[Value of SOX1 and PAX1 Gene Methylation Detection in Secondary Triage of High-Grade Cervical Lesions].

Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.

Recurrent mucinous carcinoma with sarcomatoid and sarcomatous mural nodules: a case report and literature review.

Ovarian mucinous tumors with sarcomatous mural nodules are rare. Sarcomatous nodules have a bad prognosis. Its diagnosis and treatment are controversial.It is still controversial whether malignant mural nodules represent a dedifferentiated form of mucinous tumors or collisional tumors. This is a case report of a 32-year-old female diagnosed with ovarian mucinous tumor recurred as a mucinous carcinoma combined with sarcomatoid and undifferentiated sarcoma mural nodules after surgery and chemotherapy. The primary lesion did not have a sarcomatous component after comprehensive sampling and repeated review, while the recurrent lesion had a predominantly sarcomatous component. The patient received a second operation and postoperative chemotherapy plus Anlotinib with no progression at 16 months of follow-up. Primary mucinous carcinoma and sarcomatous mural nodules revealed the same K-RAS mutation(c.35G>T, pG12V), TP53 mutation (c.817C>T, p.R273C), MLL2 mutation(c.13450C>T, p.R4484) and NF1 mutation(c.7876A>G, p.S2626G). We present a comprehensive analysis on morphologic characteristics, molecular detection results, clinical management, and prognosis of ovarian mucinous tumors with mural nodules of sarcomatoid and undifferentiated sarcoma. Mutation sharing between primary mucinous carcinoma and recurrent sarcomatous nodules supports monoclonal origin of primary and recurrent tumors, suggesting a tendency for sarcomatous differentiation during the progression of epithelial tumors. Malignant mural nodules represent dedifferentiation in mucinous ovarian tumors rather than collision of two different tumor types. Therefore, it is imperative to conduct comprehensive sampling, rigorous clinical examination, and postoperative follow-up in order to thoroughly evaluate all mural nodules of ovarian mucinous tumors due to their potential for malignancy and sarcomatous differentiation.

Niraparib enhances antitumor immunity and contributes to the efficacy of PD-L1 blockade in cervical cancer.

PURPOSE: With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can't receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear. METHODS: The alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT-PCR. RESULTS: We found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8+ T cells and the level of IFN-γ, granzyme B in vivo. CONCLUSION: Our findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.

Involvement of a rice mutation in storage protein biogenesis in endosperm and its genomic location.

MAIN CONCLUSION: A mutation was first found to cause the great generation of glutelin precursors (proglutelins) in rice (Oryza sativa L.) endosperm, and thus referred to as GPGG1. The GPGG1 was involved in synthesis and compartmentation of storage proteins. The PPR-like gene in GPGG1-mapped region was determined as its candidate gene. In the wild type rice, glutelins and prolamins are synthesized on respective subdomains of rough endoplasmic reticulum (ER) and intracellularly compartmentalized into different storage protein bodies. In this study, a storage protein mutant was obtained and characterized by the great generation of proglutelins combining with the lacking of 13 kD prolamins. A dominant genic-mutation, referred to as GPGG1, was clarified to result in the proteinous alteration. Novel saccular composite-ER was shown to act in the synthesis of proglutelins and 14 kD prolamins in the mutant. Additionally, a series of organelles including newly occurring several compartments were shown to function in the transfer, trans-plasmalemmal transport, delivery, deposition and degradation of storage proteins in the mutant. The GPGG1 gene was mapped to a 67.256 kb region of chromosome 12, the pentatricopeptide repeat (PPR)-like gene in this region was detected to contain mutational sites.

[A multicenter study of neonatal stroke in Shenzhen, China]. / 深圳市新生儿脑卒中多中心现况调查.

