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Single-cell analysis of the multiple myeloma microenvironment after γ-secretase inhibition and CAR T-cell therapy
Abstract Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by γ-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the γ-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of nonclassical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions after exposure to GSI. Although many genes with altered expression are associated with γ-secretase–dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (PFS; median PFS, 57 vs 861 days). GSIs are being explored in combination with the full spectrum of BCMA-targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.
Pulmonary artery denervation by noninvasive stereotactic radiotherapy: a pilot study in swine models of pulmonary hypertension
Development of oats flour and bitter gourd fortified cookies: Effects on physicochemical, antioxidant, antimicrobial, and sensory attributes
The objective of this study was the develop of fortified cookies enriched with oats flour and bitter gourd powder and monitoring the effects of these enrichments on the physicochemical, antioxidant, antimicrobial, and sensory attributes. This study was subjected to four treatments: control (0% oats flour and bitter gourd powder), T1 (10% oats flour), T2 (3% bitter gourd powder), and T3 (7% oats flour and 3% bitter gourd powder). Various physical properties of the cookies, including weight, thickness, diameter, spread ratio, baking loss, pH, and color values (L*, a*, and b*), were measured. Proximate analysis revealed moisture (4.23–4.70%), ash (1.17–1.67%), fat (13.62–15.09%), crude protein (7.02–7.36%), carbohydrate (71.78–72.97%), energy (442.62–452.40 kcal), and crude fiber (8.02–3.33%). Mineral contents included Na (787–754 mg/100g), Ca (873–435 mg/100g), and Zn (66.7–58.8 mg/100g). Additionally, DPPH free radical scavenging activity ranged from 13.14 to 75.51%, while TBARS activity varied from 0.78 to 1.33 mg MDA/kg. T2 cookies exhibited the highest antimicrobial activity, with control cookies showing the lowest. The 5-point hedonic scale indicated that T2 cookies had lower overall acceptability, while T3 cookies were better received. In conclusion, the study suggests that fortified cookies have a more significant impact than regular or control cookies.
Lower-intensity therapy for good-risk B-ALL
Hypoxia-induced conversion of sensory Schwann cells into repair cells is regulated by HDAC8
Abstract After a peripheral nerve injury, Schwann cells (SCs), the myelinating glia of the peripheral nervous system, convert into repair cells that foster axonal regrowth, and then remyelinate or re-ensheath regenerated axons, thereby ensuring functional recovery. The efficiency of this mechanism depends however on the time needed for axons to regrow. Here, we show that ablation of histone deacetylase 8 (HDAC8) in SCs accelerates the regrowth of sensory axons and sensory function recovery. We found that HDAC8 is specifically expressed in sensory SCs and regulates the E3 ubiquitin ligase TRAF7, which destabilizes hypoxia-inducible factor 1-alpha (HIF1α) and counteracts the phosphorylation and upregulation of c-Jun, a major inducer of the repair SC phenotype. Our study indicates that this phenotype switch is regulated by different mechanisms in sensory and motor SCs and is accelerated by HDAC8 downregulation, which promotes sensory axon regeneration and sensory function recovery.
The influence of perceived landscape value on tourists’ behavioral intentions in historical and cultural blocks
Historic cultural blocks are areas where a city’s material cultural heritage and humanistic characteristics converge, showcasing the city’s unique features and preserving rich and complete urban memories. Research on historic blocks primarily involves strategies related to protection, renewal, planning, and enhancement. However, there is a paucity of studies that explore the relationship between landscape value perception and tourist behavioral intentions from the perspective of recreation participants during the development and renewal of historic cultural blocks. This study uses the Zhongshan Road and Sifang Road historic cultural blocks in Qingdao as a case example. By collecting multi-source data such as online texts, tourist questionnaires, and interviews, and employing qualitative analysis and structural equation modeling as quantitative analysis methods, the study reveals the structural relationship between landscape value perception, place identity, and tourist behavioral intentions: (1) Landscape value perception has a significant positive effect on tourist behavioral intentions; (2) Landscape value perception has a significant positive effect on place identity; (3) Place identity, as a mediating variable, does not mediate the relationship between ecological landscape value perception and skill education value perception, but partially mediates the relationship between historical cultural value perception and recreational value perception. Based on the research results, feedback on the development effectiveness of historic cultural blocks from the perspective of recreation participants can be visually obtained. This helps identify the pain points in the renewal and development process, pinpoint the perceptual dimensions of landscape value that need improvement, and effectively enhance the multiple dimensions of landscape value perception in the blocks. This, in turn, activates the tourism vitality of historic cultural blocks and forms a virtuous cycle model for their development.
Iron accelerates MDS progression
The master male sex determinant Gdf6Y of the turquoise killifish arose through allelic neofunctionalization
Abstract Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 ( gdf6Y ) in Nothobranchius furzeri , an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele ( gdf6X ). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3 , the mRNA decay activator zfp36l2 as a new GDF6 signaling target.
