Substance Use Disorders among Patients with Type 2 Diabetes: a Dangerous but Understudied Combination.

PURPOSE OF REVIEW: This paper reviews research on substance use and disorders (SUDs) among adults with diabetes. It describes epidemiological data on SUDs in persons with type 2 diabetes, overviews effects of substance use on diabetes outcomes, and discusses treatments for SUDs in patients with diabetes. RECENT FINDINGS: Rates of current smoking range from 10 to 26% and alcohol use disorders are 0-5%. Rates of illicit SUDs are 3-4%, but there are no population-based studies using nationally representative samples. Smoking increases the risk for long-term diabetes complications and premature death. Alcohol and illicit drug use can also impact long-term diabetes complications by impairing glucose homeostasis and adversely influencing self-management behaviors. There is mixed evidence about psychosocial smoking cessation interventions in adults with diabetes and little on alcohol and illicit SUD interventions. Limited data exist on pharmacotherapies for SUDs in this population, but a recent study suggests that varenicline is safe and effective for treating smoking in patients with diabetes. Substance use is an understudied problem in type 2 diabetes, and addressing substance use holds potential for improving outcomes. Additional large population-based epidemiological studies in those with type 2 diabetes are needed, particularly for alcohol and illicit SUDs. Longitudinal studies should be conducted to better understand the time course of diabetes onset and outcomes in relation to SUDs. Randomized controlled trials are needed to assess safety and efficacy of promising psychosocial and pharmacological interventions.

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events.

Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.

Patients with diabetes respond well to contingency management treatment targeting alcohol and substance use.

Alcohol and drug use contribute to the pathogenesis of diabetes and are associated with adverse health outcomes, but little research exists on treatments for substance use disorders (SUDs) in patients with diabetes. The aim of this study was to evaluate contingency management (CM) treatments targeting substance use in patients with diabetes. A secondary analysis evaluated the main and interactive effects of diabetes status and treatment condition on outcomes of 681 substance abusers. All participants were enrolled in randomized clinical trials comparing CM to standard care (SC). Overall, CM treatment improved outcomes. There was also a significant treatment condition X diabetes status interaction effect in terms of duration of abstinence achieved and proportion of negative samples submitted; patients with diabetes responded even more favorably than their counterparts without diabetes when receiving CM. Analyses of post-treatment effects revealed that patients with diabetes, regardless of the type of SUD treatment to which they were earlier assigned, were more likely than those without diabetes to be abstinent at the nine-month follow-up. The findings suggest CM may be an effective treatment for this vulnerable subgroup of substance-abusing patients.

Response effort and resurgence.

This study provides an initial translational examination of response effort and resurgence. Eleven typically developing adults and five adolescents with autism served as participants across two experiments. Participants received points for touching moving stimuli on a computer screen. The resurgence evaluation consisted of three phases: establishment wherein R1 was reinforced, elimination wherein R1 was placed on extinction while R2 was reinforced, and extinction wherein R1 and R2 no longer resulted in reinforcement. Rate of R1 during extinction was compared across three conditions: intermediate, easy, and difficult. Disparity in effort was created by manipulations of the size and speed of objects that moved about on a computer screen. In Experiment 2, control stimuli were added to the experimental arrangement. Across the two experiments, the magnitude of resurgence was greater when R1 was easy. In Experiment 2, both R1 and control responding were greater in the extinction phase than in the elimination phase in all conditions with all participants. The present study supports the hypothesis that response effort affects resurgence and that less effortful responses are likely to recur with greater magnitude under conditions that produce resurgence than are their more effortful counterparts.

Suspected tetanus in an unvaccinated pediatric patient.