OBJECTIVES: To investigate the incidence rate, clinical characteristics, and prognosis of neonatal stroke in Shenzhen, China. METHODS: Led by Shenzhen Children's Hospital, the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022. The incidence, clinical characteristics, treatment, and prognosis of neonatal stroke in Shenzhen were analyzed. RESULTS: The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137, 1/6 060, and 1/7 704, respectively. Ischemic stroke accounted for 75% (27/36); boys accounted for 64% (23/36). Among the 36 neonates, 31 (86%) had disease onset within 3 days after birth, and 19 (53%) had convulsion as the initial presentation. Cerebral MRI showed that 22 neonates (61%) had left cerebral infarction and 13 (36%) had basal ganglia infarction. Magnetic resonance angiography was performed for 12 neonates, among whom 9 (75%) had involvement of the middle cerebral artery. Electroencephalography was performed for 29 neonates, with sharp waves in 21 neonates (72%) and seizures in 10 neonates (34%). Symptomatic/supportive treatment varied across different hospitals. Neonatal Behavioral Neurological Assessment was performed for 12 neonates (33%, 12/36), with a mean score of (32±4) points. The prognosis of 27 neonates was followed up to around 12 months of age, with 44% (12/27) of the neonates having a good prognosis. CONCLUSIONS: Ischemic stroke is the main type of neonatal stroke, often with convulsions as the initial presentation, involvement of the middle cerebral artery, sharp waves on electroencephalography, and a relatively low neurodevelopment score. Symptomatic/supportive treatment is the main treatment method, and some neonates tend to have a poor prognosis.

Association between viral infection and bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

Bronchopulmonary dysplasia (BPD) is the most common serious complication of very preterm infants (VPI) or very low birth weight (VLBW) infants. Studies implicate viral infections in etiopathogenesis. The aim of this study was to summarize the relationship between viral infections and BPD through a systematic review and meta-analysis. We searched PubMed, Embase, the Web of Science Core Collection, and the Cochrane Database on December 19, 2023. We included observational studies that examined the association between viral infections and BPD in preterm infants. We extracted data on study methods, participant characteristics, exposure assessment, and outcome measures. We assessed study risk of bias using the Newcastle-Ottawa Scale (NOS). We included 17 and 15 studies in the qualitative review and meta-analysis, respectively. The meta-analysis showed a significant association between viral infection and BPD diagnosed at 36 weeks postmenstrual age (odds ratio (OR): 2.42, 95% confidence interval: 1.89-3.09, 13 studies, very low certainty of evidence). In a subgroup analysis of specific viruses, cytomegalovirus (CMV) proved to be significantly associated with BPD diagnosed at 36 weeks postmenstrual age (OR: 2.34, 95% confidence interval: 1.80-3.05, 11 studies). We did not find an association between viral infection and BPD diagnosed on the 28th day of life, probably due to the small sample size of the included prospective studies.  Conclusion: Viral infections, especially CMV, are associated with an increased risk of BPD in preterm infants. Methodologically reliable prospective studies with large samples are needed to validate our conclusions, and high-quality randomized controlled studies are needed to explore the effect of prevention or treatment of viral infections on the incidence of BPD. What is Known: • Studies have attempted to identify viral infections and bronchopulmonary dysplasia in preterm infants; however, results have been inconsistent. What is New: • Systematic demonstration that viral infections, particularly cytomegalovirus, are positively associated with bronchopulmonary dysplasia diagnosed in preterm infants at the 36th week of postmenstrual age. • The importance of screening for viral infections in preterm infants, especially cytomegalovirus. More high-quality studies should be produced in the future to investigate the causal relationship between viral infections and bronchopulmonary dysplasia.

Botulinum Toxin Type A Alleviates Androgenetic Alopecia by Inhibiting Apoptosis of Dermal Papilla Cells via Targeting circ_0135062/miR-506-3p/Bax Axis.

Botulinum toxin type A (BTXA) has the potential to treat androgenetic alopecia (AGA); however, its impact on the apoptosis of dermal papillary cells (DPCs) is not yet fully understood. Noncoding RNAs play a crucial role in AGA. In this study, we investigated the potential mechanism by which BTXA alleviates apoptosis induced by dihydrotestosterone (DHT) in DPCs. We assessed the mRNA levels of circ_0135062, miR-506-3p, and Bax using qRT-PCR. Binding interactions were analyzed using RNA pulldown and dual-luciferase assays. Cell viability was determined using a cell counting kit-8 assay, and cell apoptosis was assessed using flow cytometry, TUNEL assays, and western blotting. Our findings revealed that BTXA inhibited the apoptosis of DPCs treated with DHT. Moreover, circ_0135062 overexpression counteracted the protective effect of BTXA on DHT-treated DPCs. MiR-506-3p was found to interact with Bax and inhibit apoptosis in DPCs by suppressing Bax expression in response to DHT-induced damage. Furthermore, circ_0135062 acted as a sponge for miR-506-3p, thereby inhibiting the targeting of Bax expression by miR-506-3p. In conclusion, BTXA exhibited an antiapoptotic effect on DHT-induced DPC injury via the circ_0135062/miR-506-3p/Bax axis.Level of Evidence II This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth.

