High-fidelity gates and mid-circuit erasure conversion in an atomic qubit.

The development of scalable, high-fidelity qubits is a key challenge in quantum information science. Neutral atom qubits have progressed rapidly in recent years, demonstrating programmable processors1,2 and quantum simulators with scaling to hundreds of atoms3,4. Exploring new atomic species, such as alkaline earth atoms5-7, or combining multiple species8 can provide new paths to improving coherence, control and scalability. For example, for eventual application in quantum error correction, it is advantageous to realize qubits with structured error models, such as biased Pauli errors9 or conversion of errors into detectable erasures10. Here we demonstrate a new neutral atom qubit using the nuclear spin of a long-lived metastable state in 171Yb. The long coherence time and fast excitation to the Rydberg state allow one- and two-qubit gates with fidelities of 0.9990(1) and 0.980(1), respectively. Importantly, a large fraction of all gate errors result in decays out of the qubit subspace to the ground state. By performing fast, mid-circuit detection of these errors, we convert them into erasure errors; during detection, the induced error probability on qubits remaining in the computational space is less than 10-5. This work establishes metastable 171Yb as a promising platform for realizing fault-tolerant quantum computing.

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Hypoxia-related THBD+ macrophages as a prognostic factor in glioma: Construction of a powerful risk model.

Glioma is a prevalent malignant tumour characterized by hypoxia as a pivotal factor in its progression. This study aims to investigate the impact of the most severely hypoxic cell subpopulation in glioma. Our findings reveal that the THBD+ macrophage subpopulation is closely associated with hypoxia in glioma, exhibiting significantly higher infiltration in tumours compared to non-tumour tissues. Moreover, a high proportion of THBD+ cells correlates with poor prognosis in glioblastoma (GBM) patients. Notably, THBD+ macrophages exhibit hypoxic characteristics and epithelial-mesenchymal transition features. Silencing THBD expression leads to a notable reduction in the proliferation and metastasis of glioma cells. Furthermore, we developed a THBD+ macrophage-related risk signature (THBDMRS) through machine learning techniques. THBDMRS emerges as an independent prognostic factor for GBM patients with a substantial prognostic impact. By comparing THBDMRS with 119 established prognostic features, we demonstrate the superior prognostic performance of THBDMRS. Additionally, THBDMRS is associated with glioma metastasis and extracellular matrix remodelling. In conclusion, hypoxia-related THBD+ macrophages play a pivotal role in glioma pathogenesis, and THBDMRS emerges as a potent and promising prognostic tool for GBM, contributing to enhanced patient survival outcomes.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

Face-to-face Assembly Strategy of Au Nanocubes: Induced Generation of Broad Hotspot Regions for SERS-Fluorescence Dual-Signal Detection of Intracellular miRNAs.

While designing anisotropic noble metal nanoparticles (NPs) can enhance the signal intensity of Raman dyes, more sensitive surface-enhanced Raman scattering (SERS) probes can be designed by oriented self-assembly of noble metal nanomaterials into dimers or higher-order nanoclusters. In this study, we engineered a self-assembly strategy in living cells for real-time fluorescence and SERS dual-channel detection of intracellular microRNAs (miRNAs), using Mg2+-dependent 8-17E DNAzyme sequences as the driving motors, gold nanocubes (AuNCs) as the driver components, and three-branched double-stranded DNA as the linking tool. The assembly selects adenine in DNA as a reporter molecule, simplifying the labeling process of Raman reporter molecules and reducing the synthesis process. In addition, adenine is stably distributed between the faces of AuNCs and the wide hotspot region gives good reproducibility of the adenine SERS signal. In this strategy, the SERS channel was consistently stable and more sensitive compared to the fluorescence channel. Among them, the detection limit of the SERS channel was 2.1 pM and the coefficient of variation was 1.26% in the in vitro liquid phase and 1.49% in MCF-7 cells. The strategy successfully achieved accurate tracking and quantification of miRNA-21 in cancer cells, showing good reproducibility in complex samples as well as cells. The reported strategy provides ideas for exploring intracellular specific triggering of nanoparticles for precise control of self-assembly.

EBD: an eye biomarker database.