Tetanus is a vaccine-preventable neuromuscular disease with a high mortality rate. The incidence of tetanus in developed countries has significantly declined due to preventive vaccination measures, but the potential for long-term complications and mortality from this disease remains high in the unvaccinated population. There are only a few individual case reports of tetanus in the pediatric population in the United States. We present a case of suspected tetanus in a 10-year-old unvaccinated child in Central Texas who sustained multiple cardiovascular and pulmonary complications during a 1-month hospitalization course. This case highlights the importance of pediatric immunization for prevention of this potentially fatal disease process and its long-term complications. Physicians should maintain a high clinical suspicion for tetanus infection in unvaccinated children to prevent delay in necessary treatment.

Retropharyngeal abscess in the setting of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a potentially severe inflammatory syndrome following recent infection with SARS-CoV-2 (COVID-19). In this report, we describe a 13-year-old boy with a retropharyngeal abscess unresponsive to initial antibiotic therapy who was found to have findings consistent with MIS-C, which included elevated interleukin-6, ferritin, and troponin levels. The patient had COVID-19 infection due to the Omicron variant.

The effects of a workplace intervention on employees' cortisol awakening response.

Work-related stressors are known to adversely affect employees' stress physiology, including the cortisol awakening response (CAR) - or the spike in cortisol levels shortly after people wake up that aids in mobilizing energy. A flat or blunted CAR has been linked to chronic stress and burnout. This daily diary study tested the effects of a workplace intervention on employed parents' CAR. Specifically, we tested whether the effects of the intervention on CAR were moderated by the type of days (workday versus non-work day). Data came from 94 employed parents from an information technology firm who participated in the baseline and 12-month diurnal cortisol components of the Work, Family, and Health Study, a group-randomized field experiment. The workplace intervention was designed to reduce work-family conflict (WFC) and implemented after the baseline data collection. Diurnal salivary cortisol was collected on 4 days at both baseline and 12 months. Multilevel modeling revealed that the intervention significantly increased employees' CAR at 12 months on non-workdays, but this was not evident on workdays or for employees in the usual practice condition. The results provide evidence that the intervention was effective in enhancing employees' biological stress physiology particularly during opportunities for recovery that are more likely to occur on non-work days.

Palladin is overexpressed in the non-neoplastic stroma of infiltrating ductal adenocarcinomas of the pancreas, but is only rarely overexpressed in neoplastic cells.

BACKGROUND: It has recently been suggested that overexpression of palladin in sporadic pancreatic cancer may contribute to pancreatic cancer's invasive and migratory abilities. This hypothesis was based on reverse transcriptase-polymerase chain reaction analyses of bulk pancreatic tissue, yet pancreatic cancer is a complex admixture of neoplastic epithelial cells and desmoplastic stroma. DESIGN: Immunohistochemical labeling of tissue microarrays was used to define the patterns of palladin protein expression in 177 ductal adenocarcinomas of the pancreas. Western blot analysis was used to determine the epitope(s) of palladin recognized by the antibody as well as the relative levels of palladin expression in short-term cultures of stromal fibroblasts, non-neoplastic ductal cells and pancreatic cancer cell lines. RESULTS: Immunolabeling revealed that the palladin protein was strongly overexpressed in non-neoplastic stromal cells in 171 (96.6%) of the 177 evaluable pancreatic cancers. By contrast, the overexpression of palladin protein by the neoplastic epithelial cells relative to normal pancreatic epithelium was observed in only 22 (12.4%) of the 177 cancers. Western blot analysis confirmed that the antibody recognizes the -90 kDa isoform of palladin, and demonstrated that fibroblast cell lines had higher expression of palladin than pancreatic cancer cell lines. CONCLUSIONS: The overexpression of palladin relative to normal pancreas in the majority of pancreatic cancers is limited to non-neoplastic stromal cells. This observation highlights the limitations of relying on bulk tissues when analyzing gene expression. Since palladin is not overexpressed in most pancreatic cancer cells, the overexpression of palladin is not likely to be responsible for pancreatic cancer cells invasive and migratory abilities.

StressHacker: Towards Practical Stress Monitoring in the Wild with Smartwatches.

