Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells

Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiation-induced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into ‘neighborhoods’ comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cell-based system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns.     

Optimizing Efforts to Promote Mental Health on College and University Campuses: Recommendations to Facilitate Usage of Services,Resources, and Supports

The Journal of Behavioral Health Services & Research - Mental health has long been a challenge on college and university campuses. Though it has historically taken a back seat to physical...     

Public discourse and policy change: Absence of harm from increased oversight and transparency in OPO performance

The Centers for Medicare and Medicaid Services announced changes to the Final Rule for organ procurement organizations (OPOs) in November 2020, after a 23-month period of public debate. One concern among transplant stakeholders was that public focus on OPO underperformance would harm deceased donation. Using CDC-WONDER data, we studied whether donation performance dropped during the era of public debate about OPO reform (December 2018–February 2020). Overall OPO performance as measured relative to cause, age, and location-consistent deaths rose by 12.3% in 2019, compared to a median annual change of 2.5% 2009–2019. Organ recoveries exceeded seasonally adjusted forecasts by 4.2% in the first half of 2019, by 8.1% following the Executive Order issuing a mandate for OPO metric reform, and by 14.1% between the Notice of Public Rule Making and the onset of COVID-19-related systemic disruptions. We describe changes in donor phenotype in the period of increased performance; improvement was greatest for older and donation after cardiac death (DCD) donors, and among decedents who did not have a drug-related mechanism of death. In summary, performance during an era of intense public debate and proposed regulatory changes yielded 692 additional donors over expectations, and no detriment to organ donation was observed.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

Nursing Case Management Strategies for Adults with Serious Mental Illness Seeking Dental Services

A university-community partnership initiated a dental screening and nursing case management program for Medicaid-insured adults with serious mental illness (SMI). Forty-three adults with SMI participated in dental screening; 72% participated in case management. Per client, an average of six case management contacts was made. After 6 months, 87% (27/31) had attended at least one dental appointment, with a 13% no-show rate; 8 completed treatment, 4 had ongoing treatment, 12 had interrupted care, and 3 were lost to follow-up. Adults with SMI experienced high unmet dental needs; nursing case management strategies aided clients to initiate and complete dental care.     

