Integration of transcription regulation and functional genomic data reveals lncRNA SNHG6's role in hematopoietic differentiation and leukemia.

BACKGROUND: Long non-coding RNAs (lncRNAs) are pivotal players in cellular processes, and their unique cell-type specific expression patterns render them attractive biomarkers and therapeutic targets. Yet, the functional roles of most lncRNAs remain enigmatic. To address the need to identify new druggable lncRNAs, we developed a comprehensive approach integrating transcription factor binding data with other genetic features to generate a machine learning model, which we have called INFLAMeR (Identifying Novel Functional LncRNAs with Advanced Machine Learning Resources). METHODS: INFLAMeR was trained on high-throughput CRISPR interference (CRISPRi) screens across seven cell lines, and the algorithm was based on 71 genetic features. To validate the predictions, we selected candidate lncRNAs in the human K562 leukemia cell line and determined the impact of their knockdown (KD) on cell proliferation and chemotherapeutic drug response. We further performed transcriptomic analysis for candidate genes. Based on these findings, we assessed the lncRNA small nucleolar RNA host gene 6 (SNHG6) for its role in myeloid differentiation. Finally, we established a mouse K562 leukemia xenograft model to determine whether SNHG6 KD attenuates tumor growth in vivo. RESULTS: The INFLAMeR model successfully reconstituted CRISPRi screening data and predicted functional lncRNAs that were previously overlooked. Intensive cell-based and transcriptomic validation of nearly fifty genes in K562 revealed cell type-specific functionality for 85% of the predicted lncRNAs. In this respect, our cell-based and transcriptomic analyses predicted a role for SNHG6 in hematopoiesis and leukemia. Consistent with its predicted role in hematopoietic differentiation, SNHG6 transcription is regulated by hematopoiesis-associated transcription factors. SNHG6 KD reduced the proliferation of leukemia cells and sensitized them to differentiation. Treatment of K562 leukemic cells with hemin and PMA, respectively, demonstrated that SNHG6 inhibits red blood cell differentiation but strongly promotes megakaryocyte differentiation. Using a xenograft mouse model, we demonstrate that SNHG6 KD attenuated tumor growth in vivo. CONCLUSIONS: Our approach not only improved the identification and characterization of functional lncRNAs through genomic approaches in a cell type-specific manner, but also identified new lncRNAs with roles in hematopoiesis and leukemia. Such approaches can be readily applied to identify novel targets for precision medicine.

Bacterial hydrogen sulfide drives cryptic redox chemistry in gut microbial communities.

Microbial biochemistry contributes to a dynamic environment in the gut. Yet, how bacterial metabolites such as hydrogen sulfide (H2S) mechanistically alter the gut chemical landscape is poorly understood. Here we show that microbially generated H2S drives the abiotic reduction of azo (R-N = N-R') xenobiotics, which are commonly found in Western food dyes and drugs. This nonenzymatic reduction of azo compounds is demonstrated in Escherichia coli cultures, in human faecal microbial communities and in vivo in male mice. Changing dietary levels of the H2S xenobiotic redox partner Red 40 transiently decreases mouse faecal sulfide levels, demonstrating that a xenobiotic can attenuate sulfide concentration and alleviate H2S accumulation in vivo. Cryptic H2S redox chemistry thus can modulate sulfur homeostasis, alter the chemical landscape in the gut and contribute to azo food dye and drug metabolism. Interactions between chemicals derived from microbial communities may be a key feature shaping metabolism in the gut.

Doppler Gyroscopes: Frequency vs Phase Estimation.

We consider the fundamental roles of frequency versus phase in parameter estimation, specifically in the Sagnac effect. We describe a novel, ultrasensitive gyroscope based on the extremely steep frequency-dependent gain of a liquid crystal light valve. We provide compelling experimental evidence that the Doppler shift is fundamental in the Sagnac effect giving clarity to a long-debated question. We experimentally show orders of magnitude improvement in sensitivity relative to the standard quantum limit of a gyroscope based on phase estimation.

Bioaccumulation as a mechanism of microbiome/drug interactions.

Microbes of the human gut can change drug disposition in the human body and gut ecology via 'bioaccumulation', a process in which bacteria take up compounds intracellularly without chemically modifying them or experiencing changes in growth, as described in Klünemann et al. This work expands current understanding of the types of drug-bacterial interactions in the gut environment.

