Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development.

The mammalian kidney maintains fluid homeostasis through diverse epithelial cell types generated from nephron and ureteric progenitor cells. To extend a developmental understanding of the kidney's epithelial networks, we compared chromatin organization (single-nuclear assay for transposase-accessible chromatin sequencing [ATAC-seq]; 112,864 nuclei) and gene expression (single-cell/nuclear RNA sequencing [RNA-seq]; 109,477 cells/nuclei) in the developing human (10.6-17.6 weeks; n = 10) and mouse (post-natal day [P]0; n = 10) kidney, supplementing analysis with published mouse datasets from earlier stages. Single-cell/nuclear datasets were analyzed at a species level, and then nephron and ureteric cellular lineages were extracted and integrated into a common, cross-species, multimodal dataset. Comparative computational analyses identified conserved and divergent features of chromatin organization and linked gene activity, identifying species-specific and cell-type-specific regulatory programs. In situ validation of human-enriched gene activity points to human-specific signaling interactions in kidney development. Further, human-specific enhancer regions were linked to kidney diseases through genome-wide association studies (GWASs), highlighting the potential for clinical insight from developmental modeling.

Silibinin Mitigates Vanadium-induced Lung Injury via the TLR4/MAPK/NF-κB Pathway in Mice.

BACKGROUND/AIM: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury. MATERIALS AND METHODS: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts. RESULTS: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils. CONCLUSION: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

Influence of cutoff radius and tip atomic structure on energy barriers encountered during AFM tip sliding on 2D monolayers.

In computational studies using the Lennard-Jones (LJ) potential, the widely adopted 2.5σcutoff radius effectively truncates pairwise interactions across diverse systems (Santraet al2008J. Chem. Phys.129234704, Chen and Gao 2021Friction9502-12, Bolintineanuet al2014Part. Mech.1321-56, Takahiro and Kazuhiro 2010J. Phys.: Conf. Ser.215012123, Zhouet al2016Fuel180718-26, Toxvaerd and Dyre 2011J. Chem. Phys.134081102, Toxvaerd and Dyre 2011J. Chem. Phys.134081102). Here, we assess its adequacy in determining energy barriers encountered by a Si monoatomic tip sliding on various two-dimensional (2D) monolayers, which is crucial for understanding nanoscale friction. Our findings emphasize the necessity of a cutoff radius of at least 3.5σto achieve energy barrier values exceeding 95% accuracy across all studied 2D monolayers. Specifically, 3.5σcorresponds to 12.70 Å in graphene, 12.99 Å in MoS2and 13.25 Å in MoSe2. The barrier values calculated using this cutoff support previous experiments comparing friction between different orientations of graphene and between graphene and MoS2(Almeidaet al2016Sci. Rep.631569, Zhanget al2014Sci. China57663-7). Furthermore, we demonstrate the applicability of the 3.5σcutoff for graphene on an Au substrate and bilayer graphene. Additionally, we investigate how the atomic configuration of the tip influences the energy barrier, finding a nearly threefold increase in the barrier along the zigzag direction of graphene when using a Si(001) tip composed of seven Si atoms compared to a monoatomic Si tip.

Flavonoid gossypetin protects alveolar bone and limits inflammation in ligature-induced periodontitis in mice.

BACKGROUND: Bacterial-induced inflammation instigates the destruction of hard and soft tissues surrounding teeth in periodontitis. In severe cases, the increased number and activity of osteoclasts induces the resorption of alveolar bones, ultimately leading to tooth loss. Because of their diverse chemical structures and bioactivities, natural compounds are often suggested to treat a wide variety of diseases, including inflammatory disorders. METHODS: In the present study, we demonstrated an inhibitory effect of gossypetin, a hexahydroxy flavone, on osteoclast differentiation and bone resorption using in vitro culture of osteoclasts from mouse bone marrow macrophage (BMM) precursors and in vivo model of ligature-induced periodontitis in mice. RESULTS: Gossypetin significantly reduced the differentiation of osteoclasts from mouse BMM precursors in the presence of the receptor activator of nuclear factor κB ligand (RANKL). In vitro, gossypetin inhibited critical signaling events downstream of RANKL including the auto-amplification of nuclear factor of activated T-cells, cytoplasmic 1, Ca2+ oscillations, and the generation of reactive oxygen species. In a mouse ligature-induced periodontitis model, the administration of gossypetin significantly reduced osteoclastogenesis and alveolar bone resorption. Furthermore, gossypetin prevented the ligature-induced increase in macrophages and T cells and reduced the production of tumor necrosis factor-α and interleukin-6. CONCLUSION: Taken together, these results show anti-osteoclastogenic and anti-inflammatory effects of gossypetin, suggesting the potential use of this natural compound in periodontitis.

