Immunotherapy against antigenic tumors: a game with a lot of players

Our understanding of how immune responses are generated and regulated drives the design of possible immunotherapies for cancer patients. For that reason, we first describe briefly the actual immunological theories and their common perspectives about cancer vaccine development. Second, we describe cancer vaccines that are able to induce tumor-specific immune responses in cancer patients. However, these responses are not always followed by tumor rejection. At the end of the review, we discuss two possible reasons that might explain this dichotomy of cancer immunology. First, the immune response generated, although detectable, may not be quantitatively sufficient to reject the tumor. Second, the tumor microenvironment may modulate tumor cell susceptibility to the systemic immune response induced by the immunization. Finally, we discuss what, in our opinion, might be the best way to improve cancer vaccine strategies and how the relationship between the tumor and its surroundings might be studied in more details. Received 21 June 2001; received after revision 15 August 2001; accepted 15 August 2001     

Recombinational DNA double-strand breaks in mice precede synapsis

In Saccharomyces cerevisiae, meiotic recombination is initiated by Spo11-dependent double-strand breaks (DSBs), a process that precedes homologous synapsis. Here we use an antibody specific for a phosphorylated histone (gamma-H2AX, which marks the sites of DSBs) to investigate the timing, distribution and Spo11-dependence of meiotic DSBs in the mouse. We show that, as in yeast, recombination in the mouse is initiated by Spo11-dependent DSBs that form during leptotene. Loss of gamma-H2AX staining (which in irradiated somatic cells is temporally linked with DSB repair) is temporally and spatially correlated with synapsis, even when this synapsis is 'non-homologous'.     

Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

Metallothioneins I+II (MT-I+II) are antioxidant, neuroprotective factors. We previously showed that MT-I+II deficiency during experimental autoimmune encephalomyelitis (EAE) leads to increased disease incidence and clinical symptoms. Moreover, the inflammatory response of macrophages and T cells, oxidative stress, and apoptotic cell death during EAE were increased by MT-I+II deficiency. We now show for the first time that demyelination and axonal damage are significantly increased in MT-I+II deficient mice during EAE. Furthermore, oligodendroglial regeneration, growth cone formation, and tissue repair including expression of trophic factors were significantly reduced in MT-I+II-deficient mice during EAE. Accordingly, MT-I+II have protective and regenerative roles in the brain. Received 31 October 2002; received after revision 23 November 2002; accepted 26 November 2002 RID="*" ID="*"Corresponding author. M. Penkowa and C. Espejo contributed equally to this paper.     

Large Cretaceous sphenodontian from Patagonia provides insight into lepidosaur evolution in Gondwana

Sphenodontian reptiles successfully radiated during Triassic and Jurassic times, but were driven almost to extinction during the Cretaceous period. The sparse Early Cretaceous record of sphenodontians has been interpreted as reflecting the decline of the group in favour of lizards, their suspected ecological successors. However, recent discoveries in Late Cretaceous beds in Patagonia partially modify this interpretation. Numerous skeletons of a new sphenodontian, Priosphenodon avelasi gen. et sp. nov., were collected from a single locality in the Cenomanian-Turonian Candeleros Formation, where it is more abundant than any other tetrapod group recorded in the quarry (for example, Crocodyliformes, Serpentes, Dinosauria and Mammalia). Adult specimens of Priosphenodon reached one metre in length, larger than any previously known terrestrial sphenodontian. Here we propose, using available evidence, that sphenodontians were not a minor component of the Cretaceous terrestrial ecosystems of South America, and that their ecological replacement by squamates was delayed until the early Tertiary. The new discovery helps to bridge the considerable gap in the fossil record (around 120 million years) that separates the Early Cretaceous sphenodontians from their living relatives (Sphenodon).     

The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles

The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrP^C). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20–50, 100–200, and 300–400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrP^C. STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrP^C-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1–PrP^C signaling.     

Heart rate variability during high-intensity exercise

The aim of this paper is to describe and analyse the behaviour of heart rate variability (HRV) during constant-load, high-intensity exercise using a time frequency analysis (Wavelet Transform). Eleven elite cyclists took part in the study (age: 18.6±3.0 years; VO_2max: 4.88±0.61 litres·min^?1). Initially, all subjects performed an incremental cycloergometer test to determine load power in a constant load-test (379.55±36.02 W; 89.0%). HRV declined dramatically from the start of testing (p <0.05). The behaviour of power spectral density within the LF band mirrored that of total energy, recording a significant decrease from the outset LF peaks fell rapidly thereafter, remaining stable until the end of the test. HF-VHF fell sharply in the first 20 to 30 seconds. The relative weighting (%) of HF-VHF was inverted with the onset of fatigue, [1.6% at the start, 7.1 (p <0.05) at the end of the first phase, and 43.1% (p <0.05) at the end of the test]. HF-VHF_peak displayed three phases: a moderate initial increase, followed by a slight fall, thereafter increasing to the end of the test. The LF/HF-VHF ratio increased at the start, later falling progressively until the end of the first phase and remaining around minimal values until the end of the test.     

Demography of the Yarrow's spiny lizard, Sceloporus jarrovii , from the central Chihuahuan Desert

The demography of a population of Yarrow's spiny lizard, Sceloporus jarrovii , was examined from 2004 to 2006 in the canyon Las Piedras Encimadas, located in Gomez Palacio, Durango, México. Lizards were studied using a mark-recapture technique. Reproduction in females occurred between November and May, coinciding with dry conditions. Reproductive activity was highest (percent of females with vitellogenic follicles or embryos) in the middle of the dry season (November and December). Thirteen percent of females reached sexual maturity at an average age of 8.5 months. The population structure was similar in spring and fall, but not in summer. A notable feature of summer, coinciding with the wet season, was the greater number of hatchlings and juveniles. The overall sex ratio did not differ from 1:1. The density of adults varied from 12 to 62 animals ? 0.5 ha –1 . Temperate and arid-adapted populations of S. jarrovii exhibited broad similarity in timing of the reproductive season, whereas factors such as density, growth, age at sexual maturity, and survivorship differed.