Tetraspanin CD151 plays a key role in skin squamous cell carcinoma

Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size, and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared to other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3, a regulator of cell proliferation and apoptosis. CD151 also supports PKCα-α6β4 integrin association and PKC-dependent β4 S1424 phosphorylation, while regulating α6β4 distribution. CD151-PKCα effects on integrin β4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including DMBA (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting EGFR, PKC, Jak2/Tyk2, and STAT3. Hence, CD151 ‘co-targeting’ may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151-laminin-binding integrin complexes

Orthotopic liver transplantation for alcoholic liver disease

Alcohol abuse is the most common cause of end‐stage liver disease in the United States, but many transplant centers are unwilling to accept alcoholic patients because of their supposed potential for recidivism, poor compliance with the required immunosuppression regimen and resulting failure of the allograft. There is also concern that alcohol‐induced injury in other organs will preclude a good result. From July 1, 11982, to April 30, 1988, 73 patients received orthotopic liver transplants at the University of Pittsburgh for end‐stage alcoholic liver disease. Fifty‐two (71%) of these were alive at 25 ± 9 mo (mean ± S. D.) after transplantation, when a phone survey of these patients, their wives/husbands, and their physicians was performed to evaluate their subsequent use of alcohol, current medical condition and employment. Data obtained were compared with those for nonalcoholic patients selected as transplant controls. The recidivism rate has been 11.5%, with most patients drinking only socially. Fifty‐four percent of the survivors are employed, 21% classify themselves as homemakers and only 11 (21%) are unable to work. Twenty‐one patients died after transplantation; the most frequent cause of death was sepsis (43%), and intraoperative death was the next most common cause (28.6%). These data demonstrate that alcoholic patients can be transplanted successfully and achieve good health not significantly different from that of individuals transplanted for other causes. Thus orthotopic liver transplantation is a therapeutic option that should be considered for individuals with end‐stage alcoholic liver disease who desire such therapy. Copyright © 1990 American Association for the Study of Liver Disease

Efficacy and safety of simeprevir and sofosbuvir with and without ribavirin in subjects with recurrent genotype 1 hepatitis C postorthotopic liver transplant: the randomized GALAXY study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136282/1/tri12896.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136282/2/tri12896_am.pd

Checking bounded reachability in asynchronous systems by symbolic event tracing

This report presents a new symbolic technique for checking reachability properties of asynchronous systems by reducing the problem to satisfiability in restrained difference logic. The analysis is bounded by fixing a finite set of potential events, each of which may occur at most once in any order. The events are specified using high-level Petri nets. The logic encoding describes the space of possible causal links between events rather than possible sequences of states as in Bounded Model Checking. Independence between events is exploited intrinsically without partial order reductions, and the handling of data is symbolic. On a family of benchmarks, the proposed approach is consistently faster than Bounded Model Checking. In addition, this report presents a compact encoding of the restrained subset of difference logic in propositional logic

Analysis of Globule Types in Malignant Melanoma

Objective: To identify and analyze subtypes of globules based on size, shape, network connectedness, pigmentation, and distribution to determine which globule types and globule distributions are most frequently associated with a diagnosis of malignant melanoma. Design: Retrospective case series of dermoscopy images with globules. Setting: Private dermatology practices. Participants: Patients in dermatology practices. Intervention: Observation only. Main Outcome Measure: Association of globule types with malignant melanoma. Results: The presence of large globules (odds ratio [OR], 5.25) and globules varying in size (4.72) or shape (5.37) had the highest ORs for malignant melanoma among all globule types and combinations studied. Classical globules (dark, discrete, convex, and 0.10-0.20 mm) had a higher risk (OR, 4.20) than irregularly shaped globules (dark, discrete, and not generally convex) (2.89). Globules connected to other structures were not significant in the diagnosis of malignant melanoma. Of the different configurations studied, asymmetric clusters have the highest risk (OR, 3.02). Conclusions: The presence of globules of varying size or shape seems to be more associated with a diagnosis of malignant melanoma than any other globule type or distribution in this study. Large globules are of particular importance in the diagnosis of malignant melanoma

Symbolic Model Checking of Concurrent Programs Using Partial Orders and On-the-Fly Transactions

Abstract. The state explosion problem is one of the core bottlenecks in the model checking of concurrent software. We show how to ameliorate the problem by combining the ability of partial order techniques to reduce the state space of the concurrent program with the power of symbolic model checking to explore large state spaces. Our new verification methodology involves translating the given concurrent program into a circuit-based model which gives us the flexibility to then employ any model checking technique of choice – either SAT or BDD-based – for verifying a broad range of linear time properties, not just safety. The reduction in the explored state-space is obtained by statically augmenting the symbolic encoding of the program by additional constraints. These constraints restrict the scheduler to choose from a minimal conditional stubborn set of transitions at each state. Another key contribution of the paper, is a new method for detecting transactions on-the-fly which takes into account patterns of lock acquisition and yields better reductions than existing methods which rely on a lockset based analysis. Moreover unlike existing techniques, identifying on-the-fly transactions does not require the program to follow a lock discipline in accessing shared variables. We have applied our techniques to the Daisy test bench and shown the existence of several bugs.

Integrin-Blocking Antibodies Delay Keratinocyte Re-Epithelialization in a Human Three-Dimensional Wound Healing Model

The α6β4 integrin plays a significant role in tumor growth, angiogenesis and metastasis through modulation of growth factor signaling, and is a potentially important therapeutic target. However, α6β4-mediated cell-matrix adhesion is critical in normal keratinocyte attachment, signaling and anchorage to the basement membrane through its interaction with laminin-5, raising potential risks for targeted therapy. Bioengineered Human Skin Equivalent (HSE), which have been shown to mimic their normal and wounded counterparts, have been used here to investigate the consequences of targeting β4 to establish toxic effects on normal tissue homeostasis and epithelial wound repair. We tested two antibodies directed to different β4 epitopes, one adhesion-blocking (ASC-8) and one non-adhesion blocking (ASC-3), and determined that these antibodies were appropriately localized to the basal surface of keratinocytes at the basement membrane interface where β4 is expressed. While normal tissue architecture was not altered, ASC-8 induced a sub-basal split at the basement membrane in non-wounded tissue. In addition, wound closure was significantly inhibited by ASC-8, but not by ASC-3, as the epithelial tongue only covered 40 percent of the wound area at 120 hours post-wounding. These results demonstrate β4 adhesion-blocking antibodies may have adverse effects on normal tissue, whereas antibodies directed to other epitopes may provide safer alternatives for therapy. Taken together, we conclude that these three-dimensional tissue models provide a biologically relevant platform to identify toxic effects induced by candidate therapeutics, which will allow generation of findings that are more predictive of in vivo responses early in the drug development process

Identification of epitopes recognised by mucosal CD4+ T-cell populations from cattle experimentally colonised with Escherichia coli O157:H7

Additional file 5. Sequence alignment of Intimin epitopes against Intimin sequences from non-O157 EHEC serotypes. Alignment of Intimin CD4+ T-cell epitope sequences with representative Intimin sequences from EHEC serotypes O145, O127, O26, O103, O121, O45 and O111. Percentage values indicate % similarity to the EHEC O157:H7 reference sequence