Bowdoin Science Journal

Emma Cheung

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation

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Obsessive-compulsive disorder (OCD) can be severely disabling, and some patients do not respond to standard treatments like medication and therapy. Deep brain stimulation (DBS), an invasive neurosurgical intervention where thin electrodes are connected to a neuro-pacemaker and introduced into subcortical central structures of the brain to modulate pathological neuronal activity with electrical current, has shown promise for these treatment-resistant cases. However, responses to DBS vary widely, prompting a need to identify genetic factors that might predict which patients will benefit. Understanding these genetic markers may ultimately lead to more personalized, effective approaches for treatment-resistant OCD.

This study (Chen et al, 2023) conducted a preliminary genomic analysis on a small cohort of patients with severe, treatment-resistant OCD who received DBS. Researchers sequenced the patients’ DNA to examine specific genetic variants. These included instances where a single nucleotide in a genomic sequence was altered in a phenomenon known as single nucleotide variants and among other genetic markers previously associated with psychiatric disorders and traits related to treatment resistance. Statistical analysis was then applied to explore any associations between these genetic markers and the clinical outcomes of DBS in these patients.

The results identified several genetic markers such as missense variants in the gene KNCB1 that seemed to correlate with positive or negative DBS responses. However, because the study involved a small number of participants, these findings are considered preliminary. Certain genetic variants showed potential as predictors for treatment outcomes, but further research with a larger sample size is needed to validate these associations and understand the mechanisms by which they influence DBS response.

This study provides initial evidence that genetics may play a role in how patients with treatment-resistant OCD respond to DBS. If validated by larger studies, these findings could pave the way for genetically-informed approaches to selecting and optimizing DBS candidates, contributing to more precise, personalized treatment strategies for severe OCD cases.

References:

Long Long Chen, Matilda Naesström, Matthew Halvorsen, Anders Fytagoridis, David Mataix-Cols, Christian Rück, James J Crowley, Diana Pascal (2023) Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation, medRxiv , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153313/

Ferroptosis-Related LncRNAs Found in Colon Cancer

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Colon cancer is the malignant growth of tumor cells in the large intestine. It is the third most common cancer and has the fourth highest death rate out of all types of cancer. Current treatments are limited, as they can be painful for the patient by killing healthy cells alongside cancer cells, and there is no guarantee that the treatments will completely eliminate all cancer cells.

Ferroptosis is a type of programmed cell death caused by high intracellular iron levels, which in turn activates cell death pathways. It differs from traditional cell death, apoptosis, since it is triggered by high iron intracellular concentrations. Rather than affecting the cell’s genetic material or plasma membrane, ferroptosis causes cell death through shrinking mitochondria and increasing mitochondrial membrane density. 

Long noncoding RNAs (lncRNAs) are a type of RNA that does not code for protein synthesis. While they don’t code for protein, lncRNAs have other functions, such as controlling gene regulation through unwinding chromatin for transcription and consequent translation and RNA processing. In regards to cancer, lncRNAs have been proven to contribute to proliferation, metastasis, and reproduction of malignant cells, and can therefore be indicators of the disease and its prognosis. Ferroptosis-related lncRNAs (FRLs), which influence the titular cellular process, in particular have been identified as possible indicators of cancer prognosis, yet not much is known.

The purpose of Wu et al (2022)’s study was to determine the molecular functions of FRLs in colon cancer. In this experiment, RNA sequencing data and genes related to ferroptosis were obtained from databases. In addition, human intestinal epithelial cells and various human colon cancer cell lines and colon cancer cell samples taken from patients at the Gastrointestinal Surgery Department of Xiangya 3rd Hospital were tested for cell composition via CIBERSORT, and had their RNA extracted for qRT-PCR and analysis. Malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS), and IC50 levels of various drugs were also tested in these cells, as they all have a role in controlling ferroptosis and the consequent cell death. It was found that 26 different FRLs had some relationship to colon cancer, most of them being risk genes, genes specifically associated with the onset of cancer. Two lncRNAs, AP003555.1 and AC005841.1, had a significant relationship to colon cancer, as seen by the increased MDA, Fe2+, and ROS levels in cells with those two lncRNAs silenced and their knockout inhibiting cell proliferation.

 

Figure 1: Construction and validation of the ferroptosis-related lncRNA signature model in the training cohort, validation and overall groups. (A–C) The distribution of the risk scores and the distributions of overall survival status and risk score in the training, validation and overall groups. (D–F) The Kaplan–Meier curves for survival status and survival time in the training, validation and overall groups. (G–I) The receiver operating characteristic (ROC) curve shows the potential of the prognostic ferroptosis-related lncRNAs signature in predicting 1-, 2-, and 3-year overall survival (OS) in the training, validation and overall groups. (J–L) AUC of ROC curves comparing the prognostic accuracy of the risk score and other prognostic factors in the training, validation and overall groups.