MOTIVATION: Many ophthalmic disease biomarkers have been identified through comprehensive multiomics profiling, and hold significant potential in advancing the diagnosis, prognosis, and management of diseases. Meanwhile, the eye itself serves as a natural biomarker for several systemic diseases including neurological, renal, and cardiovascular systems. We aimed to collect and standardize this eye biomarkers information and construct the eye biomarker database (EBD) to provide ophthalmologists with a platform to search, analyze, and download these eye biomarker data. RESULTS: In this study, we present the EBD , a world-first online compilation comprising 889 biomarkers for 26 ocular diseases and 939 eye biomarkers for 181 systemic diseases. The EBD also includes the information of 78 "nonbiomarkers"-the objects that have been proven cannot be biomarkers. Biological function and network analysis were conducted for these ocular disease biomarkers, and several hub pathways and common network topology characteristics were newly identified, which may promote future ocular disease biomarker discovery and characterizes the landscape of biomarkers for eye diseases at the pathway and network level. The EBD is expected to yield broader utility among developmental biologists and clinical scientists in and outside of the eye field by assisting in the identification of biomarkers linked to eye disorders and related systemic diseases. AVAILABILITY AND IMPLEMENTATION: EBD is available at http://www.eyeseeworld.com/ebd/index.html.

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Advancements in the preparation technology of small molecule artificial antigens and their specific antibodies: a comprehensive review.

Small molecules find extensive application in medicine, food safety, and environmental studies, particularly in biomedicine. Immunoassay technology, leveraging the specific recognition between antigens and antibodies, offers a superior alternative to traditional physical and chemical analysis methods. This approach allows for the rapid and accurate detection of small molecular compounds, owing to its high sensitivity, specificity, and swift analytical capabilities. However, small molecular compounds often struggle to effectively stimulate an immune response due to their low molecular weight, weak antigenicity, and limited antigenic epitopes. To overcome this, coupling small molecule compounds with macromolecular carriers to form complete antigens is typically required to induce specific antibodies in animals. Consequently, the preparation of small-molecule artificial antigens and the production of efficient specific antibodies are crucial for achieving precise immunoassays. This paper reviews recent advancements in small molecule antibody preparation technology, emphasizing the design and synthesis of haptens, the coupling of haptens with carriers, the purification and identification of artificial antigens, and the preparation of specific antibodies. Additionally, it evaluates the current technological shortcomings and limitations while projecting future trends in artificial antigen synthesis and antibody preparation technology.

RUNX1, FUS, and ELAVL1-induced circPTPN22 promote gastric cancer cell proliferation, migration, and invasion through miR-6788-5p/PAK1 axis-mediated autophagy.

BACKGROUND: An increasing number of studies have demonstrated the association of circular RNAs (circRNAs) with the pathological processes of various diseases and their involvement in the onset and progression of multiple cancers. Nevertheless, the functional roles and underlying mechanisms of circRNAs in the autophagy regulation of gastric cancer (GC) have not been fully elucidated. METHODS: We used transmission electron microscopy and the mRFP-GFP-LC3 dual fluorescent autophagy indicator to investigate autophagy regulation. The cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, Transwell assay, and Western blot assay were conducted to confirm circPTPN22's influence on GC progression. Dual luciferase reporter assays validated the binding between circPTPN22 and miR-6788-5p, as well as miR-6788-5p and p21-activated kinase-1 (PAK1). Functional rescue experiments assessed whether circPTPN22 modulates PAK1 expression by competitively binding miR-6788-5p, affecting autophagy and other biological processes in GC cells. We investigated the impact of circPTPN22 on in vivo GC tumors using a nude mouse xenograft model. Bioinformatics tools predicted upstream regulatory transcription factors and binding proteins of circPTPN22, while chromatin immunoprecipitation and ribonucleoprotein immunoprecipitation assays confirmed the binding status. RESULTS: Upregulation of circPTPN22 in GC has been shown to inhibit autophagy and promote cell proliferation, migration, and invasion. Mechanistically, circPTPN22 directly binds to miR-6788-5p, subsequently regulating the expression of PAK1, which activates protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation. This modulation ultimately affects autophagy levels in GC cells. Additionally, runt-related transcription factor 1 (RUNX1) negatively regulates circPTPN22 expression, while RNA-binding proteins such as FUS (fused in sarcoma) and ELAVL1 (recombinant ELAV-like protein 1) positively regulate its expression. Inhibition of the autophagy pathway can increase FUS expression, further upregulating circPTPN22 in GC cells, thereby exacerbating the progression of GC. CONCLUSION: Under the regulation of the transcription factor RUNX1 and RNA-binding proteins FUS and ELAVL1, circPTPN22 activates the phosphorylation of Akt and Erk through the miR-6788-5p/PAK1 axis, thereby modulating autophagy in GC cells. Inhibition of autophagy increases FUS, which in turn upregulates circPTPN22, forming a positive feedback loop that ultimately accelerates the progression of GC.

Benthic primary production decreases internal phosphorus loading from lake sediments under light supplement.

