Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
Figure 1: Standard 3D body estimation methods predict bodies that may be inconsistent with the 3D scene even though the results may look reasonable from the camera viewpoint. To address this, we exploit the 3D scene structure and introduce scene constraints for contact and inter-penetration. From left to right: (1) RGB image (top) and 3D scene reconstruction (bottom), (2) overlay of estimated bodies on the original RGB image without (yellow) and with (gray) scene constraints, 3D rendering of both the body and the scene from (3) camera view, (4) top view and (5) side view.
AbstractTo understand and analyze human behavior, we need to capture humans moving in, and interacting with, the world. Most existing methods perform 3D human pose estimation without explicitly considering the scene. We observe however that the world constrains the body and vice-versa. To motivate this, we show that current 3D human pose estimation methods produce results that are not consistent with the 3D scene. Our key contribution is to exploit static 3D scene structure to better estimate human pose from monocular images. The method enforces Proximal Relationships with Object eXclusion and is called PROX. To test this, we collect a new dataset composed of 12 different 3D scenes and RGB sequences of 20 subjects moving in and interacting with the scenes. We represent human pose using the 3D human body model SMPL-X and extend SMPLify-X to estimate body pose using scene constraints. We make use of the 3D scene information by formulating two main constraints. The inter-penetration constraint penalizes intersection be-tween the body model and the surrounding 3D scene. The contact constraint encourages specific parts of the body to be in contact with scene surfaces if they are close enough in distance and orientation. For quantitative evaluation we capture a separate dataset with 180 RGB frames in which the ground-truth body pose is estimated using a motion capture system. We show quantitatively that introducing scene constraints significantly reduces 3D joint error and vertex error. Our code and data are available for research at https://prox.is.tue.mpg.de.
A hexanucleotide repeat expansion represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which the expansion cause neurodegeneration are poorly understood. We report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signalling and accumulation of protein-linked DNA breaks. We further reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration. These findings identify R-Loops, DSBs, and defective ATM-mediated repair as pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked neurodegeneration is driven, at least in part, by genomic instability.
Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) seems to be an important tumor suppressor gene in melanoma. Because the PTEN gene is only infrequently deleted or mutated, and because the PTEN protein is low to absent in a significant number of melanomas, we investigated alternative methods of epigenetic silencing. We did quantitative positional methylation analysis (pyrosequencing) on 37 sera from melanoma patients and on 21 pairs of corresponding sera and melanoma specimens in addition to Taqman reverse transcription-PCR. We report significant positional PTEN promoter methylation in 62% of circulating DNA isolated from sera of patients with metastatic melanoma. The percentage of methylation of a selected CpG island in blood showed a correlation with methylation levels in the corresponding melanoma tissue. Moreover, high percentages of PTEN methylation were associated with low PTEN transcription levels. Using the demethylation agent 5-aza-2 ¶-deoxycytidine, reduced methylation and a corresponding increase in PTEN protein were observed in BLM melanoma cells, leading to reduced AKT activity in an in vitro kinase assay. In summary, epigenetic PTEN silencing seems to be a relevant mechanism of inactivating this tumor suppressor gene in melanoma that may promote melanoma development by derepression of the AKT pathway.
Mycetoma is a chronic infective condition of tropical and subtropical regions. It is commoner in males, especially those in their third or fourth decade who work on the land. The clinical triad of subcutaneous nodule, sinuses and discharge usually leads to diagnosis; the disease is commonly painless. Treatment is by extensive surgical excision of affected areas and may include limb amputation. Recurrence is common, rates ranging from 20 to 90 per cent. Medical treatment may be used on its own or as an adjunct to surgery. Although such therapy may cure over half of those with actinomycetoma (caused by bacteria, mainly aerobic actinomycetes), those affected by eumycetoma (caused by fungi) have a poorer prognosis and may require many years of drug therapy.
scite is a Brooklyn-based startup that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.