Autologous CD7 CAR-T cells generated without T cell pre-selection in pediatric patients with relapsed/refractory T-ALL: A phase I trial.

Chimeric antigen receptor (CAR)-T cell therapy showed preliminary activity in patients with refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL). However, many obstacles remain, including manufacturing difficulties and risk of infections. This phase I study (NCT04840875) evaluated autologous CD7 CAR-T cells manufactured without pre-selection of healthy T cells in r/r T-ALL. Thirty patients (29 children and one adult) with a median of two lines of prior therapy but without detectable peripheral leukemia were enrolled. Excluding three cases of manufacturing failures, a total of 27 (90%) patients received infusions after products were confirmed free of leukemia contamination, including 16 (59%) meeting planned target doses. Common adverse events within 30 days included grade 3-4 cytopenias (100%), grade 1-2 (70%) and 3-4 (7%, including one dose-limiting toxicity) cytokine release syndrome, grade 1 neurotoxicity (7%), grade 2 infection (4%), and grade 2 graft-versus-host disease (4%). Two patients developed grade 2 infections after day 30. At day 30, 96% responded and 85% achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). Seventy-four percent underwent transplantation. Twelve-month progression-free survival with and without censoring transplantation was 22% (95% confidence interval 4%-100%) and 57% (41%-81%), respectively. These results support that autologous CD7 CAR-T therapy without T cell pre-selection is feasible in patients with r/r T-ALL.

A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Protein-protein interaction network with machine learning models and multiomics data reveal potential neurodegenerative disease-related proteins.

Research of protein-protein interaction in several model organisms is accumulating since the development of high-throughput experimental technologies and computational methods. The protein-protein interaction network (PPIN) is able to examine biological processes in a systematic manner and has already been used to predict potential disease-related proteins or drug targets. Based on the topological characteristics of the PPIN, we investigated the application of the random forest classification algorithm to predict proteins that may cause neurodegenerative disease, a set of pathological changes featured by protein malfunction. By integrating multiomics data, we further showed the validity of our machine learning model and narrowed down the prediction results to several hub proteins that play essential roles in the PPIN. The novel insights into neurodegeneration pathogenesis brought by this computational study can indicate promising directions for future experimental research.

Blubber Cortisol-Based Approach to Explore the Endocrine Responses of Indo-Pacific Humpback Dolphins (Sousa chinensis) to Diet Shifts and Contaminant Exposure.

The detrimental effects of contaminant exposure and changes in the availability of food resources are still of concern for Indo-Pacific humpback dolphins (Sousa chinensis) of the Pearl River Estuary (PRE). Here, we validated and applied a blubber cortisol biomarker approach to assess the physiological responses of PRE dolphins to various pollutants and diet changes during 2008-2018 (n = 70). For calves, generalized additive models (GAMs) revealed that cortisol levels varied significantly by month and were positively correlated with the body length, owing to significant maternal transfer of hormones. The significantly positive correlation between length-adjusted cortisol levels in calf and the annual calf mortality ratios suggested that during years of high calf mortality, these animals were highly stressed before they die. For noncalves, blubber cortisol levels in diseased animals were significantly higher than those in "healthy" ones. Chromium (Cr) and dichlorodiphenyltrichloroethanes displayed a significant and positive relationship with blubber cortisol levels, suggesting that contaminant-mediated endocrine disruption effects may have occurred in noncalves. The GAMs indicated a decreasing trend of noncalf's blubber cortisol levels over an 11-year span, which can be explained by their declining contaminant accumulation levels due to a significant dietary shift from eating highly contaminated fishes to less polluted ones.

Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL.

INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation.

The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single-target CD19 or CD22 chimeric antigen receptor (CAR) T-cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B-ALL, it could not maintain a durable remission in most patients. To prolong relapse-free survival, we sequentially combined CD19 and CD22 CAR-T cells to treat post-transplant relapsed B-ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient-derived donor cells were collected to produce CAR-T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3ζ and 4-1BB. The second T-cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR-T treatment. Twenty-seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR-T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR-T and were followed-up for a median of 19.7 (range, 5.6-27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan-Meier survival analysis showed overall survival and event-free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR-T associated graft-versus-host disease (GVHD) occurred in 23% of patients, with 8% new-onset acute GVHD and 15% persistent or worsened pre-existing cGVHD before CAR-T. This combination strategy of sequential CD19 and CD22 CAR-T therapy significantly improved the long-term survival in B-ALL patients who relapsed after transplantation.

CRISPR/Cas9-mediated sheep MSTN gene knockout and promote sSMSCs differentiation.

