Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy.

BACKGROUND AIMS: Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. METHODS: We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. RESULTS: The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. CONCLUSIONS: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial.

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

ADAMTS5 Promotes Permeability of the Blood-Brain Barrier during Treponema pallidum Subspecies pallidum Invading the Central Nervous System.

The pathogenesis of neurosyphilis remains unclear. A previous study found a noteworthy up-regulation of a disintegrin and metalloproteinase with thrombospondin type 1 motif 5 (ADAMTS5) gene in human brain microvascular endothelial cells cocultured with Treponema pallidum subspecies pallidum (Tp). To investigate the ADAMTS5 role in Tp invading the central nervous system (CNS), we conducted relevant experiments. Our study revealed that Tp caused an increase in human cortical microvascular endothelial cell/D3 (hCMEC/D3) barrier permeability and significantly enhanced ADAMTS5 expression. The heightened permeability of the hCMEC/D3 barrier was effectively mitigated by inhibiting ADAMTS5. During this process, Tp promoted interleukin-1ß production, which, in turn, facilitated ADAMTS5 expression. Furthermore, Tp significantly reduced the glycocalyx on the surface of hCMEC/D3 cells, which was also ameliorated by inhibiting ADAMTS5. Additionally, ADAMTS5 and endothelial glycocalyx components notably increased in the cerebrospinal fluid of HIV-negative neurosyphilis patients. This research provided the first demonstration of the ADAMTS5 role in Tp invading the CNS and offered new insight into neurosyphilis pathogenesis.

Design, synthesis and biological evaluation of MNK-PROTACs.

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases. In this study, DS33059, a small-molecule compound modified based on the ongoing clinical trials drug ETC-206, was chosen as the target protein ligand. A series of novel MNK-PROTACs were designed, synthesized and evaluated biological activity. Several compounds showed good inhibitory activities against MNK1/2. Besides, compounds exhibited moderate to excellent anti-proliferative activity in A549 and TMD-8 cells in vitro. In particular, compound II-5 significantly inhibited A549 (IC50 = 1.79 µM) and TMD-8 (IC50 = 1.07 µM) cells. The protein degradation assay showed that compound II-5 had good capability to degrade MNK1. The MNK-PROTACs strategy represents a new direction in treating tumors and deserves further exploration.

Low-sodium diet with adequate water intake improved the clinical efficacy in Ménière's disease.

BACKGROUND: Ménière's disease (MD) is a common idiopathic inner ear disorder in otorhinolaryngology characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and ear fullness. OBJECTIVE: To study the effects of low-sodium diet with adequate water intake on the clinical efficacy in MD. METHODS: Fifty patients diagnosed with stage-3 unilateral MD were randomly divided into control group(n = 25) and experimental group(n = 25). The control group was given routine medication therapy, and the experimental group was restricted to an sodium intake of 1500 mg/d and a water intake of 35 ml/kg/d based in addition to the routine medication therapy. The two groups were assessed using pure tone audiometry, electrocochleography, Tinnitus Handicap Inventory (THI), and Dizziness Handicap Inventory (DHI). RESULTS: The pure tone audiometry and electrocochleography showed better improvements after treatment in the experimental group than the control group (p < 0.05). The THI improved values in the experimental group were significantly higher than the control group (p < 0.001). The DHI improved values in the experimental group were significantly higher than the control group (p = 0.004). CONCLUSIONS AND SIGNIFICANCE: Low-sodium diet with adequate water intake improved the hearing and alleviated vertigo and tinnitus in MD patients.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects.

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.

Direct-coating of cellulose hydrogel on PVDF membranes with superhydrophilic and antifouling properties for high-efficiency oil/water emulsion separation.

