MEG3-4 is a miRNA decoy that regulates IL-1ß abundance to initiate and then limit inflammation to prevent sepsis during lung infection.

Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1ß (IL-1ß), thereby increasing IL-1ß abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice. MEG3-4-mediated sponging of miR-138 in the cytoplasm increased the autocrine activity of IL-1ß that subsequently induced a negative feedback mechanism mediated by nuclear factor κB that decreased MEG3-4 abundance and inflammatory cytokine production. This timely reduction in MEG3-4 abundance tempered proinflammatory responses in mice with pulmonary bacterial infection, preventing the progression to sepsis. Together, these findings reveal that MEG3-4 dynamically modulates pulmonary inflammatory responses through transcriptional regulation of immune response genes, extending the decoy and sponge mechanism associated with lncRNAs to antibacterial immunity, which affects both response and disease progression.

Acute Subdural Hemorrhage Associated With Both Metastatic Adenocarcinoma of the Dura and Minor Head Trauma: A Case Report and Review of the Literature.

While reportedly a relatively common finding at the autopsy of decedents with metastatic neoplasms, dural metastases are infrequently described in the medical literature and only 55 cases of subdural hemorrhage associated with dural metastases have been described, with only one of these cases associated with head trauma. We report a 50-year-old incarcerated male who died as the result of acute and chronic subdural hemorrhage associated with recent minor head trauma and dural metastases, which were most likely of pancreatic origin. He had sustained a fall, possibly due to a seizure in his jail cell, developed an acute subdural hemorrhage, and died, necessitating an autopsy. Metastatic tumor in the dura and other organs was identified upon histologic examination and found to be CK7 and CK20 positive and TTF-1 and CDX2 negative, consistent with a pancreatic adenocarcinoma. In addition, marantic endocarditis was identified, which can occur in individuals with mucinous tumors, such as a pancreatic neoplasm. This case report offers the second description of a subdural hemorrhage occurring in association with both dural metastases and recent head trauma and confirms the importance of histologic examination of the subdural hemorrhage and adjacent dura at autopsy for reasons other than just timing of the event.

Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue.

We reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. We investigated the effects of resveratrol on DNMT and miRNA expression in normal and tumor mammary tissue in a rodent model of estrogen dependent mammary carcinoma. Eighty-nine female ACI rats received estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 wk of treatment, animals were sacrificed and mammary glands harvested. Matched tumor/normal tissues were available from 36 rats. DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (P = .04) and hi (P = .007) resveratrol and Aza treatment. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204, and -489 >twofold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, -204, and -489 in normal and/or tumor tissue. Treatment with resveratrol differentially influences tumor vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation.

Noncritically phase-matched fourth harmonic generation of Nd:glass lasers in partially deuterated KDP crystals.

Noncritically phase-matched (NCPM) fourth harmonic generation (FHG) of Nd:glass laser radiation in partially deuterated dihydrogen phosphate (KD*P) crystals has been demonstrated. At an Nd:glass laser wavelength of 1053.0 nm, NCPM FHG is achieved in 70% deuterated KD*P at a crystal temperature of 18.5±0.1 °C. Tuning the fundamental laser wavelength from 1052.9 to 1053.2 nm, FHG in KD*P is NCPM by changing the crystal temperature from 17.9 °C to 20.5 °C. When driven with 2.4 J of second harmonic radiation in a 3 ns flat-top pulse, corresponding to 1 GW/cm(2) 2ω drive intensity, 1.9 J of fourth harmonic radiation was generated in a 6 mm long KD*P crystal, yielding a second to fourth harmonic energy conversion efficiency of 79%.

Alternating systemic and hepatic artery infusion therapy for resected liver metastases from colorectal cancer: a North Central Cancer Treatment Group (NCCTG)/ National Surgical Adjuvant Breast and Bowel Project (NSABP) phase II intergroup trial, N9945/CI-66.