State Firearm Legislation and Nonfatal Firearm Injuries

Objectives. We investigated whether stricter state-level firearm legislation was associated with lower hospital discharge rates for nonfatal firearm injuries.Methods. We estimated discharge rates for hospitalized and emergency department–treated nonfatal firearm injuries in 18 states in 2010 and used negative binomial regression to determine whether strength of state firearm legislation was independently associated with total nonfatal firearm injury discharge rates.Results. We identified 26 744 discharges for nonfatal firearm injuries. The overall age-adjusted discharge rate was 19.0 per 100 000 person-years (state range = 3.3–36.6), including 7.9 and 11.1 discharges per 100 000 for hospitalized and emergency department–treated injuries, respectively. In models adjusting for differences in state sociodemographic characteristics and economic conditions, states in the strictest tertile of legislative strength had lower discharge rates for total (incidence rate ratio [IRR] = 0.60; 95% confidence interval [CI] = 0.44, 0.82), assault-related (IRR = 0.58; 95% CI = 0.34, 0.99), self-inflicted (IRR = 0.18; 95% CI = 0.14, 0.24), and unintentional (IRR = 0.53; 95% CI = 0.34, 0.84) nonfatal firearm injuries.Conclusions. There is significant variation in state-level hospital discharge rates for nonfatal firearm injuries, and stricter state firearm legislation is associated with lower discharge rates for such injuries.Each year from 2005 to 2010, an average of 103 000 Americans were injured or killed by a firearm—approximately 282 individuals per day.1 Most public attention and research has focused on fatal firearm injuries because they are a leading cause of injury death and account for more than 30 000 deaths annually.1 Firearm injuries were the third leading cause of injury-related deaths in 2010 after poisoning and motor vehicle accidents and were the second most frequent cause of traumatic death related to a consumer product.1,2 However, a majority of firearm-related injuries in the United States are nonfatal.1,3,4 In 2010, nearly 5 individuals suffered nonfatal firearm injuries for every 2 who died as a result of firearm violence.1 The age-adjusted fatal firearm injury rate in that year was 10.1 per 100 000 person-years, less than half of the age-adjusted nonfatal injury rate (24.0 per 100 000 person-years).1 This high prevalence of nonfatal firearm injuries in the United States is associated with significant physical and psychological morbidity among injury survivors.5–7 It is also a substantial economic burden for victims, taxpayers, and the United States.8–12Numerous state and federal laws have been implemented in attempts to reduce firearm-related violence in the United States.13 Household firearm ownership rates have been shown to be associated with states’ rates of firearm-related suicides and homicides; thus, legislation might reduce firearm injuries by limiting overall firearm ownership.14,15 A strong association has also been demonstrated between safer firearm storage practices and a lower risk of suicide and unintentional firearm deaths.16–19 Hence, legislation aimed at increasing safe firearm storage may decrease firearm-related injuries, particularly in homes with children and adolescents. In addition, laws that promote background checks before firearm purchase and those that limit private firearm transactions and transfers may help limit firearm access by those most likely to harm themselves or others.Overall, the effectiveness of these laws individually or as a whole remains unclear. Two studies evaluated the relationship between state firearm legislation and firearm injuries using measures of state firearm legislation on the basis of annual scorecards created by the Brady Center to Prevent Gun Violence.20,21 These studies found lower rates of total firearm deaths, including homicides and suicides,20 as well as lower rates of firearm injuries in children,21 in states with more restrictive firearm legislation. Previous studies have also shown that laws related to background checks and limitations on handgun possession and transfer are associated with lower rates of firearm deaths, including suicides and homicides.22–25 A study of the 1994 Brady Handgun Violence Prevention Act (Pub L. No. 103-159, 107 Stat. 1536, USC 921–922, HR 1025, 103rd Congress), which established a mandatory waiting period and background check requirement for handgun sales through licensed firearm dealers, found that the law led to a decline in the suicide rate for those aged 55 years and older, although these findings may have been driven by the implementation of the waiting period rather than the background check itself.26Laws focused on preventing children’s access to firearms are associated with lower rates of both unintentional deaths and suicides.27,28 A cross-sectional, time series analysis of pooled data from 1979 to 2000 found that unintentional firearm deaths among children were declining nationally and that most states that enacted child access laws experienced greater declines in those injuries than did states that had not.29 Notably, state-level comparisons of child access laws can be driven largely by the few states with the strictest child access legislation (e.g., felony conviction for violations).29,30Additionally, several studies suggest that laws aimed at easing access to and use of firearms may be associated with higher rates of firearm injuries, including homicides.31–33 One study found that the 2007 repeal of Missouri’s permit to purchase law requiring firearm purchasers to obtain a license verifying that they passed a background check led to an increase in firearm-related homicides.33 Conversely, other studies have observed no association between stricter firearm laws and firearm violence,26,34,35 and a recent systematic review of various federal and state firearm laws found insufficient evidence to determine their effectiveness in reducing firearm-related violence and injuries.36Several studies have examined the relationship between firearm legislation and fatal firearm injuries, although little is known about the relationship between firearm legislation and nonfatal firearm outcomes.37 This relationship may differ from that observed with fatal injuries because of the different circumstances under which nonfatal firearm injuries occur, including differences in the age of the injured,1,3 the type of firearms involved,38 and injury intent.3 For instance, unintentional shootings are more likely to prove nonfatal than are intentional shootings, and a vast majority of self-inflicted injuries (i.e., suicide attempts) result in death.3,39 Because of the higher prevalence of nonfatal firearm injuries, studies of nonfatal injuries may also have greater statistical power to determine associations between legislation and firearm outcomes that might not be observed in studies of fatal injuries.We have described state variation in discharge rates for nonfatal firearm injuries in 2010 and determined whether stricter state-level firearm legislation was associated with lower discharge rates for nonfatal firearm injuries.     

Microbiota That Affect Risk for Shigellosis in Children in Low-Income Countries

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17–0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8–220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.–induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.     