The Impact of the Psychiatrist on the Life Care Plan.

A life care plan is a tool that is used for medical treatment planning and management purposes in many settings, including legal and forensic applications. This article summarizes the life care planning process and emphasizes the role of the psychiatrist in establishing a strong medical foundation for the plan. The psychiatrist's expertise in determining the nature and extent of the evaluee's psychiatric illness, prognosis, need for and likely benefit from treatment, and costs of care inform the life care planning process. Advising life care planners on these matters is a natural extension of the work of psychiatrists and forensic psychiatrists, who are accustomed to providing medical opinions to the courts. There are specific challenges when the psychiatrist creates recommendations for the life care plan; they include determining long-term prognosis, devising treatment plans, and identifying malingering. These questions are explored to assist the psychiatrist in providing the foundation for a life care plan.

STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models.

Multiple myeloma (MM) remains an incurable hematological malignancy. Combination regimens of conventional and novel drugs have improved patient's survival. However, most patients inevitably relapse and become refractory to the current therapeutic armamentarium. We investigated the efficacy of combining the microtubule-targeting agent STK405759 with dexamethasone or bortezomib in vitro and in vivo. STK405759 combined with dexamethasone or bortezomib had synergistic cytotoxic activity in RPMIS, CAG and MM1.S human MM cell lines through activation of caspase 2, 3, 8, 9 and PARP. These treatments remained cytotoxic in the presence of bone marrow stroma cells. In other MM cells, including cells resistant to vincristine, melphalan, mitoxantrone or dexamethasone, these combinations decreased significantly survival as compared to single agents. In in vivo studies, STK405759 disrupted existing blood vessels in xenograft tumors, acting not only as a cytotoxic agent but also as an anti-angiogenic drug. Mice treated with STK405759 in combination with dexamethasone or bortezomib resulted in greater tumor growth inhibition, increased overall response and prolonged survival as compared to as compared to BTZ or DEXA alone. Their anticancer activity was mediated by activation of apoptosis and reduction of tumor microvessel density. These preclinical studies provide the rationale for future clinical trials of STK405759, dexamethasone and bortezomib combinations to improve the outcome of multiple myeloma patients.

Experience and Opinions of Forensic Psychiatrists Regarding PTSD in Criminal Cases.

By the end of 2014, 1.5 million veterans of the Second Iraq and Afghan wars were to have returned home, up to 35 percent with PTSD. The potential use of PTSD as the basis for legal claims in criminal defense is therefore a pressing problem. Using a Web-based survey, we examined the experiences and attitudes of members of the American Academy of Psychiatry and the Law (AAPL) regarding PTSD in the criminal forensic setting. Of 238 respondents, 50 percent had been involved in a criminal case involving PTSD, 41 percent in the previous year. Eighty-six percent of cases involved violent crime and 40 percent homicides. Forty-two percent of defendants were soldiers in active service or veterans, of whom 89 percent had had combat exposure, mostly in the Second Iraq and Afghan wars. Outcomes reported were not guilty by reason of insanity (NGRI) (7%), guilty on the original charge (40%), and pleading guilty to a lesser charge (23%). The findings suggest that many forensic psychiatrists will be asked to evaluate PTSD in the criminal setting, with a growing number of cases related to combat exposure in recent veterans. The implications of these findings for the practice of forensic psychiatry are discussed.

Restoration of Firearm Rights in New York.

The National Instant Criminal Background Check System (NICS) Improvement Amendments Act of 2007 encouraged states to create processes by which individuals who have lost their rights to firearm possession for mental-illness-related reasons could receive relief from restrictions. Over 20 states have created relief processes for this sub-group, but there still exists considerable state-by-state heterogeneity. The spectrum ranges from states that require a physician's opinion regarding appropriateness for restoration to those that rely solely on judicial proceedings without input from psychiatrists or other mental health professionals. This article reviews the restoration process in New York State, a model in which psychiatrists participate in the process of assessing whether an individual's firearm rights can be restored. It discusses the legislative background of these regulations, the specific policies and procedures governing the restoration process, and clinical considerations for the forensic evaluation.