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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Also, there were no significant differences between patients with either 2-5% or 5-20% CPCs and those with >= 20% CPCs in PFS and OS ( I P i > 0.05). Compared to patients with < 2% CPCs, median PFS and OS of patients with 2-20% CPCs were 11.2 months (vs 18.8 months, I P i = 0.0001; Fig. [Extracted from the article]

An efficient and practical approach for the synthesis of triaryl allenyl sulfones from easily accessible propargylic alcohols was developed, by using sodium sulfinates as a sulfonyl source in the presence of Brønsted acid. The reaction proceeded via allenyl carbocation as the key intermediate and was followed by a nucleophilic attack of sodium sulfinates to produce allenyl sulfones in moderate to excellent yields. [ABSTRACT FROM AUTHOR]

A practical and environmentally friendly approach is presented for the efficient construction of propargyl organothiophosphates and allenyl organothiophosphates from easily prepared secondary propargylic alcohols and O, O‐diethyl phosphorothioic acid [(EtO)2P(O)SH]. The reaction proceeds smoothly in moderate to excellent yields without additional acid promoters or additives under mild conditions with water as the only by‐product. The divergent products are selectively obtained depending on substrates bearing different substituents on the aromatic ring. Notably, the developed reaction system can be scaled up to gram quantities. [ABSTRACT FROM AUTHOR]

Dear Editor, Leukoencephalopathy is a term given to any disorder that affects the white matter in the CNS [[1]]. On August 19, the brain MRI revealed patchy T2/fluid-attenuated inversion recovery (FLAIR) hyperintense signal in bilateral frontal and parietal white matter, centrum semiovale, and corona radiate (Fig. Whereas daratumumab-associated AEs involving CNS are relatively rare (e.g., only one case of progressive multifocal leukoencephalopathy reported thus far in the trials involving daratumumab) [[2]], DRL has been reported in at least three cases [[3]], showing DRL as a late AE after long-term use of daratumumab (Supplemental Table S1). [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Natural killer (NK)-based immunotherapeutic strategies are showing promise in the clinic, particularly against acute myeloid leukemia (AML). Similar treatments for T-cell acute lymphoblastic leukemia (T-ALL) have been less successful, which is due to the higher resistance of T-ALL blasts to the cytotoxic function of NK cells. Herein, microRNA-29b (miR-29b) upregulation was identified in NK cells in both neurogenic locus notch homolog protein 1 (Notch1)-T-ALL mice and patients with T-ALL. Furthermore, miR-29b expression levels were downregulated in T-ALL blast cells. In addition, there was a selective downregulation of an immature subset of NK cells, as well as a reduction in interferon γ (IFNγ) production and natural killer receptor group 2, member D (NKG2D) expression level by NK cells in Notch1-T-ALL mice and patients with T-ALL. Furthermore, when miR-29b knock-out NK cells were adoptively transfused into Notch1-T-ALL mice, partial restoration of IFNγ production and NKG2D expression was observed in NK cells, accompanied by retarded ALL progression and improved survival time. These results implied that T-ALL blast immune evasion occurred via miR-29b-mediated dysregulation in NK cells in the T-ALL microenvironment. [ABSTRACT FROM AUTHOR]

para‐TsOH‐promoted cascade reaction of easily prepared ortho‐propynol phenyl azides for the synthesis of 4‐methoxy quinolines has been developed. This reaction proceeded in a new way to generate 4‐methoxy quinolines through a concerted nucleophilic mechanism of propargyl methyl ether. It is worth noting that propargyl methyl ether can be successfully transformed into 4‐methoxy quinolines only when substrates contain a strong electron‐donating group (OR). Let's cycle to quinoline! para‐TsOH‐promoted cascade reaction of easily prepared ortho‐propynol phenyl azides for the synthesis of 4‐methoxy quinolines has been developed. This reaction proceeded in a new way to generate 4‐methoxy quinolines through a concerted nucleophilic mechanism of propargyl methyl ether. It is worth noting that propargyl methyl ether can be successfully transformed into 4‐methoxy quinolines only when substrates contain a strong electron‐donating group. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • p -TsOH promoted synthesis of 4-tosyloxy-2 H -chromenes in moderate to excellent yields. • p -TsOH acts not only as a promoter in this reaction, and also as the sulfonate source. • The 4-tosyloxy-2 H -chromenes are versatile intermediates in organic synthesis. • This method can be enlarged to gram scale. Abstract A novel and efficient p -TsOH-promoted cascade cyclization of 2-propynolphenols is developed to give 4-tosyloxy-2 H -chromenes in moderate to efficient yields. It is noted that p -TsOH acts not only as a promoter in this reaction, and also as the sulfonate source. Importantly, the obtained 4-tosyloxy-2 H -chromenes can be used as versatile intermediates for the synthesis of various functionalized compounds through diverse metal-catalyzed cross-coupling reactions. Moreover, this method can be enlarged to gram scale. [ABSTRACT FROM AUTHOR]