As a well-known natural and innocuous plant constituent, cellulose consists of abundant hydroxyl groups and can tightly adsorb onto material surfaces hydrogen bonding, resulting in a superhydrophilic surface. In this work, the hydrophobic polyvinylidene fluoride (PVDF) membranes were modified by immersing them in cellulose hydrogel using a simple one-step process. The modified PVDF membrane exhibited excellent resistance to fouling and oil adhesion, making it highly effective in separating various oil-in-water emulsions. The cellulose-modified PVDF membranes achieved a high oil rejection rate (>99 %) and a maximum separation flux of 2675.2 L·m-2·h-1. Furthermore, even an oil-in-water emulsion containing bovine serum albumin maintained a steady permeation flux after four filtration cycles. Additionally, these cellulose-modified PVDF membranes demonstrated excellent underwater superoleophobicity across a wide range of pH levels and high saline conditions. Overall, these cellulose-modified superhydrophilic PVDF membranes are sustainable, environmentally friendly, easily scalable, and hold great promise for practical applications in oily wastewater treatment.

Successful treatment of epidermodysplasia verruciformis with a combination of 5-aminolevulinic acid photodynamic therapy and surgery.

Epidermodysplasia verruciformis (EV) is a rare inherited immune disease characterized by pityriasis versicolor-like macules, hyperpigmented or hypopigmented warty papules and irregular reddish-brown plaques, mainly on the face, neck and extremities. Some therapeutic options include medications, lifestyle changes, ALA-PDT, surgery and so on. But there is no cure for EV and thus the clinical management is challenging. We report a case of EV that was refractory to multiple therapies and achieved an encouraging result with a combination therapy of surgery and 5-aminolevulinic acid photodynamic therapy (ALA-PDT).

Long-term analysis of cellular immunity in patients with RRMM treated with CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy exhibits remarkable efficacy against refractory or relapsed multiple myeloma (RRMM); however, the immune deficiency following CAR-Ts infusion has not been well studied. In this study, 126 patients who achieved remission post-CAR-Ts infusion were evaluated for cellular immunity. Following lymphodepletion (LD) chemotherapy, the absolute lymphocyte count (ALC) and absolute counts of lymphocyte subsets were significantly lower than baseline at D0. Grade ≥ 3 lymphopenia occurred in 99% of patients within the first 30 days, with most being resolved by 180 days. The median CD4+ T-cell count was consistently below baseline and the lower limit of normal (LLN) levels at follow-up. Conversely, the median CD8+ T-cell count returned to the baseline and LLN levels by D30. The median B-cell count remained lower than baseline level at D60 and returned to baseline and LLN levels at D180. In the first 30 days, 27 (21.4%) patients had 29 infections, with the majority being mild to moderate in severity (21/29; 72.4%). After day 30, 44 (34.9%) patients had 56 infections, including 20 severe infections. One patient died from bacteremia at 3.8 months post-CAR-Ts infusion. In conclusion, most patients with RRMM experienced cellular immune deficiency caused by LD chemotherapy and CAR-Ts infusion. The ALC and most lymphocyte subsets gradually recovered after day 30 of CAR-Ts infusion, except for CD4+ T cells. Some patients experience prolonged CD4+ T-cell immunosuppression without severe infection.

The Association between Dietary Habits and Rapid Postoperative Recovery of Rotator Cuff Repair.

Some nutritional factors have been suggested to improve postoperative outcomes in rotator cuff (RC) repair, but dietary effects on the recovery speed after the surgery remain undefined. To investigate the potential roles of dietary habits in this context, we analyzed the 12-month follow-up data of 55 patients with RC repair and found that these patients could be categorized into a rapid recovery group (n = 35) and slow recovery group (n = 20) according to their postoperative recovery patterns. Group-based logistic analysis revealed that habitual intakes of meat (OR = 1.84, 95%CI, 1.22-2.76, p = 0.003), fruits (OR = 2.33, 95%CI, 1.26-5.67, p = 0.01), and wheat-flour foods (OR = 1.62, 95%CI, 1.2-2.25, p = 0.002) were significantly associated with rapid recovery. Moreover, among all intakes of wheat-flour foods, intakes of steamed and boiled flour products were also associated with rapid recovery. Further mediation analysis showed that eosinophilic granulocytes (EOs) significantly mediated the association between rapid RC recovery and the habitual intakes of meat (mediation proportion = 17.5%, P-mediation < 0.0001), fruits (17.9%, p < 0.0001), and wheat-flour foods (11.4%, p < 0.0001). Thus, our study suggests that certain dietary habits play beneficial roles in the context of postoperative recovery for RC repair.

Effects and mechanisms of tanshinone IIA on PTSD-like symptoms.

