A

Abstract:  Studies show that patients with type 2 diabetes (DM2) have a higher risk of developing some type of cancer. Objective: to analyze the incidence and association between DM2 and cancer in patients from the “San Ricardo Pampuri” health center in Villa Carlos Paz. A retrospective observational study was carried out analyzing the medical records of 42,948 patients (years 2000-2018), 17,109 (39.8%) had DM2 and 332 had cancer (186M and 146H). The data analyzed were age, sex, type of cancer and suffering from DM2. Incidence ratios between sexes (RS = incidence in Men / incidence in Women) were calculated for some types of cancer. The work has ethical approval and corresponding confidentiality. Data were statistically analyzed with Infostat. Average age was 72 (DS 11) years for men and 68.5 (DS 12) for women (56% of the patients). 162 patients who developed cancer had DM2 (93M and 69H). In women with DM2 the incidences were: breast (51.6%), endometrium (7.5%), colon, pancreas and cervix (all with 6.5%). In women without DM2: breast (41.1%), colon (14.4%), cervix (7.8%), ovary and thyroid (both with 5.6%). In men with DM2 the incidences: prostate (27.9%), colon (19.1%), pancreas (8.8%), kidney (7.4%), Non-Hodgkin\u27s Lymphoma and bladder (both with 5.9 %). In those without DM2 they were: prostate (40%), colon (18.8%), bladder (12.5%) and melanoma (5%). The highest incidence rates between sexes (SR) for patients with DM2 were: lung (4.1), colon (3), Non-Hodgkin\u27s Lymphoma (2.7), kidney (2.3) and myeloma (2); in patients without DM2 they were bladder (3.8) and leukemia (2.3). It was observed that diabetic patients have a higher risk for pancreatic cancer (OR = 6.96; p = 0.01) and kidney (OR = 4.96; p = 0.01). Men showed a slightly increased risk for: colon (OR = 0.49; p = 0.02), bladder (OR = 0.16; p = 0.05) and kidney (OR = 0.29; p = 0 , 05). It was observed that patients without DM2 showed a slightly elevated risk for bladder cancer (OR = 0.33; p = 0.05) and melanoma (OR = 0.13; p = 0.05). Conclusions: Positive correlations were observed between cancer and age, for some tumors it could also be established with sex and DM2. Patients with DM2 showed an increased risk for pancreatic and kidney cancer and a small decrease in risk for bladder and melanoma.Resumen:  Numerosos estudios demuestran que pacientes con diabetes tipo 2 (DM2) tienen mayor riesgo de desarrollar algún tipo de cáncer. Objetivo del estudio: analizar la incidencia y asociación entre DM2 y cáncer en pacientes del centro de salud “San Ricardo Pampuri” de Villa Carlos Paz.  Se realizó un estudio observacional retrospectivo analizando historias clínicas de 42948 pacientes  (años 2000-2018), 17109 (39,8%) padecían DM2 y 332  presentaron  cáncer (186M y 146H). Los datos analizados fueron edad, sexo, tipo de cáncer y padecer DM2. Se calcularon ratios de incidencia entre sexos (RS=incidencia Hombres/incidencia Mujeres) para algunos tipos de cáncer.  El trabajo cuenta con  aprobación ética y confidencialidad correspondiente. Se analizaron los datos estadísticamente con Infostat. Edad promedio fue 72(DS 11) años hombres y 68,5 (DS 12) mujeres (56% de los pacientes). 162 pacientes que desarrollaron cáncer tenían DM2 (93M y 69H). En mujeres con DM2  incidencias fueron: mama (51,6%), endometrio (7,5%), colon, páncreas y cuello de útero (todos con 6,5%). En mujeres sin DM2: mama (41,1%), colon (14,4%), cuello de útero (7,8%) ovario y tiroides (ambos con 5,6%). En hombres con DM2 las incidencias: próstata (27,9%), colon (19,1%), páncreas (8,8%), riñón (7,4%), Linfoma No Hodgkin y vejiga (ambos con 5,9%). En aquellos sin DM2 fueron: próstata (40%), colon (18,8%), vejiga (12,5%) y melanoma (5%). Las ratios de incidencia entre sexos (RS) más altos para pacientes con DM2 fueron: pulmón (4,1), colon (3), Linfoma No Hodgkin (2,7), riñón (2,3) y mieloma (2); en pacientes sin DM2 fueron vejiga (3,8) y leucemia (2,3). Se observó que pacientes diabéticos tienen un riesgo mayor para cáncer de páncreas (OR=6,96; p=0,01) y riñón (OR=4,96; p=0,01). Los hombres mostraron un riesgo levemente aumentado para: colon (OR=0,49; p=0,02), vejiga (OR=0,16; p=0,05) y riñón (OR=0,29; p=0,05). Se observó que pacientes sin DM2 mostraron un riesgo ligeramente elevado para cáncer de vejiga (OR=0,33; p=0,05) y melanoma (OR=0,13; p=0,05).  Conclusiones:  Se observaron correlaciones positivas entre cáncer y edad, para algunos tumores también se pudieron establecer con sexo y DM2.  Los pacientes con DM2 mostraron un riesgo mayor para cáncer de páncreas y riñón y una pequeña disminución del riesgo para vejiga y melanoma.