Early life is a time of increased susceptibility to infectious diseases and development of allergy. Innate lymphocytes are crucial components of the initiation and regulation of immune responses at mucosal surfaces, but functional differences in innate lymphocytes early in life are not fully described. We aimed to characterize the abundance and function of different innate lymphocyte cell populations in cord blood in comparison to that of adults. Blood was collected from adult donors and umbilical vessels at birth. Multicolor flow cytometry panels were used to identify and characterize lymphocyte populations and their capacity to produce hallmark cytokines. Lymphocytes were more abundant in cord blood compared to adults, however, mucosal-associated invariant T cells and natural killer T (NKT)-like cells, were far less abundant. The capacity of NKT-like cells to produce cytokines and their expression of the cytotoxic granule protein granzyme B and the marker of terminal differentiation CD57 were much lower in cord blood than in adults. In contrast, natural killer (NK) cells were as abundant in cord blood as in adults, they could produce IFNγ, and their expression of granzyme B was not significantly different from that of adult NK cells, although CD57 expression was lower. All innate lymphoid cell (ILC) subsets were more abundant in cord blood, and ILC1 and ILC2 were capable of production of IFNγ and IL-13, respectively. In conclusion, different innate lymphoid cells differ in both abundance and function in peripheral blood at birth and with important implications for immunity in early life.

Treatment of Chin Retrusion With Botulinum Toxin Plus Hyaluronic Acid Filler in Comparison With Hyaluronic Acid Filler Alone: A Randomized, Evaluator-Blinded, Controlled Study.

BACKGROUND: Hyaluronic acid (HA) has already been widely administered for chin augmentation. Patients with chin retrusion frequently present with increased chin hypertonia. Monotherapy with HA falls short in addressing the multifaceted cosmetic concerns associated with chin retrusion. OBJECTIVES: This study aimed to investigate the clinical efficacy and safety of the combination therapy involving botulinum toxin (BTX) and HA in the treatment of chin retrusion. METHODS: We enrolled patients with moderate to severe chin retrusion for 9 months of follow-up after they received either combined treatment with BTX plus HA or monotreatment with HA. We also calculated the surface-volume coefficient with 3-dimensional digital scanning technique, and evaluated outcomes based on the Allergan Chin Retrusion Scale (ACRS), the Global Aesthetic Improvement Scale (GAIS), and treatment-related adverse events (TRAEs). RESULTS: A total of 50 patients were recruited and randomized to the treatment group (BTX plus HA) or control group (HA alone) in a 1:1 ratio. Patients in the treatment group exhibited significantly higher surface-volume coefficients during the first 6 months (P < .05). ACRS scores and responder rates in the 2 groups remained similar throughout the follow-up (P > .05). Within the initial 3 months, the GAIS responder rate in the treatment group was significantly higher than that in the control group (P < .05). Mild TRAEs were observed in both groups, and subsided within 7 days. There was no increase in adverse effects with the combined treatment. CONCLUSIONS: In comparison to monotherapy, the combined treatment not only improved the surface-volume coefficient of hyaluronic acid but also achieved similar ACRS scores with less HA volume. Furthermore, the combination treatment yielded superior treatment outcomes for individuals with chin retrusion.

Advances in Cardiac Organoids.

Cardiovascular diseases rank as the leading cause of death worldwide and are a major contributor to disability, posing a significant threat to human health. Organoids offer a partial simulation of the structure and function of the tissue of origin. It is a promising model that can supplement the disadvantages of two-dimensional culture and animal models. Due to the complexity of heart development, the research of cardiac organoids is still maturing. The advancement of technology has helped address certain challenges, but it has also unveiled new issues and complexities. This paper summarizes the application of organoids technology in the cardiovascular field, the common construction methods of cardiac organoids, and the latest progress of cardiac organoids in the fields of disease model construction, cardiac development research, drug research, and regenerative medicine. The future development and challenges of cardiac organoids are also addressed.

Yak milk promotes renal calcium reabsorption in mice with osteoporosis via the regulation of TRPV5.