Efficacy and safety of candidate biosimilar CT-P41 versus reference denosumab: a double-blind, randomized, active-controlled, Phase 3 trial in postmenopausal women with osteoporosis.

This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. PURPOSE: To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. METHODS: This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80-125% (for 95% CIs associated with geometric LS mean ratios). RESULTS: Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: - 0.139 [- 0.826, 0.548] in the full analysis set and - 0.280 [- 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. CONCLUSIONS: CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Intermediate Disturbances Enhance Microbial Enzyme Activities in Soil Ecosystems.

The Intermediate Disturbance Hypothesis (IDH) posits that maximal plant biodiversity is attained in environments characterized by moderate ecological disturbances. Although the applicability of the IDH to microbial diversity has been explored in a limited number of studies, there is a notable absence of experimental reports on whether soil microbial 'activity' demonstrates a similar response to the frequency or intensity of environmental disturbances. In this investigation, we conducted five distinct experiments employing soils or wetland sediments exposed to varying intensities or frequencies of disturbances, with a specific emphasis on disturbances associated with human activity, such as chemical contamination, hydrologic changes, and forest thinning. Specifically, we examined the effects of bactericide and heavy metal contamination, long-term drainage, tidal flow, and thinning management on microbial enzyme activities in soils. Our findings revealed that microbial enzyme activities were highest at intermediate disturbance levels. Despite the diversity in experiment conditions, each trial consistently demonstrated analogous patterns, suggesting the robustness of the IDH in elucidating microbial activities alongside diversity in soils. These outcomes bear significant implications for ecological restoration and management, as intermediate disturbance may expedite organic matter decomposition and nutrient cycles, crucial for sustaining ecosystem services in soils.

Wrinkle-Improving Effect of Novel Peptide That Binds to Nicotinic Acetylcholine Receptor.

Wrinkles, one of the most common signs of aging, are primarily caused by the continuous contraction of muscles. Muscle contraction is induced by the binding of acetylcholine (ACh), released at the neuromuscular junction, to nicotinic acetylcholine receptor (nAChR) present on the muscle cell surface. In this study, we aimed to develop a wrinkle-improving peptide that inhibits the binding of ACh to nAChR using peptide phage display technology. Our peptide showed a remarkably high binding affinity to nAChR subunit α1, with a value below 1 µM, and was found to inhibit the action of ACh through its interaction with these receptors. Furthermore, it increased collagen synthesis in skin cells and upregulated the expression of the aquaporin-3 (AQP3) and hyaluronan synthase-2 (HAS2) genes. These results confirm that the peptide effectively inhibits muscle contraction and enhances skin elasticity and hydration, contributing to its wrinkle-reducing effects. Clinical studies on humans observed significant improvement in wrinkles after three weeks of use, with substantial reduction observed after six weeks. In conclusion, these findings demonstrate the efficacy of the peptide (named Medipep) in reducing wrinkles.

Stable and reusable calcium-responsive biopolymer for affinity precipitation of therapeutic antibodies.

Affinity precipitation is an attractive method for protein purification due to its many advantages, including the rapid capture of target proteins, simple processing, high specificity, and ease of scale-up. We previously reported a robust antibody purification method using Ca2+-dependent precipitation of ZZ-hCSQ2, a fusion protein of human calsequestrin 2, and the antibody-binding protein ZZ. However, the stability of this fusion protein was not sufficiently high for industrial use because the antibody recovery yield decreased to 60% after being reused 10 times. To identify a more stable calsequestrin (CSQ), we calculated Rosetta energy values for the folding stabilities of various CSQ homologs and selected human CSQ1 (hCSQ1) with lowest energy value (-992.6) as the new CSQ platform. We also identified that the linker sequence between ZZ and CSQ was vulnerable to proteases and alkaline pH by N-terminal protein sequencing. Therefore, we changed the linker to four asparagine (4N) sequences, which were shorter and less flexible than the previous glycine-rich linker. The new version of ZZ-CSQ, ZZ-4N-hCSQ1, was stable in a protease-containing conditioned medium obtained from the cultured Chinese hamster ovary cell or high pH condition (0.1M sodium hydroxide) for more than 5 days and could be reused at least 25 times for antibody purification without loss of recovery yield. The antibodies purified by ZZ-4N-hCSQ1 precipitation also showed greater purity (~33.6-fold lower host cell DNA and ~6.4-fold lower host cell protein) than those purified by protein A chromatography. These data suggest that ZZ-4N-hCSQ1 precipitation is more efficient and can achieve cost-effectiveness of up to 12.5-fold cheaper than previous antibody purification methods and can lower the production costs of therapeutic antibodies.

Molecular insights into regulatory RNAs in the cellular machinery.