A

Abstract:  Type 2 diabetes (DBT2) affects the central nervous system (CNS) and vision. Environmental enrichment (EA), allows to develop greater physical activity and neurocognitive stimulation, being able to help in experimental animals in the treatment of CNS pathologies. Objective: To study the effect of exposure to EA on the ultrastructure of the optic nerve and metabolic markers in diabetic animals. We used 24 12-month-old male Wistar rats, divided into 6 groups, 4 with a diet with 30% saturated fat (HFD) and / or moderate consumption (0.42 g / kg weight / day) of alcohol (Alc). The 2 non-diabetic control groups (C), consumed a standard chow diet. The EA groups were housed in large cages, with treadmills and ramps, the other groups in standard animal cages. The trial lasted 16 months. Metabolic markers (lipidemia, glycemia and weight) were measured. At the end of the test, the optic nerves were extracted, fixed and processed for electron microscopy. The data obtained were analyzed by ANOVA, p≤0.05. The animals presented DBT2 at 7 months of the test, in groups HFD, Alc, HFD + Alc, hypertriglyceridemia and hypercholesterolemia and obesity were observed. Animals with EA at the end of the trial decreased their glycemic values ​​(118 ± 5 mg / dl) and had a normal weight. In the optic nerves, signs of atrophy, alteration of the shape of mitochondria and their crests were observed in the animals on the HFD and / or Alcohol diet, compared with the control groups (C and C + AE). The HFD, Alc, HFD + Alc and HFD + Alc + AE groups showed thickening of the myelin sheaths (between 39 and 233%, p = 0.01). In the animals with the HFD diet, more intracytoplasmic electrodense deposits were found, in HFD + Alc and HFD + Alc + AE the myelin sheath was observed with a greater separation of the axon (75 and 50% more, p = 0.05) than in the group C. In the Alc group, larger mitochondria were observed (119 vs 107 nm, p = 0.05) than in C. Diet and lack of physical activity led the animals to develop DBT2. This condition affected the ultrastructure of the optic nerve. Exposure to an enriched environment partially improved metabolic and ultrastructural alterations.Resumen:  La diabetes tipo 2 (DBT2) afecta el sistema nervioso central (SNC) y la visión. El enriquecimiento ambiental (AE), permite desarrollar mayor actividad física y estímulo neurocognitivo, pudiendo ayudar en animales experimentales en el tratamiento de patologías del SNC. Objetivo: Estudiar el efecto de la exposición a un AE sobre la ultraestructura del nervio óptico y marcadores metabólicos en animales diabéticos. Utilizamos 24 ratas Wistar macho de 12 meses, divididas en 6 grupos, 4 con una dieta con 30% de grasas saturadas (HFD) y/o consumo moderado (0,42 g/kg peso/día) de alcohol (Alc). Los 2 grupos controles no diabéticos (C), consumieron una dieta chow estándar. Los grupos con AE se alojaron en jaulas grandes, con ruedas de correr y rampas, los otros grupos en jaulas estándar de bioterio. El ensayo duró 16 meses. Se midieron marcadores metabólicos (lipidemia, glucemia y peso). Al finalizar el ensayo los nervios ópticos fueron extraídos, fijados y procesados para microscopía electrónica. Los datos obtenidos se analizaron mediante ANOVA, p≤0,05. Los animales presentaron DBT2 a los 7 meses del ensayo, en grupos HFD, Alc, HFD+Alc se observó hipertrigliceridemia e hipercolesterolemia y obesidad. Los animales con AE al final del ensayo disminuyeron sus valores glucémicos (118 ±5 mg/dl) y tuvieron un peso normal.  En los nervios ópticos se observaron signos de atrofia, alteración de la forma de mitocondrias y sus crestas en los animales con dieta HFD y/o Alcohol, comparados con los grupos control (C y C+AE). Los grupos HFD, Alc, HFD+Alc y HFD+Alc+AE mostraron engrosamientos de las vainas de mielina (entre 39 y 233%, p=0.01). En los animales con dieta HFD se hallaron más depósitos electrodensos intracitoplasmáticos, en HFD+Alc y HFD+Alc+AE la vaina de mielina se observó con una mayor separación del axón (75 y 50% más, p=0.05) que en el grupo C. En el grupo Alc se observaron mitocondrias de mayor tamaño (119 vs 107 nm, p=0.05) que en C.  La dieta y falta de actividad física llevaron a los animales a desarrollar DBT2. Esta condición afectó la ultraestructura del nervio óptico. La exposición a un ambiente enriquecido logró mejorar parcialmente las alteraciones metabólicas y ultraestructurales.

