Artificial intelligence for disease diagnostics still has a long way to go.

Artificial intelligence (AI) can sometimes resolve difficulties that other advanced technologies and humans cannot. In medical diagnostics, AI has the advantage of processing figure recognition, especially for images with similar characteristics that are difficult to distinguish with the naked eye. However, the mechanisms of this advanced technique should be well-addressed to elucidate clinical issues. In this letter, regarding an original study presented by Takayama et al, we suggest that the authors should effectively illustrate the mechanism and detailed procedure that artificial intelligence techniques processing the acquired images, including the recognition of non-obvious difference between the normal parts and pathological ones, which were impossible to be distinguished by naked eyes, such as the basic constitutional elements of pixels and grayscale, special molecules or even some metal ions which involved into the diseases occurrence.

Future therapeutic implications of new molecular mechanism of colorectal cancer.

High incidence (10.2%) and mortality (9.2%) rates led to the ranking of colorectal cancer (CRC) as the second most malignant tumor spectrum worldwide in 2020. Treatment strategies are becoming highly dependent on the molecular characteristics of CRC. The classical theories accept two models depicting the origin of CRC: The progression of adenoma to cancer and transformation from serrated polyps to cancer. However, the molecular mechanism of CRC development is very complex. For instance, CRCs originating from laterally spreading tumors (LST) do not adhere to any of these models and exhibit extremely serious progression and poor outcomes. In this article, we present another possible pathway involved in CRC development, particularly from LST, with important molecular characteristics, which would facilitate the design of a novel strategy for targeted therapy.

Comparison of clonogenic assay with premature chromosome condensation assay in prediction of human cell radiosensitivity.

AIM: To determine whether the number of non-rejoining G2-chromatid breaks can predict the radiosensitivity of human cell lines. METHODS: Cell lines of human ovary carcinoma cells (HO8910), human hepatoma cells (HepG2) and liver cells (L02) were irradiated with a range of doses and assessed both of cell survival and non-rejoining G2-chromatid breaks at 24 h after irradiation. Cell survival was documented by a colony assay. Non-rejoining G2-chromatid breaks were measured by counting the number of non-rejoining G2 chromatid breaks at 24 h after irradiation, detected by the prematurely chromosome condensed (PCC) technique. RESULTS: A linear-quadratic survival curve was observed in three cell lines, and HepG2 was the most sensitive to gamma-radiation. A dose-dependent linear increase was observed in radiation-induced non-rejoining G2-PCC breaks measured at 24 h after irradiation in all cell lines, and HepG2 was the most susceptible to induction of non-rejoining G2-PCC breaks. A close correlation was found between the clonogenic radiosensitivity and the radiation-induced non-rejoining G2-PCC breaks (r = 0.923). Furthermore, survival-aberration correlations for two or more than two doses lever were also significant. CONCLUSION: The number of non-rejoining G2 PCC breaks holds considerable promise for predicting the radiosensitivity of normal and tumor cells when two or more than two doses lever is tested.

Comparative study on radiosensitivity of various tumor cells and human normal liver cells.

AIM: To investigate the radiation response of various human tumor cells and normal liver cells. METHODS: Cell lines of human hepatoma cells (SMMC-7721), liver cells (L02), melanoma cells (A375) and cervical tumor (HeLa) were irradiated with (60)Co gamma-rays. Cell survive was documented by a colony assay. Chromatid breaks were measured by counting the number of chromatid breaks and isochromatid breaks immediately after prematurely chromosome condensed by Calyculin-A. RESULTS: Linear quadratic survival curve was observed in all of four cell lines, and dose-dependent increase in radiation-induced chromatid and isochromatid breaks were observed in GB2B phase. Among these four cell lines, A375 was most sensitive to radiation, while, L02 had the lowest radiosensitivity. For normal liver cells, chromatid breaks were easy to be repaired, isochromatid breaks were difficult to be repaired. CONCLUSION: The results suggest that the gamma-rays induced chromatid breaks can be possibly used as a good predictor of radiosensitivity, also, unrejoined isochromatid breaks probably tightly related with cell cancerization.

Mechanism of artemisinin phytotoxicity action: induction of reactive oxygen species and cell death in lettuce seedlings.

Artemisinin has been recognized as an allelochemical that inhibits growth of several plant species. However, its mode of action is not well clarified. In this study, the mechanism of artemisinin phytotoxicity on lettuce seedlings was investigated. Root and shoot elongation of lettuce seedlings were inhibited by artemisinin in a concentration-dependent manner. The compound effectively arrested cell division and caused loss of cell viability in root tips of lettuce. Overproduction of reactive oxygen species (ROS) was induced by artemisinin. Lipid peroxidation, proline overproduction and reduction of chlorophyll content in lettuce seedlings were found after treatments. These results suggested that artemisinin could induce ROS overproduction, which caused membrane lipids peroxidation and cell death, and impacted mitosis and physiological processes, resulting in growth inhibition of receptor plants.

Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats.

The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4+ T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of TH2/TH3 cytokines IL-4, IL-10 and TGF-beta. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.