BACKGROUND: In recent years, Salvia miltiorrhiza and its active substances have remarkably progressed in treating central neurological disorders. Tanshinone IIA (TSA) is an active ingredient derived from the rhizome of Salvia miltiorrhiza that has been found to alleviate the symptoms of several psychiatric illnesses. Post-traumatic stress disorder (PTSD) is a mental disorder that results after experiencing a serious physical or psychological injury. The currently used drugs are not satisfactory for the treatment of PTSD. However, it has been reported that TSA can improve PTSD-like symptoms like learning and memory, cognitive disorder, and depression through multi-target regulation. PURPOSE: This paper discusses the ameliorative effects of TSA on PTSD-like symptoms and the possible mechanisms of action in terms of inhibition of neuronal apoptosis, anti-neuroinflammation, and anti-oxidative stress. Based on the pathological changes and clinical observations of PTSD, we hope to provide some reference for the clinical transformation of Chinese medicine in treating PTSD. METHODS: A large number of literatures on tanshinone in the treatment of neurological diseases and PTSD were retrieved from online electronic PubMed and Web of Science databases. CONCLUSION: TSA is a widely studied natural active ingredient against mental illness. This review will contribute to the future development of TSA as a new clinical candidate drug for improving PTSD-like symptoms.

Single Atomic Defect Conductivity for Selective Dilute Impurity Imaging in 2D Semiconductors.

Precisely controlled impurity doping is of fundamental significance in modern semiconductor technologies. Desired physical properties are often achieved at impurity concentrations well below parts per million level. For emergent two-dimensional semiconductors, development of reliable doping strategies is hindered by the inherent difficulty in identifying and quantifying impurities in such a dilute limit where the absolute number of atoms to be detected is insufficient for common analytical techniques. Here we report rapid high-contrast imaging of dilute single atomic impurities by using conductive atomic force microscopy. We show that the local conductivity is enhanced by more than 100-fold by a single impurity atom due to resonance-assisted tunneling. Unlike the closely related scanning tunneling microscopy, the local conductivity sensitively depends on the impurity energy level, allowing minority defects to be selectively imaged. We further demonstrate subsurface impurity detection with single monolayer depth resolution in multilayer materials.

Ferromagnetic transition-metal dopedɛ-phosphorene.

Various stable 2D phosphorus allotropes have been experimentally synthesized or theoretically predicted, such as puckered blackα-, puckered blueß-, and buckledɛ-phosphorene. Here, we present a systematic study of the magnetic properties ofɛ-phosphorene doped with 3dtransition-metal (TM) atoms, as well as its gas-sensing capabilities, using first-principles and non-equilibrium Green's function formalism. Our results show that 3dTM dopants strongly bind ontoɛ-phosphorene. Sc, Ti, V, Cr, Mn, Fe, and Co-dopedɛ-phosphorene exhibit spin polarization with magnetic moments up to 6 µB, stemming from exchange and crystal-field splitting of the 3dorbital. Among them, V-dopedɛ-phosphorene exhibits the highest Curie temperature.

Magnetic ε-Phosphorene for Sensing Greenhouse Gas Molecules.

It is critical for gas sensors that sense greenhouse gas molecules to have both good sensitivity and selectivity for water molecules in the ambient environment. Here, we study the charge transfer, IV curves, and electric field tuning of vanadium-doped monolayer ϵ-phosphorene as a sensor for NO, NO2, and H2O gas molecules via first-principle and transport calculations. We find that the paramagnetic toxic molecules of NO and NO2 have a high adsorption energy on V-ϵ-phosphorene, which originates from a large amount of charge transfer driven by the hybridisation of the localised spin states of the host with the molecular frontier orbital. Using the non-equilibrium Green's function, we investigate the IV responses with respect to the adsorption of different molecules to study the performance of gas molecule sensors. Our IV curves show a larger amount of changes in resistance of the paramagnetic NO and NO2 than nonmagnetic H2O gas molecules, suggesting both sensitivity and selectivity. Moreover, our calculations show that an applied external electric field (gate voltage) can effectively tune the amount of charge transfer. More charge transfer makes the sensor more sensitive to the molecule, while less charge transfer can reduce the adsorption energy and remove the adsorbed molecules, allowing for the repeated use of the sensor.

