Hydroxychloroquine enhances anticancer effect of DOX/folate-phytosterol-carboxymethyl cellulose nanoparticles in A549 lung cancer cells

Purpose: To study the in vitro anticancer effect of doxorubicin-loaded folate-phytosterol-carboxymethyl cellulose nanoparticles (DOX/FPCMC NPs), alone and in combination with the antimalarial drug hydroxychloroquine (HCQ) on human lung cancer cells (A549 cells). Methods: Human lung adenocarcinoma A549 cell line was treated with blank FPCMC NPs, HCQ, free DOX, DOX/FPCMC NPs, free DOX + HCQ or DOX/FPCMC NPs + HCQ. The concentrations of HCQ, DOX and FPCMC NPs varied within the ranges of 20-120 μmol/L, 2-12 mg/L and 50-500 mg/L, respectively. Cell viability and free folate competitive inhibition were determined using MTT assay. Cell proliferation and migration were investigated with wound healing assay, while confocal laser scanning microscopy (CLSM) was used to determine cellular uptake of drugs. Results: In all formulations, the DOX/FPCMC NPs + HCQ produced the highest cytotoxicity in A549 cells due to high cytotoxicity arising from folate-receptor-mediated endocytosis and HCQ-induced inhibition of autophagy. Free folate competitively inhibited the cytotoxicity of DOX/FPCMC NPs on A549 cells. Wound healing assay showed that A549 cells treated with DOX/FPCMC NPs + HCQ had the lowest cell levels of proliferation and migration capacity. The cellular uptake of DOX/FPCMC NPs by A549 cells was higher than that of free DOX. Conclusion: The combination of DOX/FPCMC NPs and HCQ produced the best antitumor effect and had a promising potential for reversal of MDR Keywords: Folate-phytosterol-carboxymethyl cellulose, Doxorubicin, Hydroxychloroquine, Anticancer, Lung cance

Sequential Star Formation in the filamentary structures of Planck Galactic cold clump G181.84+0.31

We present a multi-wavelength study of the Planck cold clump G181.84+0.31, which is located at the northern end of the extended filamentary structure S242. We have extracted 9 compact dense cores from the SCUBA-2 850 um map, and we have identified 18 young stellar objects (YSOs, 4 Class I and 14 Class II) based on their Spitzer, Wide-field Infrared Survey Explorer (WISE) and Two-Micron All-Sky Survey (2MASS) near- and mid-infrared colours. The dense cores and YSOs are mainly distributed along the filamentary structures of G181.84 and are well traced by HCO$^{+}$(1-0) and N$_{2}$H$^{+}$(1-0) spectral-line emission. We find signatures of sequential star formation activities in G181.84: dense cores and YSOs located in the northern and southern sub-structures are younger than those in the central region. We also detect global velocity gradients of about 0.8$\pm$0.05 km s$^{-1}$pc$^{-1}$ and 1.0$\pm$0.05 km s$^{-1}$pc$^{-1}$ along the northern and southern sub-structures, respectively, and local velocity gradients of 1.2$\pm$0.1 km s$^{-1}$pc$^{-1}$ in the central substructure. These results may be due to the fact that the global collapse of the extended filamentary structure S242 is driven by an edge effect, for which the filament edges collapse first and then further trigger star formation activities inward. We identify three substructures in G181.84 and estimate their critical masses per unit length, which are $\sim$ 101$\pm$15 M$_{\odot}$ pc$^{-1}$, 56$\pm$8 M$_{\odot}$ pc$^{-1}$ and 28$\pm$4 M$_{\odot}$ pc$^{-1}$, respectively. These values are all lower than the observed values ($\sim$ 200 M$_{\odot}$ pc$^{-1}$), suggesting that these sub-structures are gravitationally unstable.Comment: 20 pages, 17 figures, article, accepte

Male Populus cathayana than female shows higher photosynthesis and less cellular injury through ABA-induced manganese transporting inhibition under high manganese condition