The Ca2+-selective epithelial channel TRPV5 plays a significant role in renal calcium reabsorption and improving osteoporosis (OP). In this study, we investigated the mechanisms of yak milk on osteoporosis mice in TRPV5-mediated Ca2+ reabsorption in the kidney. We observed that treatment of OP mice with yak milk reconstructed bone homeostasis demonstrated by increasing the levels of OPG as well as decreasing the levels of TRAP and ALP in serum. Additionally, yak milk reduced the level of parathyroid hormone (PTH) and elevated 1,25-(OH)2D3 and calcitonin (CT), and inhibited the excretion of Ca/Cr and Pi/Cr in OP mice, which explained by regulating hormone levels and thus enhance the renal Ca2+ reabsorption. Further analysis exhibited that yak milk upregulated the expression of TRPV5 protein and mRNA as well as calbindin-D28k in OP mice kidneys. Overall, these outcomes demonstrate that yak milk enhances renal Ca2+ reabsorption through the TRPV5 pathway synergistically with calbindin-D28k, thus ameliorating OP mice. This provides a new perspective for yak milk as a nutritional supplement to prevent osteoporosis.

Increasing human monoclonal antibody cloning efficiency with a whole-cell modified immunoglobulin-capture assay (mICA).

Expression cloning of fully human monoclonal antibodies (hmAbs) is seeing powerful utility in the field of vaccinology, especially for elucidating vaccine-induced B-cell responses and novel vaccine candidate antigen discovery. Precision of the hmAb cloning process relies on efficient isolation of hmAb-producing plasmablasts of interest. Previously, a novel immunoglobulin-capture assay (ICA) was developed, using single protein vaccine antigens, to enhance the pathogen-specific hmAb cloning output. Here, we report a novel modification of this single-antigen ICA using formalin-treated, fluorescently stained whole cell suspensions of the human bacterial invasive pathogens, Streptococcus pneumoniae and Neisseria meningitidis. Sequestration of IgG secreted by individual vaccine antigen-specific plasmablasts was achieved by the formation of an anti-CD45-streptavidin and biotin anti-IgG scaffold. Suspensions containing heterologous pneumococcal and meningococcal strains were then used to enrich for polysaccharide- and protein antigen-specific plasmablasts, respectively, during single cell sorting. Following application of the modified whole-cell ICA (mICA), ~61% (19/31) of anti-pneumococcal polysaccharide hmAbs were cloned compared to 14% (8/59) obtained using standard (non-mICA) methods - representing a ~4.4-fold increase in hmAb cloning precision. A more modest ~1.7-fold difference was obtained for anti-meningococcal vaccine hmAb cloning; ~88% of hmAbs cloned via mICA versus ~53% cloned via the standard method were specific for a meningococcal surface protein. VDJ sequencing revealed that cloned hmAbs reflected an anamnestic response to both pneumococcal and meningococcal vaccines; diversification within hmAb clones occurred by positive selection for replacement mutations. Thus, we have shown successful utilization of whole bacterial cells in the ICA protocol enabling isolation of hmAbs targeting multiple disparate epitopes, thereby increasing the power of approaches such as reverse vaccinology 2.0 (RV 2.0) for bacterial vaccine antigen discovery.

Effect of a New Hyaluronic Acid Hydrogel Dermal Filler Cross-Linked With Lysine Amino Acid for Skin Augmentation and Rejuvenation.

BACKGROUND: Hyaluronic acid (HA) fillers are the most popular filler agents for skin rejuvenation. Although 1,4-butanediol diglycidyl ether is regarded as a relatively safe cross-linker, it still exhibits certain cytotoxicity. OBJECTIVES: We presented here an amino acid-cross-linked HA (ACHA) which was obtained by an amidation reaction with lysine and HA. This study aimed to investigate ACHA's efficacy and safety for skin augmentation and rejuvenation. METHODS: Rheology, compressive tests, and swelling experiments were conducted to investigate ACHA's mechanical and viscoelastic properties. The effects of ACHA on the human keratinocytes (HaCaT) cells and the human dermal fibroblast (HDF) were investigated by Transwell and wound healing assays. Its impacts on the epithelial thickness and collagen synthesis were further examined in a mouse experimental model. We recruited 50 patients with moderate to severe nasolabial folds (NLFs). The patients were randomly allocated to receive ACHA or Restylane injections. The resulting retention rates of HA and the Wrinkle Severity Rating Scale and Global Aesthetic Improvement Scale outcomes were evaluated and compared. RESULTS: ACHA exhibited good viscoelasticity. It not only promoted migration and proliferation of HaCat and HDF and secretion of various growth factors but also increased skin thickness and promoted the generation of collagen. Patients who received ACHA had more residual volume 12 months after treatment. ACHA exhibited a promising augmentation effect in NLF correction with few adverse reactions. CONCLUSIONS: ACHA has shown promise as a biomaterial with excellent biocompatibility and viscoelastic characteristics in both research and the clinic.See the abstract translated into Hindi, Portuguese, Korean, German, Italian, Arabic, Chinese, and Taiwanese online here: https://doi.org/10.1093/asj/sjad169.