Treatment of severe hidradenitis suppurativa with a combination of 5-aminolevulinic acid photodynamic therapy, surgery, and secukinumab.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by nodules, abscesses, fistulas, sinus tracts, and scars, typically in intertriginous areas (Sabat et al., 2022). Therapeutic options include medications, surgical interventions, and physiotherapy; however, clinical management is challenging. We report a case of HS that was refractory to multiple treatments and achieved complete remission with a combination therapy of surgery, 5-aminolevulinic acid photodynamic therapy (ALA-PDT), and secukinumab.

Syntaphilin mediates axonal growth and synaptic changes through regulation of mitochondrial transport: a potential pharmacological target for neurodegenerative diseases.

Mitochondria are a crucial energy source for maintaining neuronal growth and synaptic function. Neurons possess unique morphological characteristics, which make the proper regulation of mitochondrial transport essential for meeting their energy demands. Syntaphilin (SNPH) is capable of specifically targeting the outer membrane of axonal mitochondria, anchoring them to microtubules, and thereby preventing their transport. SNPH also interacts with other mitochondrial proteins to regulate mitochondrial transport. The regulation of mitochondrial transport and anchoring mediated by SNPH is indispensable for axonal growth during neuronal development, maintenance of ATP levels during neuronal synaptic activity, and regeneration of mature neurons following damage. Precise blocking of SNPH may be an effective therapeutic strategy for neurodegenerative diseases and related mental disorders.

The role of RNA splicing factor PTBP1 in neuronal development.

Alternative pre-mRNA splicing, which produces various mRNA isoforms with distinct structures and functions from a single gene, is regulated by specific RNA-binding proteins and is an essential method for regulating gene expression in mammals. Recent studies have shown that abnormal change during neuronal development triggered by splicing mis-regulation is an important feature of various neurological diseases. Polypyrimidine tract binding protein 1 (PTBP1) is a kind of RNA-binding proteins with extensive biological functions. As a well-known splicing regulator, it affects the neuronal development process through its involvement in axon formation, synaptogenesis, and neuronal apoptosis, according to the most recent studies. Here, we summarized the mechanism of alternative splicing, structure and function of PTBP1, and the latest research progress on the role of alternative splicing events regulated by PTBP1 in axon formation, synaptogenesis and neuronal apoptosis, to reveal the mechanism of PTBP1-regulated changes in neuronal development process.

A combination of pre-infusion serum ferritin, CRP and IL-6 predicts outcome in relapsed/refractory multiple myeloma patients treated with CAR-T cells.

Background: Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity. Methods: This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers. Results: We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS (P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs. 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion. Conclusions: Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis.

High-Performance Sliding Ferroelectric Transistor Based on Schottky Barrier Tuning.

Sliding ferroelectricity associated with interlayer translation is an excellent candidate for ferroelectric device miniaturization. However, the weak polarization gives rise to the poor performance of sliding ferroelectric transistors with a low on/off ratio and a narrow memory window, which restricts its practical application. To address the issue, we propose a facile strategy by regulating the Schottky barrier in sliding ferroelectric semiconductor transistors based on γ-InSe, in which a high performance with a large on/off ratio (106) and a wide memory window (4.5 V) was ultimately acquired. Additionally, the memory window of the device can be further modulated by electrostatic doping or light excitation. These results open up new ways for designing novel ferroelectric devices based on emerging sliding ferroelectricity.

Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzofuran IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma.

Interleukin-1 receptor associated kinase 4 (IRAK4) is a critical mediator of MYD88 L265P-induced NF-κB activation, indicating it is a promising therapeutic target for diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of 2,3-dihydrobenzofuran IRAK4 inhibitors through structure-based drug design. The representative compound 22 exhibited strong IRAK4 inhibitory potency (IRAK4 IC50 = 8.7 nM), favorable kinase selectivity and high antiproliferative activity against the MYD88 L265P DLBCL cell line (OCI-LY10 IC50 = 0.248 µM). Compound 22 also exhibited the ability to inhibit the activation of IRAK4 signaling pathway and induce apoptosis in MYD88 L265P DLBCL cell line. In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.