다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

CA : A Cancer Journal for Clinicians

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

The DNA Damage Response: Making It Safe to Play with Knives

Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.

ROS and the DNA damage response in cancer.

The earliest known response to chromosomal DNA breakage is the phosphorylation of the histone H2AX. Ayoub et al. have now identified a dynamic change in chromatin that promotes this phosphorylation step. DNA breaks swiftly mobilize the chromatin factor HP1-β, and via a previously unrecognized signalling cascade involving a phosphorylation step carried out by casein kinase 2, H2AX becomes phosphorylated and the DNA damage response is under way. A phosphorylation step carried out by casein kinase 2, coupled with mobilization of the chromatin factor HP1-β, helps to initiate the DNA damage response by promoting phosphorylation of histone H2AX. Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK1. Phosphorylated (γ)-H2AX—which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair2,3—is the earliest known marker of chromosomal DNA breakage. Here we identify a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilize heterochromatin protein 1 (HP1)-β (also called CBX1), a chromatin factor bound to histone H3 methylated on lysine 9 (H3K9me). Local changes in histone-tail modifications are not apparent. Instead, phosphorylation of HP1-β on amino acid Thr 51 accompanies mobilization, releasing HP1-β from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase 2 (CK2), an enzyme implicated in DNA damage sensing and repair4,5,6, suppresses Thr 51 phosphorylation and HP1-β mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-β mutant, diminishes H2AX phosphorylation. Our findings reveal an unrecognized signalling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone-code mediator protein, HP1, but not the code itself.

HP1-β mobilization promotes chromatin changes that initiate the DNA damage response

Defective DNA repair is a common hallmark of cancer. Homologous recombination is a DNA repair pathway of clinical interest due to the sensitivity of homologous recombination-deficient cells to poly-ADP ribose polymerase (PARP) inhibitors. The measurement of homologous recombination deficiency (HRD) in cancer is therefore vital to the appropriate design of clinical trials incorporating PARP inhibitors. However, methods to identify HRD in tumors are varied and controversial. Understanding existing and new methods to measure HRD is important to their appropriate use in clinical trials and practice. The aim of this review is to summarize the biology and clinical validation of current methods to measure HRD, to aid decision-making for patient stratification and translational research in PARP inhibitor trials. We discuss the current clinical development of PARP inhibitors, along with established indicators for HRD such as germline BRCA1/2 mutation status and clinical response to platinum-based therapy. We then examine newer assays undergoing clinical validation, including 1) somatic mutations in homologous recombination genes, 2) "genomic scar" assays using array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) analysis or mutational signatures derived from next-generation sequencing, 3) transcriptional profiles of HRD, and 4) phenotypic or functional assays of protein expression and localization. We highlight the strengths and weaknesses of each of these assays, for consideration during the design of studies involving PARP inhibitors.

Biomarkers for Homologous Recombination Deficiency in Cancer.

Members of the lysine (K)-specific demethylase 4 (KDM4) A–D family of histone demethylases are dysregulated in several types of cancer. Here, we reveal a previously unrecognized role of KDM4D in the DNA damage response (DDR). We show that the C-terminal region of KDM4D mediates its rapid recruitment to DNA damage sites. Interestingly, this recruitment is independent of the DDR sensor ataxia telangiectasia mutated (ATM), but dependent on poly (ADP-ribose) polymerase 1 (PARP1), which ADP ribosylates KDM4D after damage. We demonstrate that KDM4D is required for efficient phosphorylation of a subset of ATM substrates. We note that KDM4D depletion impairs the DNA damage-induced association of ATM with chromatin, explaining its effect on ATM substrate phosphorylation. Consistent with an upstream role in DDR, KDM4D knockdown disrupts the damage-induced recombinase Rad51 and tumor protein P53 binding protein foci formation. Consequently, the integrity of homology-directed repair and nonhomologous end joining of DNA breaks is impaired in KDM4D-deficient cells. Altogether, our findings implicate KDM4D in DDR, furthering the links between the cancer-relevant networks of epigenetic regulation and genome stability.

https://www.pnas.org/content/pnas/111/7/E728.full.pdf

PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair

Spectrofluorometric imaging microscopy is demonstrated in a confocal microscope using a supercontinuum laser as an excitation source and a custom-built prism spectrometer for detection. This microscope system provides confocal imaging with spectrally resolved fluorescence excitation and detection from 450 to 700 nm. The supercontinuum laser provides a broad spectrum light source and is coupled with an acousto-optic tunable filter to provide continuously tunable fluorescence excitation with a 1-nm bandwidth. Eight different excitation wavelengths can be simultaneously selected. The prism spectrometer provides spectrally resolved detection with sensitivity comparable to a standard confocal system. This new microscope system enables optimal access to a multitude of fluorophores and provides fluorescence excitation and emission spectra for each location in a 3D confocal image. The speed of the spectral scans is suitable for spectrofluorometric imaging of live cells. Effects of chromatic aberration are modest and do not significantly limit the spatial resolution of the confocal measurements.

Anand D. Jeyasekharan

Papers

ROS and the DNA damage response in cancer.

HP1-β mobilization promotes chromatin changes that initiate the DNA damage response

Biomarkers for Homologous Recombination Deficiency in Cancer.

PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair

A white light confocal microscope for spectrally resolved multidimensional imaging