Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

Summary Bacteria residing within biofilm communities can coordinate their behavior through cell-to-cell signaling. However, it remains unclear if these signals can also influence the behavior of distant cells that are not part of the community. Using a microfluidic approach, we find that potassium ion channel-mediated electrical signaling generated by a Bacillus subtilis biofilm can attract distant cells. Integration of experiments and mathematical modeling indicates that extracellular potassium emitted from the biofilm alters the membrane potential of distant cells, thereby directing their motility. This electrically-mediated attraction appears to be a generic mechanism that enables cross-species interactions, as Pseudomonas aeruginosa cells also become attracted to the electrical signal released by the B. subtilis biofilm. Cells within a biofilm community can thus not only coordinate their own behavior, but also influence the behavior of diverse bacteria at a distance through long-range electrical signaling.

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BackgroundStargardt disease (SD) is characterized by the accumulation of the age-pigment lipofuscin in the retinal pigment epithelium (RPE) and subsequent neuroretinal degeneration. The disease leads to vision loss early in life. Here, we investigate age-dependent ultrastructural changes in three SD mouse models: albino Abca4-/- and pigmented Abca4-/- and Abca4-/-.Rdh8-/- mice. Since we found indications for oxidative stress primarily in albino SD mice, we tested RPE melanin for its antioxidative capabilities.MethodsSD mouse eyes were investigated by light, fluorescence and electron microscopy and were compared to the respective albino and pigmented wild type mice and to a human donor SD eye. To confirm the role of RPE melanin in scavenging oxidative stress, melanin from S. officinalis as a standard and porcine RPE were tested for their capability to quench superoxide anions.ResultsHistological alterations indicative of oxidative stress and/or lysosomal dysfunction were present in albino Abca4-/- and Abca4-/-.Rdh8-/- mice. Retinal damage, such as inner segment rupture and pyknotic or free photoreceptor nuclei in the subretinal space and RPE vacuolization were exclusively found in albino Abca4-/- mice. Shortened and disorganized photoreceptor outer segments and dead RPE cells were found in albino Abca4-/- and Abca4-/-.Rdh8-/- mice, with earlier onset in albino Abca4-/- mice. Undegraded phagosomes and lipofuscin accumulation were present in the RPE of all three SD strains, but numbers were highest in Abca4-/-.Rdh8-/- mice. Lipofuscin morphology differed between SD strains: (melano-)lipofuscin granules in pigmented Abca4-/- mice had a homogenous electron density and sharp demarcations, while lipofuscin in albino Abca4-/- mice had a flocculent electron density and often lacked a surrounding membrane, indicating loss of lysosomal integrity. Young Abca4-/-.Rdh8-/- mice showed (melano-)lipofuscin granules with homogenous electron density, while in aged animals granules with flocculent electron density predominated. Both strains of pigmented SD mice had melanolipofuscin clusters as found in the human SD eye. Like melanin from S. officinalis, porcine RPE melanin can also quench superoxide anions.DiscussionThe presented pathologies in albino Abca4-/- and Abca4-/-.Rdh8-/- mice suggest oxidative stress and/or lysosomal dysfunction within the RPE. Since albino Abca4-/- mice have the earliest onset and severest damage and as absence of melanin and also melanin turnover with age are known to diminish RPEs anti-oxidative properties, we assume that RPE melanin plays a role in SD related damages. A lack of pathology in pigmented Abca4-/- mice due to lower stress levels as compared to the Abca4-/-.Rdh8-/- mice underlines this hypothesis. It is also supported by the finding that RPE melanin can quench superoxide anions. We therefore suppose that RPE melanin is important in retinal health and we discuss its role as an oxidative stress scavenger.

BackgroundThe prognosis of pancreatic carcinoma (PC) remains poor and the American Joint Committee on Cancer (AJCC) 8th staging system for survival prediction in PC patients after curative resection is still limited. Thus, the aim of this study is to refine a valuable prognostic model and novel staging system for PC with curative resection.MethodsThe data of 3,458 patients used in this study were retrieved from the Surveillance, Epidemiology, and End Results database registry of National Cancer Institute. The prognostic value of lymph node ratio (LNR) was analyzed in the primary cohort and prognostic nomogram based on the LNR was established to create a novel staging system. Then, analyses were conducted to evaluate the application of the formulated nomogram staging system and the AJCC 8th staging system. The predictive performance of model was further validated in the internal validation cohort.ResultsSignificant positive correlations were found between LNR and all factors except for surgical procedures. The results of univariate and multivariate analyses showed that LNR was identified as an independent prognostic indicator for overall survival (OS) in both primary and validation cohorts (all P < 0.001). A prognostic nomogram based on the LNR was formulated to obtain superior discriminatory abilities. Compared with the AJCC 8th staging system, the formulated nomogram staging system showed higher hazard ratios of stage II, III, and IV disease (reference to stage I disease) that were 1.637, 2.300, and 3.521, respectively, by univariate analyses in the primary cohort and the distinction between stage I, II, and III disease at the beginning or end of the survival curves was more apparent. All these results were further verified in the validation cohort.ConclusionLNR can be considered as a useful independent prognostic indicator for PC patients after curative resection regardless of the surgical procedures. Compared with the AJCC 8th staging system, the formulated nomogram showed superior predictive accuracy for OS and its novel staging system revealed better risk stratification.

HKM is a dynamic and spatiotemporally regulated process in the developing retina. Epigenetic regulation of gene transcription by Ezh2- and G9a-mediated HKM plays crucial roles in retinal neuron survival and may represent novel epigenetic targets to enhance viability in retinal neurodegenerative diseases such as glaucoma.

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