Progress in construction of mouse models to investigate the pathogenesis and immune therapy of human hematological malignancy.

Hematological malignancy is a disease arisen by complicate reasons that seriously endangers human health. The research on its pathogenesis and therapies depends on the usage of animal models. Conventional animal model cannot faithfully mirror some characteristics of human features due to the evolutionary divergence, whereas the mouse models hosting human hematological malignancy are more and more applied in basic as well as translational investigations in recent years. According to the construction methods, they can be divided into different types (e.g. cell-derived xenograft (CDX) and patient-derived xenograft model (PDX) model) that have diverse characteristics and application values. In addition, a variety of strategies have been developed to improve human hematological malignant cell engraftment and differentiation in vivo. Moreover, the humanized mouse model with both functional human immune system and autologous human hematological malignancy provides a unique tool for the evaluation of the efficacy of novel immunotherapeutic drugs/approaches. Herein, we first review the evolution of the mouse model of human hematological malignancy; Then, we analyze the characteristics of different types of models and summarize the ways to improve the models; Finally, the way and value of humanized mouse model of human immune system in the immunotherapy of human hematological malignancy are discussed.

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration.

Age-related macular degeneration, Stargardt disease, and their Abca4-/- mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O2•-) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O2•- or nitric oxide (•NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O2•- plus •NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed "chemiexcitation"), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.

Human growth hormone supplement promotes human lymphohematopoietic cell reconstitution in immunodeficient mice.

Aim: To investigate the potential of human growth hormone (hGH) to improve human hematopoietic reconstitution in humanized mice. Materials & methods: Immunodeficient mice were conditioned by total body irradiation and transplanted with human CD34+ fetal liver cells. Peripheral blood, spleen and bone marrow were harvested, and levels of human lymphohematopoietic cells were determined by flow cytometry. Results: Supplementation with hGH elevated human lymphohematopoietic chimerism by more than twofold. Treatment with hGH resulted in significantly increased reconstitution of human B cells and myeloid cells in lymphoid organs, enhanced human erythropoiesis in the bone morrow, and improved engraftment of human hematopoietic stem cells. Conclusion: hGH supplementation promotes human lymphohematopoietic reconstitution in humanized mice.

Humanized mice generated by human hematopoietic stem cell transplantation play crucial roles in biomedical investigations. One of the factors hindering the efficacy of their construction is the lack of or insufficient interaction of human cells to mouse cytokines and growth hormones (GHs) that are crucial for hematopoiesis and immune cell differentiation. In this study, we show that injection of human GH significantly improved human hematopoietic stem cell engraftment and function, as well as immune cell reconstitution in humanized mice. Our findings indicate that human cells may not efficiently respond to mouse GH, and generation of immunodeficient mice producing human GH may improve the efficacy of humanized mouse construction.

Quantitative analysis of retinal intermediate and deep capillary plexus in patients with retinal deep vascular complex ischemia.

AIM: To quantitatively analyze the retinal intermediate and deep capillary plexus (ICP and DCP) in patients with retinal deep vascular complex ischemia (RDVCI), using 3D projection artifacts removal (3D PAR) optical coherence tomography angiography (OCTA). METHODS: RDVCI patients and gender- and age-matched healthy controls were assessed and underwent OCTA examinations. The parafoveal vessel density (PFVD) of retinal deep vascular complex (DVC), ICP, and DCP were analyzed, and the percentage of reduction (PR) of PFVD was calculated. RESULTS: Twenty-four eyes in 22 RDVCI patients (20 in acute phase and 4 in chronic phase) and 24 eyes of 22 healthy subjects were enrolled as the control group. Significant reduction of PFVD in DVC, ICP, and DCP was observed in comparison with the controls (DVC: acute: 43.59%±6.58% vs 49.92%±5.49%, PR=12.69%; chronic: 43.50%±3.33% vs 51.20%±3.80%, PR=15.04%. ICP: acute: 40.28%±7.91% vs 46.97%±7.14%, PR=14.23%; chronic: 41.48%±2.87% vs 46.43%±3.29%, PR=10.66%. DCP: acute: 45.44%±8.27% vs 51.51%±9.97%, PR=11.79%; chronic: 37.78%±3.48% vs 51.73%±5.17%, PR=26.97%; all P<0.05). No significant PR difference was found among DVC, ICP, and DCP of RDVCI in acute phase (P=0.812), but significant difference in chronic phase (P=0.006, DVC vs DCP, ICP vs DCP). No significant difference in PR between acute and chronic phases in the DVC (P=0.735) or ICP (P=0.681) was found, but significant difference in the DCP (P=0.041). CONCLUSION: The PFVD of DVC, ICP, and DCP in RDVCI is significantly decreased in both acute and chronic phases. ICP impairment is stabilized from acute to chronic phase in RDVCI, whereas subsequent DCP impairment is uncovered and can be explained by ischemia-reperfusion damage.

Humanized Rodent Models for Cancer Research.

