Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness.

Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC. Cancer Immunol Res; 6(5); 528-38. ©2018 AACR.

The many flavors of tumor-associated B cells.

Little is known on the role of distinct B-cell subtypes in human malignancies. We have recently performed a multiplex characterization of B cells in patient-derived tumor-associated tissues, documenting the activation and antigen-driven differentiation of B cells in metastatic lymph nodes and neoplastic lesions. Here we discuss the role of B lymphocytes as antigen-presenting cells and catalysts of T cell-based immunotherapies in view of these findings.

Cigarette smoking in methadone maintained patients: an up-to-date review.

Tobacco dependence is the leading cause of preventable death and disability in the United States. While smoking prevalence among U.S. adults is 19.3%, the prevalence of smoking among methadone-maintained patients ranges between 73.5% and 94%. Most methadone-maintained smokers (76%-80%) desire to quit smoking; however only a minority of these smokers receive cessation treatment or referrals for smoking cessation intervention. Smoking cessation treatment in methadone-maintained patients has generally been successful in reducing the daily number of cigarettes smoked. Unfortunately, sustained cessation rates using nicotine replacement therapy and behavioral interventions have generally been low (0%-11%). Poor cessation outcomes may be partially explained by pharmacodynamic interactions between nicotine and methadone leading to increased reinforcement of smoking behavior. Further research is needed to improve smoking cessation rates in methadone-maintained patients.

Questioning the role of abuse in behavioral spells and epilepsy.

Past sexual trauma is frequently linked to the development of behavioral spells, present among 30% of patients admitted for video/EEG monitoring. Current attempts to verify and explore mechanisms in this reported association revealed that patients with epilepsy (n=58) and those with behavioral spells (n=38) did not differ in their self-report of past sexual trauma (among approximately 38% in each group). Ninety percent (90%) of men with behavioral spells endorsed past physical abuse, however, compared with 45% of men with epilepsy, and 40% of men with spells likely met current criteria for posttraumatic stress disorder. Among all patients, the presence of past physical, but not sexual, abuse positively predicted the diagnosis of spells rather than epilepsy. Current findings do not support a preponderance of sexual trauma in behavioral spells, yet within the subset of men with spells, greater exposure to physical abuse and current symptoms of posttraumatic stress disorder may be important etiological and sustaining factors.

Sexual abuse and lifetime diagnosis of psychiatric disorders: systematic review and meta-analysis.

OBJECTIVE: To systematically assess the evidence for an association between sexual abuse and a lifetime diagnosis of psychiatric disorders. PATIENTS AND METHODS: We performed a comprehensive search (from January 1980-December 2008, all age groups, any language, any population) of 9 databases: MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO, ACP Journal Club, CCTR, CDSR, and DARE. Controlled vocabulary supplemented with keywords was used to define the concept areas of sexual abuse and psychiatric disorders and was limited to epidemiological studies. Six independent reviewers extracted descriptive, quality, and outcome data from eligible longitudinal studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I(2) statistic was used to assess heterogeneity. RESULTS: The search yielded 37 eligible studies, 17 case-control and 20 cohort, with 3,162,318 participants. There was a statistically significant association between sexual abuse and a lifetime diagnosis of anxiety disorder (OR, 3.09; 95% CI, 2.43-3.94), depression (OR, 2.66; 95% CI, 2.14-3.30), eating disorders (OR, 2.72; 95% CI, 2.04-3.63), posttraumatic stress disorder (OR, 2.34; 95% CI, 1.59-3.43), sleep disorders (OR, 16.17; 95% CI, 2.06-126.76), and suicide attempts (OR, 4.14; 95% CI, 2.98-5.76). Associations persisted regardless of the victim's sex or the age at which abuse occurred. There was no statistically significant association between sexual abuse and a diagnosis of schizophrenia or somatoform disorders. No longitudinal studies that assessed bipolar disorder or obsessive-compulsive disorder were found. Associations between sexual abuse and depression, eating disorders, and posttraumatic stress disorder were strengthened by a history of rape. CONCLUSION: A history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.

Clinical utility of varenicline for smokers with medical and psychiatric comorbidity.

Chronic obstructive pulmonary disease (COPD) is a costly and deadly disease afflicting an estimated 210 million people and accounting for 5% of all global deaths. Exposure to cigarette smoke is the greatest risk factor for COPD in the developed world. Smoking cessation improves respiratory symptoms and lung function and reduces mortality among patients with COPD. Cigarette smokers with COPD and other co-morbid conditions such as cardiovascular disease and psychiatric illnesses should receive comprehensive tobacco treatment interventions incorporating efficacious pharmacotherapies. Varenicline, an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist, is the newest and most effective drug currently available to promote smoking cessation. In conjunction with behavioral interventions and clinical monitoring for potential side effects, varenicline offers great hope for reducing smoking-attributable death and disability.

Sexual abuse and lifetime diagnosis of somatic disorders: a systematic review and meta-analysis.