In modern life, the nonstop and pervasive stress tends to keep us on long-lasting high alert, which over time, could lead to a broad range of health problems from depression, metabolic disorders to heart diseases. However, there is a stunning lack of practical tools for effective stress management that can help people navigate through their daily stress. This paper presents the feasibility evaluation of StressHacker, a smartwatch-based system designed to continuously and passively monitor one's stress level using bio-signals obtained from the on-board sensors. With the proliferation of smartwatches, StressHacker is highly accessible and suited for daily use. Our preliminary evaluation is based on 300 hours of data collected in a real-life setting (12 subjects, 29 days). The result suggests that StressHacker is capable of reliably capturing daily stress dynamics (precision = 86.1%, recall = 91.2%), thus with great potential to enable seamless and personalized stress management.

"Waste not, want not": determining the optimal priming volume for intravenous insulin infusions.

BACKGROUND: Insulin adsorbs to plastics used for intravenous (IV) tubing. As a result, clinical IV insulin infusion procotols advise an initial priming volume of up to 50 mL, which may be wasteful-especially since most institutions use 100-mL IV solution bags. In this brief report, we sought to determine the optimal priming volume required for clinical IV insulin infusions. METHODS: One hundred units of regular human insulin was dissolved into 100 mL of 0.9% NaCl. Employing a standard polypropylene infusion set, a priming infusion was started. At 10- mL intervals, from 0 to 50 mL, effluent was collected directly into glass vials. After dilution (1:10,000) using a proprietary buffer, insulin concentrations were then measured using a double antibody radioimmunoassay. Twenty individually prepared insulin bags were tested in this manner. RESULTS: Insulin levels without prime were 15.8% [95% confidence interval (CI), 9.1-22.6%] lower than insulin levels following 50 mL of prime (designated as "maximal values"). After a priming volume of 10 mL, insulin adsorption losses fell to a marginally significant 6.6% (95% CI, 0.1-13.1%). Following 20 mL of prime, insulin concentrations were indistinguishable from maximal values (3.4% loss, 95% CI, -0.2% to 7.1%). CONCLUSIONS: For standard IV insulin infusions, a priming volume of 20 mL is sufficient to minimize the effect of insulin adsorption losses to IV lines. Priming volumes exceeding 20 mL are wasteful, increase costs, and generate unnecessary work for nurses and pharmacists.

Motivation and Contingency Management Treatments for Substance Use Disorders.

Contingency management (CM) is a highly efficacious psychosocial treatment for substance use disorders based on the principles of behavioral analysis. CM involves delivering a tangible positive reinforcer following objective evidence of submission of a drug-negative urine sample. Although CM interventions primarily involve applying extrinsic rewards, a patient's intrinsic motivation to change substance use behavior may also be impacted by CM. This chapter provides an introduction to CM interventions for substance use disorders and examines the impact of CM on intrinsic motivation . It also addresses applications of this intervention to other conditions and patient populations.

Lifetime suicide attempt history, quality of life, and objective functioning among HIV/AIDS patients with alcohol and illicit substance use disorders.

This cross-sectional study evaluated lifetime prevalence of suicide attempts in 170 HIV/AIDS patients with substance use disorders and the impact of suicide attempt history on subjective indices of quality of life and objective indices of cognitive and physical functioning. All patients met the diagnostic criteria for past-year cocaine or opioid use disorders and 27% of patients also had co-occurring alcohol use disorders. Compared to their counterparts without a history of a suicide attempt, patients with a history of a suicide attempt (n = 60, 35.3%) had significantly poorer emotional and cognitive quality of life scores (ps < .05), but not physical, social, or functional/global quality-of-life scores. Lifetime suicide attempt status was unrelated to objective indices of cognitive functioning, but there was a non-significant trend (p = .07) toward lower viral loads in those with a lifetime suicide attempt relative to those without. The findings indicate that suicide attempt histories are prevalent among HIV/AIDS patients with substance use disorders and relate to poorer perceived emotional and cognitive quality of life, but not objective functioning. HIV/AIDS patients with substance use disorders should be screened for lifetime histories of suicide attempts and offered assistance to improve perceived emotional and cognitive functioning.