Ischemic conditioning is defined as a transient and subcritical period of ischemia integrated in an experimental paradigm that involves a stimulus of injurious ischemia, activating endogenous tissue repair mechanisms that lead to cellular protection under pathological conditions like stroke. Whereas ischemic pre-conditioning is irrelevant for stroke treatment, ischemic post-conditioning, and especially non-invasive remote ischemic post-conditioning (rPostC) is an innovative and potential strategy for stroke treatment. Although rPostC has been shown to induce neuroprotection in stroke models before, resulting in some clinical trials on the way, fundamental questions with regard to its therapeutic time frame and its underlying mechanisms remain elusive. Hence, we herein used a model of non-invasive rPostC of hind limbs after cerebral ischemia in male C57BL6 mice, studying the optimal timing for the application of rPostC and its underlying mechanisms for up to 3 months. Mice undergoing rPostC underwent three different paradigms, starting with the first cycle of rPostC 12 h, 24 h, or 5 days after stroke induction, which is a very delayed time point of rPostC that has not been studied elsewhere. rPostC as applied within 24 h post-stroke induces reduction of infarct volume on day three. On the contrary, very delayed rPostC does not yield reduction of infarct volume on day seven when first applied on day five, albeit long-term brain injury is significantly reduced. Likewise, very delayed rPostC yields sustained neurological recovery, whereas early rPostC (i.e., <24 h) results in transient neuroprotection only. The latter is mediated via heat shock protein 70 that is a well-known signaling protein involved in the pathophysiological cellular cascade of cerebral ischemia, leading to decreased proteasomal activity and decreased post-stroke inflammation. Very delayed rPostC on day five, however, induces a pleiotropic effect, among which a stimulation of angioneurogenesis, a modulation of the ischemic extracellular milieu, and a reversal of the stroke-induced immunosuppression occur. As such, very delayed rPostC appears to be an attractive tool for future adjuvant stroke treatment that deserves further preclinical attention before large clinical trials are in order, which so far have predominantly focused on early rPostC only. [ABSTRACT FROM AUTHOR]

Autophagy plays an important role in multiple myeloma (MM) for homeostasis, survival and drug resistance, but which genes participate in this process is unclear. We identified several cytoskeleton genes upregulated in MM patients by gene expression profiling (GEP) datasets; in particular, patients with high profilin 1 (PFN1) expression had poor prognosis in MM. In vitro, overexpressed PFN1 promotes proliferation and bortezomib (BTZ) resistance in MM cells. Further study indicated overexpression of PFN1 significantly promoted the process of autophagy and induced BTZ resistance in MM. Otherwise, knockdown of PFN1 blocked autophagy and sensitized MM to BTZ. Co‐immunoprecipitation in MM cells indicated that PFN1 could bind Beclin1 complex and promote the initiation of autophagy. Inhibition of autophagy by blocking the formation of Beclin1 complex could reverse the phenotype of BTZ resistance in MM. Our findings suggested that PFN1 could promote autophagy through taking part in Beclin1 complex and contribute to BTZ resistance, which may become a novel molecular target in the therapy of MM. [ABSTRACT FROM AUTHOR]

Abstract: 1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM. [ABSTRACT FROM AUTHOR]

