Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi) has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies

Aging-Related Reduced Expression of CXCR4 on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects

Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of CXCR4 expression on BM mesenchymal stem cells (MSC) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM MSC from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old MSC to support HSPC function is associated with reduced expression of CXCR4 on BM MSC of old mice. Deletion of the CXCR4 gene in young MSC accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with CXCR4 deficient MSC also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, CXCR4 signaling prevents BM MSC dysfunction by suppressing oxidative stress, as treatment of old or CXCR4 deficient MSC with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in CXCR4 expression on BM MSC impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/CXCR4 axis in MSC may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function

The NuA4 acetyltransferase and histone H4 acetylation promote replication recovery after topoisomerase I-poisoning

BACKGROUND: Histone acetylation plays an important role in DNA replication and repair because replicating chromatin is subject to dynamic changes in its structures. However, its precise mechanism remains elusive. In this report, we describe roles of the NuA4 acetyltransferase and histone H4 acetylation in replication fork protection in the fission yeast Schizosaccharomyces pombe. RESULTS: Downregulation of NuA4 subunits renders cells highly sensitive to camptothecin, a compound that induces replication fork breakage. Defects in NuA4 function or mutations in histone H4 acetylation sites lead to impaired recovery of collapsed replication forks and elevated levels of Rad52 DNA repair foci, indicating the role of histone H4 acetylation in DNA replication and fork repair. We also show that Vid21 interacts with the Swi1-Swi3 replication fork protection complex and that Swi1 stabilizes Vid21 and promotes efficient histone H4 acetylation. Furthermore, our genetic analysis demonstrates that loss of Swi1 further sensitizes NuA4 and histone H4 mutant cells to replication fork breakage. CONCLUSION: Considering that Swi1 plays a critical role in replication fork protection, our results indicate that NuA4 and histone H4 acetylation promote repair of broken DNA replication forks

Improvement in thermoregulation outcomes following the implementation of a thermoregulation bundle for preterm infants

Aim: Hypothermia is associated with increased morbidity and mortality in preterm infants. A local audit revealed 60% preterm infants ≤32 weeks gestation and/or very low birth weight (VLBW) infants (<1500 g) had an abnormal body temperature at admission. This study compares thermoregulatory outcomes before and after the implementation of a thermoregulation bundle in the birthing environment. Methods: This retrospective cohort study reviewed thermoregulatory data for all inborn preterm (≤32 weeks) and/or VLBW infants for a period of 30 months before (Group 1: 1st January 2013 to 30 June 2015) and after changes to thermoregulation practice (Group 2: 1st July 2015 to 31 December 2017). The key practice changes included: improved anticipation and staff preparedness, wrapping infant in a polyethylene sheet, using a polyethylene lined bonnet, using servo-control mode at birth and during transport. Results: There were 282 and 286 infants in group 1 and group 2 respectively, with similar baseline characteristics. A clinically and statistically significant improvement was observed in the proportion of infants with normothermia (33% in group 1 to 60% in group 2, P < 0.0001) including the sub-group of extremely preterm (<28 weeks gestation) infants (38 to 60%, P = 0.0083). A higher mean admission temperature was observed for group 2 (36.10°C ± 0.78 in group 1 vs 36.52°C ± 0.61 in group 2, P < 0.0001). Moderate hypothermia was reduced by two-thirds in group 2 (41–12%, P = <0.0001). Conclusions: The introduction of a thermoregulation bundle improved admission temperature, improved the proportion of normothermia and reduced moderate hypothermia in preterm infants

Targeting NAD+ Metabolism to Enhance Radiation Therapy Responses

Nicotinamide adenine dinucleotide (NAD+) metabolism is integrally connected with the mechanisms of action of radiation therapy and is altered in many radiation-resistant tumors. This makes NAD+ metabolism an ideal target for therapies that increase radiation sensitivity and improve patient outcomes. This review provides an overview of NAD+ metabolism in the context of the cellular response to ionizing radiation, as well as current therapies that target NAD+ metabolism to enhance radiation therapy responses. Additionally, we summarize state-of-the-art methods for measuring, modeling, and manipulating NAD+ metabolism, which are being used to identify novel targets in the NAD+ metabolic network for therapeutic interventions in combination with radiation therapy

Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing

Atmospheric Peroxyacetyl Nitrate (PAN): A Global Budget and Source Attribution

Peroxyacetyl nitrate (PAN) formed in the atmospheric oxidation of non-methane volatile organic compounds (NMVOCs) is the principal tropospheric reservoir for nitrogen oxide radicals $(NO_x = NO + NO_2)$. PAN enables the transport and release of $NO_x$ to the remote troposphere with major implications for the global distributions of ozone and OH, the main tropospheric oxidants. Simulation of PAN is a challenge for global models because of the dependence of PAN on vertical transport as well as complex and uncertain NMVOC sources and chemistry. Here we use an improved representation of NMVOCs in a global 3-D chemical transport model (GEOS-Chem) and show that it can simulate PAN observations from aircraft campaigns worldwide. The immediate carbonyl precursors for PAN formation include acetaldehyde (44% of the global source), methylglyoxal (30%), acetone (7%), and a suite of other isoprene and terpene oxidation products (19%). A diversity of NMVOC emissions is responsible for PAN formation globally including isoprene (37%) and alkanes (14%). Anthropogenic sources are dominant in the extratropical Northern Hemisphere outside the growing season. Open fires appear to play little role except at high northern latitudes in spring, although results are very sensitive to plume chemistry and plume rise. Lightning $NO_x$ is the dominant contributor to the observed PAN maximum in the free troposphere over the South Atlantic.Engineering and Applied Science

Management of Fracture Risk in Patients with Chronic Obstructive Pulmonary Disease (COPD): Building a UK Consensus Through Healthcare Professional and Patient Engagement

Introduction: Osteoporosis and bone fractures are common in chronic obstructive pulmonary disease (COPD) and contribute significantly to morbidity and mortality. Current national guidance on COPD management recommends addressing bone health in patients, however, does not detail how. This consensus outlines key elements of a structured approach to managing bone health and fracture risk in patients with COPD.Methods: A systematic approach incorporating multifaceted methodologies included detailed patient and healthcare professional (HCP) surveys followed by a roundtable meeting to reach a consensus on what a pathway would look like.Results: The surveys revealed that fracture risk was not always assessed despite being recognised as an important aspect of COPD management by HCPs. The majority of the patients also stated they would be receptive to discussing treatment options if found to be at risk of osteoporotic fractures. Limited time and resource allocation were identified as barriers to addressing bone health during consultations. The consensus from the roundtable meeting was that a proactive systematic approach to assessing bone health should be adopted. This should involve using fracture risk assessment tools to identify individuals at risk, investigating secondary causes of osteoporosis if a diagnosis is made and reinforcing non-pharmacological and preventative measures such as smoking cessation, keeping active and pharmacological management of osteoporosis and medicines management of corticosteroid use. Practically, prioritising patients with important additional risk factors, such as previous fragility fractures, older age and long-term oral corticosteroid use for an assessment, was felt required.Conclusion: There is a need for integrating fracture risk assessment into the COPD pathway. Developing a systematic and holistic approach to addressing bone health is key to achieving this. In tandem, opportunities to disseminate the information and educational resources are also required

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

Objectives: The aim of the present study was to systematically evaluate the prodrome to mania in youth. Methods: New-onset/worsening symptoms/signs of \u3e= moderate severity preceding first mania were systematically assessed in 52 youth (16.2 +/- 2.8 years) with a research diagnosis of bipolar I disorder (BD-I). Youth and/or caregivers underwent semi-structured interviews, using the Bipolar Prodrome Symptom Scale-Retrospective. Results: The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid-onset-and-deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring \u3e= 3 symptoms, lasted 10.3 +/- 14.4 months [95% confidence interval (CI): 6.3-14.4], being present for \u3e= 4 months in 65.4% of subjects. Among prodromal symptoms reported in \u3e= 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had \u3e= 1 (84.6%), \u3e= 2 (48.1%), or \u3e= 3 (26.9%) \u27specific\u27 subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 +/- 14.9 months (95% CI: 5.0-14.0), 3.5 +/- 3.5 months (95% CI: 2.0-4.9), and 3.0 +/- 3.2 months (95% CI: 1.0-5.0) for \u3e= 1, \u3e= 2, or \u3e= 3 specific symptoms, respectively. Conclusions: In youth with BD-I, a relatively long, predominantly slowonset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania

Utilization of case presentations in medical microbiology to enhance relevance of basic science for medical students

Background : Small-group case presentation exercises (CPs) were created to increase course relevance for medical students taking Medical Microbiology (MM) and Infectious Diseases (ID) Methods : Each student received a unique paper case and had 10 minutes to review patient history, physical exam data, and laboratory data. Students then had three minutes to orally present their case and defend why they ruled in or out each of the answer choices provided, followed by an additional three minutes to answer questions. Results : Exam scores differed significantly between students who received the traditional lecture-laboratory curriculum (Group I) and students who participated in the CPs (Group II). In MM, median unit exam and final exam scores for Group I students were 84.4% and 77.8%, compared to 86.0% and 82.2% for Group II students (P&#x200A;&#60;&#x200A;0.018; P&#x200A;&#60;&#x200A;0.001; Mann-Whitney Rank Sum Test). Median unit and final ID exam scores for Group I students were 84.0% and 80.0%, compared to 88.0% and 86.7% for Group II students (P&#x200A;&#60;&#x200A;0.001; P&#x200A;&#60;&#x200A;0.001). Conclusion : Students felt that the CPs improved their critical thinking and presentation skills and helped to prepare them as future physicians