Controllable dimensionality conversion between 1D and 2D CrCl3 magnetic nanostructures.

The fabrication of one-dimensional (1D) magnetic systems on solid surfaces, although of high fundamental interest, has yet to be achieved for a crossover between two-dimensional (2D) magnetic layers and their associated 1D spin chain systems. In this study, we report the fabrication of 1D single-unit-cell-width CrCl3 atomic wires and their stacked few-wire arrays on the surface of a van der Waals (vdW) superconductor NbSe2. Scanning tunneling microscopy/spectroscopy and first-principles calculations jointly revealed that the single wire shows an antiferromagnetic large-bandgap semiconducting state in an unexplored structure different from the well-known 2D CrCl3 phase. Competition among the total energies and nanostructure-substrate interfacial interactions of these two phases result in the appearance of the 1D phase. This phase was transformable to the 2D phase either prior to or after the growth for in situ or ex situ manipulations, in which the electronic interactions at the vdW interface play a nontrivial role that could regulate the dimensionality conversion and structural transformation between the 1D-2D CrCl3 phases.

CircAGK regulates high dihydrotestosterone-induced apoptosis in DPCs through the miR-3180-5p/BAX axis.

The incidence of androgen alopecia (AGA), also known as seborrheic alopecia, has surged in recent years, and onset is occurring at younger ages. Dermal papilla cells (DPCs) are key to maintaining hair cycling, and apoptosis-driven processes in DPCs are closely related to hair follicle regeneration. Circular RNAs (circRNAs) are widely present in the human body and are closely related to the occurrence and development of many diseases. Currently, the biological functions of circRNAs in AGA are largely unknown. Whole-transcriptome sequencing was used to screen differential circRNA expression profiles between AGA patients and non-AGA patients. We found that hsa_circ_0002980 (circAGK) was significantly highly expressed in the AGA group. CircAGK promoted DPC apoptosis in the presence of high dihydrotestosterone (DHT) (15 nmol/L). By regulating the miR-3180-5p/BAX axis, circAGK promotes DPC apoptosis in a high DHT environment in vitro and inhibits hair growth in AGA mice in vivo, indicating that circAGK is a potential target for the clinical treatment of AGA.

Application of lncRNA-miRNA-mRNA ceRNA network analysis in the treatment of androgenic alopecia.

BACKGROUND: Long noncoding RNAs (lncRNAs) can be used as competitive endogenous RNAs (ceRNAs) to bind to microRNAs (miRNAs) to regulate gene expression. Previous studies have demonstrated that ceRNAs play an important role in the development of tumors. However, it is not clear whether the lncRNA-miRNA-mRNA ceRNA network plays a role in androgenic alopecia (AGA). METHODS: The hair follicles of three AGA patients and three healthy individuals were collected for high-throughput whole transcriptome sequencing to screen for differentially expressed lncRNAs. Differentially expressed lncRNA target genes were subjected to databases to predict miRNA-mRNA and lncRNA-miRNA relationship pairs, and a ceRNA network was constructed using Cytoscape software. Relative expression was verified by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: 84 lncRNAs were significantly differentially expressed between the hair follicles of AGA patients and those of healthy individuals; 30 were upregulated, and 54 were downregulated. The top 10 upregulated lncRNAs were ENST00000501520, ENST00000448179, ENST00000318291, ENST00000568280, ENST00000561121, ENST00000376609, ENST00000602414, ENST00000573866, ENST00000513358, and ENST00000564194. The top 10 downregulated lncRNAs were ENST00000566804, ENST00000561973, ENST00000587680, ENST00000569927, ENST00000340444, ENST00000424345, ENST00000589787, NR_024344, NR_073026, and NR_110001. The qRT-PCR validation results and receiver-operating characteristic curve analysis indicated that one upregulated lncRNA, LOXL1-AS1 (ENST00000564194), had the most significant clinical diagnostic potential. After further analysis, it was concluded that LOXL1-AS1 could be used as a sponge to target hsa-miR-5193, thereby regulating TP53 expression. CONCLUSION: The ceRNA network-regulating AGA was constructed through high-throughput sequencing. Our study also identified a key lncRNA that is possibly related to the AGA pathological process.