Myostatin (MSTN) is an important gene involved in the regulation of embryonic muscle cells and adult muscle development; it has a good application prospect in transgenic animal production by improving the yield of muscle. The purpose of this study is to construct MSTN gene knockout vector using clustered regularly interspaced short palindromic repeats ( CRISPR)/CRISPR-associated protein 9 ( Cas9). The knockout efficiency was evaluated in sheep ear fibroblasts (SEFs) by cleavage activity of transcription of guide RNA ( gRNA), luciferase-single-strand annealing assay, T7 endonuclease I assay (T7E1), and TA clone sequence (10/38); and above all, detection showed that the cleavage activity of CRISPR/Cas9-mediated MSTN reached 29%. MSTN-Cas9/gRNA4 was transfected into sheep skeletal muscle satellite cell (sSMSC) to confirm the function of MSTN in myotomes formation induced by starvation in low-serum medium. The results showed that myotubes formation efficiency were 11.2 ± 1.3% and 19.5 ± 2.1% in the control group and knockout group, respectively. The average length of myotomes was 22 ± 5.3 and 47 ± 3.6 µm, displaying that MSTN knockout can promote sSMSC differentiation in number and length. The unlabeled MSTN-Cas9/gRNA4 was transfected into SEFs and monoclonal positive cells was obtained after 48 hours transfection. The MSTN-positive cells were used as donor cells to perform somatic cell nuclear transplantation to produce transgenic sheep. A total of 20 embryos were transplanted into surrogate mothers, four of them normally produce offspring. The genomic DNA of surviving lambs were used as a template, three positive individuals were identified by T7E1 digestion. All the results demonstrated that the CRISPR/Cas9 system has the potential to become an important and applicable gene engineering tool in animal breeding.

Acetyl-coenzyme A acyltransferase 2 promote the differentiation of sheep precursor adipocytes into adipocytes.

The acetyl CoA acyltransferase 2 (ACAA2) is a key enzyme of the fatty acid oxidation pathway, catalyzing the last step of the mitochondrial beta oxidation, thus playing an important role in the fatty acid metabolism. The purpose of this study was to investigate the effect of knocking out ACAA2 on the expression of genes lipoprteinlipase (LPL), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase, fat mass and obesity-associated gene, adipocyte fatty acid-binding protein (AP2) in precursor adipocytes and their differentiation into adipocytes. The knockout vector was constructed using CRISPR-Cas RNA-guided nuclease technology with an efficiency of 23.80%, and the vector was transfected into precursor adipocyte cells, while an overexpression vector of the ACAA2 gene was also transfected in another group of preadipocytes. Quantitative polymerase chain reaction showed that the expression of the PPAR-γ, LPL, and AP2 was significantly lower in the knockout compared with the overexpression group, while there was no difference in cell growth. After induction of adipocyte precursor cells into adipocytes using dexamethasone, insulin, and IBMX, oil red staining showed a significantly different number of lipid droplets in the knockout group. These results provide a preliminary indication for a possible involvement of the ACAA2 gene in adipocyte differentiation in vitro.

CREPT and p15RS regulate cell proliferation and cycling in chicken DF-1 cells through the Wnt/ß-catenin pathway.

The CREPT (cell cycle-related and expression elevated protein in tumor, also known as RPRD1B) and p15RS (p15INK4b -related sequence, also known as RPRD1A) have been shown to regulate cell proliferation and alter the cell cycle through Wnt/ß-catenin pathway downstream genes in human. Although several studies have revealed the mechanism by which CREPT and p15RS regulate cell proliferation in human and mammals, it is still unclear how these genes function in poultry. In order to determine the function of CREPT and p15RS in chicken, we examined the expression of CREPT and p15RS in a variety of chicken tissues and DF-1 cells. Then, we determined the effect of overexpression or depletion of CREPT or p15RS, by transiently transfecting chicken DF-1 cells with overexpression and short hairpin RNA (shRNA) vectors respectively, on the regulation of cell proliferation. The results showed that CREPT and p15RS had different expression patterns and opposite effects on the cell cycling and proliferation. Knockdown of p15RS expression or overexpression of CREPT facilitated cell proliferation by promoting the cell-cycle transition from G0/G1 to S-phase and G2/M, whereas knockdown of CREPT or overexpression of p15RS inhibited cell proliferation. Mechanistically, CREPT and p15RS control DF-1 cell proliferation by regulating the expression of Wnt/ß-catenin pathway downstream regulatory genes, including ß-catenin, TCF4, and Cyclin D1. In conclusion, CREPT and p15RS regulate cell proliferation and the cell-cycle transition in chicken DF-1 cells by regulating the transcription of Wnt/ß-catenin pathway downstream regulatory genes.