Eukaryotic Flagella: Variations in Form, Function, and Composition during Evolution

The microtubule axoneme is an iconic structure in eukaryotic cell biology and the defining structure in all eukaryotic flagella (or cilia). Flagella occur in taxa spanning the breadth of eukaryotic evolution, which indicates that the organelle's origin predates the radiation of extant eukaryotes from a last common ancestor. During evolution, the flagellar architecture has been subject to both elaboration and moderation. Even conservation of 9+2 architecture—the classic microtubule configuration seen in most axonemes—belies surprising variation in protein content. Classically considered as organelles of motility that support cell swimming or fast movement of material across a cell surface, it is now clear that the functions of flagella are also far broader; for instance, the involvement of flagella in sensory perception and protein secretion has recently been made evident in both protists and animals. Here, we review and discuss, in an evolutionary context, recent advances in our understanding of flagellum function and composition

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Nature America for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 12 (2009): 864-871, doi:10.1038/nn.2346.Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.This work was supported by 2007/2008 MBL summer fellowship to GM; an HDSA grant to GM; NIH grants MH066179 to GB; and ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to STB

The Retrograde IFT Machinery of C. elegans Cilia: Two IFT Dynein Complexes?

We analyzed the relatively poorly understood IFT-dynein (class DYNC2)-driven retrograde IFT pathway in C. elegans cilia, which yielded results that are surprising in the context of current models of IFT. Assays of C. elegans dynein gene expression and intraflagellar transport (IFT) suggest that conventional IFT-dynein contains essential heavy (CHE-3), light-intermediate (XBX-1), plus three light polypeptide chains that participate in IFT, but no “essential” intermediate chain. IFT assays of XBX-1::YFP suggest that IFT-dynein is transported as cargo to the distal tip of the cilium by kinesin-2 motors, but independent of the IFT-particle/BBSome complexes. Finally, we were surprised to find that the subset of cilia present on the OLQ (outer labial quadrant) neurons assemble independently of conventional “CHE-3” IFT-dynein, implying that there is a second IFT-dynein acting in these cilia. We have found a novel gene encoding a dynein heavy chain, DHC-3, and two light chains, in OLQ neurons, which could constitute an IFT-dynein complex in OLQ neuronal cilia. Our results underscore several surprising features of retrograde IFT that require clarification

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD

Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders

<div><h3>Background</h3><p>It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.</p> <h3>Methodology/Principal Findings</h3><p>In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ_17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ_1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.</p> <h3>Conclusions/Significance</h3><p>The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.</p> </div

Accumulation of intraneuronal Aβ correlates with ApoE4 genotype

In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD

Characterization of Granulations of Calcium and Apatite in Serum as Pleomorphic Mineralo-Protein Complexes and as Precursors of Putative Nanobacteria

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features