Polymerase-based DNA reactions for molecularly computing cancerous diagnostic valences of multiple miRNAs.

Conventional miRNA-based diagnostic methods often treat all biomarkers equally, overlooking the fact that each miRNA contributes differently to disease classification. This differential diagnostic importance is captured by the concept of Cancerous Diagnostic Valence (CDV)-a metric that quantifies both the direction (oncogenic or protective) and magnitude of each miRNA's association with cancer. Here, we introduce a polymerase-based DNA molecular computing system that directly encodes and integrates CDVs to perform weighted molecular classification of non-small cell lung cancer (NSCLC).

Simultaneous Determination of 32 Polyphenolic Compounds in Berries via HPLC-MS/MS.

An HPLC-MS/MS method for the simultaneous determination of 32 polyphenolic compounds in berries was established. For method validation, the berry samples were extracted with 80% ethanol, purified on an HLB column, and separated on a C18 column via gradient elution with an acetonitrile-water mobile phase system before mass spectrometry detection with electrospray ionization in negative mode and multiple reaction monitoring. The results revealed that the 32 polyphenolic compounds had a good linear relationship in the concentration range of 1-500 μg/L, with R > 0.

Analysis of Volatile and Non-Volatile Components of Dried Chili Pepper ( L.).

As an important crop in the world, dried pepper is widely used in various foods. However, the sensory quality, fruit shape index, edible index, nutrition index, and volatile components of dried pepper have not been comprehensively analyzed. This study elucidated the differences between different varieties of dried pepper and provided the basis for the selection of raw materials for different varieties of dried pepper products.

Prognostic risk factors of pneumonia associated with COVID-19 in patients with lymphoma.

Objective: Patients with hematological malignancies have an elevated risk of developing pneumonia after contracting COVID-19. Lymphoma is the most prevalent hematologic malignancy. It is critical to identify patients at high risk of contracting COVID-19-associated pneumonia.

Zanubrutinib plus R-CHOP for the treatment of newly diagnosed double-expressor lymphoma: A phase 2 clinical study.

Background: Double-expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B-cell lymphoma (DLBCL). This study is a multicenter, prospective, single-arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R-CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.

Methods: From November 2020 to July 2022, 48 newly diagnosed patients were enrolled.

Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma.

Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC.

Simultaneous determination of triazole fungicides in animal-origin food by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.

A method for the simultaneous determination of 21 triazole fungicides in animal-origin foods was established by using UPLC-MS/MS. The dilution solvent, extraction solvent, and QuEChERS purification adsorbent composition, were optimized. The response value of the target compound was the highest and the chromatographic peak shape was optimal under the following conditions: water-acetonitrile as the mobile phase, acetonitrile to extract the target compound, C18 (100 mg) as the adsorbent, and water-acetonitrile as the diluent.

Targeting BCMA in Multiple Myeloma: Advances in Antibody-Drug Conjugate Therapy.

Multiple myeloma (MM) is an incurable cancer of the plasma cells. In the last twenty years, treatment strategies have evolved toward targeting MM cells-from the shotgun chemotherapy approach to the slightly more targeted approach of disrupting important MM molecular pathways to the immunotherapy approach that specifically targets MM cells based on protein expression. Antibody-drug conjugates (ADCs) are introduced as immunotherapeutic drugs which utilize an antibody to deliver cytotoxic agents to cancer cells distinctively.

Case report: Successful management of a refractory double-expressor diffuse large B-cell lymphoma patient under the guidance of high-throughput drug sensitivity test.

Introduction: Double-expressor diffuse large B-cell lymphoma (DEL), harboring double expression of MYC and BCL2, has an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). We initiated a clinical trial to treat newly diagnosed DEL with R-CHOP plus Bruton's tyrosine kinase (BTK) inhibitor (BTKi) zanubrutinib (ZR-CHOP) and achieved a high complete response (CR) rate while four patients progressed during therapy, one of them carrying ATM and CD58 mutations. We applied an high-throughput drug sensitivity test for the prediction of clinical responses to different drugs in this patient.

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation.

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.

Improving the Quality of Frozen Lamb by Microencapsulated Apple Polyphenols: Effects on Cathepsin Activity, Texture, and Protein Oxidation Stability.

This study aimed to evaluate the efficiency of microencapsulated apple polyphenols (MAP) in controlling cathepsin activity and texture, as well as inhibiting protein oxidation and metmyoglobin formation in lamb meat during frozen storage at -18 °C for 40 weeks. The effects of degradation in vitro on cathepsin and the microstructure in lamb were also evaluated. Results indicated that relative to the control group, the lamb treated with MAP exhibited increased cathepsin activity and inhibited metmyoglobin production.

Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma.

The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment.

BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression.

Purpose: Efforts are required to improve the potency and durability of CD38- and BCMA-based immunotherapies in human multiple myeloma. We here delineated the molecular and cellular mechanisms underlying novel immunomodulatory effects triggered by BCMA pyrrolobenzodiazepine (PBD) antibody drug conjugate (ADC) MEDI2228 which can augment efficacy of these immunotherapies.

Experimental Design: MEDI2228-induced transcriptional and protein changes were investigated to define significantly impacted genes and signaling cascades in multiple myeloma cells.

ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment.

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 () knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal-regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation.

VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo.

Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively.

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models.

We investigated here the novel immunomodulation and anti-multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell-dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM).

Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma.

Chimeric antigen receptor (CAR) T-cell therapy remains limited to select centers that can carefully monitor adverse events. To broaden use of CAR T cells in community clinics and in a frontline setting, we developed a novel CD8+ CAR T-cell product, Descartes-08, with predictable pharmacokinetics for treatment of multiple myeloma. Descartes-08 is engineered by mRNA transfection to express anti-BCMA CAR for a defined length of time.

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma.

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages.

The yin and yang functions of extracellular ATP and adenosine in tumor immunity.

Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors.

A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma.

To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes.

Determination of five Alternaria toxins in wolfberry using modified QuEChERS and ultra-high performance liquid chromatography-tandem mass spectrometry.

A modified quick, easy, cheap, effective, rugged, and safe method coupled with ultra-high performance liquid chromatography-tandem mass spectrometry was established for the simultaneous detection of five Alternaria toxins (tenuazonic acid, alternariol, alternariol monomethyl ether, altenuene, and tentoxin) in wolfberry. The sample pretreatment conditions including the dilution solvent, the extraction solvent and the QuEChERS purification parameters were optimized. Detection of the five Alternaria toxins was performed in MRM mode under ESI + conditions.

APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications.

We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e.