PURPOSE Prior trials have shown that surgery followed by hepatic artery infusion (HAI) of floxuridine (FUDR) alternating with systemic fluorouracil improves survival rates. Oxaliplatin combined with capecitabine has demonstrated activity in advanced colorectal cancer. Based on this observation a trial was conducted to assess the potential benefit of systemic oxaliplatin and capecitabine alternating with HAI of FUDR. The primary end point was 2-year survival. PATIENTS AND METHODS Patients with liver-only metastases from colorectal cancer amenable to resection or cryoablation were eligible. HAI and systemic therapy was initiated after metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m(2)/d FUDR and dexamethasone, day 1 through 14 weeks 1 and 2. Systemic therapy included oxaliplatin 130 mg/m(2) day 1 with capecitabine at 1,000 mg/m(2) twice daily, days 1 through 14, weeks 4 and 5. Two additional 3-week courses of systemic therapy were given. Capecitabine was reduced to 850 mg/m(2) twice daily after interim review of toxicity. Results Fifty-five of 76 eligible patients were able to initiate protocol-directed therapy and completed median of six cycles (range, one to six). Three postoperative or treatment-related deaths were reported. Overall, 88% of evaluable patients were alive at 2 years. With a median follow-up of 4.8 years, a total of 30 patients have had disease recurrence, 11 involving the liver. Median disease-free survival was 32.7 months. CONCLUSION Alternating HAI of FUDR and systemic capecitabine and oxaliplatin met the prespecified end point of higher than 85% survival at 2 years and was clinically tolerable. However, the merits of this approach need to be established with a phase III trial.

Unexpected neoplasia in autopsies: potential implications for tissue and organ safety.

CONTEXT: -Medical examiner cases are increasingly used as tissue donor referral sources to meet the ever-growing need for transplant tissues. The assumption is often made that traumatic and sudden deaths have minimal risk of unsuspected neoplasia. An autopsy of a registered tissue donor with strong preautopsy clinical assessment of a saddle pulmonary embolus revealed unsuspected acute lymphoblastic leukemia, prompting a review of the incidence of unsuspected neoplasia from a regional forensic autopsy practice. OBJECTIVE: -To determine the incidence of (1) unsuspected neoplasia, (2) clinical concordance of known neoplasia, and (3) potential donor referral in a regional forensic autopsy service. DESIGN: -A retrospective, 5-year review of 412 autopsies from a regional, primarily forensic, autopsy service to determine the incidence of unsuspected neoplasia, clinical concordance of known neoplasia, and the preautopsy assessment of potential donor referral suitability. RESULTS: -Unsuspected neoplasia rate at autopsy was 7% (29 of 412 patients); cancer was the cause of death in 41% (12 of 29 patients) of these individuals. In patients with a history of cancer, the discordance of cancer diagnosis was 44% (4 of 9 patients [11 patients with known cancer, 2 who refused medical evaluation were excluded from the study]). Nearly 60% (17 of 29 patients) of the unsuspected cancer cases had no apparent reason for deferral of tissue procurement before the autopsy examination. CONCLUSIONS: -The 7% incidence of unsuspected cancer in a forensic autopsy practice raises concern for the potential introduction of neoplastic tissue in the donor pool. To ensure the safety of this vital resource, mandatory complete autopsies on deceased donors are advocated as well as a tissue-recipient registry to track donor-related neoplasia.

Sexually transmitted Human Papillomavirus type variations resulting in high grade cervical dysplasia in North-East North Dakota and North-West Minnesota.

BACKGROUND: A review of Pap smear diagnoses from a reference laboratory in Grand Forks, North Dakota over a 3-year period (07/00 to 10/03) revealed a two-fold higher rate of high grade squamous intraepithelial lesion in a community in northwest Minnesota (Roseau, 0.486%) than in northeast North Dakota (Grand Forks, 0.249%), in spite of both having similar rates of low-grade squamous intraepithelial lesion (1.33% vs.1.30% respectively) OBJECTIVES: To identify the different types of HPV present in patient populations showing high-grade dysplasia in Grand Forks, ND and Roseau, MN. STUDY DESIGN: Formaldehyde-fixed paraffin-embedded cervical tissue samples were analyzed using polymerase chain reaction (PCR) to detect the presence of HPV type 16, 18 and 31. RESULTS: Our studies showed that 41% of samples from Roseau were triply infected with HPV serotypes 16, 18 and 31 in comparison to 12 % from Grand Forks. CONCLUSION: Due to the small sample size we were unable to prove the study to be statistically significant. However, our results suggest that the presence of HPV 16, 18 and 31 in triply infected samples may be the cause of the higher percentage of high-grade dysplasia in Roseau, MN when compared to Grand Forks, ND.