Experimental Study of Collared Lizards: Effects of Habitat and Male Quality on Fitness

Zoolog

Some lizard-habitat relationships in the Northern Great Basin

Five sympatric species of desert lizards (leopard lizards (Garnbelia wizlizeni), sagebrush lizards (Sceloporus graciosus), side-blotched. lizards (Uta stansburiana), desert horned lizards (Phrynosoma platyrhinos), and Western whiptails (Cnemidophorus tigris)) were studied in June and July of 1978 and 1979 in northern Nevada on the Charles Sheldon National Wildlife Refuge. Lizard distribution, relative abundance, and diversity were determined from bi-monthly, live-capture censuses on 3 different vegetational stands. Stands, characterized by different shrub species and substrates (Budsage-Desert Pavement, Greasewood- Hard Pan, Sagebrush-Sand), were sampled monthly with random line transects for ground cover, shrub height cover, and shrub spacing. The indices to density of Sceloporus graciosus were significantly greater on the Sagebrush-Sand stand than on the other 2, and this species was significantly correlated (R²=0.60) with shrub heights of 61-75 and 91-105 cm. Uta stansburiana was significantly correlated (R² =0.58) with shrub heights of 0-15 cm and occurred exclusively on the Budsage-Desert Pavement stand. Lizard abundances on the Budsage-Desert Pavement stand were twice as high as on the other stands, largely because of the presence of Uta stansburiana. Diversity indices were significantly correlated (R²=0.42) with shrub spacing and shrub heights of 61-75cm. Shrub heights, in conjunction with characteristic substrates, appeared influential in determining lizard distribution, relative abundance, and diversity

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1β-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumor-associated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials

Deficiency for the Cysteine Protease Cathepsin L Impairs Myc-Induced Tumorigenesis in a Mouse Model of Pancreatic Neuroendocrine Cancer

Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycER(TAM); Bcl-x(L) model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycER(TAM); Bcl-x(L) tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAP-HRas(V12) mouse model crossed into the p53ER(TAM) background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER(TAM) allele. The p53ER(TAM) protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas(V12);p53(+/KI) mice abrogate the p53 pathway by mutating p19(ARF)/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER(TAM) allele. By contrast, gliomas arising in GFAP-HRas(V12);p53(KI/KI) mice develop in the absence of functional p53. Such tumors retain a functional p19(ARF)/MDM2-signaling pathway, and restoration of p53ER(TAM) allele triggers p53-tumor–suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14(ARF)/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas(V12);p53(KI/KI) animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER(TAM) activity mitigated the selective pressure to inactivate the p19(ARF)/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance

Providing for the Casualties of War: The American Experience Since WWII

War has always been a dangerous business, bringing injury, wounds, and death, and -- until recently -- often disease. What has changed over time, most dramatically in the last 150 or so years, is the care these casualties receive and who provides it. Medical services have become highly organized and are state sponsored. Diseases are now prevented through vaccination and good sanitation. Sedation now ameliorates pain, and antibiotics combat infection. Wounds that once meant amputation or death no longer do so. Transfers from the field to more-capable hospitals are now as swift as aircraft can make them. The mental consequences of war are now seen as genuine illnesses and treated accordingly, rather than punished to the extreme. Likewise, treatment of those disabled by war and of veterans generally has changed markedly -- along with who supplies these and other benefits. This book looks at the history of how humanity has cared for its war casualties, from ancient times through the aftermath of World War II. For each historical period, the author examines the care the sick and wounded received in the field and in hospitals, the care given to the disabled veteran and his dependents, and who provided that care and how. He shows how the lessons of history have informed the American experience over time. Finally, the author sums up this history thematically, focusing on changes in the nature and treatment of injuries, organization of services on and off the battlefield, the role of the state in providing care, and the invisible wounds of war