Hsd3b2 associated in modulating steroid hormone synthesis pathway regulates the differentiation of chicken embryonic stem cells into spermatogonial stem cells.

Steroid hormones regulate differentiation of various types of cell during embryogenesis. Testosterone is one of the androgens that bind to receptors to regulate gene expression and promote spermatogenesis. Our results showed that testosterone, as a product of steroid hormones synthesis pathway, could facilitate the differentiation of embryonic stem cells (ESCs) into spermatogonial stem cells (SSCs). The analysis of the steroid hormones synthesis pathway demonstrated that 3beta-hydroxysteroid dehydrogenase2 (Hsd3b2) plays a major role in the synthesis of testosterone. In the absence of Hsd3b2, the expression of downstream genes such as Cyp1a1, Ugt1a1, and Hsd17b7 was not maintained. This reduction is probably due to the down-regulation of the steroid hormones synthesis pathway. Furthermore, qRT-PCR, immunofluorescence, and flow cytometry analysis confirmed that the steroid hormones synthesis pathway could facilitate the differentiation of ESCs. Altogether, these results lead to a model in which Hsd3b2 regulates ESCs differentiation via modulating the activity of steroid hormones synthesis pathway.

A case of Chediak-Higashi syndrome presented with accelerated phase could be treated effectively by unrelated cord blood transplantation.

CHS is a rare immunodeficiency syndrome with defects in the functions of cytotoxic cells and neutrophils. Approximately 85% of patients with CHS undergo an AP within the first decade, which is similar to FHLH. Chemotherapy could induce transient remission, but only allogeneic HCT could correct the underlying genetic defect and prevent relapse. We reported a case of CHS diagnosed at 19 months, who had an elder brother who had previously succumbed to the same disease. The little girl presented with severe AP manifestations including recurrent high fever, enlarged superficial lymph nodes, and extraordinary hepatosplenomegaly occupying the whole abdominal and pelvic cavity. Comprehensive therapies including HLH 2004 protocol, supportive care, and antibiotics, especially antituberculous agents, were given to her to induce remission. After remission, the patient received fully HLA-matched UCBT. The transplantation course was uneventful, except for fluctuation of donor chimerism. The patient has been alive for 36 months without infection and neurologic manifestations and is under further follow-up. Our result provides another case that UCBT can be effective for treating patients with CHS and remission before HCT is important for good prognosis.

Haploidentical hematopoietic stem cell transplantation for a case with X-linked chronic granulomatous disease.

CGD is a rare primary immunodeficiency with high mortality rates when treated conventionally, especially for the X-chromosome-linked form. HSCT is the only curative therapy for CGD; however, haploidentical transplantation in CGD is rare. Here, we report a case of X-linked CGD treated successfully by haploidentical HSCT. The patient showed a positive result with full donor chimerism, good quality of life, and the absence of recurrent infectious diseases at follow-up (68 months). Thus, haploidentical HSCT may serve as an acceptable treatment approach for patients who have CGD, but no HLA-matched related or unrelated donor.

Low Major Histocompatibility Complex Class II Variation in the Endangered Indo-Pacific Humpback Dolphin (Sousa chinensis): Inferences About the Role of Balancing Selection.

It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis.

Ultrasonic frogs show hyperacute phonotaxis to female courtship calls.

Sound communication plays a vital role in frog reproduction, in which vocal advertisement is generally the domain of males. Females are typically silent, but in a few anuran species they can produce a feeble reciprocal call or rapping sounds during courtship. Males of concave-eared torrent frogs (Odorrana tormota) have demonstrated ultrasonic communication capacity. Although females of O. tormota have an unusually well-developed vocal production system, it is unclear whether or not they produce calls or are only passive partners in a communication system dominated by males. Here we show that before ovulation, gravid females of O. tormota emit calls that are distinct from males' advertisement calls, having higher fundamental frequencies and harmonics and shorter call duration. In the field and in a quiet, darkened indoor arena, these female calls evoke vocalizations and extraordinarily precise positive phonotaxis (a localization error of <1 degrees ), rivalling that of vertebrates with the highest localization acuity (barn owls, dolphins, elephants and humans). The localization accuracy of O. tormota is remarkable in light of their small head size (interaural distance of <1 cm), and suggests an additional selective advantage of high-frequency hearing beyond the ability to avoid masking by low-frequency background noise.

Novel ASO therapeutic target designed against hyperlipidemia via PCSK9 knockdown.