High Mn poisoned male and female Populus cathayana. The toxicity could be alleviated by exogenous ABA application. Intriguingly, ABA granted higher resistance to males than to females under high Mn stress because ABA could induce more blocking of Mn translocation to leaf in males than in females. Abscisic acid (ABA) is involved in plants' adaptive responses to various environmental stresses. However, little is known about the sex-related detoxification of ABA in plants under excess manganese (Mn) conditions. To reveal potentially different ABA detoxification mechanisms between Populus cathayana males and females against excess Mn exposure, photosynthesis performance, Mn2+ concentrations and morphologic changes were investigated. High Mn stress led to a more severe chloroplast destruction and, thus, greater reduction in the photosynthesis of P. cathayana females when compared to males. Under high Mn conditions, Mn reallocated mainly to leaves in females, while in males, it was distributed equally to roots and leaves. With the application of ABA, photosynthesis was restored more in males and more integrated grana in males than in females. It should be noted that Mn concentrations in males were lower in leaves and higher in roots and stems than those in females when treated with the combination of Mn and ABA. Conclusively, due to the reduction of root-shoot Mn transportation induced by ABA in P. cathayana males, males experienced less physiological injuries than do females, which suggest that males possess greater ABA-inducible resistance to Mn stress than do females.Peer reviewe

Edge collapse and subsequent longitudinal accretion in Filament S242

Filament S242 is 25 pc long with massive clumps and YSO clusters concentrated in its end regions; it is considered a good example of edge collapse. We mapped this filament in the $^{12}$CO(1-0) and $^{13}$CO(1-0) lines. A large-scale velocity gradient along filament S242 has been detected; the relative velocity between the two end-clumps is $\sim$ 3 km s$^{-1}$, indicating an approaching motion between them. These signatures are consistent with the filament S242 being formed through the collapse of a single elongated entity, where an effect known as "gravitational focusing" drives the ends of the filament to collapse (edge collapse). Based on this picture, we estimate a collapse timescale of $\sim$ 4.2 Myr, which is the time needed for a finite and elongated entity evolving to the observed filament S242. For the whole filament, we find that increases in surface densities lead to increases in velocity dispersion, which can be consistently explained as the result of self-gravity. We also calculated the contribution of longitudinal collapse to the observed velocity dispersion and found it to be the dominant effect in driving the gas motion near the end-clumps. We propose that our filament S242 is formed through a two-stage collapse model, where the edge collapse of a truncated filament is followed by a stage of longitudinal accretion toward the dense end-clumps.Comment: 14 pages, 11 figures; Accepted for publication in A&

Salvage CD20-SD-CART therapy in aggressive B-cell lymphoma after CD19 CART treatment failure

Background and aimsPatients with relapsed/refractory aggressive B-cell lymphoma(r/r aBCL)who progressed after CD19-specific chimeric antigen receptor T-cell therapy (CD19CART) had a poor prognosis. Application of CAR T-cells targeting a second different antigen (CD20) expressed on the surface of B-cell lymphoma as subsequent anti-cancer salvage therapy (CD20-SD-CART) is also an option. This study aimed to evaluate the survival outcome of CD20-SD-CART as a salvage therapy for CD19 CART treatment failure.MethodsThis retrospective cohort study enrolled patients with aBCL after the failure of CD19 CART treatment at Beijing Gobroad Boren Hospital from December 2019 to May 2022. Patients were subsequently treated with CD20CART therapy or non-CART therapy (polatuzumab or non-polatuzumab).ResultsA total of 93 patients were included in the study, with 54 patients receiving CD20-SD-CART therapy. After a median follow-up of 18.54 months, the CD20-SD-CART group demonstrated significantly longer median progression-free survival (4.04 months vs. 2.27 months, p=0.0032) and median overall survival (8.15 months vs. 3.02 months, p<0.0001) compared to the non-CART group. The complete response rate in the CD20-SD-CART group (15/54, 27.8%) was also significantly higher than the non-CART group (3/38, 7.9%, p=0.03). Multivariate analysis further confirmed that CD20CART treatment was independently associated with improved overall survival (HR, 0.28; 95% CI, 0.16–0.51; p<0.0001) and progression-free survival (HR, 0.46; 95% CI, 0.27–0.8; p=0.005).ConclusionCD20-SD-CART could serve as an effective therapeutic option for patients with relapsed or refractory aggressive B-cell lymphoma after CD19CART treatment failure

