Individualized dynamic frailty-tailored therapy (DynaFiT) in elderly patients with newly diagnosed multiple myeloma: a prospective study.

It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.

LncRNAs-circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers.

As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non-coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.

Tislelizumab and radiation therapy in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type: a phase II study protocol.

Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).

Direct Synthesis of Benzo[b]fluorenyl Thiophosphates via Tandem Cyclization of Diynols with (RO)2P(O)SH.

A general and metal-free protocol for the construction of benzo[b]fluorenyl thiophosphates was developed through the cascade cyclization of easily prepared diynols and (RO)2P(O)SH, with water as the only byproduct. The novel transformation involved the allenyl thiophosphate as the key intermediate, followed by Schmittel-type cyclization to achieve the desired products. Notably, (RO)2P(O)SH acted not only as a nucleophile but also as an acid-promoter to initiate the reaction.

Proposed risk-scoring model for estimating the prognostic impact of 1q gain in patients with newly diagnosed multiple myeloma.

1q gain (+1q) is the most common high-risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097-1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk-scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re-stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression-free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high-risk patients, therefore underlining the necessity for their re-stratification. The proposed simple risk-scoring model can estimate the outcomes of patients with +1q, which may help guide risk-adapted treatment for such patients.

Levetiracetam alleviates cognitive decline in Alzheimer's disease animal model by ameliorating the dysfunction of the neuronal network.

Background: Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD. Methods: We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. Results: Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/ß, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid ß-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid ß-peptide (Aß) by reducing the expression of ß-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice. Conclusion: Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.

Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy.

The introduction of various targeted agents into the armamentarium of cancer treatment has revolutionized the standard care of patients with cancer. However, like conventional chemotherapy, drug resistance, either preexisting (primary or intrinsic resistance) or developed following treatment (secondary or acquired resistance), remains the Achilles heel of all targeted agents with no exception, via either genetic or non-genetic mechanisms. In the latter, emerging evidence supports the notion that intracellular signaling pathways for tumor cell survival act as a mutually interdependent network via extensive cross-talks and feedback loops. Thus, dysregulations of multiple signaling pathways usually join forces to drive oncogenesis, tumor progression, invasion, metastasis, and drug resistance, thereby providing a basis for so-called "bypass" mechanisms underlying non-genetic resistance in response to targeted agents. In this context, simultaneous interruption of two or more related targets or pathways (an approach called dual-targeted therapy, DTT), via either linear or parallel inhibition, is required to deal with such a form of drug resistance to targeted agents that specifically inhibit a single oncoprotein or oncogenic pathway. Together, while most types of tumor cells are often addicted to two or more targets or pathways or can switch their dependency between them, DTT targeting either intrinsically activated or drug-induced compensatory targets/pathways would efficiently overcome drug resistance caused by non-genetic events, with a great opportunity that those resistant cells might be particularly more vulnerable. In this review article, we discuss, with our experience, diverse mechanisms for non-genetic resistance to targeted agents and the rationales to circumvent them in the treatment of cancer, emphasizing hematologic malignancies.

Diverse Epigenetic Regulations of Macrophages in Atherosclerosis.

Emerging research on epigenetics has resulted in many novel discoveries in atherosclerosis (AS), an inflammaging-associated disease characterized by chronic inflammation primarily driven by macrophages. The bulk of evidence has demonstrated the central role of epigenetic machinery in macrophage polarization to pro- (M1-like) or anti-inflammatory (M2-like) phenotype. An increasing number of epigenetic alterations and their modifiers involved in reprogramming macrophages by regulating DNA methylation or histone modifications (e.g., methylation, acetylation, and recently lactylation) have been identified. They may act to determine or skew the direction of macrophage polarization in AS lesions, thereby representing a promising target. Here we describe the current understanding of the epigenetic machinery involving macrophage polarization, to shed light on chronic inflammation-driving onset and progression of inflammaging-associated diseases, using AS as a prototypic example, and discuss the challenge for developing effective therapies targeting the epigenetic modifiers against these diseases, particularly highlighting a potential strategy based on epigenetically-governed repolarization from M1-like to M2-like phenotype.

Decoding DNA methylation in epigenetics of multiple myeloma.

Dysregulation of DNA methylation in B cells has been observed during their neoplastic transformation and therefore closely associated with various B-cell malignancies including multiple myeloma (MM), a malignancy of terminally differentiated plasma cells. Emerging evidence has unveiled pronounced alterations in DNA methylation in MM, including both global and gene-specific changes that can affect genome stability and gene transcription. Moreover, dysregulated expression of DNA methylation-modifying enzymes has been related with myelomagenesis, disease progression, and poor prognosis. However, the functional roles of the epigenetic abnormalities involving DNA methylation in MM remain elusive. In this article, we review current understanding of the alterations in DNA methylome and DNA methylation modifiers in MM, particularly focusing on DNA methyltransferases (DNMTs) and tet methylcytosine dioxygenases (TETs). We also discuss how these DNA methylation modifiers may be regulated and function in MM cells, therefore providing a rationale for developing novel epigenetic therapies targeting DNA methylation in MM.

Comprehensive geriatric assessment in newly diagnosed older myeloma patients: a multicentre, prospective, non-interventional study.

BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.

The mechanisms and therapeutic targets of ferroptosis in cancer.

