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Does flat epithelial atypia have rounder nuclei than columnar cell change/hyperplasia? A morphometric approach to columnar cell lesions of the breast.

Columnar cell lesions of the breast encompass columnar cell change/hyperplasia (CCC/CCH) and flat epithelial atypia (FEA). These have attracted researchers because emerging data suggest that FEA may represent the earliest histologically detectable non-obligate precursor of breast cancer. However, it is occasionally difficult to distinguish FEA from CCC/CCH because of similar histology. Although the nuclei of FEA are frequently described as relatively round compared with those of CCC/CCH, there are few morphometric studies to support this statement. The aim of this study was to provide objective data as to the nuclear shape in columnar cell lesions. As a shape descriptor, we adopted ellipticity that is defined by the formula 2b/2a, where a is the length of the long axis of the ellipse and b is the length of the short axis. Contrary to circularity, ellipticity reflects the overall configuration of an ellipse irrespective of surface irregularity. Our image analysis included generating whole slide images, extracting glandular cell nuclei, measuring nuclear ellipticity, and superimposing graded colors based on execution of results on the captured images. A total of 7917 nuclei extracted from 22 FEA images and 5010 nuclei extracted from 13 CCC/CCH images were analyzed. There was a significant difference in nuclear roundness between FEA and CCC/CCH with mean ellipticity values of 0.723 and 0.679, respectively (p &lt; 0.001, Welch’s t test). Furthermore, FEA with malignancy had significantly rounder nuclei than FEA without malignancy (p &lt; 0.001). Our preliminary results suggest that nuclear ellipticity is a key parameter in reproducibly classifying columnar cell lesions of the breast.

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Helicobacter pylori: Past, Current, Future treatment strategies with gasrtoretentive drug delivery systems.

H. pylori have been subject to intense investigation since its discovery from gastric biopsy in 1982. This gastropathogen has been regarded as serious public health problem due to its association with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. In vivo eradication of established H. pylori infections is difficult due to several factors such as gastric niche, coccoid form due to sub minimum inhibitory concentration of antimicrobials, bacterial load, primary antibiotic resistance, patient compliance and stability of therapeutics in gastric acid secretion. Considering these factors, a logical way to improve the outcome of the treatment is to develop dosage forms which are able to deliver the anti-helicobacter agents in the gastric niche for both local and systemic action, simultaneously taking care of stability of therapeutics in acidic environment. Such dosage forms, which are popularly known as gastro retentive drug delivery systems (GRDDS), have the immense potential to effectively counter the problem of high bacterial load; prevent induction of coccoid bacteria thereby improving treatment outcome and compliance. This review describes efficacy of various therapeutic agents, treatment strategies and status of different GRDDS until now.

Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.

Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or &quot;slow&quot; substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.

Celator® Pharmaceuticals Announces New Data for VYXEOS™ in FLT3-ITD Mutated AML Cells Derived from Patients with Newly Diagnosed AML to be Presented at the American Association for Cancer Research Annual Meeting

On March 31, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that data for VYXEOS (cytarabine:daunorubicin) Liposome for Injection (also known as CPX-351), its lead product candidate, will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, April 16-20, 2016 (Press release, Celator Pharmaceuticals, MAR 31, 2016, View Source [SID:1234510229]).

The research was conducted in the laboratory of Dr. Jeffrey Tyner at Oregon Health & Science University. The objective of the research was to examine the ex vivo sensitivity of acute myeloid leukemia (AML) cells derived from newly diagnosed patients to VYXEOS. This work supports the observed clinical benefit of VYXEOS in high-risk AML patients and may provide a means of identifying patient genotypes/phenotypes most sensitive to VYXEOS.

"We continue to learn more about the unique activity of VYXEOS in AML and enhance our ability to match this performance with specific patient characteristics that could be predictive of improved outcomes," said Lawrence Mayer, Ph.D., President and Chief Scientific Officer at Celator. "The research being undertaken by Dr. Tyner reflects Celator’s goal to elucidate the clinical benefits of VYXEOS by expanding our scientific understanding of its mechanism of action, particularly in AML cells with important molecular phenotypes."

Details on the AACR (Free AACR Whitepaper) poster presentation:

Presentation Title:
CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes
Date/Time:
Sunday, April 17, 2016 – 1:00pm-5:00pm
Session Category:
Poster Presentation
Session Title:
ET01-03, Combination Chemotherapy
Location:
New Orleans Convention Center, Halls G-J Poster Section 15
Abstract Number:
287

The poster will be available on Celator’s website (www.celatorpharma.com) at the conclusion of the AACR (Free AACR Whitepaper) meeting.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.
VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.
Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).
VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.