Kinetic Control of Interpenetration in Fe-Biphenyl-4,4 '-dicarboxylate Metal-Organic Frameworks by Coordination and Oxidation Modulation

Phase control in the self-assembly of metal–organic frameworks (MOFs) is often a case of trial and error; judicious control over a number of synthetic variables is required to select the desired topology and control features such as interpenetration and defectivity. Herein, we present a comprehensive investigation of self-assembly in the Fe–biphenyl-4,4′-dicarboxylate system, demonstrating that coordination modulation can reliably tune between the kinetic product, noninterpenetrated MIL-88D(Fe), and the thermodynamic product, two-fold interpenetrated MIL-126(Fe). Density functional theory simulations reveal that correlated disorder of the terminal anions on the metal clusters results in hydrogen bonding between adjacent nets in the interpenetrated phase and this is the thermodynamic driving force for its formation. Coordination modulation slows self-assembly and therefore selects the thermodynamic product MIL-126(Fe), while offering fine control over defectivity, inducing mesoporosity, but electron microscopy shows MIL-88D(Fe) persists in many samples despite not being evident by diffraction. Interpenetration control is also demonstrated using the 2,2′-bipyridine-5,5′-dicarboxylate linker; it is energetically prohibitive for it to adopt the twisted conformation required to form the interpenetrated phase, although multiple alternative phases are identified due to additional coordination of Fe cations to its N donors. Finally, we introduce oxidation modulation—the use of metal precursors in different oxidation states from that found in the final MOF—to kinetically control self-assembly. Combining coordination and oxidation modulation allows the synthesis of pristine MIL-126(Fe) with BET surface areas close to the predicted maximum for the first time, suggesting that combining the two may be a powerful methodology for the controlled self-assembly of high-valent MOFs

Tumour inflammatory infiltrate predicts survival following curative resection for node-negative colorectal cancer

<b>Background</b>: A pronounced tumour inflammatory infiltrate is known to confer a good outcome in colorectal cancer. Klintrup and colleagues reported a structured assessment of the inflammatory reaction at the invasive margin scoring low grade or high grade. The aim of the present study was to examine the prognostic value of tumour inflammatory infiltrate in node-negative colorectal cancer. <b>Methods</b>: Two hundred patients had undergone surgery for node-negative colorectal cancer between 1997 and 2004. Specimens were scored with Jass’ and Klintrup’s criteria for peritumoural infiltrate. Pathological data were taken from the reports at that time. <b>Results</b>: Low-grade inflammatory infiltrate assessed using Klintrup’s criteria was an independent prognostic factor in node-negative disease. In patients with a low-risk Petersen Index (n = 179), low-grade infiltrate carried a threefold increased risk of cancer death. Low-grade infiltrate was related to increasing T stage and an infiltrating margin. <b>Conclusion</b>: Assessment of inflammatory infiltrate using Klintrup’s criteria provides independent prognostic information on node-negative colorectal cancer. A high-grade local inflammatory response may represent effective host immune responses impeding tumour growth

Carcinoid Tumour of the Appendix: An Analysis of 1,485 Consecutive Emergency Appendectomies

Aim: The aim of this study is to conduct a retrospective analysis of the incidence and long-term results of carcinoid tumours of the appendix in emergency appendectomies. Methods: A retrospective review of 1,485 appendectomies was performed in two centres from January 2000 until January 2006. Demographic data, clinical presentation, histopathology, operative reports and survival were scored and compared with the literature. Results: In three women and four men, carcinoid tumours were identified (0.47%). The mean age was 32.7 years (range, 20-59 years). The clinical presentation was resembling the symptoms of acute appendicitis in all cases. Laparoscopic appendectomy was the treatment of choice in five patients; in one of these patients, a conversion to laparotomy was necessary. The other two patients underwent primary open appendectomy. Five patients underwent additional surgery after the pathology report became available. Four patients underwent ileocecal resection; one other patient underwent right hemicolectomy. In none of the re-operation specimens was residual carcinoid tumour detected. After a mean follow-up of 65 months (range, 25-92), all patients were alive and disease- and symptom-free. Conclusion: Carcinoid tumours of the appendix most often present as acute appendicitis. It also emphasises the value of histopathological analysis of every removed appendix. The long-term prognosis of incidentally found carcinoids of the appendix is good

Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies

Identification and validation of oncologic miRNA biomarkers for Luminal A-like breast cancer

Introduction: Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Methods: Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n=54) and controls (n=56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n=10 Luminal A-like; n=10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n=44 Luminal A; n=46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated. Results: Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis ( miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652 ). The biomarker potential of 4 miRNAs ( miR-29a, miR-181a , miR-223 and miR-652 ) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p=0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs ( miR-29a, miR-181a and miR-652 ) could reliably differentiate between cancers and controls with an AUC of 0.80. Conclusion: This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype- specific breast tumor detection