It is apparent that various functional units within the cellular machinery are derived from RNAs. The evolution of sequencing techniques has resulted in significant insights into approaches for transcriptome studies. Organisms utilize RNA to govern cellular systems, and a heterogeneous class of RNAs is involved in regulatory functions. In particular, regulatory RNAs are increasingly recognized to participate in intricately functioning machinery across almost all levels of biological systems. These systems include those mediating chromatin arrangement, transcription, suborganelle stabilization, and posttranscriptional modifications. Any class of RNA exhibiting regulatory activity can be termed a class of regulatory RNA and is typically represented by noncoding RNAs, which constitute a substantial portion of the genome. These RNAs function based on the principle of structural changes through cis and/or trans regulation to facilitate mutual RNA‒RNA, RNA‒DNA, and RNA‒protein interactions. It has not been clearly elucidated whether regulatory RNAs identified through deep sequencing actually function in the anticipated mechanisms. This review addresses the dominant properties of regulatory RNAs at various layers of the cellular machinery and covers regulatory activities, structural dynamics, modifications, associated molecules, and further challenges related to therapeutics and deep learning.

Early dose reduction of dasatinib does not compromise clinical outcomes in patients with chronic myeloid leukemia: A comparative analysis of two prospective trials.

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 administered by auto-injector or pre-filled syringe: a randomized, open­label, single-dose phase I study.

BACKGROUND: This study compared the pharmacokinetics (PK), immunogenicity, and safety of candidate tocilizumab biosimilar, CT-P47, administered via auto-injector (CT-P47 AI) or pre-filled syringe (CT-P47 PFS), in healthy Asian adults. RESEARCH DESIGN AND METHODS: In this phase I, multicenter, open-label study, participants were randomized 1:1 to receive a single 162 mg/0.9 mL dose of CT-P47 via AI or PFS. Primary endpoints were area under the concentration - time curve from time zero to infinity (AUC0-inf) and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the predefined 80-125% equivalence margin. Secondary PK parameters, immunogenicity, and safety outcomes were also assessed. RESULTS: Of 314 participants randomized (155 CT-P47 AI; 159 CT-P47 PFS), 310 received the study drug (153 CT-P47 AI; 157 CT-P47 PFS). Primary and secondary PK results, immunogenicity and safety were similar between groups. Ninety percent CIs for the ratio of gLSMs were within the predefined equivalence margin for AUC0-inf (85.87-102.94) and Cmax (82.98-98.16). CONCLUSIONS: PK equivalence between CT-P47 AI and CT-P47 PFS was demonstrated in healthy Asian adults, with comparable immunogenicity and safety between the two devices. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05617183.

Tocilizumab is a biologic medicine used to treat inflammatory diseases, such as rheumatoid arthritis. A biosimilar is a drug that is an almost identical copy of an approved original ('reference') biologic medicine; it has identical efficacy and safety to the original medicine but is typically less expensive. CT­P47 is in development as a possible tocilizumab biosimilar.Some patients prefer injections using an auto-injector (AI) rather than a pre-filled syringe (PFS), for reasons including ease of use and convenience. With an AI, medicine is delivered automatically by firmly pressing the device against the skin, whereas, with a PFS, a needle is inserted into the skin and medicine delivered by depressing the plunger. The injection of CT­P47 using a PFS has shown comparable pharmacokinetics (i.e., the uptake, metabolism and excretion of the drug by the body) and safety to tocilizumab. Therefore, if the pharmacokinetics and safety of CT­P47 administered via AI and PFS were shown to be similar, this might expand the choice of administration devices available to patients.In this study, 310 healthy adults received a single injection of CT­P47 via AI or PFS. Blood samples were taken over 43 days to analyze pharmacokinetics. The uptake, metabolism and elimination of CT­P47 by the body was similar when administered by each device, suggesting that CT­P47 can be administered by either AI or PFS.

Diagnostic Performance of a Molecular Assay in Synovial Fluid Targeting Dominant Prosthetic Joint Infection Pathogens.

Prosthetic joint infection (PJI) is one of the most serious complications of joint replacement surgery among orthopedic surgeries and occurs in 1 to 2% of primary surgeries. Additionally, the cause of PJIs is mostly bacteria from the Staphylococcus species, accounting for more than 98%, while fungi cause PJIs in only 1 to 2% of cases and can be difficult to manage. The current gold-standard microbiological method of culturing synovial fluid is time-consuming and produces false-negative and -positive results. This study aimed to identify a novel, accurate, and convenient molecular diagnostic method. The DreamDX primer-hydrolysis probe set was designed for the pan-bacterial and pan-fungal detection of DNA from pathogens that cause PJIs. The sensitivity and specificity of DreamDX primer-hydrolysis probes were 88.89% (95% CI, 56.50-99.43%) and 97.62% (95% CI, 87.68-99.88%), respectively, compared with the microbiological method of culturing synovial fluid, and receiver operating characteristic (ROC) area under the curve (AUC) was 0.9974 (*** p < 0.0001). It could be concluded that the DreamDX primer-hydrolysis probes have outstanding potential as a molecular diagnostic method for identifying the causative agents of PJIs, and that host inflammatory markers are useful as adjuvants in the diagnosis of PJIs.