Exploring factors influencing university students’ entrepreneurial intentions: The role of attitudes, beliefs, and environmental support
Entrepreneurship is an increasingly popular career choice among students, driven by the transformative impact of emerging technologies and evolving professional landscapes. This study focuses on how higher education shapes students’ professional identities and entrepreneurial intentions, particularly among business school students. Utilizing the Theory of Planned Behavior (TPB) as the foundational framework, the study examines the factors influencing entrepreneurial intentions, with a specific emphasis on the moderating role of departmental identification. The primary aim of this research is to explore how students’ identification with their academic departments influences the relationship between entrepreneurial attitude, self-efficacy, and environmental support with entrepreneurial intentions. The study hypothesizes that the stronger the departmental identification, the more significant these relationships become. A survey is conducted among students from several public universities in the eastern provinces of Mainland China, yielding 1,632 valid responses. The results confirm a positive correlation between entrepreneurial attitude, self-efficacy, and environmental support with entrepreneurial intentions. Furthermore, departmental identification moderates these relationships, amplifying the effects when students identify strongly with their academic departments. These findings emphasize the critical role of departmental identity in shaping entrepreneurial aspirations. They highlight the need for higher education institutions to leverage departmental identity as a strategic tool to guide students’ career trajectories. By fostering a supportive academic environment that strengthens departmental identity, institutions can better prepare their students for entrepreneurial success in a rapidly evolving professional world.
Long-term follow-up of the STOPAGO study
Abstract In an open prospective, multicenter study enrolling 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation.
Integrated healthy lifestyle even in late-life mitigates cognitive decline risk across varied genetic susceptibility
AbstractIt remains unclear whether the benefits of adhering to a healthy lifestyle outweigh the effects of high genetic risk on cognitive decline. We examined the association of combined lifestyle factors and genetic risk with changes in cognitive function and six specific dimensions of cognition among older adults from the Chinese Longitudinal Healthy Longevity Survey (1998–2018, n = 18,811, a subset of 6301 participants with genetic information). Compared to participants with an unfavorable lifestyle, those with a favorable lifestyle showed a 46.81% slower rate of cognitive decline, with similar results across most cognitive domains. High genetic risk was associated with a 12.5% faster rate of cognitive decline. Individuals with a high genetic risk and a favorable lifestyle have slower cognitive decline than those with a low genetic risk and an unfavorable lifestyle. These data suggest that the benefits of a favorable lifestyle outweigh genetic factors, and therefore that adhering to a favorable lifestyle may offset the genetic risk for accelerated cognitive decline.
Self- versus clinician-collected swabs in anal cancer screening: A clinical trial
Background Risk of anal cancer is high in certain populations and screening involves collection of anal swabs for HPV DNA and/or cytology testing. However, barriers exist, such as the need for an intimate examination, and stigma around HIV status, sexual orientation, and sexual practices. Self-collected anal swabs (SCA) are a proposed alternative to clinician-collected swabs (CCA) to overcome these barriers. Methods Participants were order-randomised to undergo SCA or CCA first, with a second swab taken immediately afterwards. Sample adequacy was assessed for HPV DNA and cytology testing. CCA was used as the gold standard to calculate sensitivity and specificity of SCA for cytology and HPV results. Acceptability of swab collection was assessed following the procedure. Results There was no significant difference in sample validity for HPV DNA testing between SCA and CCA (p = 0.564). Concordance was >90% for detection of any HR-HPV and HPV16. There was no significant difference in cellular adequacy for cytological testing between SCA and CCA, (p = 0.162). Concordance for cytologic prediction was 88.2% for any cytologic abnormality. Almost half (48.5%) of participants expressed no preference for SCA versus CCA; 15.2% preferred SCA and 35.4% CCA. Conclusions SCA may be an acceptable and feasible alternative to CCA for detecting HPV and cytological abnormalities in a clinic population.
Doubling down on GPRC5D in multiple myeloma
Systematically developing a registry of splice-site creating variants utilizing massive publicly available transcriptome sequence data
Abstract Genomic variants causing abnormal splicing play important roles in genetic disorders and cancer development. Among them, variants that cause the formation of novel splice-sites (splice-site creating variants, SSCVs) are particularly difficult to identify and often overlooked in genomic studies. Additionally, these SSCVs are frequently considered promising candidates for treatment with splice-switching antisense oligonucleotides (ASOs). To leverage massive transcriptome sequence data such as those available from the Sequence Read Archive, we develop a novel framework to screen for SSCVs solely using transcriptome data. We apply it to 322,072 publicly available transcriptomes and identify 30,130 SSCVs. Among them, 5121 SSCVs affect disease-causing variants. By utilizing this extensive collection of SSCVs, we reveal the characteristics of Alu exonization via SSCVs, especially the hotspots of SSCVs within Alu sequences and their evolutionary relationships. We discover novel gain-of-function SSCVs in the deep intronic region of the NOTCH1 gene and demonstrate that their activation can be suppressed using splice-switching ASOs. Collectively, we provide a systematic approach for automatically acquiring a registry of SSCVs, which facilitates the elucidation of novel biological mechanisms underlying splicing and serves as a valuable resource for drug discovery. The catalogs of SSCVs identified in this study are accessible on the SSCV DB ( https://sscvdb.io ).
