Bileaflet Aortic Valve Prosthesis Pivot Geometry Influences Platelet Secretion and Anionic Phospholipid Exposure

The clinical histories of the Medtronic Parallel (MP) and St. Jude Medical (SJM) Standard valves suggest pivot geometry influences the thrombogenic characteristics of bileaflet prostheses. This work studied the effects of various pivot geometries on markers of platelet damage in a controlled, in vitro apparatus. The Medtronic Parallel valve, two St. Jude Medical valves, and two demonstration prostheses were used to study the effects of bileaflet pivot design, gap width, and size on platelet secretion and anionic phospholipid expression during leakage flow. A centrifugal pump was used to drive blood through a circuit containing a bileaflet prosthesis. Samples were taken at set time intervals after the start of the pump. These samples were analyzed by cell counting, flow cytometry, and enzyme-linked immunosorbant assay. No significant differences were observed in platelet secretion or anionic phospholipid expression between experiments with the SJM 27 Standard regular leaker, the SJM 20 regular leaker, and the MP 27 valves. Significant differences in platelet secretion and anionic phospholipid expression were observed between a SJM 27 Standard regular leaker and a SJM 27 high leaker valve. These studies suggest that leakage gap width within bileaflet valve pivots has a significant effect on platelet damage initiated by leakage flow. © 2001 Biomedical Engineering Society. PAC01: 8719Uv, 8719Tt, 8380Lz, 8768+z     

Linkage mapping of a nonspecific form of X-linked mental retardation (MRX53) in a large Pakistani family

Nonspecific X-linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X-linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2-26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081.     

Evaluation of CINtec PLUS® testing as an adjunctive test in ASC‐US diagnosed SurePath® preparations

The CINtec PLUS® system is an immunohistochemical cocktail composed of antibodies against p16^INK4a (surrogate of HPV infection) and Ki‐67 (proliferation marker) meant to improve the sensitivity and specificity for detecting high‐grade dysplasia (HGD). In the presence of dysplasia, a red chromogen marks Ki‐67 expression in the nucleus and a brown chromogen marks cytoplasmic p16^INK4a expression. Only cells showing dual staining are interpreted as positive. This retrospective study examined the performance of CINtec PLUS testing when performed on ASC‐US diagnosed samples. Comparison was made to high‐risk HPV DNA test results and colposcopic biopsy results. Technical considerations in the interpretation of this immunohistochemical stain are additionally discussed. CINtec PLUS showed modest sensitivity (64%) and specificity (53%) in identifying the presence of HGD at surgical biopsy. Positive and negative predictive values for HGD were 28% and 83%, respectively. HR‐HPV DNA test yielded sensitivity of 100% and specificity of 21%. During interpretation, squamous metaplasia and endocervical cells were seen to show individual staining for p16^INK4a or Ki‐67. Individual staining, when present within three dimensional cellular groups common to SurePath® preparations, can be time‐intensive to interpret necessitating thoughtful examination at high power. The Pap test with HR‐HPV DNA testing is a highly sensitive test. A specific test is needed to prevent false positives and over treatment. The CINtec® system provides a modest increase in specificity beyond HR‐HPV DNA testing. Future study of its appropriateness and cost‐ffectiveness in a treatment algorithm are warranted. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies

Introduction: Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME.

Areas covered: The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists.

Expert opinion: Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.     

Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database

The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results–Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab?+?intravenous chemotherapy (R?+?IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R?+?IV Chemo were the youngest and had the lowest comorbidity burden (p?<?0.0001). In the multivariate survival analysis, receipt of R?+?IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR)?=?0.73; 95 % confidence interval (CI) 0.62–0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR?=?0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.     

p40 (ΔNp63) is more specific than p63 and cytokeratin 5 in identifying squamous cell carcinoma of bronchopulmonary origin: A review and comparative analysis

The therapeutic options now available for pulmonary squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) are very different. The increasing demand to make a diagnosis on minimal tissue, ancillary techniques such as immunohistochemistry (IHC) are need to be highly sensitive and specific. The IHC marker p40 (ΔNp63) is a truncated isoform of p63 that is a promising IHC marker for SQCC. In this study, we have compared the specificity of p40(ΔNp63) IHC with p63 and cytokeratin 5 (CK5) on fine‐needle aspiration (FNA) cell blocks (CB). Thirty cases of pulmonary SQCC and 30 cases of pulmonary ADC with CB were selected. IHC for p40(ΔNp63), p63, and CK5 were performed on all paraffin‐embedded CB serial sections. All cases (n = 30) of SQCC stained positive for p40(ΔNp63). All cases of bronchopulmonary ADC were negative for both p40(ΔNp63) and CK5. Six cases (20%) of bronchopulmonary ADC demonstrated nuclear staining for p63 in at least 10% of malignant cells. Our data support p40(ΔNp63) to be more sensitive and specific and possess a greater positive and negative predictive value for SQCC in comparison to p63. This study also documents that p40(ΔNp63) does not stain ADC, which p63 does in 20% of the cases. We also found that p40(ΔNp63) shows a greater sensitivity and negative predictive value when compared to CK5. In paucicellular CB the increased indices p40(ΔNp63) provides may be extremely helpful in confirming the diagnosis of SQCC, which may have significant therapeutic implications. Diagn. Cytopathol. 2014;42:453–458. © 2013 Wiley Periodicals, Inc.     

Lanthanide-Doped Upconversion Luminescent Nanoparticles—Evolving Role in Bioimaging,Biosensing, and Drug Delivery

Upconverting luminescent nanoparticles (UCNPs) are “new generation fluorophores” with an evolving landscape of applications in diverse industries, especially life sciences and healthcare. The anti-Stokes emission accompanied by long luminescence lifetimes, multiple absorptions, emission bands, and good photostability, enables background-free and multiplexed detection in deep tissues for enhanced imaging contrast. Their properties such as high color purity, high resistance to photobleaching, less photodamage to biological samples, attractive physical and chemical stability, and low toxicity are affected by the chemical composition; nanoparticle crystal structure, size, shape and the route; reagents; and procedure used in their synthesis. A wide range of hosts and lanthanide ion (Ln³⁺) types have been used to control the luminescent properties of nanosystems. By modification of these properties, the performance of UCNPs can be designed for anticipated end-use applications such as photodynamic therapy (PDT), high-resolution displays, bioimaging, biosensors, and drug delivery. The application landscape of inorganic nanomaterials in biological environments can be expanded by bridging the gap between nanoparticles and biomolecules via surface modifications and appropriate functionalization. This review highlights the synthesis, surface modification, and biomedical applications of UCNPs, such as bioimaging and drug delivery, and presents the scope and future perspective on Ln-doped UCNPs in biomedical applications.