With the gradual improvement of individuals' living standards, there has been a concurrent escalation in the consumption of fats and sugars in the daily dietary habits. Consequently, an increasing number of individuals are afflicted by hyperlipidemia, a condition that, could elevate blood viscosity, thereby engendering serious complications in a long run. Traditional lipid-lowering medications, such as statins, manifest substantial side effects, thereby imposing a significant metabolic burden on the liver and kidneys. Conversely, antisense oligonucleotides (ASOs) exhibit attributes such as rapid absorption, prolonged efficacy, and minimal side effects. In light of these considerations, a novel ASO was meticulously designed, sebsequently, its efficacy and toxicity assessments were conducted both in vitro and in vivo. The results unequivocally demonstrate the effectiveness and safety of this ASO.

Construction of a multi-tissue compound-target interaction network of Qingfei Paidu decoction in COVID-19 treatment based on deep learning and transcriptomic analysis.

The Qingfei Paidu decoction (QFPDD) is a widely acclaimed therapeutic formula employed nationwide for the clinical management of coronavirus disease 2019 (COVID-19). QFPDD exerts a synergistic therapeutic effect, characterized by its multi-component, multi-target, and multi-pathway action. However, the intricate interactions among the ingredients and targets within QFPDD and their systematic effects in multiple tissues remain undetermined. To address this, we qualitatively characterized the chemical components of QFPDD. We integrated multi-tissue transcriptomic analysis with GraphDTA, a deep learning model, to screen for potential compound-target interactions of QFPDD in multiple tissues. We predicted 13 key active compounds, 127 potential targets and 27 pathways associated with QFPDD across six different tissues. Notably, oleanolic acid-AXL exhibited leading affinity in the heart, blood, and liver. Molecular docking and molecular dynamics simulation confirmed their strong binding affinity. The robust interaction between oleanolic acid and the AXL receptor suggests that AXL is a promising target for developing clinical intervention strategies. Through the construction of a multi-tissue compound-target interaction network, our study further elucidated the mechanisms through which QFPDD effectively combats COVID-19 in multiple tissues. Our work also establishes a framework for future investigations into the systemic effects of other Traditional Chinese Medicine (TCM) formulas in disease treatment.

The de Winter pattern in a single precordial lead caused by high-grade stenosis of the proximal left anterior descending artery with plaque rupture: A case report.

The de Winter electrocardiogram (ECG) pattern indicates severe stenosis or occlusion of the left anterior descending artery (LAD). We present a 72-year-old female with 1.5-h chest pain. Angiography and optical coherence tomography (OCT) revealed 90 % LAD stenosis with plaque rupture, but no ST-segment elevation in the precordial leads. The de Winter pattern, characterized by upsloping ST-segment depression in V1-V6, appeared only in lead V2. Following successful percutaneous coronary intervention (PCI), the de Winter pattern disappeared. This case underscores the significance of the de Winter pattern in one precordial lead, necessitating prompt angiography and PCI for improved patient outcomes.

Allogeneic CD5-specific CAR-T therapy for relapsed/refractory T-ALL: a phase 1 trial.

Refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL) patients have poor prognoses, due to the lack of effective salvage therapies. Recently, CD7-targeting chimeric antigen receptor (CAR)-T therapies show efficacy in patients with r/r T-ALL, but relapse with CD7 loss is common. This study evaluates a CD5-gene-edited CAR-T cell therapy targeting CD5 in 19 r/r T-ALL patients, most of whom had previously failed CD7 CAR-T interventions. CAR-T products were derived from previous transplant donors (Cohort A) or newly matched donors (Cohort B). Primary endpoints were dose-limiting toxicity at 21 days and adverse events within 30 days. Secondary endpoints were responses, pharmacokinetics and severe adverse events after 30 days. A total of 16 received infusions, 10 at target dose of 1 × 106 kg-1. All encountered grade 3-4 cytopenias and one had a grade 3 infection within 30 days. All patients (100%) achieved complete remission or complete remission with incomplete blood count recovery by day 30. At a median follow-up of 14.3 months, four received transplantation; three were in remission and one died of infection. Of 12 untransplanted patients, 2 were in remission, 3 relapsed, 5 died of infection and 2 of thrombotic microangiopathy. CAR-T cells persisted and cleared CD5+ T cells. CD5- T cells, mostly CD5-gene-edited, increased but remained below normal levels. These results suggest this CD5-specific CAR-T intervention has a high remission rate for T-ALL patients. Evidence also suggests the risk of late-onset severe infection may be mitigated with consolidative transplantation. This study provides insights that could help to optimize this promising intervention. ClinicalTrials.gov registration: NCT05032599 .