Examining the risk of delirium in patients hospitalized with COVID-19: Insights from the homeless population
For patients hospitalized with COVID-19, delirium is a serious and under-recognized complication, and people experiencing homelessness (PEH) may be at greater risk. This retrospective cohort study compared delirium-associated risk factors and clinical outcomes between PEH and non-PEH. This study used patient records from 154 hospitals discharged from 2020–2021 from the Texas Inpatient Public Use Data file. Study subjects (n = 878) were patients, aged 18–69 years, who were hospitalized with COVID-19 and were identified as homeless. The baseline group included (n = 176,518) patients with COVID-19 aged 18–69 years who were not homeless. Logistic regression models were used to identify risk factors for delirium. Relevant risk factors included chronic comorbidities, substance use disorders, and traumatic brain injury (TBI). Seven of the delirium-associated risk factors were more prevalent among PEH compared to baseline. PEH had higher rates of TBI, alcohol, cannabis, and opioid use disorders. PEH had significantly higher rates of delirium (10.6% vs. 8.1%; P<0.01). However, PEH had fewer respiratory complications, including pneumonia (48.5% vs. 81.9%; P<0.001) and respiratory failure (28.7% vs. 61.9%; P<0.001), and lower in-hospital mortality (3.3% vs. 9.5%; P<0.001). The anti-viral Remdesivir had a protective effect against delirium (AOR = 0.63; CI: 0.60, 0.66). Mean hospital length of stay (LOS) was more than twice as long for delirious patients compared with non-delirious patients (18.4 days vs. 7.7 days; P<0.001). Delirium greatly increased the risk of in-hospital mortality (AOR = 3.8; CI: 3.6, 4.0). For PEH (n = 29) who died from COVID-19, delirium was present in more than half (52%) of cases. Hospitals should screen PEH for delirium and adopt nursing protocols to prevent delirium and reduce its severity.
Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma
Abstract Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. “Off-the-shelf” T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GPRC5D) have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format. Bivalent binding of forimtamig to GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D -negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.
High-impedance microwave resonators with two-photon nonlinear effects
AbstractNonlinear effects play a central role in photonics as they form the foundation for most of the device functionalities such as amplification and quantum state preparation and detection. Typically the nonlinear effects are weak and emerge only at high photon numbers with strong drive. Here we present an experimental study of a Josephson junction -based high-impedance resonator. We show that by taking the resonator to the limit of consisting effectively only of one junction, results in strong nonlinear effects already for the second photon while maintaining a high impedance of the resonance mode. Our experiment yields thus resonators with strong interactions both between individual resonator photons and from the resonator photons to other electric quantum systems. We also present an energy diagram technique which enables to measure, identify and analyse different multi-photon optics processes along their energy conservation lines.
Retrospective study of incidence/prevalence of pigmentary maculopathy and retinopathy in patients receiving pentosan polysulfate sodium
Purpose To evaluate prevalence and incidence rates of pigmentary maculopathy and retinopathy (PM/PR), and visual acuity (VA) changes in patients exposed to pentosan polysulfate sodium (PPS) and in patients with interstitial cystitis (IC) not exposed to PPS. Methods This is a retrospective cohort study (January 2015–March 2021) which included adult de-identified patients from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) and Komodo Health database. Three patient cohorts were identified: two PPS-exposed patient cohorts, and Non-PPS-exposed IC patient cohort. Key study outcomes included PM/PR/Any (defined based on prior literature regardless of PPS exposure) and PM/PR/PPS (further defined by an algorithm that was based on clinical notes and other protocol-prespecified criteria in PPS-exposed patients), and VA changes in each respective cohort. Results Prevalence of PM/PR/Any was relatively common in patients prior to PPS exposure (4.16%–8.43%). Incidence rate of PM/PR/PPS was uncommon in both PPS-exposed cohorts (0.13–0.15 per 100 person-years). Crude incidence rates of PM/PR/Any (based on ITT analysis) varied slightly across 3 study cohorts (2.13–2.81 and 2.38 per 100-person-years for PPS-exposed cohorts and Non-PPS-exposed IC cohort, respectively). Across all 3 study cohorts, patients with PM/PR/Any appeared to have approximately 2-fold higher proportion of 3 lines of VA worsening than those without PM/PR/Any. Conclusion Prevalence of PM/PR was common in patients prior to PPS exposure. Incidence of PM/PR/PPS that may be associated with PPS exposure was relatively uncommon. Crude incidence rates of PM/PR appeared similar across all patient cohorts regardless of PPS exposure.
Outcomes in patients with <i>ETV6</i>::<i>RUNX1</i> or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies
Abstract Children with ETV6::RUNX1 or high-hyperdiploid B-cell acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low risk, regardless of their National Cancer Institute (NCI) risk classification, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV/XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable between NCI standard-risk and high-risk patients and between SJ low-risk and standard-risk patients. Of the 40 NCI high-risk patients, 37 who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, NCI high-risk patients had worse EFS than standard-risk patients (87.6% ± 4.5% vs 96.4% ± 1.3%; P = .016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = .719). However, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% vs 98.0% ± 2.2%; P = .004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = .013) and pancreatitis (P = .011) than those who received SJ standard/high-risk therapy. MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.