In aquatic ecosystems, light penetrating the sediment surface in shallow lakes may regulate the internal phosphorus (P) release through benthic primary production, which subsequently affects oxidation, pH levels, and alkaline phosphatase activity in the upper sediment. To study the effects of light exposure on the P dynamics at the sediment-water interface under eutrophic conditions, a two-month mesocosm experiment was conducted in twelve cement tanks (1000 L each). The tanks were equipped with Light-Emitting Diode (LED) lights, and surface sediments collected from eutrophic Lake Nanhu (China) were exposed to four different light intensities (0, 50, 100, 200 µmol m-2 s-1). The results revealed that: 1) Both the total phosphorus concentration and the phosphorus release flux from the sediment were lower in the light treatments (mean value, 0.59-0.71 mg L-1 and 0.00-0.01 mg m-2 d-1, respectively) than in the control treatment (0.77 mg L-1 and 0.01 mg m-2 d-1, respectively), indicating that light supplement could decrease the internal P release. 2) Benthic primary production promoted by light directly absorbed soluble reactive phosphorus and decreased the internal P release. The resulting improved production could also increase dissolved oxygen concentrations at the sediment-water interface, thus indirectly inhibiting internal P release. 3) The relative contributions of direct absorption and indirect inhibition on the internal P release ranged between 23% to 69% and 31% to 77% depending on the light intensity.

Unveiling the Anticancer Mechanism of Echinops davuricus: Isolation and Evaluation of AKR1B10 Inhibitors.

Five compounds (1-5), one long-chain fatty acid (1), two thiophenes (2 and 3), one alkaloid (4), and one phenyl ester (5), were isolated from the aerial part of Echinops davuricus. The structures of the products were established by performing detailed nuclear magnetic resonance (NMR) analysis, and the structure of compound 1 was determined via high-resolution electrospray ionization mass spectrometry (HRESIMS) and NMR. Compounds 1, 4, and 5 were isolated from Echinops davuricus for the first time. Based on network pharmacology methods, AKR1B10 was selected as a key anticancer target. Compounds 1 and 5 exhibited significant AKR1B10 inhibitory activities, with IC50 values of 156.0±1.00 and 146.2±1.50 nM, respectively, with epalrestat used as the positive control (81.09±0.61 nM). Additionally, the interactions between the active compounds and AKR1B10 were evaluated via molecular docking. Ultimately, the GO and KEGG enrichment analysis indicated that the key signaling pathways associated with the active compounds may be related to the PI3K-Akt, MAPK, apoptotic, cellular senescence, and TNF signaling pathways and the human diseases corresponding to the targets are cancer. Our study reveals for the first time the anticancer properties of Echinops davuricus and provides a comprehensive understanding of its application in traditional medicine.

Growth of Hg0.7Cd0.3Te on Van Der Waals Mica Substrates via Molecular Beam Epitaxy.

In this paper, we present a study on the direct growth of Hg0.7Cd0.3Te thin films on layered transparent van der Waals mica (001) substrates through weak interface interaction through molecular beam epitaxy. The preferred orientation for growing Hg0.7Cd0.3Te on mica (001) substrates is found to be the (111) orientation due to a better lattice match between the Hg0.7Cd0.3Te layer and the underlying mica substrate. The influence of growth parameters (mainly temperature and Hg flux) on the material quality of epitaxial Hg0.7Cd0.3Te thin films is studied, and the optimal growth temperature and Hg flux are found to be approximately 190 °C and 4.5 × 10-4 Torr as evidenced by higher crystalline quality and better surface morphology. Hg0.7Cd0.3Te thin films (3.5 µm thick) grown under these optimal growth conditions present a full width at half maximum of 345.6 arc sec for the X-ray diffraction rocking curve and a root-mean-square surface roughness of 6 nm. However, a significant number of microtwin defects are observed using cross-sectional transmission electron microscopy, which leads to a relatively high etch pit density (mid-107 cm-2) in the Hg0.7Cd0.3Te thin films. These findings not only facilitate the growth of HgCdTe on mica substrates for fabricating curved IR sensors but also contribute to a better understanding of growth of traditional zinc-blende semiconductors on layered substrates.

A Review of the Phytochemistry and Biological Activities of Echinopsis Radix.

The main varieties of Echinopsis Radix recorded in the Chinese Pharmacopoeia are the roots of Echinops latifolius Tausch or Echinops grijsii Hance. However, the chemical constituents and biological activities of this herb have not been reviewed. In order to clarify the chemical constituents of the main varieties of this herb and improve the quality of Chinese medicinal material resources, this paper systematically reviewed their chemical constituents and related biological activities. Phytochemical investigations reveal eighty-five compounds including fort y-nine thiophenes (1-49), eight flavonoids (50-57), seven caffeic acids and its derivatives (58-64), eight sesquiterpenoids (65-72), and thirteen triterpenoids and other compounds (73-85) were reported from Echinopsis Radix. The review of biological activities suggests that thiophenes are the main secondary metabolites of the medicinal material which exert antitumor, insecticidal and antifungal activities. In addition, caffeic acid and its derivatives and sesquiterpenes are potential active ingredients worthy of further study. This review provides an important scientific basis for the development of active ingredients and resource quality evaluation of Echinopsis Radix.