As one of the most popular laboratory animal models, rodents have been playing crucial roles in mechanistic investigations of oncogenesis as well as anticancer drug or regimen discoveries. However, rodent tumors show different or no responses to therapies against human cancers, and thus, in recent years, increased attention has been given to mouse models with xenografted or spontaneous human cancer cells. By combining with the human immune system (HIS) mice, these models have become more sophisticated and robust, enabling in vivo exploration of human cancer immunology and immunotherapy. In this review, we summarize the pros and cons of these humanized mouse models, with a focus on their potential as an in vivo platform for human cancer research. We also discuss the strategies for further improving these models.

Multimodal Imaging in Fibrinous Central Serous Chorioretinopathy Compared with Exudative Maculopathy.

AIMS: To analyze ocular fundus characteristics of patients finally diagnosed with fibrinous central serous chorioretinopathy (CSC) using multimodal imaging and compare the characteristics with images of other confusable exudative maculopathies. METHODS: We retrospectively reviewed the records from 189 patients with CSC and found records on 16 patients with fibrinous CSC. Some of these 16 patients were misdiagnosed with another exudative maculopathy and were treated inappropriately. Multimodal imaging comprised fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), indocyanine green angiography (ICGA), and OCT angiography (OCTA), and the results were compared with those of other exudative maculopathy patients from this study. RESULTS: Twenty-one eyes of 16 patients with a mean age of 45.44 ± 10.66 years were included in the study. The mean central choroidal thickness was 401.6 ± 47.6 µm. Eight of the 16 patients with fibrinous CSC had initially been misdiagnosed (such as with uveitis or exudative retinal detachment). On fundoscopy, a typical dark spot was seen in 19 eyes, surrounded by yellow-white exudate, corresponding to the site of leakage on FA. A hyporeflective oval-shaped vacuole-like area was observed in 14 patients. All patients showed FA signs of dye leakage and dilated choroidal vessels on ICGA. Among the patients misdiagnosed with choroidal neovascularization (CNV), OCTA showed a legible branching vessel and no signs of a blood flow signal breaking Bruch's membrane. CONCLUSIONS: A dark spot on fundus photography images and a hyporeflective vacuole on OCT are important clinical signs that can help avoid misdiagnosing fibrinous CSC. With some small confusing lesions suspected as CNV or chronic CSC in elderly patients, OCTA may help in their identification. FA/ICGA still helps to show dye leakage sites and typical dilated choroidal vessels in fibrinous CSC, similar to other common CSCs. Multimodal imaging is mandatory in order to establish an appropriate diagnosis.

Upregulation of SLAMF3 on human T cells is induced by palmitic acid through the STAT5-PI3K/Akt pathway and features the chronic inflammatory profiles of type 2 diabetes.

Metabolic stress-induced low-grade chronic inflammation plays an important role in the development of insulin-resistance and type 2 diabetes (T2D). Emerging evidence highlights the importance of directly elucidating T-cell activation under the obesity-induced metabolic stress condition, as T cells primed under such conditions were found to acquire a unique phenotype and function. Herein, we found a significant upregulation of signaling lymphocytic activation molecule family member 3 (SLAMF3) expression on T cells from T2D patients compared to those of healthy controls. Importantly, SLAMF3 upregulation was associated with an increased ability to produce proinflammatory cytokines. Significantly increased SLAMF3 expression was seen in T2D patient T cells that produce IFN-γ or IL-17 upon short (4-h) stimulation, compared to non-cytokine-producing T cells. In line with this finding, SLAMF3high T cells were significantly more sensitive than SLAMF3low T cells to TCR stimulation with anti-CD3/CD28 antibodies. Furthermore, treatment with palmitic acid (PA) led to significant upregulation of SLAMF3 on human T cells primed by anti-CD3/CD28 antibodies and on Jurkat cells, a human T-cell line. RNA sequencing revealed strong activation of the PI3K/Akt signaling pathway in T cells that were primed with PA. Further mechanistic studies showed that inhibition of PI3K/Akt signaling, or its upstream mediator STAT5 can prevent PA-induced SLAMF3 upregulation on T cells. These results indicate that SLAMF3 upregulation is associated with T-cell activation and cytokine production in T2D patients, and suggest that elevated saturated fatty acids in T2D patients may induce SLAMF3 upregulation on T cells via activation of the STAT5-PI3K/Akt signaling pathway.

Discovery of a new species of Inocelliidae (Insecta: Raphidioptera) in an altitude of nearly 3500 m in China.

A new snakefly species of the family Inocelliidae is described from China: Inocellia occidentalis sp. nov. The new species belongs to the Inocellia crassicornis species group.

New species of the snakefly genus Mongoloraphidia (Raphidioptera: Raphidiidae) from China.

Two new snakefly species of the family Raphidiidae are described from China: Mongoloraphidia lini sp. nov. and Mongoloraphidia triangulata sp. nov. Biogeographical considerations on secondary refugial centers of the large Sino-Tibetan primary center are presented.