NAD+ METABOLISM RESTRICTION BOOSTS HIGH-DOSE MELPHALAN EFFICACY IN PATIENTS WITH MULTIPLE MYELOMA.

Elevated levels of the nicotinamide adenine dinucleotide (NAD+)-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in Multiple Myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials due to the existence of alternative NAD+ production routes utilizing NAD+ precursors other than nicotinamide.

Comparing Outcomes Between CPX-351 and Fludarabine-Based Induction in Secondary Acute Myeloid Leukemia in the Real-World Setting: The Prognostic Role of Measurable Residual Disease.

Secondary acute myeloid leukemia (s-AML) is associated with inferior outcomes with conventional chemotherapy, and fludarabine combinations (FLAG-Ida) have been tested to improve results. More recently, CPX-351 resulted superior to conventional 3 + 7 in s-AML patients. In the UK NCRI AML19 trial, AML patients were randomized to receive either FLAG-Ida or CPX-351.

Clonal hematopoiesis impacts frailty in newly diagnosed multiple myeloma patients: a retrospective multicenter analysis.

Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5-1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated.

Critical evaluation of non-uniform optical phased arrays for real-world beam-steering applications.

Optical phased arrays (OPAs) are a promising technology for the realization of fast and compact non-mechanical optical beam steering. While many experimental demonstrations of integrated OPAs exist in the literature, it is challenging to evaluate their suitability for real-world applications due to the lack of system-level performance requirements. Here, we derive such performance requirements for two of the most promising OPA applications - namely free space optical communications (FSOC) and light detection and ranging (LIDAR) - and show that traditional uniformly spaced OPA architectures likely cannot reach the required performance.

Assessment of performance and comparison of three commercial HDV RNA detection assays: implications for diagnosis and treatment monitoring.

Objectives: Precise HDV-RNA detection and quantification are pivotal for diagnosis and monitoring of response to newly approved treatment. We evaluate the performance of three HDV RNA detection and quantification assays.

Methods: Hepatitis Delta RT-PCR system kit, EurobioPlex HDV assay, and RoboGene HDV RNA Quantification kit 2.

A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

Introduction: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1.

Objectives And Methods: We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life.

Results: At IRd initiation, 34% of pts were aged ≥75 (median 72.

The Bern Birth Cohort (BeBiCo) to study the development of the infant intestinal microbiota in a high-resource setting in Switzerland: rationale, design, and methods.

Background: Microbiota composition is fundamental to human health with the intestinal microbiota undergoing critical changes within the first two years of life. The developing intestinal microbiota is shaped by maternal seeding, breast milk and its complex constituents, other nutrients, and the environment. Understanding microbiota-dependent pathologies requires a profound understanding of the early development of the healthy infant microbiota.

Cyclic fasting bolsters cholesterol biosynthesis inhibitors' anticancer activity.

Identifying oncological applications for drugs that are already approved for other medical indications is considered a possible solution for the increasing costs of cancer treatment. Under the hypothesis that nutritional stress through fasting might enhance the antitumour properties of at least some non-oncological agents, by screening drug libraries, we find that cholesterol biosynthesis inhibitors (CBIs), including simvastatin, have increased activity against cancers of different histology under fasting conditions. We show fasting's ability to increase CBIs' antitumour effects to depend on the reduction in circulating insulin, insulin-like growth factor-1 and leptin, which blunts the expression of enzymes from the cholesterol biosynthesis pathway and enhances cholesterol efflux from cancer cells.

Harnessing Immune Response in Acute Myeloid Leukemia.

Despite the results achieved with the evolution of conventional chemotherapy and the inclusion of targeted therapies in the treatment of acute myeloid leukemia (AML), survival is still not satisfying, in particular in the setting of relapsed/refractory (R/R) disease or elderly/unfit patients. Among the most innovative therapeutic options, cellular therapy has shown great results in different hematological malignancies such as acute lymphoblastic leukemia and lymphomas, with several products already approved for clinical use. However, despite the great interest in also expanding the application of these new treatments to R/R AML, no product has been approved yet for clinical application.

Daratumumab in the treatment of C3 glomerulopathy with monoclonal gammopathy: a case report and literature review.

Although rare, C3 glomerulopathy (C3G) is increasingly recognized thanks to the currently available diagnostic skills. C3G is not a single disease but a group of disorders with distinct pathogenesis and progression. Thus, an essential step for its management remains an in-depth characterization of the specific form and the identification of underlying conditions, which may also impact treatment choices as well.

Toward the use of mixed microbial cultures for the biological production of adipic and levulinic acid.

Biological synthesis of high added-value compounds like adipic acid (AA), levulinic acid (LA), or polyhydroxybutyrate (PHB) using pure culture has been separately reported. However, pure culture requires sterile conditions and the use of specific carbon sources resulting in high operating costs. Different alternatives based on the use of mixed microbial cultures (MMC) have been explored to resolve this problem.

