Robust CAR-T memory formation and function via hematopoietic stem cell delivery

Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.     

Dual emission of Ce3+,Mn2+‐coactivated Ca3YNa(PO4)3F via energy transfer: a single component white/yellow‐emitting phosphor

A series of Ce³⁺,Mn²⁺‐coactivated Ca₃YNa(PO₄)₃F phosphors were synthesized via a traditional solid‐state reaction under a reductive atmosphere. X‐Ray powder diffraction was used to confirm that the crystal structure and diffraction peaks of Ce³⁺/Mn²⁺‐doped samples matched well with the standard data. A spectral overlap between the emission band of Ce³⁺ and the excitation band of Mn²⁺ suggested the occurrence of energy transfer from Ce³⁺ to Mn²⁺. With increasing Mn²⁺ content, the emission intensities and lifetime values of the Ce³⁺ emission for Ca₃YNa(PO₄)₃F:Ce³⁺,Mn²⁺ phosphors linearly decrease, whereas the energy transfer efficiencies gradually increase to 89.35%. By adjusting the relative concentrations of Ce³⁺ and Mn²⁺, the emission hues are tuned from blue to white and eventually to yellow. These results suggest that Ca₃YNa(PO₄)₃F:Ce³⁺,Mn²⁺ phosphors have promising application as white‐emitting phosphors for near‐ultraviolet light‐emitting diodes.     

Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes

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Focal Adhesion Kinase Knockdown in Carcinoma‐Associated Fibroblasts Inhibits Oral Squamous Cell Carcinoma Metastasis via Downregulating MCP‐1/CCL2 Expression

Carcinoma‐associated fibroblasts (CAFs) have been demonstrated to play an important role in the occurrence and development of oral squamous cell carcinoma (OSCC). The aim of this study is to investigate the influence of CAFs on OSCC cells and to explore the role of focal adhesion kinase (FAK) in this process. The results showed that oral CAFs expressed a higher level of FAK than normal human gingival fibroblasts (HGFs), and the conditioned medium (CM) of CAFs could induce the invasion and migration of SCC‐25, one oral squamous carcinoma cell line. However, knockdown of FAK by small interfering RNA (siRNA) resulted in inhibition of CAF–CM induced cell invasion and migration in SCC‐25, probably by reducing the production of monocyte chemoattractant protein‐1 (MCP‐1/CCL2), one of downstream target chemokines. Therefore, our findings indicated that targeting FAK in CAFs might be a promising strategy for the treatment of OSCC in the future.     

Downregulation of Microrna‐148a in Cancer‐Associated Fibroblasts from Oral Cancer Promotes Cancer Cell Migration and Invasion by Targeting Wnt10b

It is well established that crosstalk between cancer‐associated fibroblasts (CAFs) and cancer cells plays a critical role in the occurrence and development of oral squamous cell carcinoma (OSCC). The molecular mechanisms underlying such interaction, however, remain far from clear. Accumulating data have indicated that microRNAs involved in tumor microenvironment, particularly in CAFs, contribute to the activation of fibroblasts and metastasis of cancer cells. Here, we showed that miR‐148a was downregulated in CAFs compared with normal fibroblasts isolated from clinical OSCC tissue. Investigation of miR‐148a function in fibroblasts demonstrated that overexpression of miR‐148a in CAFs significantly impaired the migration and invasion of oral carcinoma cells (SCC‐25) by directly targeting WNT10B. Taken together, these data suggested that miR‐148a might be a novel candidate target for the treatment of OSCC.     

玫瑰花渣成份研究初探

本文研究了玫瑰花渣的有效成份,测定了其葡萄糖、淀粉、微量元素、各种氨基酸的含量;发现玫瑰花渣中不含有任何有害的元素,其中含葡萄糖18.33—23.66％,含淀粉21.75—22.63％,且含有丰富的各种氨基酸,其氨基酸总量高达10.9％,比玉米或麸皮中氨基酸总和都高。结果证明:玫瑰花渣有充分的利用价值。