Citations

Abstract The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. The clinically applicable small-molecule BET inhibitor JQ1 suppressed the outgrowth of cisplatin-treated ovarian cancer cells both in vitro and in vivo. Combination of JQ1 and cisplatin improved the survival of ovarian cancer–bearing mice in an orthotopic model. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and other stem-related genes in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using clinically applicable small-molecule inhibitors, such as JQ1, is a promising strategy for targeting ALDH activity in epithelial ovarian cancer. Cancer Res; 76(21); 6320–30. ©2016 AACR.

Abstract Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.

Abstract Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.

Advances in the field of defibrillation have brought to practice different types of devices that include the transvenous implantable cardioverter-defibrillator (ICD) with or without cardiac resynchronization therapy, the subcutaneous ICD (S-ICD), and the wearable cardioverter-defibrillator. To ensure optimal use of these devices and to achieve best patient outcomes, clinicians need to understand how these devices work, learn the characteristics of patients who qualify them for one type of device versus another, and recognize the remaining gaps in knowledge surrounding these devices. The transvenous ICD has been shown in several randomized clinical trials to improve the survival of patients resuscitated from near-fatal ventricular fibrillation and those with sustained ventricular tachycardia with syncope or systolic heart failure as a result of ischemic or nonischemic cardiomyopathy despite receiving guideline-directed medical therapy. Important gaps in knowledge regarding the transvenous ICD involve the role of the ICD in patient subgroups not included, or not well represented, in clinical trials and the need to refine the selection criteria for the ICD in patients who are indicated for it. S-ICDs were recently introduced into the clinical arena as another option for many patients who have an approved indication for a transvenous ICD. The main advantage of the S-ICD is a lower risk of infection and lead-related complications; however, the S-ICD does not offer bradycardia or antitachycardia pacing. The S-ICD may be ideal for patients with limited vascular access, high infection risk, or some congenital heart diseases. However, more data are needed regarding the efficacy and effectiveness of the S-ICD in comparison to transvenous ICDs, the extent of defibrillation testing required, and the use of the S-ICD with other novel technologies, including leadless pacemakers. Cardiac resynchronization therapy-defibrillators are indicated in patients with a left ventricular ejection fraction ≤35%, QRS width ≥130 ms, and New York Heart Association class II, III, or ambulatory IV symptoms despite treatment with guideline-directed medical therapy. Multiple randomized controlled trials have shown that the cardiac resynchronization therapy-defibrillator improves survival, quality of life, and several echocardiographic measures. One main challenge related to cardiac resynchronization therapy-defibrillators is the 30% nonresponse rate. Many initiatives are underway to address this challenge including improved cardiac resynchronization therapy and imaging technologies and enhanced selection of patients and device programming.

SummaryA 51‐year‐old male was admitted to the intensive care unit following a cardiac arrest during which he received chest compressions and suffered rib fractures. The patient's condition subsequently improved and tracheal extubation was eventually planned. However, he was unable to tolerate spontaneous breathing trials due to pain from his rib fractures. Systemic analgesia provided either insufficient pain control or over‐sedation. Neuraxial techniques were contraindicated as he was receiving systemic anticoagulation and antiplatelet medications. Intercostal nerve blocks with liposomal bupivacaine were performed under ultrasound guidance without complications. Approximately six hours after the injections, the patients trachea was successfully extubated with no further need for respiratory support through to discharge. In appropriately selected patients, intercostal nerve blocks with liposomal bupivacaine can adequately treat pain from rib fractures and improve respiratory mechanics.

Air embolism is a rarely encountered but much dreaded complication of surgical procedures that can cause serious harm, including death. Cases that involve the use of endovascular techniques have a higher risk of air embolism; therefore, a heightened awareness of this complication is warranted. In particular, central venous catheters and arterial catheters that are often placed and removed in most hospitals by a variety of medical practitioners are at especially high risk for air embolism. With appropriate precautions and techniques it can be preventable. This article reviews the causes of air embolism, clinical management and prevention techniques.

Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 ( MMP1 , ANLN , CEP55 , and TFPI2 ) are known to play a role in ATC progression; however, 6/10 genes ( TMEM158 , CXCL5 , E2F7 , DLGAP5 , MME , and ASPM ) had not been specifically implicated in ATC. Similarly, 3/10 ( SFTA3 , LMO3 , and C2orf40 ) of the most globally downregulated genes were novel in this context, while 7/10 genes ( SLC26A7 , TG , TSHR , DUOX2 , CDH1 , PDE8B , and FOXE1 ) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors ( KLF16 , SP3 , ETV6 , FOXC1 , SP1 , EGFR1 , and MAFK ) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that “mitotic cell cycle” is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p -value <10 −30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.