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110ß.

Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110ß D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived.

A higher prevalence of epigenetic inactivation of tumor suppressor genes has been reported in cancer cell line populations compared to primary cancer populations. Cancer-related genes are commonly methylated in cancer cell lines but it is not known the extent to which tumor suppressor genes may be artificially methylated in vitro. We therefore examined 10 pancreatic cancer cell lines and corresponding primary tumors for aberrant DNA methylation of promoter CpG islands of eight genes and seven CpG islands. Using methylation-specific PCR (MSP), methylation was not detected at any of the 15 CpG islands in 15 normal pancreata or in an immortalized normal pancreatic duct epithelial (HPDE) cell line. Of 150 loci examined, 49 loci were methylated in both primary carcinomas and their corresponding cell lines, 95 loci were not methylated in either cell lines or their corresponding primary carcinomas. There were four loci methylated only in cell lines while another two loci were methylated only in primary carcinomas. Overall, the methylation status of primary carcinomas and their cell lines were concordant in 96% of cases (144 of 150) (J statistic; J=0.92, P<0.0001). We conclude that most of the DNA methylation of tumor suppressor genes observed in cancer cell lines is present in the primary carcinomas from which they were derived.

Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues.

PURPOSE: Hypermethylation of CpG islands in the promoters of selected genes is a common feature of neoplasia. Aberrant methylation of cyclin D2 has been observed in several cancers. We investigated the methylation of cyclin D2 in aging and pancreatic neoplastic development, and the utility of cyclin D2 methylation as a marker of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Methylation-specific PCR was performed on DNA from 165 resected pancreatic exocrine neoplasms [109 adenocarcinomas, 46 intraductal papillary-mucinous neoplasms (IPMNs), and 10 mucinous cystic neoplasms], 14 pancreatic intraepithelial neoplasms, 13 microdissected-normal pancreatic ductal epithelia, 25 normal pancreatic parenchyma, 51 specimens of pancreatic juice obtained perioperatively, 15 pancreatic cancer xenografts, 22 pancreatic cancer cell lines, 59 specimens of normal duodenum, and 49 gallbladders affected by cholecystitis. Cyclin D2 RNA expression was determined in pancreatic cancer cell lines, before and after 5-AZA-2'-deoxycytidine treatment, by reverse transcription-PCR. RESULTS: Methylation of cyclin D2 was identified in 65.1% (71 of 109) of primary pancreatic adenocarcinomas, in 50% (23 of 46) of IPMNs, and in 70% (7 of 10) of mucinous cystic neoplasms, but was detected infrequently in microdissected samples of normal pancreatic epithelia [7.7% (1 of 13)] and in pancreatic intraepithelial neoplasms [14.3% (2 of 14)]. Cyclin D2 methylation was also recognized in 10 of 15 (66.7%) pancreatic cancer xenografts and in 19 of 22 (86.4%) pancreatic cancer cell lines. All of 10 pancreatic cancer cell lines completely methylated at cyclin D2 showed no expression by reverse transcription-PCR. Four of these 10 cell lines were treated with 5-AZA-2'-deoxycytidine, and all 4 showed increased RNA expression of cyclin D2 after treatment. In pancreatic juice, cyclin D2 methylation was detected in 9 of 22 (40.9%) samples from patients with pancreatic cancer and in 6 of 9 (66.7%) patients with IPMNs, but in none of 20 non-neoplastic controls, respectively (P = 0.0013 and P < 0.0001, respectively). Methylation of cyclin D2 was also observed more in non-neoplastic tissues and with increasing age (P = 0.041 in the pancreas, P = 0.047 in the duodenum, and P = 0.0008 in the gallbladder). CONCLUSIONS: The promoter region of cyclin D2 undergoes age-related methylation in multiple tissues, but aberrant methylation is more often detected in tissues and juice samples of pancreatic cancer than in normal tissues. The detection of cyclin D2 methylation in pancreatic juice may aid in the diagnosis of pancreatic adenocarcinoma.

