Developmental Context Determines Latency of MYC-Induced Tumorigenesis

One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis

Towards housing first and harm reduction : addressing opioid dependence and homelessness in Tshwane during the COVID-19 pandemic

Pandemics can increase mortality and drug-related harms among people experiencing homelessness. The Housing First approach prioritises housing and service access. Harm reduction, a principle of Housing First, minimises the consequences of drug use. This chapter presents lessons learnt from the application of Housing First and harm reduction principles with homeless people in Tshwane, South Africa, between April 2020 and March 2021. Quantitative service delivery data were retrospectively reviewed and analysed using descriptive statistics. Accounts by authors who participated in the COVID-19 response were collectively discussed in relation to the Housing First and harm reduction actors and process. Issues were synthesised in relation to two six-month periods. A task team was established to co-ordinate Tshwane’s response. In the first six months, 1 440 temporary bed-spaces were created at 25 shelters, and 2 066 people at shelters received food, social support and on-site healthcare services. Across shelters, 1 076 residents were started on methadone to manage opioid withdrawal. By the second six-month period, many gains were lost. Changes in political leadership stalled plans to reintegrate people housed in temporary shelters, and reduced funding led to shelter closures. By April 2021, more shelters operated than in pre-COVID-19 times, harm reduction capacitation for shelter staff continued, and local government committed to establish a street homelessness unit.Through a combination of funding and collaboration, progress was made towards Housing First and harm reduction for homeless people in Tshwane. A national policy on homelessness should be developed, funded and implemented. This should be informed by additional research, developed in partnership with affected populations, and built on a common understanding of Housing First and harm reduction.http://www.journals.co.za/content/journal/healthrFamily Medicin

On the nature of arene eta(6) interactions in the solid state and the use of cylindrophanes as ligands for sandwich complexation of metals with longer-range interactions with the benzene ring

The interactions between diethyltin dichloride and 5′-CMP, 5′-dCMP, and 5′-UMP in aqueous solution were investigated by multinuclear 1D and 2D NMR techniques including 119Sn, 15N and 31P nuclei. These studies were combined with electrospray mass spectrometry, infrared spectroscopy, solid state 13C, 31P and 117Sn CP-MAS NMR, and elemental analysis. As demonstrated by 31P-1H HOESY spectroscopy, the diethyltin moiety interacts with the phosphate group of the pyrimidic mononucleotides in the pH range 0.5–3.5. Compound 8 (X = Cl), the solid isolated in this pH range from 5′-CMP, contains two tin atoms bridged by one oxygen and one chlorine atom, each tin atom being linked to the phosphate group of a nucleotide moiety. For 5′-UMP the solid isolated (12) has a dimeric structure with two different tin atoms; it can be formed by dimerization of compound 11 with the elimination of two water molecules. As demonstrated by 1H-119Sn HMQC correlation NMR data and the 2J(119Sn–O–117Sn) coupling constant of 156 Hz, the diethyltin moiety reacts with the O(2′) and O(3′) oxygen atoms of the nucleotides to form a dimeric diethyldioxastannolane at pH > 9.0. Between pH 5.0 and 9.0, no evidence for any interaction between the diethyltin moiety and the nucleotides was found.FLWINinfo:eu-repo/semantics/publishe

On the nature of arene eta(6) interactions in the solid state and the use of cylindrophanes as ligands for sandwich complexation of metals with longer-range interactions with the benzene ring

The interactions between diethyltin dichloride and 5′-CMP, 5′-dCMP, and 5′-UMP in aqueous solution were investigated by multinuclear 1D and 2D NMR techniques including 119Sn, 15N and 31P nuclei. These studies were combined with electrospray mass spectrometry, infrared spectroscopy, solid state 13C, 31P and 117Sn CP-MAS NMR, and elemental analysis. As demonstrated by 31P-1H HOESY spectroscopy, the diethyltin moiety interacts with the phosphate group of the pyrimidic mononucleotides in the pH range 0.5–3.5. Compound 8 (X = Cl), the solid isolated in this pH range from 5′-CMP, contains two tin atoms bridged by one oxygen and one chlorine atom, each tin atom being linked to the phosphate group of a nucleotide moiety. For 5′-UMP the solid isolated (12) has a dimeric structure with two different tin atoms; it can be formed by dimerization of compound 11 with the elimination of two water molecules. As demonstrated by 1H-119Sn HMQC correlation NMR data and the 2J(119Sn–O–117Sn) coupling constant of 156 Hz, the diethyltin moiety reacts with the O(2′) and O(3′) oxygen atoms of the nucleotides to form a dimeric diethyldioxastannolane at pH > 9.0. Between pH 5.0 and 9.0, no evidence for any interaction between the diethyltin moiety and the nucleotides was found.FLWINinfo:eu-repo/semantics/publishe

DDC and CCl₄ Cooperate with MYC to Induce Accelerated Liver Tumorigenesis.

<p>Shown are Kaplan-Meier survival curves for 6–8 w adult mice that overexpressed MYC and were simultaneously treated with: nothing (filled black square), DDC (filled blue circle), or CCl₄ (filled blue diamond). Adult mice treated with hepatotoxins in the absence of MYC overexpression (MYC OFF) are displayed with the corresponding open shape: nothing (empty black square), with DDC (empty blue circle), or CCl₄ (empty blue diamond). Also shown are survival curves of neonatal mice in which MYC was either overexpressed (filled red triangle), or remained inactive (empty red triangle) starting at birth. Cohorts consisted of 5–10 mice. MYC transgene expression was activated by removal of doxycycline from the mouse drinking water on the day of hepatotoxin treatment initiation. Mice were sacrificed when moribund with tumor burden.</p

MYC Overexpression Does Not Contribute to Oval Cell Expansion.

<p>A6 Immunohistochemistry of: (A) a normal adult liver, (B) an adult liver in which MYC has been activated for 30 days, (C) an adult liver treated with DDC for 7 days, (D) an adult liver that overexpressed MYC in conjunction with DDC treatment for 7 days, (E) an adult liver treated with DDC for 17 days, (F) an adult liver that overexpressed MYC in conjunction with DDC treatment for 17 days, (G) an adult liver treated with DDC for 28 days, and (H) an adult liver with adjacent tumor foci that stemmed from MYC and DDC treatment for 28 days. A6 positive cells are evident in the periportal areas but not in the tumors. Representative data is shown.</p