Three water-stable isostructural metal–organic frameworks (MOFs) of the general formula [M2(TCS)(BPY)] (M = Co(1), Ni(2) and Cu(3); H4TCS = tetrakis(4-carboxyphenyl) silane, BPY = 4,4′-bipyridine) were synthesized and fully characterized. MOFs 1–3 are stable in pH = 5–11, 2–11, 3–11 aqueous solution respectively for at least 24 h at room temperature. Although H4TCS absorbs only UV light, MOFs 1–3 absorb both UV and visible light in broad ranges (250–800 nm) and absorb more visible light than the ligand BPY. The rapid anodic photocurrent responses of MOFs 1–3 under UV and visible light illumination were observed. The photocurrent densities increase in the order of MOF 3 ＜ 1 ＜ 2 under visible light illumination (430 nm). The band gaps of MOFs 1–3 determined based on UV-Vis diffuse reflectance spectra and electrochemical (EC) analysis are 1.28, 1.35 and 0.67 eV, respectively. MOF 1 is able to photocatalyze the reduction of CO2 to CH4 under visible light, producing CH4 (1.44 μmol g−1 in 8 h), which is unprecedented in MOFs. The catalytic activity of MOF 1 (0.75 μmol g−1 after 4 h) under the irradiation of a 300 W xenon lamp is significantly better than those of MOFs 2 and 3 (0.14 μmol g−1 after 4 h). The band structures, density of states and band gaps of MOFs 1–3 were calculated by the GGA-PBE and GGA-PBE+U method implemented in VASP code. The calculations show that all the three compounds can be viewed as bulk intermediate band (IB) materials. The density of states of the IB in MOF 1 is high, which could suppress the non-radiative recombination. The density of states of the IB levels in MOFs 2 and 3 are low, making these levels very effective recombination centres, thus jeopardizing the photocatalytic activities of MOFs 2 and 3. The calculated results are in good agreement with experimental results and explain the photocatalytic activity differences. This study is the first to successfully address the question of how the types of unpaired electron containing electron-rich metal ions (i.e. Cu(ii), Co(ii), Ni(ii)) affect the band gaps and band structures of MOFs and thus their photoelectronic properties. [ABSTRACT FROM AUTHOR]

Based on the ligands tetrakis(4-carboxyphenyl)silane (TCS) and 4,4′-bipy, a novel 3D doubly interpenetrated Zn(ii)-paddlewheel metal–organic framework Zn2TCS(4,4′-bipy) (1) was synthesized via facile conversion of its non-interpenetrated isomer (2) upon solvent removal at ambient temperature. It exhibits high CO2 and CH4 adsorption capacities and exceptional water stability. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between total homocysteine (tHcy) and carotid intima-media thickness (CIMT) in brain infarction patients. Methods Sixty patients with fasting plasma tHcy levels ≤10 µmol/L (non-Hhcy group), 60 patients with fasting plasma tHcy levels >10 µmol/L and ≤15 µmol/L (H1 group), and 60 patients with fasting plasma tHcy levels >15 µmol/L (H2 group) were chosen in hospitalized patients with acute cerebral infarction. Values of CIMT were detected in three groups of patients. The clinical biochemical indicators including triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood sugar (FBS), folic acid (FA), Vitamin B12 (VitB12) and glycated hemoglobin (HbA1c) were also detected. Results There was significant difference in CIMT between three groups (P<0.01). The value of CIMT increased in H2 group [0.98(0.90, 1.05)mm] compared with that of non-Hhcy group [0.85(0.80, 0.95)mm]. The value of CIMT increased in H2 group compared with H1 group [0.98(0.90, 1.05)mm vs 0.85(0.85, 0.95)mm], P < 0.05). There were significant differences in tHcy, FA and VitB12 between three groups. Based on the log-transformed values of CIMT as the dependent variable, multiple stepwise linear regression showed significant associations of the following variables with increased CIMT: increasing age, the history of smoking, the history of diabetes, higher LDL-C and tHcy levels. Conclusion Brain infarction in patients with higher tHcy level often have lower levels of FA and VitB12, and increased CIMT. When the level of tHcy >15 µmol/L, there is more significantly higher level of CIMT. The increased CIMT level was associated with some cerebrovascular risk factors in patients with brain infarction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oncol Lett 18: 2394-2403, 2019; DOI: 10.3892/ol.2019.10559 Following the publication of this article, the authors have realized that a couple of errors went unnoticed in the text. These are explained as follows (changes to the printed text are highlighted in bold): In the "Statistical analysis" section, on p. 2396, the 7 SP th sp line, it was incorrectly stated that the RT-qPCR data were analyzed using SPSS 12.0 (SPSS, Inc.); in fact, Prism 5 (GraphPad Software, Inc.) was also used for the statistical treatment of these data. Therefore, the sentence here in its entirety should have read as: "The flow cytometry results were analyzed using FlowJo 10.0.7 software (FlowJo LLC), and the RT-qPCR data was analyzed using B Prism 5 (GraphPad Software, Inc.) b " This error does not affect the results in any way. [Extracted from the article]

Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs smoothly to generate desired products in moderate to excellent yields with good functional groups compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines. [ABSTRACT FROM AUTHOR]

Evaluation of microvascular networks was impeded until recently by the need of histological tissue sectioning, which precluded 3D analyses. Using light-sheet microscopy, we investigated microvascular network characteristics in the peri-infarct cortex of mice 3–56 days after transient middle cerebral artery occlusion. In animal subgroups, the sphingosine-1-phosphate analog FTY720 (Fingolimod) was administered starting 24 hours post-ischemia. Light-sheet microscopy revealed a striking pattern of microvascular changes in the peri-infarct cortex, that is, a loss of microvessels, which was most prominent after 7 days and followed by the reappearance of microvessels over 56 days which revealed an increased branching point density and shortened branches. Using a novel AI-based image analysis algorithm we found that the length density of microvessels expressing the arterial specification marker α-smooth muscle actin markedly increased in the peri-infarct cortex already at 7 days post-ischemia. The length and branch density of small microvessels, but not of intermediate or large microvessels increased above pre-ischemic levels within 14–56 days. FTY720 increased the length and branch density of small microvessels. This study demonstrates long-term alterations of microvascular architecture post-ischemia indicative of increased collateralization most notably of small microvessels. Light-sheet microscopy will greatly advance the assessment of microvascular responses to restorative stroke therapies. [ABSTRACT FROM AUTHOR]

• Catalyst- and additive-free synthesis of 2 H -chromen-4-yl phosphinates/phosphonates. • This reaction was achieved by cascade phosphorylation/cyclization of propargylic alcohols and R 2 P(O)OH. • This approach can be enlarged to gram scale. • R 2 P(O)OH acts not only as acid-promoter to initiate the reaction, and also as the phosphinate source. A novel, catalyst- and additive-free cascade phosphorylation/cyclization of readily available 2-propynolphenols with R 2 P(O)OH (R = aryl, OPh, OBn) was developed for the construction of 2 H -chromen-4-yl phosphinates/phosphonates and water as the only byproduct under mild conditions. The reaction was achieved by using R 2 P(O)OH as acid-promoter, but also as the phosphinate source with the formation of phosphorylation allene intermediate, and followed by 6- endo -trig pathway. Additionally, this approach avoided the use of hazardous, air sensitive or activation reagents, and performed well with good functional group tolerance and satisfied yields. [ABSTRACT FROM AUTHOR]

• TFA mediated synthesis of 4-thiocyanated 2 H -chromenes in good to excellent yields. • The 4-thiocyanated 2 H -chromenes are versatile intermediates in organic synthesis. • This approach can be enlarged to gram scale. • This process involves a SCN-containing alleneyl intermediate through S N 1 way. A metal-free, Brønsted acid-mediated cascade cyclization of 2-propynolphenols for efficient synthesis of various 4-thiocyanated 2 H -chromenes is developed by using KSCN as the thiocyanated source. This reaction was characterized by readily prepared starting materials, bearing good functional group tolerance and excellent yields. Moreover, the obtained 4-thiocyanated 2 H -chromenes could be further derivated to potential bioactive and pharmaceutical molecules. [ABSTRACT FROM AUTHOR]

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. Image 1 • Lithium prevents oxygen-glucose-deprived endothelial cells from tight junction loss. • Lithium stabilizes post-stroke blood-brain barrier via MAPK/ERK/pathway activation. • Lithium decreases activity and expression of MMP-9 independent of caveolin-1. • Lithium modulates post-stroke neutrophil and T cell extravasation via ICAM-1. [ABSTRACT FROM AUTHOR]