A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia.

ABSTRACT: Congenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony-stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in 5 CN patient groups (severe congenital neutropenia [SCN]1, SCN3, cyclic neutropenia [CyN], warts, hypogammaglobulinaemia, infections and myelokathexis [WHIM], and Shwachman-Bodian-Diamond Syndrome [SBDS]) associated with mutations in ELANE, HAX1, CXCR4, and SBDS genes. Our analysis led to the identification of 11 novel mutations in ELANE and 1 each in HAX1, CXCR4, and G6PC3 genes. Investigating bone marrow (BM) granulopoiesis and blood absolute neutrophil count after G-CSF treatment, we found that SCN1 and SCN3 presented with severe early-stage disruption between the promyelocyte and myelocyte, leading to a poor response to G-CSF. In contrast, CyN, affected at the late polymorphonuclear stage of neutrophil development, showed a strong G-CSF response. WHIM, displaying normal neutrophil development, responded robustly to G-CSF, whereas SBDS, with moderate disruption from the early myeloblast stage, exhibited a moderate response. Notably, SCN1 uniquely impeded neutrophil development, whereas SCN3, CyN, WHIM, and SBDS also affected eosinophils and basophils. In addition, SCN1, SCN3, and CyN presented with elevated serum immunoglobulins, increased BM plasma cells, and higher A Proliferation-Inducing Ligand levels. Our study reveals a strong correlation between the stage and severity of granulocyte development disruption and the efficacy of G-CSF therapy.

[Stem and leaf photosynthesis of seven desert woody species and its influencing factors]. / 7ç§è’æ¼ æœ¨æœ¬æ¤ç‰©æžå¹²ä¸Žå¶ç‰‡å ‰åˆç‰¹å¾åŠå ¶å½±å“å› ç´ .

Stem photosynthesis widely presents in desert plants, which increases carbon uptake capacity. In this study, we measured the photosynthetic characteristics of leaves and stems in seven desert woody plants (Populus euphratica, Populus alba var. pyramidalis, Populus pruinose, Haloxylon ammodendron, Calligonum rubicundum, Calligonum caput-medusae, Ammopiptanthus mongolicus) in the same habitat, using a portable Li-6400XT photosynthesis system combined with P-Chamber. We analyzed stem photosynthetic rate and its relationship with leaf photosynthetic rate. We measured the stem functional traits, including water content, stem dry matter content, chlorophyll content, water potential, non-structure carbohydrate (NSC), etc., to find out the main affecting factors of stem photosynthesis. The results showed that stem photosynthetic rate of seven species ranged from 0.72 to 1.71 µmol·m-2·s-1, with the largest of P. pruinose and the smallest of H. ammodendron. Stem photosynthetic rate could offset CO2 of stem respiration by 57%-83%. Leaf photosynthetic rate of the seven sepceis ranged from 12.80 to 22.54 µmol·m-2·s-1, with H. ammodendron and A. mongolicus being lower than those of the other five species. There was a significant positive correlation between leaf photosynthetic rate and stem photosynthetic rate. Stem water use efficiency was 2.2-7.7 times of the leaf. Chlorophyll content, NSC, stem respiration rate, and leaf photosynthetic rate were the main factors affecting stem photosynthesis.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids.

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.

Strong, elastic and degradation-tolerated hydrogels composed of chitosan, silk fibroin and bioglass nanoparticles with factor-bestowed activity for bone tissue engineering.

Polymer hydrogels intended for use in bone repair need to be strong, elastic, and capable of enduring degradation. However, many natural polymer hydrogels lack these essential properties and thus, are unsuitable for bone repair applications. Here, a new type of multi-network hydrogel with improved mechanical and degradation-resistant properties has been developed for use in bone repair. The hydrogel is composed of thiolated chitosan (TCH), silk fibroin (SF), and thiolated bioglass (TBG) nanoparticles (NPs). The multi-networks are built through sulfhydryl self-crosslinking, diepoxide crosslinker-involved linkages of amino or hydroxyl groups, and enzyme-mediated phenol hydroxyl crosslinking. Additionally, mesoporous TBG NPs serve as a vehicle for loading stromal cell-derived factor-1 (SDF-1) to provide the gel with cell-recruiting activity. The formulated TCH/SF/TBG hydrogels exhibit remarkably enhanced strength, elasticity, and improved degradation tolerance compared to some gels made from only TCH or SF. Furthermore, TCH/SF/TBG gels can support the growth of seeded cells and the deposition of matrix components. Some TCH/SF/TBG gels also demonstrate the ability to release SDF-1 in an approximately linear manner for a few weeks while retaining the chemotactic properties of the released SDF-1. Overall, the multi-network hydrogel has the potential as an in situ forming material for cell-recruiting bone repair and regeneration.