INTRODUCTION: Ferroptosis, a form of programmed cell death, is mediated primarily by lipid peroxidation via a unique iron-dependent process. The mechanisms of ferroptosis involve the metabolisms of amino acids, irons, and lipids, and the regulation of antioxidant systems. Evidence supports the roles of ferroptosis in cancer, while metabolic reprogramming (a hallmark of cancer) renders tumor cells highly vulnerable to ferroptosis and thus provides a rationale for ferroptosis-targeted therapy for cancer. AREA COVERED: This article examines the current understanding of the mechanisms and related signaling pathways involving ferroptosis; it focuses on novel targets in cancer and its treatment and drug resistance. The development of ferroptosis-targeted therapy, especially in combination with conventional or non-conventional therapies, are considered with dilemmas and key questions in this research area. EXPERT OPINION: An increasing number of potential targets and ferroptosis inducers (FINs) have been identified to treat cancer. However, no specific FIN has entered clinical trials thus far, likely due to poor efficacy and high toxicity in vivo. Thus, new FINs with high selectivity and bioavailability are required to target tumor cells more specifically and potently. Particularly, the combination of FINs with chemotherapy, radiotherapy, targeted therapy, and immunotherapy warrants clinical investigation in the future.

Targeting epigenetic modifiers to reprogramme macrophages in non-resolving inflammation-driven atherosclerosis.

Epigenomic and epigenetic research has been providing several new insights into a variety of diseases caused by non-resolving inflammation, including cardiovascular diseases. Atherosclerosis (AS) has long been recognized as a chronic inflammatory disease of the arterial walls, characterized by local persistent and stepwise accelerating inflammation without resolution, also known as uncontrolled inflammation. The pathogenesis of AS is driven primarily by highly plastic macrophages via their polarization to pro- or anti-inflammatory phenotypes as well as other novel subtypes recently identified by single-cell sequencing. Although emerging evidence has indicated the key role of the epigenetic machinery in the regulation of macrophage plasticity, the investigation of epigenetic alterations and modifiers in AS and related inflammation is still in its infancy. An increasing number of the epigenetic modifiers (e.g. TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) have been identified in epigenetic remodelling of macrophages through DNA methylation or histone modifications (e.g. methylation, acetylation, and recently lactylation) in inflammation. These or many unexplored modifiers function to determine or switch the direction of macrophage polarization via transcriptional reprogramming of gene expression and intracellular metabolic rewiring upon microenvironmental cues, thereby representing a promising target for anti-inflammatory therapy in AS. Here, we review up-to-date findings involving the epigenetic regulation of macrophages to shed light on the mechanism of uncontrolled inflammation during AS onset and progression. We also discuss current challenges for developing an effective and safe anti-AS therapy that targets the epigenetic modifiers and propose a potential anti-inflammatory strategy that repolarizes macrophages from pro- to anti-inflammatory phenotypes.

Erratum: Impact of microRNA-29b on nature killer cell in T-cell acute lymphoblastic leukemia.

[This corrects the article DOI: 10.3892/ol.2019.10559.].

Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation.

Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li-EVs) in comparison with EVs enriched from native MSCs. Indeed, Li-EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV-treated cells. Using a stroke mouse model, intravenous delivery of Li-EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV-treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li-EVs displayed significantly increased levels of miR-1906, which has been shown to be a new regulator of toll-like receptor 4 (TLR4) signaling. Li-EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase-2 expression, all of which culminated in reduced levels of poststroke cerebral inflammation. Conclusively, the present study demonstrates, for the first time, an enhanced therapeutic potential of Li-EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection and enhanced neurological recovery.

Lithium enhances post-stroke blood-brain barrier integrity, activates the MAPK/ERK1/2 pathway and alters immune cell migration in mice.

Lithium induces neuroprotection against cerebral ischemia, although the underlying mechanisms remain elusive. We have previously suggested a role for lithium in calcium regulation and (extra)cerebral vessel relaxation under non-ischemic conditions. Herein, we aimed to investigate whether or not lithium contributes to post-stroke stabilization of the blood-brain barrier (BBB) in mice. Using an oxygen-glucose-deprivation (OGD) model, we first analyzed the impact of lithium treatment on endothelial cells (EC) in vitro. Indeed, such treatment of EC exposed to OGD resulted in increased cell survival as well as in enhanced expression of tight junction proteins and P-glycoprotein. Additional in vivo studies demonstrated an increased stabilization of the BBB upon lithium treatment in stroke mice, as shown by a reduced Evans blue extravasation and an elevation of tight junction protein expression. Furthermore, stabilization of the BBB as a consequence of lithium treatment was associated with an inhibition of matrix metalloproteinase-9 activity, independent of calveolin-1 regulation. In line with this, flow cytometry analysis revealed that lithium treatment led to a decreased neutrophil invasion and an increased T cell extravasation from the blood compartment towards the brain parenchyma. We finally identified the pro-survival MAPK/ERK1/2 pathway as the key regulator of the impact of lithium on the BBB. In conclusion, we demonstrate for the first time that lithium is able to enhance post-stroke BBB integrity. Importantly, our work delivers novel insights into the exact mechanism of lithium-induced acute neuroprotection, providing critical information for future clinical trials involving lithium treatment in stroke patients.