It is clear that obesity increases the risk of many types of cancer, including breast cancer. However, the underlying molecular mechanisms by which obesity is linked to cancer risk remain to be ...defined. Herein, we report that circulating adipose fatty acid binding protein (A-FABP) promotes obesity-associated breast cancer development. Using clinical samples, we demonstrated that circulating A-FABP levels were significantly increased in obese patients with breast cancer in comparison with those without breast cancer. Circulating A-FABP released by adipose tissue directly targeted mammary tumor cells, enhancing tumor stemness and aggressiveness through activation of the IL-6/STAT3/ALDH1 pathway. Importantly, genetic deletion of A-FABP successfully reduced tumor ALHD1 activation and obesity-associated mammary tumor growth and development in different mouse models. Collectively, these data suggest circulating A-FABP as a new link between obesity and breast cancer risk, thereby revealing A-FABP as a potential new therapeutic target for treatment of obesity-associated cancers.
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•Circulating levels of A-FABP are elevated in obesity-associated breast cancer•Soluble A-FABP promotes mammary tumor stemness and aggressiveness•A-FABP-induced ALDH1 activity is dependent on IL-6/STAT3 signaling•A-FABP deficiency uncouples HFD-induced obesity and mammary tumor development
The links between obesity and cancer are not well understood. Hao et al. show that circulating adipose fatty acid binding protein (A-FABP) increases in obesity and promotes breast cancer by increasing mammary tumor stemness and aggressiveness through an IL-6/STAT3/ALDH1 axis. A-FABP could be a potential therapeutic target for obesity-associated cancers.
The diagnosis of pulmonary sarcoidosis can be established by a variety of techniques. Transbronchial lung biopsy is often the preferred approach, but it is frequently nondiagnostic and carries a risk ...of pneumothorax and bleeding. Mediastinoscopy is often suggested as the next diagnostic step but entails significant cost and associated morbidity. Endobronchial ultrasound (EBUS) with transbronchial needle aspiration (TBNA) is emerging as a safe, minimally invasive tool for the primary diagnosis of mediastinal and hilar lymphadenopathy. The purpose of this study was to assess the utility of EBUS-TBNA for pulmonary sarcoidosis.
Fifty consecutive patients who had been referred for EBUS-TBNA for suspected pulmonary sarcoidosis were included in the study. On-site cytology was used to assess the adequacy of the samples. The presence of noncaseating granulomas without necrosis in the appropriate clinical setting was deemed to be adequate for the diagnosis of pulmonary sarcoidosis. Patients with a negative EBUS-TBNA underwent further histologic biopsy or clinical follow-up to determine the final diagnosis.
Eighty-two lymph nodes with a median size of 16 mm (range, 4 to 40 mm) were punctured. EBUS-TBNA demonstrated noncaseating granulomas without necrosis in 41 of 48 patients (85%) with a final diagnosis of sarcoidosis. EBUS-TBNA, therefore, has a sensitivity of 85% for the primary diagnosis of pulmonary sarcoidosis.
EBUS-TBNA is a safe, minimally invasive tool for the primary diagnosis of pulmonary sarcoidosis that has a high diagnostic yield. EBUS-TBNA should be considered an appropriate alternative diagnostic technique for patients with suspected pulmonary sarcoidosis.
The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of ...logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant “persisters.”
Background
Factors underlying gastroparesis are not well defined.
Aims
We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative ...physiologic study.
Methods
We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations.
Results
Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities.
Conclusions
We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status.
Trail Registry
This study is registered with Clinicaltrials.gov under study # NCT03178370
https://clinicaltrials.gov/ct2/show/NCT03178370
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The objectives of this study were to characterize the appearance of normal, dysplastic, and frankly malignant airway lesion appearance under narrow-band imaging (NBI), and to determine if NBI, when ...used in conjunction with white light (WL) bronchoscopy, could improve detection of dysplasia and malignancy.
This was a prospective, partially blinded study at a university teaching hospital. Bronchoscopy was performed on 22 patients with known or suspected bronchial dysplasia or malignancy. Full airway examination was performed first under WL bronchoscopy and then under NBI. Directed endobronchial biopsies of likely dysplastic, malignant, and normal (control) areas were then performed and sent for examination by a pathologist blinded to the gross description of the lesion. Pathology interpretations were then compared to the corresponding WL and NBI images.
There were one malignant and four dysplastic lesions in 22 patients detected by NBI when findings by WL imaging were considered normal. In cases when the WL appearance was abnormal, NBI did not improve the diagnostic yield. The increased rate of detection of dysplasia and malignancy by NBI was statistically significant (p = 0.005).
NBI identified dysplasia or malignancy that was not detected by WL inspection in 23% of subjects. Further studies are needed to determine the efficacy of NBI in detection of premalignant airways lesions in an at-risk population.
Affiliation of authors Lindsay McElmurray, Dr. Michael Hughes, Dr. Hani Rashed, Dr. William Kennedy, Dr. Gwen Wendelschafer-Crabb, Dr. Xiu Yang, Dr. Mostafa Fraig and Christina Pinkston are updated ...through this erratum.
Oral IL-10 suppressed tumor growth in the APC
min/+
mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 ...and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.
Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma ...amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a physiological role for GABABR2 in the repair process of lung damage. GABABR2 agonists may play a potential therapeutic role in ALI.
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