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Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1D mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1D strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1D strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin® A as a compound restoring growth on glucose of the yeast tps1D mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1D cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism. [ABSTRACT FROM AUTHOR]

This document provides a summary of a study on proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), a kidney disease characterized by the presence of a monoclonal immunoglobulin. The study analyzed 15 patients with PGNMID in Belgium and The Netherlands and provided detailed information on patient demographics, kidney function, biopsy findings, and treatment regimens. The study found that patients who received clone-directed therapy had a better renal response compared to those who did not. Recurrence of PGNMID after kidney transplantation was common, and the study calls for further research to improve diagnostic and therapeutic strategies for this disease. [Extracted from the article]

Introduction: Teclistamab is the first approved B cell maturation antigen × CD3 bispecific antibody with precision dosing for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). We compared the effectiveness of teclistamab in MajesTEC-1 versus real-world physician's choice of therapy (RWPC) in patients from the prospective, non-interventional LocoMMotion and MoMMent studies. Methods: Patients treated with teclistamab from MajesTEC-1 (N = 165) were compared with an external control arm from LocoMMotion (N = 248) or LocoMMotion + MoMMent pooled (N = 302). Inverse probability of treatment weighting adjusted for imbalances in prognostic baseline characteristics. The relative effect of teclistamab versus RWPC for overall response rate (ORR), very good partial response or better (≥ VGPR) rate, and complete response or better (≥ CR) rate was estimated with an odds ratio using weighted logistic regression transformed into a response-rate ratio (RR) and 95% confidence interval (CI). Weighted proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Baseline characteristics were well balanced between treatment cohorts after reweighting. Patients treated with teclistamab had significantly improved outcomes versus RWPC in LocoMMotion: ORR (RR [95% CI], 2.44 [1.79–3.33]; p < 0.0001), ≥ VGPR (RR 5.78 [3.74–8.93]; p < 0.0001), ≥ CR (RR 113.73 [15.68–825.13]; p < 0.0001), DOR (HR 0.39 [0.24–0.64]; p = 0.0002), PFS (HR 0.48 [0.35–0.64]; p < 0.0001), and OS (HR 0.64 [0.46–0.88]; p = 0.0055). Teclistamab versus RWPC in LocoMMotion + MoMMent also had significantly improved outcomes: ORR (RR 2.41 [1.80–3.23]; p < 0.0001), ≥ VGPR (RR 5.91 [3.93–8.88]; p < 0.0001), ≥ CR (RR 132.32 [19.06–918.47]; p < 0.0001), DOR (HR 0.43 [0.26–0.71]; p = 0.0011), PFS (HR 0.49 [0.37–0.66]; p < 0.0001), and OS (HR 0.69 [0.50–0.95]; p = 0.0247). Conclusion: Teclistamab demonstrated significantly improved effectiveness over RWPC in LocoMMotion ± MoMMent, emphasizing its clinical benefit as a highly effective treatment for patients with TCE RRMM. Trial Registration: MajesTEC-1, ClinicalTrials.gov NCT03145181 (phase 1) and NCT04557098 (phase 2); LocoMMotion, ClinicalTrials.gov NCT04035226; MoMMent, ClinicalTrials.gov NCT05160584. [ABSTRACT FROM AUTHOR]

We provide updated guidance and standards for the indication, acquisition, and interpretation of [18F]FDG PET/CT for plasma cell disorders. Procedures and characteristics are reported and different scenarios for the clinical use of [18F]FDG PET/CT are discussed. This document provides clinicians and technicians with the best available evidence to support the implementation of [18F]FDG PET/CT imaging in routine practice and future research. [ABSTRACT FROM AUTHOR]

Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1Δ mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1Δ strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1Δ strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin ® A as a compound restoring growth on glucose of the yeast tps1Δ mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin ® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin ® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1Δ cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin ® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism., Competing Interests: JT is owner and managing director of NovelYeast bv, which filed a patent application EP 21168650.6 on 15 April 2021 covering the use of the Warbicin® compounds for therapeutic purposes. NovelYeast has been granted registration of the term Warbicin® as Trademark. S-MF has received funding from Bayer Healthcare, Merck and BlackBelt Therapeutics and has consulted for Fund+. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Vanthienen, Fernández-García, Baietti, Claeys, Van Leemputte, Nguyen, Goossens, Deparis, Broekaert, Vlayen, Audenaert, Delforge, D’Amuri, Van Zeebroeck, Leucci, Fendt and Thevelein.)

Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed., Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status., Results: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group., Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)., (Copyright © 2023 Massachusetts Medical Society.)