CONTEXT: Many patients presenting for general medical care have a history of sexual abuse. The literature suggests an association between a history of sexual abuse and somatic sequelae. OBJECTIVE: To systematically assess the association between sexual abuse and a lifetime diagnosis of somatic disorders. Data Sources and Extraction A systematic literature search of electronic databases from January 1980 to December 2008. Pairs of reviewers extracted descriptive, quality, and outcome data from included studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I(2) statistic was used to assess heterogeneity. STUDY SELECTION: Eligible studies were longitudinal (case-control and cohort) and reported somatic outcomes in persons with and without history of sexual abuse. RESULTS: The search identified 23 eligible studies describing 4640 subjects. There was a significant association between a history of sexual abuse and lifetime diagnosis of functional gastrointestinal disorders (OR, 2.43; 95% CI, 1.36-4.31; I(2) = 82%; 5 studies), nonspecific chronic pain (OR, 2.20; 95% CI, 1.54-3.15; 1 study), psychogenic seizures (OR, 2.96; 95% CI, 1.12-4.69, I(2) = 0%; 3 studies), and chronic pelvic pain (OR, 2.73; 95% CI, 1.73-4.30, I(2) = 40%; 10 studies). There was no statistically significant association between sexual abuse and a lifetime diagnosis of fibromyalgia (OR, 1.61; 95% CI, 0.85-3.07, I(2) = 0%; 4 studies), obesity (OR, 1.47; 95% CI, 0.88-2.46; I(2) = 71%; 2 studies), or headache (OR, 1.49; 95% CI, 0.96-2.31; 1 study). We found no studies that assessed syncope. When analysis was restricted to studies in which sexual abuse was defined as rape, significant associations were observed between rape and a lifetime diagnosis of fibromyalgia (OR, 3.35; 95% CI, 1.51-7.46), chronic pelvic pain (OR, 3.27; 95% CI, 1.02-10.53), and functional gastrointestinal disorders (OR, 4.01; 95% CI, 1.88-8.57). CONCLUSION: Evidence suggests a history of sexual abuse is associated with lifetime diagnosis of multiple somatic disorders.

Beta-defensin production by human colonic plasma cells: a new look at plasma cells in ulcerative colitis.

BACKGROUND: Previously, we showed that colonic epithelium of ulcerative colitis (UC) patients expresses increased levels of mRNA for 3 antimicrobial peptides, human beta-defensin 2 (hBD-2), hBD-3, and hBD-4 compared to controls. METHODS: Human colon mucosa was analyzed using double immunofluorescence staining, in situ hybridization, immunoelectron microscopy, and quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) with specific antibodies and probes in the respective assays. RESULTS: We demonstrate that lamina propria in colon from UC patients, Crohn's colitis patients, and controls contain cells that express hBD-2. These cells were identified as mature plasma cells by the highly specific CD138 marker, by their prominent IgA or IgG expression, and by their ultrastructural characteristics. By immunoelectron microscopy it was furthermore shown that the hBD-2 peptide was expressed in rough endoplasmic reticulum, the Golgi complex, and cytoplasmic vesicles, reflecting consecutive steps of synthesis and transport for secretion. Plasma cells were 2-3 times more abundant in UC colon than in control colon and Crohn's colitis. Moreover, plasma cells in UC colon expressed hBD-3 and hBD-4 mRNA. Additionally, hBD-2 mRNA expression was demonstrated in 3 out of 4 well-characterized plasma cell lines. CONCLUSIONS: Mature colonic plasma cells can express multiple beta-defensins. In UC, defensin production by plasma cells is probably clinically relevant since plasma cells accumulate in large numbers between the distorted crypts and muscularis mucosae, first focally than diffusely, so as to protect against microbial attack.

Vancomycin-resistant enterococci: colonization, infection, detection, and treatment.

Vancomycin-resistant enterococci (VRE) are becoming a major concern in medical practice. Their increased prevalence and their ability to transfer vancomycin resistance to other bacteria (including methicillin-resistant Staphylococcus aureus) have made them a subject of close scrutiny and intense investigation. Colonization is usually acquired by susceptible hosts in an environment with a high rate of patient colonization with VRE (eg, intensive care units, oncology units). Vancomycin-resistant enterococci can survive in the environment for prolonged periods (>1 week), can contaminate almost any surface, and can be passed from one patient to another by health care workers. Whether VRE colonization leads to infection depends on the health status of the patient. Whereas immunocompetent patients colonized with VRE are at low risk for infection, weakened hosts (patients with hematologic disorders, transplant recipients, or severely ill patients) have an increased likelihood of developing infection following colonization. Quinupristin-dalfopristin and linezolid are among the anti-infective agents that have recently become available to treat infection caused by VRE. Other antimicrobials are currently under development. Molecular techniques such as polymerase chain reaction and standard culture studies are being used to detect VRE colonization, infection, and outbreaks.

Epidemiology and mechanisms of glycopeptide resistance in enterococci.

PURPOSE OF REVIEW: This review updates epidemiologic trends and our understanding of glycopeptide resistance in enterococci. RECENT FINDINGS: Colonization and infection rates with vancomycin resistant enterococci continue to increase throughout the world while factors contributing to this rise continue to be defined. While no interventions exist to eradicate colonization, infection control procedures are cost effective and decrease the prevalence of vancomycin resistant enterococcal colonization and infection. New molecular methods show great promise in strengthening our ability to detect colonization with these bacteria. Furthermore, our understanding of the origin of vancomycin resistant enterococci continues to grow. Paenibacillus species found in soil have been found to carry homologues of vanA-associated glycopeptide resistance genes found in enterococci. Also, additional evidence supports previous data that VanB-associated resistance may have been horizontally transferred from gastrointestinal tract bacteria to enterococci. Finally, glycopeptide resistance has been transferred to methicillin-resistant Staphylococcus aureus in clinical practice on several occasions. SUMMARY: The prevalence of vancomycin resistant enterococci will likely continue to increase. Implementation of infection control strategies, in conjunction with deployment of advanced technologies for detection of vancomycin resistant enterococci, may curb this rise. The emergence of vancomycin resistant S. aureus is of concern.