α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport Syndrome

Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt–induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2–deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2–null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1–dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology.Alport syndrome is characterized by delayed-onset progressive glomerulonephritis associated with sensorineural hearing loss and retinal flecks.¹ The most common form (80%) is X-linked and caused by mutations in the type IV collagen COL4A5 gene.² The two autosomal forms of the disease account for the remaining 20% of Alport patients, and result from mutations in the COL4A3 and COL4A4 genes.³ The α3(IV), α4(IV), and α5(IV) proteins form a heterotrimer that is assembled into a subepithelial network in the glomerular basement membrane (GBM) that is physically and biochemically distinct from a subendothelial type IV collagen network comprising α1(IV) and α2(IV) heterotrimers.⁴ Mutations in any one of the three type IV collagen genes that cause Alport syndrome result in the absence of all three proteins in the GBM due to an obligatory association to form functional heterotrimers.⁵ Thus, the net result for all genetic forms of Alport syndrome is the absence of the α3(IV) α4(IV) α5(IV) subepithelial collagen network, resulting in a GBM type IV collagen network comprising only α1(IV) and α2(IV) heterotrimers.This change in basement membrane composition does not result in immediate pathology. The GBM appears to function adequately for the first few years of life and sometimes past the first decade.⁶ This delayed onset predicts a triggering mechanism for glomerular disease initiation and a theoretical window for therapeutic intervention that may arrest or significantly ameliorate Alport renal disease in its earliest stages. The activation of genes encoding GBM matrix molecules, matrix metalloproteinases (MMPs), and proinflammatory cytokines have all been linked to the progression of Alport glomerular disease. These, however, are events that occur after the onset of proteinuria, and therefore, downstream of disease initiation events.^7–11 Consistent with this notion, experiments aimed at blocking these pathways have offered only limited therapeutic benefit in mouse models for Alport syndrome.^8–10,12 One of the earliest events we have documented is the appearance of an irregular deposition of laminin 211 in the GBM of Alport mice,⁸ an observation confirmed in both Alport dogs and human patients with the disease.¹³ This laminin is normally found only in the mesangium of the glomerulus, and is not expressed in the GBM at any stage of embryonic development.¹⁴ Indeed, several other mesangial matrix proteins appear in the GBM of Alport mice, including laminin 111 and fibronectin.^15,16In the Alport glomerulus, the podocytes are exposed to GBM that has an embryonic type IV collagen composition.^17,18 This could result in altered cell signaling that may trigger the onset of the disease. It has been proposed that this type of mechanism may account for the reactivation of laminin 111 expression in podocytes,¹⁹ because laminin 111 is found in the GBM during development.¹⁴ Because the α1(IV)/α2(IV) collagen network contains significantly fewer interchain disulfide crosslinks,²⁰ and the Alport GBM is thinner than normal,²¹ the Alport GBM is likely to be more elastic, resulting in elevated biomechanical strain on the glomerular cells at their points of contact with the GBM. Consistently, glomeruli from Alport mice have been shown to have elevated deformability relative to wild-type glomeruli,²² and salt-induced hypertension has been shown to accelerate glomerular disease progression in Alport mice.²³In this work, we show that the cellular origin of GBM laminin 211 in Alport glomeruli is mesangial cell process invasion, and that deletion of laminin 211 in Alport mice ameliorates the mesangial process invasion of the glomerular capillary loops in Alport mice. Salt-mediated hypertension exacerbates this mesangial process invasion. A knockout mouse for the integrin α3β1 coreceptor CD151 also develops mesangial process invasion of the capillary loops with GBM deposition of laminin 211, demonstrating the same phenotype for a completely unrelated component of the capillary structural barrier. The CD151 knockout mouse model also shows accelerated glomerular disease progression in response to hypertension.²⁴ We show that biomechanical stretching of cultured mesangial cells induces promigratory cytokines transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF), both known to be induced in Alport glomeruli.^7,12 Inhibitor studies indicate that mesangial cell migration is mediated by integrin α1β1 signaling through the Rho GTPases RAC1 and CDC42. Consistently, integrin α1 deletion in Alport mice was previously shown to ameliorate glomerular disease progression and slow the accumulation of laminin 211 in Alport GBM.⁸ Here, we show that mesangial process invasion of the capillary loops is ameliorated in integrin α1–null Alport mice. These data define a role for biomechanical strain-mediated induction of mesangial cell process invasion as a key aspect of Alport glomerular disease initiation, and set the stage for defining novel therapeutic targets aimed at blocking this process.