Biosimilar candidate CT-P42 in diabetic macular edema: 24-week results from a randomized, active-controlled, Phase III study.

OBJECTIVE: To demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DESIGN: Randomized, active-controlled, double-masked, Phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. METHODS: Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. MAIN OUTCOME MEASURES: The primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. RESULTS: Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI -0.73, 1.88 [global]; 90% CI -0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. CONCLUSIONS: This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Tacrolimus-loaded chitosan-based nanoparticles as an efficient topical therapeutic for the effective treatment of atopic dermatitis symptoms.

Atopic dermatitis (AD) is a chronic cutaneous disease with a complex underlying mechanism, and it cannot be completely cured. Thus, most treatment strategies for AD aim at relieving the symptoms. Although corticosteroids are topically applied to alleviate AD, adverse side effects frequently lead to the withdrawal of AD therapy. Tacrolimus (TAC), a calcineurin inhibitor, has been used to treat AD, but its high molecular weight and insolubility in water hinder its skin permeability. Herein, we developed and optimized TAC-loaded chitosan-based nanoparticles (TAC@CNPs) to improve the skin permeability of TAC by breaking the tight junctions in the skin. The prepared nanoparticles were highly loadable and efficient and exhibited appropriate characteristics for percutaneous drug delivery. TAC@CNP was stable for 4 weeks under physiological conditions. CNP released TAC in a controlled manner, with enhanced skin penetration observed. In vitro experiments showed that CNP was non-toxic to keratinocyte (HaCaT) cells, and TAC@CNP dispersed in an aqueous solution was as anti-proliferative as TAC solubilized in a good organic solvent. Importantly, an in vivo AD mouse model revealed that topical TAC@CNP containing ~1/10 of the dose of TAC found in commercially used Protopic® Ointment exhibited similar anti-inflammatory activity to that of the commercial product. TAC@CNP represents a potential therapeutic strategy for the management of AD.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY).

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

Interferon-Gamma Release Assay Combined with Renal Indicators to Reduce the False-Negativity of Latent Tuberculosis Infection in End-Stage Renal Disease with Hemodialysis Patients.

BACKGROUND: Tuberculosis (TB) is still the main cause of mortality due to a single transfectant, Mycobacterium tuberculosis (MTB). Latent tuberculosis infection (LTBI) is a condition characterized by the presence of tuberculosis (TB) that is not clinically apparent but nonetheless shows a sustained response to MTB. Presently, tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are mainly used to detect LTBI via cell-mediated immunity of T-cells. For people with end-stage renal disease (ESRD), the diagnosis of patients infected with MTB is difficult because of T-cell dysfunction. To get more accurate diagnosis results of LTBI, it must compensate for the deficiency of IGRA tests. METHODS: Sixty-seven hemodialysis (HD) patients and 96 non-HD patients were enrolled in this study and the study population is continuously included. IFN-γ levels were measured by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test. Kidney function indicators, blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR) were used to compensate for the declined IFN-γ levels in the IGRA test. RESULTS: In individuals who were previously undetected, the results of compensation with serum Cr increased by 10.81%, allowing for about 28% more detection, and compensation with eGFR increased by 5.41%, allowing for approximately 14% more detectable potential among them and employing both of them could enhance the prior shortcomings of IGRA tests. when both are used, the maximum compensation results show a sensitivity increase rate of 8.81%, and approximately 23% of patients who were previously undetectable may be found. CONCLUSION: Therefore, the renal function markers which are routine tests for HD patients to compensate for the deficiency of IGRA tests could increase the accuracy of LTBI diagnosis.

An AIE-based fluorescent probe to detect peroxynitrite levels in human serum and its cellular imaging.

An AIE-based fluorescent probe was designed to evaluate peroxynitrite levels in complex biological samples. The newly synthesized hydrazone-conjugated probe fluoresces strongly in the presence of peroxynitrite. Clinically, the peroxynitrite levels can be measured in human serum and cellular mitochondria with an LOD of 6.5 nM by fluorescence imaging in vitro.

TNF receptor 2 knockout mouse had reduced lung cancer growth and schizophrenia-like behavior through a decrease in TrkB-dependent BDNF level.

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 µg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels.