Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 41 patients with Duchenne muscular dystrophy, no ambulatory patient had scoliosis greater than 19 degrees. Non-ambulatory patients were prophylactically placed in body jackets, which kept the spine flexible and provided adequate support for sitting in the majority of patients. Ten patients had posterior spine fusion for progressive spinal collapse. The procedure was extensive with significant blood loss but boney fusion was achieved in every case. Pulmonary complications were minimized by performing preoperative tracheostomy on all patients who had vital capacities less than 40% and or non-functional coughs. Spinal fusion permitted long-term sitting stability despite the progression of the disease.
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PMID:Stabilization of the collapsing spine in duchenne muscular dystrophy. 34 97

The important role of angiogenesis as a predictive factor of response to cytotoxic and radiation therapy has been recently raised. Poor tumour oxygenation is a well recognised feature related to radio-resistance. Since the vascular density is linked to the availability of oxygen and drugs to the tumoural stroma, poor density should be a potent marker of reduced blood perfusion and, therefore, hypoxia and low drug intratumoural concentration. On the other hand, high vascular density and angiogenic ability of cancer is not synonymous with high blood flow since the geometry of the vascular/epithelial component distribution, vascular collapse due to increased interstitial blood pressure, or non-functional vasculature due to an immature structure of the vessels may not allow the establishment of an adequate blood flow, which results in tissue hypoxia. Moreover, activation of angiogenic pathways confer a cancer cell proliferation/apoptosis advantage and trigger an angiogenic regeneration process during fractionated radiotherapy or between the courses of chemotherapy, resulting in rapid tumour re-growth and failure of radiotherapy due to reasons independent of hypoxia and blood flow. The present study reviews the literature on angiogenesis and radiotherapy and suggests a classification of tumours according to their angiogenic ability, which could become a useful tool for the identification of sub-groups of patients that could benefit from specific radiotherapy schedules or combination regimens with cytotoxic and anti-angiogenic compounds.
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PMID:Tumour angiogenesis and response to radiotherapy. 1190 83

Xeroderma pigmentosum variant (XPV) cells lack the damage-specific polymerase eta and undergo a protracted arrest at the S phase checkpoint(s) following UV damage. The S phase checkpoints encompass several qualitatively different processes, and stimulate downstream events that are dependent on the functional state of p53. Primary fibroblasts with wild-type p53 arrest in S, and require a functional polymerase eta (pol eta) to carry out bypass replication, but do not recruit recombination factors for recovery. XPV cells with non-functional p53, as a result of transformation by SV40 or HPV16 (E6/E7), recruit the hMre11/hRad50/Nbs1 complex to arrested replication forks, coincident with PCNA, whereas normal transformed cells preferentially use the pol eta bypass replication pathway. The formation of hMre11 foci implies that arrested replication forks rapidly undergo a collapse involving double strand breakage and rejoining. Apoptosis occurs after UV only in cells transformed by SV40, and not in normal or XPV fibroblasts or HPV16 (E6/E7) transformed cells. Conversely, ultimate cell survival in XPV cells was much less in HPV16 (E6/E7) transformed cells than in SV40 transformed cells, indicating that apoptosis was not a reliable predictor of cell survival. Inhibition of p53 transactivation by pifithrin-alpha or inhibition of protein synthesis by cycloheximide did not induce hMre11 foci or apoptosis in UV damaged fibroblasts. Inhibition of kinase activity with wortmannin did not increase killing by UV, unlike the large increase seen with caffeine. Since HPV16 (E6/E7) transformed XPV cells were highly UV sensitive and not further sensitized by caffeine, it appears likely that caffeine sensitization proceeds through a p53 pathway. The S phase checkpoints are therefore, a complex set of different checkpoints that are coordinated by p53 with the capacity to differentially modulate cell survival, apoptosis, bypass replication and hMre11 recombination.
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PMID:Polymerase eta and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. 1250 96

Methaemoglobinaemia arises from the production of non-functional haemoglobin containing oxidised Fe(3+) which results in reduced oxygen supply to the tissues and manifests as cyanosis in the patient. It can develop by three distinct mechanisms: genetic mutation resulting in the presence of abnormal haemoglobin, a deficiency of methaemoglobin reductase enzyme and toxin-induced oxidation of haemoglobin. The normal haemoglobin fold forms a pocket to bind the haem and stabilise its complex with molecular oxygen, simultaneously preventing spontaneous oxidation of the Fe(2+) ion chelated by the haem pyrroles and the globin histidines. In the abnormal, M forms of haemoglobin (Hb Ms) amino acid substitution in or near the haem pocket creates a propensity to form methaemoglobin instead of oxyhaemoglobin in the presence of molecular oxygen. Normally, haemoglobin continually oxidises but significant accumulation of methaemoglobin is prevented by the action of a group of methaemoglobin reductase enzymes. In the autosomal recessive form of methaemoglobinaemia there is a deficiency of one of these reductase enzymes thereby allowing accumulation of oxidised Fe(3+) in methaemoglobin. Oxidising drugs and other toxic chemicals may greatly enhance the normal spontaneous rate of methaemoglobin production and if levels exceed 70% of total haemoglobin, vascular collapse occurs resulting in coma and death. Under these conditions, if the source of toxicity can be eliminated methaemoglobin levels will return to normal. Disorders of oxidised haemoglobin are relatively easily diagnosed and in most cases, except for the presence of congenitally defective haemoglobin M, can be treated successfully.
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PMID:Disorders of oxidised haemoglobin. 1560 10

During the germinal centre reaction (GC), B cells with non-functional or self-reactive antigen receptors are negatively selected by apoptosis to generate B cell repertoire with appropriate antigen specificities. We studied the molecular mechanism of Fas/CD95- and B cell receptor (BCR)-induced apoptosis to shed light on the signalling events involved in the negative selection of GC B cells. As an experimental model, we used human follicular lymphoma (FL) cell line HF1A3, which originates from a GC B cell, and transfected HF1A3 cell lines overexpressing Bcl-x(L), c-FLIP(long) or dominant negative (DN) caspase-9. Fas-induced apoptosis was dependent on the caspase-8 activation, since the overexpression of c-FLIP(long), a natural inhibitor of caspase-8 activation, blocked apoptosis induced by Fas. In contrast, caspase-9 activation was not involved in Fas-induced apoptosis. BCR-induced apoptosis showed the typical characteristics of mitochondria-dependent (intrinsic) apoptosis. Firstly, the activation of caspase-9 was involved in BCR-induced DNA fragmentation, while caspase-8 showed only marginal role. Secondly, overexpression of Bcl-x(L) could block all apoptotic changes induced by BCR. As a novel finding, we demonstrate that caspase-9 can enhance the cytochrome-c release and collapse of mitochondrial membrane potential (DeltaPsi(m)) during BCR-induced apoptosis. The requirement of different signalling pathways in apoptosis induced by BCR and Fas may be relevant, since Fas- and BCR-induced apoptosis can thus be regulated independently, and targeted to different subsets of GC B cells.
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PMID:Feedback regulation of mitochondria by caspase-9 in the B cell receptor-mediated apoptosis. 1990

Giardia lamblia parasitism accounts for the majority of cases of parasitic diarrheal disease, making this flagellated eukaryote the most successful intestinal parasite worldwide. This organism has undergone secondary reduction/elimination of entire organelle systems such as mitochondria and Golgi. However, trophozoite to cyst differentiation (encystation) requires neogenesis of Golgi-like secretory organelles named encystation-specific vesicles (ESVs), which traffic, modify and partition cyst wall proteins produced exclusively during encystation. In this work we ask whether neogenesis of Golgi-related ESVs during G. lamblia differentiation, similarly to Golgi biogenesis in more complex eukaryotes, requires the maintenance of distinct COPII-associated endoplasmic reticulum (ER) subdomains in the form of ER exit sites (ERES) and whether ERES are also present in non-differentiating trophozoites. To address this question, we identified conserved COPII components in G. lamblia cells and determined their localization, quantity and dynamics at distinct ERES domains in vegetative and differentiating trophozoites. Analogous to ERES and Golgi biogenesis, these domains were closely associated to early stages of newly generated ESV. Ectopic expression of non-functional Sar1 GTPase variants caused ERES collapse and, consequently, ESV ablation, leading to impaired parasite differentiation. Thus, our data show how ERES domains remain conserved in G. lamblia despite elimination of steady-state Golgi. Furthermore, the fundamental eukaryotic principle of ERES to Golgi/Golgi-like compartment correspondence holds true in differentiating Giardia presenting streamlined machinery for secretory organelle biogenesis and protein trafficking. However, in the Golgi-less trophozoites ERES exist as stable ER subdomains, likely as the sole sorting centres for secretory traffic.
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PMID:Export of cyst wall material and Golgi organelle neogenesis in Giardia lamblia depend on endoplasmic reticulum exit sites. 2309 58

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
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PMID:Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. 2570 6