Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

Precision medicine is modernizing strategies for clinical study design to help improve diagnoses guiding individualized treatment based on genetic or phenotypic characteristics that discriminate between patients with similar clinical presentations. Methodology to personalize treatment choices is being increasingly employed in clinical trials, yielding favorable correlations with improved response rates and survival. In patients with diffuse large B-cell lymphoma (DLBCL), disease characteristics and outcomes may vary widely, underscoring the importance of patient classification through identification of sensitive prognostic features. The discovery of distinct DLBCL molecular subtypes based on cell of origin (COO) is redefining the prognosis and treatment of this heterogeneous cancer. Owing to significant molecular and clinical differences between activated B-cell-like (ABC)- and germinal center B-cell-like (GCB)-DLBCL subtypes, COO identification offers opportunities to optimize treatment selection. Widespread adoption of COO classification would greatly improve treatment and prognosis; however, limitations in interlaboratory concordance between immunohistochemistry techniques, cost, and availability of gene expression profiling tools undermine universal integration in the clinical setting. With advanced methodology to determine COO in a real-world clinical setting, therapies targeted to specific subtypes are under development. The focus here is to review applications of precision medicine exemplified by COO determination in DLBCL patients

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma

Targeted Therapy with Nanatinostat and Valganciclovir in Recurrent EBV-Positive Lymphoid Malignancies: A Phase 1b/2 Study

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706

Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn−/− mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn−/− mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn−/− mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn−/− mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn−/− mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn−/− mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes

FGF4 Independent Derivation of Trophoblast Stem Cells from the Common Vole

The derivation of stable multipotent trophoblast stem (TS) cell lines from preimplantation, and early postimplantation mouse embryos has been reported previously. FGF4, and its receptor FGFR2, have been identified as embryonic signaling factors responsible for the maintenance of the undifferentiated state of multipotent TS cells. Here we report the derivation of stable TS-like cell lines from the vole M. rossiaemeridionalis, in the absence of FGF4 and heparin. Vole TS-like cells are similar to murine TS cells with respect to their morphology, transcription factor gene expression and differentiation in vitro into derivatives of the trophectoderm lineage, and with respect to their ability to invade and erode host tissues, forming haemorrhagic tumours after subcutaneous injection into nude mice. Moreover, vole TS-like cells carry an inactive paternal X chromosome, indicating that they have undergone imprinted X inactivation, which is characteristic of the trophoblast lineage. Our results indicate that an alternative signaling pathway may be responsible for the establishment and stable proliferation of vole TS-like cells

Antifungal Composite Fibers Based on Cellulose and Betulin

Composite fibers and films based on cellulose and betulin were spun for the first time from solutions in N-methylmorpholine-N-oxide using the dry–wet jet method. The rheological properties of the composite solutions did not reveal any fundamental difference from those of the cellulose solutions. Introduction of betulin into the cellulose matrix (up to 10%) led to a decrease in the mechanical properties of the obtained fibers. The structure of the composite fibers was analyzed using SEM and X-ray diffraction methods. It was shown that the introduction of an additive into the cellulose matrix led to a decrease in the structural ordering of the cellulose. Comparative studies of the antibacterial activity of the composite films on Escherichia coli (E. coli) were carried out. The antifungal activity of the composite films was estimated using the strain of the O-97 Trichoderma viride Pers ex Fr (Gause Institute of New Antibiotics, Moscow, Russia)

Estimating of Residual Kidney Function by Multi-Frequency Bioelectrical Impedance Analysis in Hemodialysis Patients Without Urine Collection

Background/Aims: Residual kidney function (RKF) is a pivotal predictor of better clinical outcomes in maintenance hemodialysis (MHD) patients. So far there has been no attempt to use bioimpedance analysis (BIA) measurements to calculate residual glomerular filtration rate (GFR) in dialysis population. We hypothesized that performing of multi-frequency BIA at the beginning and end of hemodialysis session can enable us to predict the measured residual GFR in MHD patients. Thus our aim was to develop and validate a new RKF prediction equation using multi-frequency BIA in MHD patients. Methods: It was diagnostic test evaluation study in a prospective cohort. Participants (n=88; mean age, 66.3±13.2 years, 59.1% males) were recruited from a single hemodialysis center. A new equation (eGFRBIA) to predict RKF, utilizing BIA measurements performed pre- and post-dialysis, was generated and cross-validated by the leave-one-out procedure. GFR estimated as the mean of urea and creatinine clearance (mGFR) using urine collections during entire interdialytic period. Results: A prediction equation for mGFR that includes both pre- and post-dialysis BIA measurements provided a better estimate than either pre- or post-dialysis measurements alone. Mean bias between predicted and measured GFR was -0.12 ml/min. Passing and Bablok regression showed no bias and no significant deviation in linearity. Concordance correlation coefficient indicated good agreement between the eGFRBIA and mGFR (0.75, P<0.001). Using cut-off predicted mGFR levels >2 ml/min/1.73 m2 yielded an area under curve of 0.96, sensitivity 85%, and specificity 89% in predicting mGFR. The κ scores for intraobserver reproducibility were consistent with substantial agreement between first and second estimation of RKF according to eGFRBIA (weighted κ was 0.60 [0.37-0.83]). Conclusion: We present a valid and clinically obtainable method to predict RKF in MHD patients. This method, which uses BIA, may prove as accurate, convenient and easily reproducible while it is operator independent

Solid-State Crystal-to-Crystal Phase Transitions and Reversible Structure–Temperature Behavior of Phosphovanadomolybdic Acid, H₅PV₂Mo₁₀O₄₀

The crystal packing and secondary structure of H₅PV₂Mo₁₂O₄₀ was followed by careful X-ray diffraction studies that revealed four unique structures and three solid phase transitions at temperatures between 25 and 55 °C, with loss of solvated water and concomitant contraction of the volume and increase of the packing density. Above 60 °C H₅PV₂Mo₁₂O₄₀ becomes amorphous and then anhydrous although the polyoxometalate cluster is stable indefinitely up to 300 °C. Above this temperature, combined IR, Raman, XRD, and XPS measurements show the decomposition of H₅PV₂Mo₁₂O₄₀ to crystalline MoO₃ and probably amorphous vanadium oxide and vanadylphosphate, the latter appearing to cover the surface of MoO₃. Importantly, H₅PV₂Mo₁₂O₄₀ can be easily recovered by dissolution in water at 80 °C

Solid-State Crystal-to-Crystal Phase Transitions and Reversible Structure–Temperature Behavior of Phosphovanadomolybdic Acid, H₅PV₂Mo₁₀O₄₀

The crystal packing and secondary structure of H₅PV₂Mo₁₂O₄₀ was followed by careful X-ray diffraction studies that revealed four unique structures and three solid phase transitions at temperatures between 25 and 55 °C, with loss of solvated water and concomitant contraction of the volume and increase of the packing density. Above 60 °C H₅PV₂Mo₁₂O₄₀ becomes amorphous and then anhydrous although the polyoxometalate cluster is stable indefinitely up to 300 °C. Above this temperature, combined IR, Raman, XRD, and XPS measurements show the decomposition of H₅PV₂Mo₁₂O₄₀ to crystalline MoO₃ and probably amorphous vanadium oxide and vanadylphosphate, the latter appearing to cover the surface of MoO₃. Importantly, H₅PV₂Mo₁₂O₄₀ can be easily recovered by dissolution in water at 80 °C