Sirtuin 6 Regulates the Activation of the ATP/Purinergic Axis in Endothelial Cells.

Sirtuin 6 (SIRT6) is a member of the mammalian NAD-dependent deac(et)ylase sirtuin family. SIRT6's anti-inflammatory roles are emerging increasingly often in different diseases and cell types, including endothelial cells. In this study, the role of SIRT6 in pro-inflammatory conditions was investigated by engineering human umbilical vein endothelial cells to overexpress SIRT6 (SIRT6+ HUVECs).

Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies.

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD production. Despite the high efficacy of several developed NAMPT inhibitors (i.

CD38-Induced Metabolic Dysfunction Primes Multiple Myeloma Cells for NAD-Lowering Agents.

Cancer cells fuel growth and energy demands by increasing their NAD biosynthesis dependency, which therefore represents an exploitable vulnerability for anti-cancer strategies. CD38 is a NAD-degrading enzyme that has become crucial for anti-MM therapies since anti-CD38 monoclonal antibodies represent the backbone for treatment of newly diagnosed and relapsed multiple myeloma patients. Nevertheless, further steps are needed to enable a full exploitation of these strategies, including deeper insights of the mechanisms by which CD38 promotes tumorigenesis and its metabolic additions that could be selectively targeted by therapeutic strategies.

A sub-wavelength Si LED integrated in a CMOS platform.

A nanoscale on-chip light source with high intensity is desired for various applications in integrated photonics systems. However, it is challenging to realize such an emitter using materials and fabrication processes compatible with the standard integrated circuit technology. In this letter, we report an electrically driven Si light-emitting diode with sub-wavelength emission area fabricated in an open-foundry microelectronics complementary metal-oxide-semiconductor platform.

Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis.

Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB-mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype.

Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial.

Background: Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk.

Flow cytometry: a tool for understanding the behaviour of polyhydroxyalkanoate accumulators.

The use of mixed microbial cultures (MMCs) is seen as an attractive strategy for polyhydroxyalkanoate (PHA) production. In order to optimize the MMC-PHA production process, tools are required to improve our understanding of the physiological state of the PHA-storing microorganisms within the MMC. In the present study, we explored the use of flow cytometry to analyse the metabolic state and polyhydroxybutyrate (PHB) content of the microorganisms from an MMC-PHA production process.

Circulating salivary and serum miRNA-182, 320a, 375 and 503 expression levels in type 2 diabetes.

Aim: Early-stage diagnosis of diabetes through non-invasive and diagnostic biofluid-like saliva has become a very popular approach to facilitate future preventive interventions and improve patient care. Meanwhile, the alteration of small non-coding RNA in human fluids has been suggested as a probable precedent for the early stages of diabetes.

Methods: In the present study, we checked the expression of miR-320a, 182-5p, 503, and 375 by using quantitative PCR in both stimulated and unstimulated saliva and blood samples of 40 adult patients with type-2 diabetes compared to 40 healthy individuals.

Real-life validation of a sample pooling strategy for screening of hepatitis C.

Objectives: To test a real-life sample pooling screening strategy which contributes to increasing the diagnostic capacity of clinical laboratories and expanding access to massive screening of hepatitis C.

Methods: After evaluating the sensitivity of the pooling strategy for seven different commercial assays which are used to determine the concentration of hepatitis C virus (HCV)-RNA in the plasma or serum, consecutive samples submitted for HCV diagnosis during the first 3 weeks of November 2021 were tested for HCV antibodies and, in parallel and in a blinded way, were pooled into 100 samples and tested for HCV-RNA. When the result was positive, a strategy to un-mask the positive(s) pool(s), which needed up to 15 total HCV-RNA tests, was used.

Myeloma Spine and Bone Damage Score (MSBDS) on Whole-Body Computed Tomography (WBCT): Multiple Reader Agreement in a Multicenter Reliability Study.

To assess the reliability of the myeloma spine and bone damage score (MSBDS) across multiple readers with different levels of expertise and from different institutions. A reliability exercise, including 104 data sets of static images and complete CT examinations of patients affected by multiple myeloma (MM), was performed. A complementary imaging atlas provided detailed examples of the MSBDS scores, including low-risk and high-risk lesions.

Identification of NAPRT Inhibitors with Anti-Cancer Properties by In Silico Drug Discovery.

Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been conceived as a promising anti-cancer strategy. Numerous inhibitors of the NAD-producing enzyme, nicotinamide phosphoribosyltransferase (NAMPT), have been developed over the past two decades. However, their limited anti-cancer activity in clinical trials raised the possibility that cancer cells may also exploit alternative NAD-producing enzymes.