Adaptation of a multiple myeloma minimal residual disease multicolor flow cytometry assay for real-world practice.

BACKGROUND: Achieving minimal residual disease (MRD) negativity following treatment for multiple myeloma (MM) is associated with improved progression free and overall survival. In the UK, MRD assessments in MM are not incorporated into routine clinical use outside trials. Widely used in other haematological malignancies, there is a role for widening the availability of myeloma MRD assays to laboratories outside larger treating centers. METHODS: We set up and assessed concordance of a multicolor flow cytometry (MCF) assay for MM MRD in collaboration with a reference center including validity following delayed processing of samples using an optimized fixation step. We then conducted a real-world snapshot of MRD results in a cohort of newly diagnosed transplant-eligible patients treated with UK standard induction therapies at the time of analysis. RESULTS: 43 MCF MRD samples run in parallel with a reference center showed high correlation and minimal bias. 24 samples were split and processed in duplicate both fixed and fresh, with strong correlation, minimal bias, and no change in plasma cell phenotype by flow markers confirming a 6-day delay in processing did not affect assay performance. A real-world snapshot found 17% (10/58) of patients were MRD-negative post-bortezomib-based triplet induction therapy. CONCLUSIONS: We successfully adopted a reference MCF MM MRD method which was stable for up to 6 days following sample collection potentially allowing broader access of this assay to smaller laboratories which would facilitate further investigation of the prognostic value and clinical utility of MRD assessments outside the trial setting in real-world practice.

Berkeleyomyces rouxiae is a causal agent of root rot complex on faba bean (Vicia faba L.).

Faba bean (Vicia faba L.) is an important food and feed legume crop in the world. The root rot complex caused by various pathogens is a main constraint in faba bean production. In April 2021, a severe disease of faba bean with symptoms of black necrosis on roots occurred in experimental fields at the Linxia Institute of Agricultural Sciences, Gansu Province, China. This study aimed to identify the pathogen and evaluate the resistance of faba bean cultivars. The pathogen was isolated from infected soils, and five representative isolates were identified as Berkeleyomyces rouxiae based on morphological characteristics, pathogenicity, and molecular phylogenetic analyses. A host range test showed that chickpea, common bean, cowpea, mung bean, rice bean, lentil, and hyacinth bean were susceptible hosts of the faba bean isolate, whereas adzuki bean, pea, and soybean were non-susceptible hosts, and maize and wheat were non-hosts. Identification of resistance among 36 faba bean cultivars was carried out, and six cultivars were found to be moderately resistant to B. rouxiae. In this study, we first reported black root rot on faba bean caused by B. rouxiae, confirmed and expanded the host range of B. rouxiae, and identified resistant faba bean cultivars.

Tailoring Dirac Fermions by In-Situ Tunable High-Order Moiré Pattern in Graphene-Monolayer Xenon Heterostructure.

We report an experimental study of a high-order moiré pattern formed in graphene-monolayer xenon heterostructure. The moiré period is in situ tuned from few nanometers to +∞, by adjusting the lattice constant of the xenon monolayer through annealing. Using angle-resolved photoemission spectroscopy, we observe that Dirac node replicas move closer and finally overlap with a gap opening, as the moiré pattern expands to +∞ and evolves into a Kekulé distortion. A moiré Hamiltonian coupling Dirac fermions from different valleys explains experimental results and indicates narrow moiré band. Our Letter demonstrates a platform to study continuous evolution of the moiré pattern, and provides an unprecedented approach for tailoring Dirac fermions with tunable intervalley coupling.

Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability.

The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBFß results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBFß-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results suggest that chemical intervention in the RUNX1 program may provide a therapeutic opportunity in ALL.