Interferon-α Regulates Glutaminase 1 Promoter through STAT1 Phosphorylation: Relevance to HIV-1 Associated Neurocognitive Disorders

HIV-1 associated neurocognitive disorders (HAND) develop during progressive HIV-1 infection and affect up to 50% of infected individuals. Activated microglia and macrophages are critical cell populations that are involved in the pathogenesis of HAND, which is specifically related to the production and release of various soluble neurotoxic factors including glutamate. In the central nervous system (CNS), glutamate is typically derived from glutamine by mitochondrial enzyme glutaminase. Our previous study has shown that glutaminase is upregulated in HIV-1 infected monocyte-derived-macrophages (MDM) and microglia. However, how HIV-1 leads to glutaminase upregulation, or how glutaminase expression is regulated in general, remains unclear. In this study, using a dual-luciferase reporter assay system, we demonstrated that interferon (IFN) α specifically activated the glutaminase 1 (GLS1) promoter. Furthermore, IFN-α treatment increased signal transducer and activator of transcription 1 (STAT1) phosphorylation and glutaminase mRNA and protein levels. IFN-α stimulation of GLS1 promoter activity correlated to STAT1 phosphorylation and was reduced by fludarabine, a chemical that inhibits STAT1 phosphorylation. Interestingly, STAT1 was found to directly bind to the GLS1 promoter in MDM, an effect that was dependent on STAT1 phosphorylation and significantly enhanced by IFN-α treatment. More importantly, HIV-1 infection increased STAT1 phosphorylation and STAT1 binding to the GLS1 promoter, which was associated with increased glutamate levels. The clinical relevance of these findings was further corroborated with investigation of post-mortem brain tissues. The glutaminase C (GAC, one isoform of GLS1) mRNA levels in HIV associated-dementia (HAD) individuals correlate with STAT1 (p<0.01), IFN-α (p<0.05) and IFN-β (p<0.01). Together, these data indicate that both HIV-1 infection and IFN-α treatment increase glutaminase expression through STAT1 phosphorylation and by binding to the GLS1 promoter. Since glutaminase is a potential component of elevated glutamate production during the pathogenesis of HAND, our data will help to identify additional therapeutic targets for the treatment of HAND

The TOP-SCOPE Survey of Planck Galactic Cold Clumps : Survey Overview and Results of an Exemplar Source, PGCC G26.53+0.17

The low dust temperatures (<14 K) of Planck Galactic cold clumps (PGCCs) make them ideal targets to probe the initial conditions and very early phase of star formation. "TOP-SCOPE" is a joint survey program targeting similar to 2000 PGCCs in J = 1-0 transitions of CO isotopologues and similar to 1000 PGCCs in 850 mu m continuum emission. The objective of the "TOP-SCOPE" survey and the joint surveys (SMT 10 m, KVN 21 m, and NRO 45 m) is to statistically study the initial conditions occurring during star formation and the evolution of molecular clouds, across a wide range of environments. The observations, data analysis, and example science cases for these surveys are introduced with an exemplar source, PGCC G26.53+0.17 (G26), which is a filamentary infrared dark cloud (IRDC). The total mass, length, and mean line mass (M/L) of the G26 filament are similar to 6200 M-circle dot, similar to 12 pc, and similar to 500 M-circle dot pc(-1), respectively. Ten massive clumps, including eight starless ones, are found along the filament. The most massive clump as a whole may still be in global collapse, while its denser part seems to be undergoing expansion owing to outflow feedback. The fragmentation in the G26 filament from cloud scale to clump scale is in agreement with gravitational fragmentation of an isothermal, nonmagnetized, and turbulent supported cylinder. A bimodal behavior in dust emissivity spectral index (beta) distribution is found in G26, suggesting grain growth along the filament. The G26 filament may be formed owing to large-scale compression flows evidenced by the temperature and velocity gradients across its natal cloud.Peer reviewe