 

Sources

Li, Jie, Feng Cao, He-liang Yin, Zi-jian Huang, Zhi-tao Lin, Ning Mao, Bei Sun & Gang Wang (2020), Ferroptosis: past, present and future, Cell Death and Disease, Volume 11, Issue 2, Page 88

 

Mármol, Inés, Cristina Sánchez-de-Diego, Alberto Pradilla Dieste, Elena Cerrada, and María Jesús Rodriguez Yoldi (2017) Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer, International Journal of Molecular Sciences, Volume 18, Issue 1, Pages 197. 

 

Qian, Yuchen, Lei Shi, and Zhong Luo (2020) Long Non-coding RNAs in Cancer: Implications for Diagnosis, Prognosis, and Therapy, Frontiers in Medicine

 

Wu, Zhiwei, Zhixing Lu1, Liang Li, Min Ma, Fei Long, Runliu Wu, Lihua Huang, Jing Chou, Kaiyan Yang, Yi Zhang, Xiaorong Li, Gui Hu, Yi Zhang, and Changwei Lin (2022) Identification and Validation of Ferroptosis-Related LncRNA Signatures as a Novel Prognostic Model for Colon Cancer, Sec. Cancer Immunity and Immunotherapy, Volume 12

 

Yao, Run-Wen, Yang Wang & Ling-Ling Chen (2019) Cellular functions of long noncoding RNAs, Nature Cell Biology, Volume 21, Issue 5, Pages 542-551

 

Yu, Haitao, Pengyi Guo, Xiaozai Xie, Yi Wang, and Gang Chen (2017) Ferroptosis, a new form of cell death, and its relationships with tumourous diseases, Journal of Cellular and Molecular Medicine, Volume 21, Issue 4, Pages 648–657

 

Zhang, Kaiming, Liqin Ping, Tian Du, Gehao Liang, Yun Huang, Zhiling Li, Rong Deng, and Jun Tang (2021) A Ferroptosis-Related lncRNAs Signature Predicts Prognosis and Immune Microenvironment for Breast Cancer, Frontiers in Molecular Bioscience

Targeting the MYC Proto-Oncogene, BHLH Transcription Factor (MYC) interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

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According to the World Health Organization (WHO), in 2020, cancer was responsible for the deaths of almost ten million people worldwide. Such statistics place cancer as a leading cause of death worldwide, second to heart disease. Cancer is when a series of mutations occurs in a cell, resulting in uncontrollable cellular division that eventually leads to interference in the function of vital organs. One of the more common types of cancer is lymphoma, the malignant growth of tumor cells of the lymphatic system. Current treatments for lymphoma include radiation therapy and chemotherapy, but these treatments can have drawbacks: they can be painful for the patient by killing healthy cells alongside cancer cells, and there is no guarantee that the treatments will completely eliminate all cancer cells. With a treatment that specifically targets the malignant cells, we can better treat lymphoma as well as other types of cancers.

MYC is a gene that when expressed in moderation, is responsible for maintaining cellular functions such as the cell cycle, apoptosis (programmed cell death), and protein production. It does so through “recruiting” enzymes such as histone acetyltransferases p300/CBP or the histone deacetylases (HDACs) to regulate expression of other genes. However, dysregulation of MYC expression can cause these cell functions to lose control as HDACs will have no means of regulation, genes to aid in the increase in cellular processes and pathways that would lead to the cell to become cancerous. MYC has also been found to be overexpressed in other types of cancers, such as uterine leiomyosarcoma.

The purpose of this project was to determine the effect of HDAC6 inhibitor Marbostat-100 (M-100) on oncogenic MYC expression levels in mice with MYC-induced aggressive B-cell lymphoma. In this experiment, mice with B-cell lymphoma as well as human B cell lymphoma cells were treated with various concentrations of M-100. It was found that all experimental concentrations of M-100 caused HDAC inhibition and reduction of MYC expression and protein levels, consequently inducing apoptosis in the murine and human cancer cells and statistically significantly increasing the mice’s survival rates. Therefore, MYC inhibition could be a possible therapeutic treatment for cancers like B-cell lymphoma.

Sources

https://www.nature.com/articles/s41388-022-02450-3

https://www.who.int/news-room/fact-sheets/detail/cancer

https://www.cancer.gov/about-cancer/treatment/types