A Canadian approach to the regionalization of testis cancer: A review

At the Canadian Testis Cancer Workshop, the rationale and feasibility of regionalization of testis cancer care were discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, and nurses, as well as patients and patient advocacy groups. This review summarizes the discussion and recommendations of one of the central topics of the workshop — the centralization of testis cancer in Canada. It was acknowledged that non-guideline-concordant care in testis cancer occurs frequently, in the range of 18–30%. The National Health Service in the U.K. stipulates various testis cancer care modalities be delivered through supra-regional network. All cases are reviewed at a multidisciplinary team meeting and aspects of care can be delivered locally through the network. In Germany, no such network exists, but an insurance-supported online second opinion network was developed that currently achieves expert case review in over 30% of cases. There are clear benefits to regionalization in terms of survival, treatment morbidity, and cost. There was agreement at the workshop that a structured pathway for diagnosis and treatment of testis cancer patients is required. Regionalization may be challenging in Canada because of geography; independent administration of healthcare by each province; physicians fearing loss of autonomy and revenue; patient unwillingness to travel long distances from home; and the inability of the larger centers to handle the ensuing increase in volume. We feel the first step is to identify the key performance indicators and quality metrics to track the quality of care received. After identifying these metrics, implementation of a “networks of excellence” model, similar to that seen in sarcoma care in Ontario, could be effective, coupled with increased use of health technology, such as virtual clinics and telemedicine

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Evidence of Chromosomal Instability in Prostate Cancer Determined by Spectral Karyotyping (SKY) and Interphase FISH Analysis

The way in which cytogenetic aberrations develop in prostate cancer (CaP) is poorly understood. Spectral karyotype (SKY) analysis of CaP cell lines has shown that they have unstable karyotypes and also have features associated with chromosomal instability (CIN). To accurately determine the incidence of de novo structural and numerical aberrations in vitro in CaP, we performed SKY analysis of three independent clones derived from one representative cell line, DU145. The frequent generation of new chromosomal rearrangements and a wide variation in the number of structural aberrations within two to five passages suggested that this cell line exhibited some of the features associated with a CIN phenotype. To study numerical cell-to-cell variation, chromosome 8 aneusomy was assessed in the LNCaP, DU145, and PC-3 cell lines and a patient cohort of 15 CaP primary tumors by interphase fluorescence in situ hybridization (FISH). This analysis showed that a high frequency of numerical alteration affecting chromosome 8 was present in both in vitro and in CaP tissues. In comparison to normal controls, the patient cohort had a statistically significant (P<.05), greater frequency of cells with one and three centromere 8 copies. These data suggest that a CIN-like process may be contributing towards the generation of de novo numerical and structural chromosome abnormalities in CaP

Experiential Education and Access-to-Justice in U.S. Law Schools: Designing and Evaluating an Access-to-Justice Service Learning Program within the First-Year Curriculum

In this Article, we describe the creation and evaluation of a curricular intervention designed to help first-year law students develop lawyering skills while fostering their ethical and social-emotional development. We call this curricular intervention an Access-to-Justice Service Learning Program. We believe that, at the time of this writing, this was the first such program administered within the first-year curriculum of a U.S. law school. We designed and launched this Access-to-Justice Service Learning Program in Fall 2016 within the first- year curriculum of the Indiana University Maurer School of Law. In so doing, we taught 187 first-year law students how to put into practice human-centered design thinking, perspective-taking, and professional skills to promote access to justice. While human-centered design thinking is increasingly being woven into law school curricula in upper-level project management courses to address access-to-justice problems—including at Stanford Law School, Harvard Law School, and Georgetown University Law Center—this Access-to-Justice Service Learning Program was introduced within the first-year curriculum to teach students the professional skills, human-centered design thinking, and problem-solving techniques necessary to enhance access to justice for low-income members of society. U.S. law schools are increasingly being called to train their students to become ethical members of society who address access-to-justice challenges that the public experiences when encountering and navigating the civil justice system. Millions of Americans lack meaningful access to justice and suffer from unmet legal needs.3 For most low-income and many middle-income people living in the United States, the inability to receive legal advice or secure legal representation renders our civil justice system inaccessible. Absent legal advice, many Americans often fail to understand that legal relief is available for the problems they encounter “at the intersection of civil law and everyday adversity” such as problems that affect human needs, including shelter, livelihood, and the care of dependents. Moreover, even when people do realize their problems are potentially addressable through law, most poor and many middle-income people are left to navigate complex procedures and bewildering bureaucracies in search of legal relief without counsel, which only serves to compound their problems. Given the reality that many Americans are unable to defend their legal rights, wide swaths of U.S. society become vulnerable to those who, casting aside ethics and morality, have an economic incentive to engage in abuse. In turn, interlocking webs of social, environmental, financial, and health problems stemming from unmet legal needs metastasize into social, psychological, environmental, financial, and health problems that imperil human well-being. This Access-to-Justice Service Learning Program was designed to help law students understand the values that guide our profession—including a commitment to the rule of law, access to justice, and public service—and to help law students empathize with those affected by the civil justice system. First-year law students learned the perspectives of affected members of the community and were matched with legal-aid partners, such as Indiana Legal Services, the United States District Court for the Southern District of Indiana, the Neighborhood Christian Legal Clinic, and the Indianapolis Legal Aid Society. These first-year law students worked with community partners to help deliver legal services more effectively to low-income members of the community by engaging in a human-centered access-to-justice design process. Our evaluation of the program reveals the curriculum may be promising as an intervention in the first-year curriculum within U.S. law schools. The first- year law students who took part grew not only as individuals, but by working together in teams, they also developed as future members of the legal profession. The Article will proceed as follows: In Part I, we will situate the curricular intervention by introducing the three apprenticeships implicit in legal education and theorized by the Carnegie Foundation’s 2007 report, as well as the rise of experiential pedagogies in law schools more generally. In Part II, we will describe human- centered civil justice design and human-centered design thinking in technologies that address access-to-justice barriers. In Part III, we will describe the creation of the program, including the ways in which we backward designed the program from the law school’s J.D. learning outcomes, and forward designed the program to address the cognitive, emotional, and experiential bottlenecks law students experience in the first-year curriculum. In Part IV, we will discuss the results of an empirical analysis of the program that harnesses a variety of quantitative and qualitative data and uses results from the Law School Survey of Student Engagement (LSSSE)

Ancrod improves survival in murine systemic lupus erythematosus

Ancrod improves survival in murine systemic lupus erythematosus. The effect of ancrod, a defibrinating agent, on murine lupus glomerulonephritis in the male BXSB mouse was studied to determine the relationship between macrophage procoagulant activity (PCA), fibrin deposition and glomerulonephritis. Marked renal disease and fibrin deposition were noted by three months of age in control mice, whereas little or no disease was seen in ancrod treated mice until five months of age. Similar high titers of anti-DNA antibodies and renal deposition of IgG were seen in both groups of mice. PC A rose with age in both ancrod treated and untreated mice, although it was significantly higher in control animals than in the ancrod treated group. Furthermore, ancrod therapy resulted in a decrease in plasma PCA inducing activity (PIF) and a decrease in the effectiveness of PIF to induce PCA in peritoneal macrophages in vitro. No mortality was observed in the 20 ancrod treated mice, whereas 10 of 20 control animals died. We conclude that defibrination with ancrod delays the development of renal fibrin deposition and glomerulonephritis and improves survival in BXSB mice. This was associated with a decrease in plasma PCA inducing activity and with an inhibitory effect on PCA induction. These results suggest that PCA contributes to injury in murine lupus glomerulonephritis by promoting fibrin deposition