B cell abnormalities and autoantibody production in patients with partial RAG deficiency.

Mutations in the recombination activating gene 1 (RAG1) and RAG2 in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.

Stable antiferromagnetic property and tunable electronic structure of two-dimensional MnPX3(X = S and Se) from pristine structure to Janus phase.

Transition-metal phosphorus trichalcogenides have been considered as very promising two-dimensional (2D) magnetic candidates up-to-date. We performed a systematical first-principles study on the electronic structures and magnetic properties of pristine MnPX3(X = S and Se) and Janus Mn2P2S3Se3monolayers. All monolayers behave as a direct-band-gap semiconductor in antiferromagnetic ground state which is caused by strong direct and indirect exchange interactions. It is found that the electronic structures and magnetic properties can be manipulated by Janus phase. The calculated band gap is 2.44 eV, 1.80 eV and 1.86 eV for MnPS3, MnPSe3and Mn2P2S3Se3with a valley polarization with consideration of spin-orbital coupling (SOC), respectively. In particular, significant energy-splittings emerge in the SOC-band structures of Janus Mn2P2S3Se3due to its broken-inversion-symmetry. Estimated by Monte Carlo simulations, the Néel temperature is 96 K, 71 K and 79 K based on Ising model while halved down to 41 K, 33 K and 36 K on the basis ofXYmodel for MnPS3, MnPSe3and Mn2P2S3Se3, respectively, indicating theXYmodel should be more reliable to describe the spin dynamics. Our research offers an insight into the magnetic mechanism and paves a feasible path to modulate the magnetism for 2D magnets in realistic applications on spintronics.

Manufacture of Bilayered Composite Hydrogels with Strong, Elastic, and Tough Properties for Osteochondral Repair Applications.

Layered composite hydrogels have been considered attractive materials for use in osteochondral repair and regeneration. These hydrogel materials should be mechanically strong, elastic, and tough besides fulfilling some basic requirements such as biocompatibility and biodegradability. A novel type of bilayered composite hydrogel with multi-network structures and well-defined injectability was thus developed for osteochondral tissue engineering using chitosan (CH), hyaluronic acid (HA), silk fibroin (SF), CH nanoparticles (NPs), and amino-functionalized mesoporous bioglass (ABG) NPs. CH was combined with HA and CH NPs to build the chondral phase of the bilayered hydrogel, and CH, SF, and ABG NPs were used together to construct the subchondral phase of the bilayer hydrogel. Rheological measurements showed that the optimally achieved gels assigned to the chondral and subchondral layers had their elastic moduli of around 6.5 and 9.9 kPa, respectively, with elastic modulus/viscous modulus ratios higher than 36, indicating that they behaved like strong gels. Compressive measurements further demonstrated that the bilayered hydrogel with an optimally formulated composition had strong, elastic, and tough characteristics. Cell culture revealed that the bilayered hydrogel had the capacity to support the in-growth of chondrocytes in the chondral phase and osteoblasts in the subchondral phase. Results suggest that the bilayered composite hydrogel can act as an injective biomaterial for osteochondral repair applications.

A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4T95R. Simultaneously, IRF4T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4T95R but not by IRF4WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.

Importance: The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. Objective: To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. Design, Setting, and Participants: This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Main Outcomes and Measures: Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Results: Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. Conclusions and Relevance: This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Multi-Crosslinked Strong and Elastic Bioglass/Chitosan-Cysteine Hydrogels with Controlled Quercetin Delivery for Bone Tissue Engineering.

