BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

Nociceptors: a phylogenetic view

The ability to react to environmental change is crucial for the survival of an organism and an essential prerequisite is the capacity to detect and respond to aversive stimuli. The importance of having an inbuilt “detect and protect” system is illustrated by the fact that most animals have dedicated sensory afferents which respond to noxious stimuli called nociceptors. Should injury occur there is often sensitization, whereby increased nociceptor sensitivity and/or plasticity of nociceptor-related neural circuits acts as a protection mechanism for the afflicted body part. Studying nociception and nociceptors in different model organisms has demonstrated that there are similarities from invertebrates right through to humans. The development of technology to genetically manipulate organisms, especially mice, has led to an understanding of some of the key molecular players in nociceptor function. This review will focus on what is known about nociceptors throughout the Animalia kingdom and what similarities exist across phyla; especially at the molecular level of ion channels

Catalytic Asymmetric Transacetalization

A catalytic enantioselective transacetalization has been developed. The chiral phosphoric acid TRIP was demonstrated to be an efficient and highly enantioselective catalyst for the activation of O,O-acetals. The reaction enables the asymmetric synthesis of acetals with the acetal carbon as the only stereogenic center

Resolution of Diols via Catalytic Asymmetric Acetalization.

A highly enantioselective kinetic resolution of diols via asymmetric acetalization has been achieved using a chiral confined imidodiphosphoric acid catalyst. The reaction is highly efficient for the resolution of tertiary alcohols, giving selectivity factors of up to >300. Remarkably, even in cases where the selectivity factors are only moderate, highly enantioenriched diols are obtained via a stereodivergent resolution to diastereomeric acetals

Integrated biostratigraphy across the Eocene/Oligocene boundary at Noro\uf1a, Cuba, and the question of the extinction of orthophragminids

Integrated biostratigraphy by means of planktic foraminifera, calcareous nannofossils and larger benthic foraminifera from a continuous marine section at Noro\uc3\ub1a (Cuba) suggests that the extinction of orthophragminids lies in the Rupelian (early Oligocene). Three levels containing larger benthic foraminifera are found in the lower and middle part of the planktic foraminiferal Zone O1(P18) and in the middle part of the calcareous nannofossil Zone NP21(CP16) (Rupelian). Furthermore, a traditional larger foraminifera Eocene marker, Fallotella cookei, is abundant in the Oligocene at the Noro\uc3\ub1a section, consistent with data reported from lower Oligocene sediments from Cuba, Florida and Jamaica. In order to solve the question of the orthophragminid extinction, which has been shown in some places to coincide with the Eocene/Oligocene boundary, data from the Noro\uc3\ub1a section are discussed in the view of the presence of these larger benthic foraminifera in lower Oligocene strata in other sections world wide. Our data from Noro\uc3\ub1a, as well as those from other previously studied sections, suggest that the extinction of the orthophragminids could be diachronous, with disappearances near the Eocene/Oligocene boundary in the low latitudes of the Indo-Pacific region (e. g., Tanzania) as opposed to the Rupelian in the low latitudes of the Caribbean-American bioprovince (e. g. Cuba and Jamaica) and in the middle latitudes of the Tethys (e. g., Italy and Spain)

Developing Catalytic Asymmetric Acetalizations

Acetals are among the most common stereocenters in Nature. They form glycosidic bonds that link together essential molecules of life, carbohydrates, including starch and cellulose, the most abundant organic material on Earth. Stereogenic acetals are also common motifs in other natural products, from small insect pheromones to highly complex spiroacetal polyketides. Although far less common than O,O-acetals, chiral N,N-, N,O-, and N,S-acetals are structural motifs also found in a number of natural products and pharmaceuticals. Here, recent progress towards chiral acetals using asymmetric Bronsted acid catalysis is summarized, with particular emphasis on O,O-acetalizations. In this context the development of novel catalyst classes, namely spirocyclic phosphoric acids and confined Bronsted acids, proved crucial and is also presented

Biostratigraphy and evolutionary tendencies of eocene heterostegines in western and central Cuba based on morphometric analyses

Megalospheric specimens of Heterostegina from four localities in Western and Central Cuba were morphometrically investigated using test characters, which are described by 15 growth-independent and growthinvariant attributes that enable complete test reconstruction in equatorial sections. The species Heterostegina cubana, H. ocalana, and Heterostegina sp. indet. were classified by nonmetric multidimensional scaling and cluster analysis. Discriminant analysis yielded significant separators between species such as the perimeter ratio of the first chamberlets, the decrease in chamberlet length from the previous spiral to the marginal side, the chamber height at the spiral side of the previous whorl, and the proloculus size. Based on a further discriminant analysis, specimens of H. ocalana from different localities, including specimens from Panama, are strongly separated by the number of operculinid chambers, the extension grade of the marginal spiral and the backward bend of chambers, documenting paleogeographic differences and apparent evolutionary trends such as the reduction of the number of operculinid chambers. In Cuba, Heterostegina is represented by H. cubana and Heterostegina sp. indet. in the Bartonian to lower Priabonian (calcareous nannofossil Zones NP 16-NP 17), while Heterostegina ocalana ranges from Priabonian (nannofossil Zones NP 17 to NP 19-20/CP 15) to probably lower Oligocene (Rupelian) in the lower and middle part of the planktic foraminiferal Zone O 1 (P 18) and in the middle part of the calcareous nannofossil Zone NP 21 (CP 16)