LincRNA ZNF529-AS1 inhibits hepatocellular carcinoma via FBXO31 and predicts the prognosis of hepatocellular carcinoma patients.

BACKGROUND: Invasion and metastasis of hepatocellular carcinoma (HCC) is still an important reason for poor prognosis. LincRNA ZNF529-AS1 is a recently identified tumour-associated molecule that is differentially expressed in a variety of tumours, but its role in HCC is still unclear. This study investigated the expression and function of ZNF529-AS1 in HCC and explored the prognostic significance of ZNF529-AS1 in HCC. METHODS: Based on HCC information in TCGA and other databases, the relationship between the expression of ZNF529-AS1 and clinicopathological characteristics of HCC was analysed by the Wilcoxon signed-rank test and logistic regression. The relationship between ZNF529-AS1 and HCC prognosis was evaluated by Kaplan‒Meier and Cox regression analyses. The cellular function and signalling pathways involved in ZNF529-AS1 were analysed by GO and KEGG enrichment analysis. The relationship between ZNF529-AS1 and immunological signatures in the HCC tumour microenvironment was analysed by the ssGSEA algorithm and CIBERSORT algorithm. HCC cell invasion and migration were investigated by the Transwell assay. Gene and protein expression were detected by PCR and western blot analysis, respectively. RESULTS: ZNF529-AS1 was differentially expressed in various types of tumours and was highly expressed in HCC. The expression of ZNF529-AS1 was closely correlated with the age, sex, T stage, M stage and pathological grade of HCC patients. Univariate and multivariate analyses showed that ZNF529-AS1 was significantly associated with poor prognosis of HCC patients and could be an independent prognostic indicator of HCC. Immunological analysis showed that the expression of ZNF529-AS1 was correlated with the abundance and immune function of various immune cells. Knockdown of ZNF529-AS1 in HCC cells inhibited cell invasion and migration and inhibited the expression of FBXO31. CONCLUSION: ZNF529-AS1 could be a new prognostic marker for HCC. FBXO31 may be the downstream target of ZNF529-AS1 in HCC.

Clinical application and detection techniques of liquid biopsy in gastric cancer.

Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology.

Humoral Immunity After COVID-19 Vaccination in Chronic Lymphocytic Leukemia and Other Indolent Lymphomas: A Single-Center Observational Study.

BACKGROUND: Chronic lymphocytic leukemia (CLL) and other non-Hodgkin's lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers. METHODS: In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab. RESULTS: Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton's tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination. CONCLUSION: Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.

Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Detection of monkeypox virus using helicase dependent amplification and recombinase polymerase amplification combined with lateral flow test.

The monkeypox virus (MPXV) is a zoonotic DNA virus that belongs to the poxvirus family. Conventional laboratory methods for detecting MPXV are complex and expensive, making them unsuitable for detecting the virus in regions with limited resources. In this study, we using the Helicase dependent amplification (HDA) method and the Recombinase polymerase amplification (RPA) technique in combination with the lateral flow test (LFT), together with a self-designed qPCR technique for the detection of the MPXV specific conserved fragment F3L, to compare the sensitivity and specificity of the three assays. By analyzing the sensitivity detection results using Probit, it can be seen that the limit of detection (LOD) of the HDA-LFT detection target is 9.86 copies/µL (95% confidence interval, CI 7.52 copies/µL lower bound), the RPA-LFT detection target is 6.97 copies/µL (95% CI 3.90 copies/µL lower bound), and the qPCR detection target is 479.24 copies/mL (95% CI 273.81 copies/mL lower bound). The specificity test results showed that the specificity of the three methods mentioned above was higher than 90% in detecting pseudoviruses of the same genus of MPXV. The simple, highly sensitive, and specific MPXV assay developed in this study is anticipated to provide a solid foundation for future applications in the early screening, diagnosis, and evaluation of the efficacy of MPXV. This is the first time the HDA-LFT assay has been utilized to detect MPXV infection.

Deficient chaperone-mediated autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH), a more severe subtype of nonalcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH-induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone-mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage-specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. METHODS: The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and flow cytometry. By constructing myeloid-specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label-free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT-qPCR. RESULTS: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte-derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver-targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA-deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. CONCLUSIONS: We proposed that the impaired CMA-induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.