Chitosan-cysteine (CH-CY) conjugate with an optimal content of thiol groups was synthesized and combined with amino-functionalized mesoporous bioglass (ABG) nanoparticles (NPs) with radially-porous architecture to build multi-crosslinked ABG/CH-CY composite hydrogels. Besides the network formed by self-crosslinking of thiol groups in CY-derived side chains, difunctionalized PEG (DF-P) crosslinkers with varying lengths of PEG segments were used to crosslink amino groups on CH-CY or ABG NPs to form other networks in the composite gels. Quercetin (Que) was loaded into ABG NPs before these NPs were incorporated into the hydrogel, intending to achieve sustainable and controllable Que release from so-built ABG/CH-CY gels. The lengths of PEG segments in DF-P were found to impose remarkable impacts on the strength or elasticity of multi-crosslinked ABG/CH-CY hydrogels. Some ABG/CH-CY hydrogels had their elastic modulus of around 8.2 kPa or higher along with yielding strains higher than 70%, specifying their mechanically strong and elastic characteristics. In addition, these gels showed the ability to release Que and Si or Ca ions in controllable ways for various durations. The optimally achieved ABG/CH-CY hydrogels were injectable and also able to support the growth of seeded MC3T3-E1 cells as well as the specific matrix deposition. The obtained results suggest that these ABG/CH-CY gels have promising potential for bone repair and regeneration.

Investigations on structural, electronic and optical properties of ZnO in two-dimensional configurations by first-principles calculations.

The electronic structures and optical properties of two-dimensional (2D) ZnO monolayers in a series of configurations were systematically investigated by first-principles calculations with HubbardUevaluated by the linear response approach. Three types of 2D ZnO monolayers, as planer hexagonal-honeycomb (Plan), double-layer honeycomb (Dlhc), and corrugated tetragonal (Tile) structures, show a mechanical and dynamical stability, while the Dlhc-ZnO is the most energetically stable configuration and Plan-ZnO is the second one. Each 2D ZnO monolayer behaves as a semiconductor with that Plan-, Dlhc-ZnO have a direct band gap of 1.81 eV and 1.85 eV at theΓpoint, respectively, while Tile-ZnO has an indirect band gap of 2.03 eV. Interestingly, the 2D ZnO monolayers all show a typical near-free-electron character for the bottom conduction band with a small effective mass, leading to a tremendous optical absorption in the whole visible and ultraviolet window, and this origination was further confirmed by the transition dipole moment. Our investigations suggest a potential candidate in the photoelectric field and provide a theoretical guidance for the exploration of wide-band-gap 2D semiconductors.

Bisindole natural products: A vital source for the development of new anticancer drugs.

Currently, the number of new cancer cases and deaths worldwide is increasing year on year. In addition to the requirement for cancer prevention, the top priority is still to seek the effective cure of cancer. In over a half century of constant exploration, increasing attention has been paid to the excellent anticancer activity of natural products, with more and more natural products isolated, identified and detected. For this study, the focus lies the natural products of bisindole, where two indole molecules are indirectly linked or directly polymerized, developing the diversity of structure and mechanism, accompanied with the better anticancer activity than monomers. There has been a long history of applying indirubin and vincristine in cancer treatment, verifying the anticancer effect of bisindoles. Vincribine, midostaurin and other anticancer drugs have also been developed and commercialized. In this paper, a review regarding the potential therapeutic effect of bisindole alkaloids extracted from various natural products was carried out, in which the progress made in research of 242 bisindole alkaloids for cancer treatment was introduced. These compounds may be applicable as medicinal products for clinical research in the future.

LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.

Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.

Background: Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM. Objective: To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Methods: Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells. Results: The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes. Conclusions: The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.

Strong and Elastic Hydrogels from Dual-Crosslinked Composites Composed of Glycol Chitosan and Amino-Functionalized Bioactive Glass Nanoparticles.

Mesoporous bioactive glass (BG) nanoparticles (NPs) with a high specific surface area were prepared. The surfaces of BG NPs were further modified using an amino-containing compound or synthesized precursors to produce three kinds of amino-functionalized bioactive glass (ABG) NPs via devised synthetic routes. The achieved ABG NPs possessed various spacer lengths with free amino groups anchored at the end of the spacer. These ABG NPs were then combined with glycol chitosan (GCH) to construct single- or dual-crosslinked ABG/GCH composite hydrogels using genipin (GN) alone as a single crosslinker or a combination of GN and poly(ethylene glycol) diglycidyl ether (PEGDE) as dual crosslinkers. The spacer length of ABG NPs was found to impose significant effects on the strength and elasticity of GN-crosslinked ABG/GCH hydrogels. After being dually crosslinked with GN and PEGDE, the elastic modulus of some dual-crosslinked ABG/GCH hydrogels reached around 6.9 kPa or higher with their yielding strains larger than 60%, indicative of their strong and elastic features. The optimally achieved ABG/GCH hydrogels were injectable with tunable gelation time, and also able to support the growth of seeded MC3T3-E1 cells and specific matrix deposition. These results suggest that the dual-crosslinked ABG/GCH hydrogels have the potential for some applications in tissue engineering.