TGF-beta1-conditioned glial cell-derived dendritic cells inhibit expansion of MBP-reactive T cells in vitro.

Resident microglial cells contribute to activation and expansion of T cells under inflammatory conditions within the CNS. However, there is no evidence how interactions between microglia and T cells affect CNS inflammation. We evaluated the effect of glial cell-derived dendritic cells (GC-DC) in expanding and eliminating myelin basic protein (MBP)-reactive T cells. GC-DC untreated with TGF-beta1 (GC-DC0) primed antigen specific T cell proliferation, whereas GC-DC treated with TGF-1 (GC-DCbeta) effectively inhibited expansion of T cells via inducing IFN-y-expressing CD8+ T cells. Augmented IFN-gamma and/orTNF-alpha might also affect the elimination of MBP-reactive T cells. These results indicate that TGF-beta1-mediated functional skewing of GC-DC plays a critical role for the elimination of MBP-reactive T cells.

TGF-beta 1 synergizes with GM-CSF to promote the generation of glial cell-derived dendriform cells in vitro.

Microglia are often considered a type of tissue macrophages analogous Langerhans' cells, while dendritic cells (DC) can be generated in vitro from cultured microglia in the presence of GM-CSF. In this study, we show that TGF-beta 1, in the presence of GM-CSF, promoted the growth and differentiation of glial cell-derived dendritic cells (GC-DC). TGF-beta 1-driven GC-DC exhibited an immature state reflected by low CD11c expression, augmented endocytosis, and reduced antigen presentation. Expression of Fas was inhibited in GM-CSF+TGF-beta 1-supplemented cell cultures and may relate to a long life span of GC-DC treated with GM-CSF+TGF-beta 1. IL-10 and IL-12 mRNA on GC-DC was not affected upon exposure to GM-CSF alone or to GM-CSF+IFN-gamma, GM-CSF+IL-10 or GM-CSF+TGF-beta 1. In sharp contrast, TGF-beta 1, in the presence of GM-CSF, dramatically up-regulated the expression of TNF-alpha and TGF-beta 1 mRNA. These results demonstrate that TGF-beta 1 seems to play a crucial role in the differentiation, functional skewing, and cytokine profile of GC-DC. TGF-beta 1-driven GC-DC awaits further investigation to facilitate a better understanding of the glia-T cell dialog as well as the pathogenesis and immunotherapy of central nervous system inflammatory and degenerative diseases.

Anti-TNF-alpha antibodies suppress the development of experimental autoimmune myasthenia gravis.

To understand the role of TNF-alpha in the induction of experimental autoimmune myasthenia gravis (EAMG) and detect a possible effect of anti-TNF-alpha antibodies in the treatment of EAMG, anti-TNF-alpha antibodies were administrated intraperitoneally to Lewis rats twice per week for 5 weeks from the day of immunization with Torpedo AChR and complete Freund's adjuvant (CFA). Administration of anti-TNF-alpha antibodies resulted in lower incidence of EAMG, and in delayed onset and only mild muscle weakness compared with control EAMG rats. These mild clinical signs were accompanied by lower AChR-specific lymphocyte proliferation, down-regulated IFN-gamma and IL-10, and up-regulated TGF-beta. The lower levels of anti-AChR IgG, Ig2a and IgG2b and decreased anti-AChR IgG affinity were found in rats treated with anti-TNF-alpha antibodies. These results demonstrate that anti-TNF-alpha antibodies can suppress the induction and development of EAMG.

Therapeutic potential of IFN-gamma-modified dendritic cells in acute and chronic experimental allergic encephalomyelitis.

Dendritic cells (DC) are antigen-presenting cells specialized to regulate immune responses. DC not only control immunity, but also maintain tolerance to self-antigens-two complementary functions that would ensure the integrity of the organism in an environment full of pathogens. Here we report that splenic DC that had been exposed in vitro to IFN-gamma (IFN-gamma-DC) exhibit therapeutic potential on acute experimental allergic encephalomyelitis (EAE) in Lewis rats, and on chronic-relapsing EAE in B6 and SJL/J mice. During incipient EAE [day 5 post-immunization (p.i.) in rats, day 7 p.i. in mice], IFN-gamma-DC were injected s.c. Severity of clinical signs of EAE was dramatically inhibited in animals injected with IFN-gamma-DC, showing normal magnetic resonance imaging (MRI) of the spinal cord and brain. In contrast, the EAE rats receiving PBS or naive DC had severe clinical signs with multiple and extensive MRI lesions in the spinal cord and brain. IFN-gamma-DC triggered an antigen-specific IFN-gamma production, and induced apoptosis of CD4(+) T cells possibly through DC expressing indoleamine 2,3-dioxygenase and/or an IFN-gamma-dependent pathway. As a result, infiltration of macrophages and CD4(+) T cells within the spinal cords was dramatically reduced in animals injected with IFN-gamma-DC as compared to animals injected with PBS or naive DC. This approach may represent a novel possibility of individualized immunotherapy using autologous, in vitro modified DC as a complement to conventional therapy in multiple sclerosis and other diseases with an autoimmune background.