Xenografting and harvesting human ductal pancreatic adenocarcinomas for DNA analysis.

Xenotransplantation (xenografting) of primary cancers or cancer cell lines into immunodeficient mice is a commonly used technique to assess tumor growth in response to a variety of experimental agents. When primary pancreatic cancers are xenografted, cancer cells proliferate in the mouse, but the human stroma does not. This growth pattern enables facile genetic analysis of cancer genetics profiles without the contamination of admixed stromal cells typical of primary cancers.

Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice.

The aim of this study was to determine the utility of detecting methylated ppENK and pi6 in pancreatic juice by methylation specific PCR as a marker of pancreatic adeno-carcinoma. Pancreatic juice samples were collected either intraoperatively, from 92 patients undergoing pancreaticoduodenectomy for benign (n=20) and malignant periampullary disease (n = 72) or endoscopically (by duodenal aspiration after secretin infusion), from 13 patients undergoing investigation for pancreatic disease. Methylated ppENK was detected in the pancreatic juice of 30 (66.7%) of 45 patients with pancreatic ductal adenocarcinoma, in 4 (44.4%) of 9 patients with intraductal papillary-mucinous adenocarcinoma, and in 7 (41.2%) of 17 patients with other periampullary carcinomas, using methylation specific PCR. Methylated pi6 was detected in a lower percentage of these patients (11.1%, 11.1% and 23.5%, respectively). In contrast, methylated ppENK and pi6 were not detected in 20 patients with non-malignant periampullary disease including 12 patients with chronic pancreatitis. Methylated ppENK was detected in 30 of 33 (90.9%) primary pancreatic adenocarcinoma and methylated pi6 was in 6/33 (1 8.2%). Despite the absence of ppENKand pi6 methylation in normal pancreas, methylated ppENK and pi6 was present in the duodenum of 90.5% and 28.6%, respectively of patients without cancer. Further, methylated ppENK and pi6 was seen in 88.9% and 11.1%, respectively of pancreatic juice samples obtained by duodenal aspiration from patients without cancer. We conclude that since ppENK and pi6 are not normally methylated in pancreatic secretions, detection of methylated ppENK and pi6 in pure pancreatic juice obtained by direct cannulation of the pancreatic duct to avoid duodenal secretions may suggest the presence of pancreatic adenocarcinoma

Discovery and development of DNA methylation-based biomarkers for lung cancer.

Lung cancer remains the primary cause of cancer-related deaths worldwide. Improved tools for early detection and therapeutic stratification would be expected to increase the survival rate for this disease. Alterations in the molecular pathways that drive lung cancer, which include epigenetic modifications, may provide biomarkers to help address this major unmet clinical need. Epigenetic changes, which are defined as heritable changes in gene expression that do not alter the primary DNA sequence, are one of the hallmarks of cancer, and prevalent in all types of cancer. These modifications represent a rich source of biomarkers that have the potential to be implemented in clinical practice. This perspective describes recent advances in the discovery of epigenetic biomarkers in lung cancer, specifically those that result in the methylation of DNA at CpG sites. We discuss one approach for methylation-based biomarker assay development that describes the discovery at a genome-scale level, which addresses some of the practical considerations for design of assays that can be implemented in the clinic. We emphasize that an integrated technological approach will enable the development of clinically useful DNA methylation-based biomarker assays. While this article focuses on current literature and primary research findings in lung cancer, the principles we describe here apply to the discovery and development of epigenetic biomarkers for other types of cancer.