Strong and Elastic Chitosan/Silk Fibroin Hydrogels Incorporated with Growth-Factor-Loaded Microspheres for Cartilage Tissue Engineering.

An emulsification method was developed for fabricating core-shell microspheres with a thick shell layer. Kartogenin (KGN) and platelet-derived growth factor BB (PDGF-BB) were respectively loaded into the core portion and the shell layer of the microspheres with high loading efficiency. The optimally built microspheres were combined with chitosan (CH) and silk fibroin (SF) to construct a new type of composite hydrogel with enhanced strength and elasticity, using genipin or/and tyrosinase as crosslinkers for the intended use in cartilage tissue engineering. The composite hydrogels were found to be thermo-responsive at physiological temperature and pH with well-defined injectability. Rheological measurements revealed that they had an elastic modulus higher than 6 kPa with a high ratio of elastic modulus to viscous modulus, indicative of their mechanically strong features. Compressive measurements demonstrated that they possessed well-defined elasticity. In addition, some gels had the ability to administer the temporal separation release of PDGF-BB and KGN in an approximately linear manner for several weeks. The released PDGF-BB was found to be bioactive based on its effects on Balb/c 3T3 cells. The composite gels supported the growth of seeded chondrocytes while preserving their phenotype. The results suggest that these composite gels have the potential for endogenous cartilage repair.

Haploidentical CD7 CAR T-cells induced remission in a patient with TP53 mutated relapsed and refractory early T-cell precursor lymphoblastic leukemia/lymphoma.

Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 is a promising therapeutic targets for chimeric antigen receptor modified T cell therapy (CART) due to its widely expression in almost all T-cell malignancies. Here we present the anti-CD7 CART therapy in a 11-year-old male with TP53 mutated relapsed/refractory ETP-ALL/LBL. The patient suffered second relapse after haploidentical hematopoietic stem cell transplantation, showing resistance to 4 lines salvage therapies including venetoclax. Nanobody derived CD7-CART cells were manufactured by co-transducing CAR-T cells with a CD7 protein expression blocker. 70.5% of blasts (CD7 expression: 92.6%) and extensive extramedullary disease (mediastinal mass, enlarged lymph nodes and spleen) were observed prior to CD7-CART-cell therapy. A total of 5 × 106/kg donor-derived CD7-CART-cells were infused. Hematological and extramedullary remission were both achieved, with persistence of CD7-CART-cells be detected until the last followup at 96th days after the infusion. Reversible adverse effects including grade 3 cytokine release syndrome and macrophage activation syndrome were observed. This case demonstrated that CD7-CART was a potent and safe salvage therapy in relapsed/refractory ETP-ALL/LBL patient with high tumor burden.Trial registration: ClinicalTrials. gov, NCT04785833 , Registered on March 8, 2021, prospectively registered.

Increased number and function of endothelial progenitor cells in breast cancer patients and the linear correlation with VEGF level.

The number of circulating endothelial progenitor cells (EPCs) was found to increase in patients with breast cancer, but the alteration in EPC function remains to be elusive. We conducted this study to evaluate the number and function of peripheral EPCs of breast cancer patients and its possible underlying mechanism. Besides, the vascular endothelial growth factor (VEGF), VCAM-1, IL-6, and IL-34 levels were measured in blood samples and also in vitro in a medium of EPCs. We found that the number of circulating EPCs in breast cancer patients was significantly higher than that in normal control and remarkably augmented in a stage-dependent manner. Meanwhile, a similar enhancement was observed in the migratory, proliferative, and adhesive activity of circulating EPCs originating from breast cancer patients. More importantly, the VEGF level in blood samples was dramatically elevated in comparison to the control, which was correlated positively with the number and activity of circulating EPCs from breast cancer patients. Moreover, in vitro medium of EPCs from breast cancer patients highly expressed VEGF compared with that from the control, which also had a positive correlation with the number and activity of circulating EPCs from breast cancer patients. This is the first time to demonstrate that the number and function of circulating EPCs are promoted in breast cancer patients, which are positively related to an enhanced VEGF production. These may provide a novel target for improving the outcome of breast cancer.