B cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty-eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver-operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty-four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0-2, extranodal sites ≤1 and stage III-IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

Cisplatin (CP)-induced nephrotoxicity is widely accepted as a model for acute kidney injury (AKI). Although cisplatin-induced chronic kidney disease (CKD) in rodent has been reported, the role of phosphate in the cisplatin-induced CKD progression is not described. In this study, we gave a single peritoneal injection of CP followed by high (2%) phosphate diet for 20 weeks. High dose CP (20 mg/Kg) led to high mortality; whereas a lower dose (10 mg/Kg) resulted in a full spectrum of AKI with tubular necrosis, azotemia, and 0% mortality 7 days after CP injection. After consuming a high phosphate diet, mice developed CKD characterized by low creatinine clearance, interstitial fibrosis, hyperphosphatemia, high plasma PTH and FGF23, low plasma 1,25(OH) Vitamin D and αKlotho, and classic uremic cardiovasculopathy. The CP model was robust in demonstrating the effect of aging, sexual dimorphism, and dietary phosphate on AKI and also AKI-to-CKD progression. Finally, we used the CP-high phosphate model to examine previously validated methods of genetically manipulated high αKlotho and therapy using exogenous soluble αKlotho protein supplementation. In this CP CKD model, αKlotho mitigated CKD progression, improved mineral homeostasis, and ameliorated cardiovascular disease. Taken together, CP and high phosphate nephrotoxicity is a reproducible and technically very simple model for the study of AKI, AKI-to-CKD progression, extrarenal complications of CKD, and for evaluation of therapeutic efficacy.

Hemophagocytic lymphohistiocytosis (HLH) can be classified into primary HLH and secondary HLH. Primary HLH usually occurs in infants and children with an underlying genetic defect, and there are also teens and occasional adults with primary HLH. Most cases with secondary HLH are adult patients with secondary triggers including infections, malignancies, and autoimmune diseases. The distinction between primary HLH and secondary HLH seems to be less straightforward, as patients with secondary HLH may also have genetic defects while primary HLH can be triggered by secondary causes. In this study, using amplicon-based targeted gene sequencing (TGS), we sequenced eighteen HLH-related genes in 112 adult HLH cases, which were mostly secondary HLH. Mutations or rare variants were identified in 48 cases (42.9%). All the variants except one were missense variants, and biallelic gene mutations were identified in 3 cases in which only one case harbored homogenous missense mutation. Recurrent variants including UNC13D p.G863D and AP3B1 p.T359A are much more prevalent in our cohort than in normal East Asian population, and in silico analysis predicted pathogenicity of these variants. In conclusion, according to our study, genetic defects may also contribute to the development of adult HLH cases or secondary HLH cases.

Circular RNAs (circRNAs) have recently been reported to play crucial roles in various regulatory processes and involved in cancer onset and progression. However, the potential mechanism of circRNAs in chronic lymphocytic leukemia (CLL) remains largely unknown. Here, we observed hsa_circ_0132266 (circ_0132266), a circRNA significantly decreased in the peripheral blood mononuclear cells (PBMCs) of CLL patients compared with healthy donors, could act as an endogenous sponge of hsa-miR-337-3p (miR-337-3p) and regulate its activity, which resulted in a downstream change of target-gene PML and a consequent influence on cell viability. Taken together, our data indicated the regulatory mechanism of circ_0132266 in CLL progression through circ_0132266/miR-337-3p/PML axis, suggesting that it may serve as a biomarker as well as an exploitable therapeutic target for CLL.

Our results suggest that NK cell count is an independent prognostic marker for OS in patients with CLL and NK cell counts ≥ 0.40 × 10/L can routinely be used to identify patients with favorable survival.

Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.

Human immunodeficiency virus (HIV) infection is associated with an increased risk of aggressive lymphoma, especially diffuse large B cell lymphoma (DLBCL). There are few data regarding HIV-associated DLBCL in China. Therefore, we analyzed the characteristics and outcomes of patients with HIV-associated DLBCL from our center. We retrospectively studied HIV-infected patients with DLBCL from 2011 to 2019. Data on HIV infection and lymphoma characteristics, treatments and outcomes were retrieved and analyzed. In 78 patients with HIV-associated DLBCL, most had poor performance status (PS) (74%), elevated lactate dehydrogenase (LDH) levels (95%), B symptoms (74%), advanced Ann Arbor stages (81%), bulky diseases (64%) and extranodal involvement (70%) at diagnosis. The median CD4 + T cell count was 162/µl, and 26 patients were already on combination antiretroviral therapy (cART) treatment at diagnosis of DLBCL. Elevated whole blood EBV DNA copy number was detected in 38 patients (66%, 38/58). Of the 45 patients evaluated at the end of treatment, 26 (58%) achieved CR, 6 (13%) achieved PR and 6 (13%) experienced progressive disease. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 56.4% and 62.7%, respectively. Factors associated with decreased PFS and OS in univariate analysis were unfavorable PS and high international prognostic index. Elevated EBV DNA copy number was inclined to be associated with worse outcome. We did not observe a significant difference in survival between R-EPOCH and R-CHOP regimens. In our population, patients with HIV-associated DLBCL presented with aggressive characteristics and exhibited poor survival outcomes, even in the modern cART era.