score were significantly higher in the observation group than in the control group (P < 0.01). The results of the questionnaire showed that the resident satisfaction level in the observation group with PBL combined with the LBL method was 96%, which was significantly higher than that of the control group with the LBL method alone (80%) (P < 0.05). CONCLUSION: The combination of PBL with the LBL method has obvious advantages over the LBL method alone in regard to the training of US residents during the COVID-19 pandemic.

A Dual Role for FADD in Human Precursor T-Cell Neoplasms.

A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case.

Weak Polyelectrolytes as Nanoarchitectonic Design Tools for Functional Materials: A Review of Recent Achievements.

The ionization degree, charge density, and conformation of weak polyelectrolytes can be adjusted through adjusting the pH and ionic strength stimuli. Such polymers thus offer a range of reversible interactions, including electrostatic complexation, H-bonding, and hydrophobic interactions, which position weak polyelectrolytes as key nano-units for the design of dynamic systems with precise structures, compositions, and responses to stimuli. The purpose of this review article is to discuss recent examples of nanoarchitectonic systems and applications that use weak polyelectrolytes as smart components. Surface platforms (electrodeposited films, brushes), multilayers (coatings and capsules), processed polyelectrolyte complexes (gels and membranes), and pharmaceutical vectors from both synthetic or natural-type weak polyelectrolytes are discussed. Finally, the increasing significance of block copolymers with weak polyion blocks is discussed with respect to the design of nanovectors by micellization and film/membrane nanopatterning via phase separation.

Multilayered Curcumin-Loaded Hydrogel Microcarriers with Antimicrobial Function.

The design of multifunctional microcarriers has attracted significant attention because they combine various functions within a single system. In this study, we developed a set of multilayered hydrogel microcarriers, which were first loaded with chemotherapeutic curcumin (CUR), then, using the layer-by-layer (LbL) technique, coated through a polyelectrolyte shell consisting of chitosan (CHIT) or poly(allylamine hydrochloride) (PAH). As an outer layer with antimicrobial function, newly synthesised alkylene quaternary ammonium salt functionalised polyelectrolytes (A-QAS-PEs) were applied. For this purpose, poly(acrylic acid) (PAA) was decorated with different hydrophobic side chains (n-hexane and n-dodecane side entities) and different degrees of substitution (m) of quaternary ammonium groups (abbreviated as PAA-C(O)O-(CH2)n-N+(CH3)3(m); n = 6, 12; m = 8-14%). The grafting approach of PAA with the alkylene quaternary ammonium salt moiety was performed under mild reaction conditions using Steglich esterification followed by quaternisation. The structure of antimicrobial decorated PAA was confirmed by 1H NMR and FTIR, and the mean diameter of all multifunctional microparticles was characterised by SEM. The viscoelastic properties of the functional layers were studied using quartz crystal microbalance with a dissipation (QCM-D). The release of CUR from the microcarriers was described using a hybrid model, i.e., a combination of first-order kinetics and the Korsmeyer-Peppas model. The antimicrobial activity of functionalised PAA and multilayered CUR-loaded hydrogel microcarriers with quaternary ammonium function was assessed against Staphylococcus aureus and Serratia marcescens by the agar diffusion assay method. Only a limited inhibition zone of PAA was observed, but in the case of both antimicrobial decorated PAA and the corresponding multilayered nanocarriers, the inhibitory activity increase was achieved against both strains of bacteria.

Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma.

BACKGROUND: Deregulated Notch signaling is implicated in T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T-ALL/T-LBL. METHODS: JJCB was a multicenter, nonrandomized, open-label, dose-escalation, phase 1 study in adult patients with relapsed/refractory T-ALL/T-LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28-day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose-limiting toxicity (DLT) at the recommended dose level. RESULTS: In total, 36 patients with T-ALL (n = 31 [86.1%]) or T-LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75-mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100-mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125-mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty-eight patients (77.8%) experienced 1 or more treatment-emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event-free survival was 1.18 months (95% confidence interval, 0.76-2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid ß levels. CONCLUSIONS: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T-ALL/T-LBL.

Prioritization of potential vaccine candidates and designing a multiepitope-based subunit vaccine against multidrug-resistant Salmonella Typhi str. CT18: A subtractive proteomics and immunoinformatics approach.

Salmonella enterica serovar Typhi (S. Typhi), a causative agent of typhoid fever, is a Gram-negative, human-restricted pathogen that causes significant morbidity and mortality, particularly in developing countries. The currently available typhoid vaccines are not recommended to children below six years of age and have poor long-term efficacy. Due to these limitations and the emerging threat of multidrug-resistance (MDR) strains, the development of a new vaccine is urgently needed. The present study aims to design a multiepitope-based subunit vaccine (MESV) against MDR S. Typhi str. CT18 using a computational-based approach comprising subtractive proteomics and immunoinformatics. Firstly, we investigated the proteome of S. Typhi str. CT18 using subtractive proteomics and identified twelve essential, virulent, host non-homologous, and antigenic outer membrane proteins (OMPs) as potential vaccine candidates with low transmembrane helices (≤1) and molecular weight (≤110 kDa). The OMPs were mapped for cytotoxic T lymphocyte(CTL) epitopes, helper T lymphocyte (HTL) epitopes, and linear B lymphocyte (LBL) epitopes using various immunoinformatics tools and servers. A total of 6, 12, and 11 CTL, HTL, and LBL epitopes were shortlisted, respectively, based on their immunogenicity, antigenicity, allergenicity, toxicity, and hydropathicity potential. Four MESV constructs (MESVCs), MESVC-1, MESVC-2, MESVC-3, and MESVC-4, were designed by linking the CTL, HTL, and LBL epitopes with immune-modulating adjuvants, linkers, and PADRE (Pan HLA DR-binding epitope) sequences. The MESVCs were evaluated for their physicochemical properties, allergenicity, antigenicity, toxicity, and solubility potential to ensure their safety and immunogenic behavior. Secondary and tertiary structures of shortlisted MESVCs (MESVC-1, MESVC-3, and MESVC-4) were predicted, modeled, refined, validated, and then docked with various MHC I, MHC II, and TLR4/MD2 complex. Molecular dynamics (MD) simulation of the final selected MESVC-4 with TLR4/MD2 complex confirms its binding affinity and stability. Codon optimization and in silico cloning verified the translation efficiency and successful expression of MESVC-4 in E. coli str. K12. Finally, the efficiency of MESVC-4 to trigger an effective immune response was assessed by an in silico immune simulation. In conclusion, our findings show that the designed MESVC-4 can elicit humoral and cellular immune responses, implying that it may be used for prophylactic or therapeutic purposes. Therefore, it should be subjected to further experimental validations.