RESUMEN
Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in CACNA1C , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in CACNA1C have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.
RESUMEN
L-type voltage-gated calcium channels (VGCCs) regulate calcium influx and excitation-contraction coupling in many types of muscle cells. Thus, VGCC mutations can cause skeletal and cardiac muscle diseases in humans, such as Duchenne muscular dystrophy and Timothy syndrome. To better understand the genetics and native expression of VGCCs, we have chosen to use the microscopic roundworm, C. elegans . The egl-19 locus is the sole L-type VGCC gene and it encodes three distinct isoforms (a, b, and c). Isoform c is curious because the protein is truncated, lacking the transmembrane domains that form the physical calcium channel. In this study, we have characterized egl-19 expression using CRISPR/Cas9 genome editing to 'knock-in' fluorescent tags of differing colors, allowing us to distinguish the expression pattern of each isoform. Not surprisingly, we found that EGL-19 is expressed in all types of muscle. In addition, we provide evidence that the truncated c isoform is expressed. Finally, although we find evidence that specific isoforms can have unique subcellular distributions, we also observed some expression patterns that appear to be artifacts. Overall, our results show interesting patterns of egl-19 expression, but also highlight the need for caution when interpreting expression of reporter genes even when they represent endogenous tags.
RESUMEN
COPA Syndrome is a rare, autosomal dominant autoimmune/autoinflammatory disease caused by mutations in COPA , which codes for the alpha subunit of the Coat Protein Complex I (COPI). COPI coated vesicles move proteins in retrograde from the Golgi Apparatus to the Endoplasmic Reticulum. At the cellular level, COPA mutations cause ER stress, though the downstream genetic mechanisms of COPA Syndrome remain undefined. Here, we model COPA Syndrome in Caenorhabditis elegans , using CRISPR/Cas9 to generate patient alleles in copa-1 , the C. elegans COPA ortholog. The two alleles made thus far are superficially wild type under normal growth conditions. However, these animals demonstrate an increased ER stress sensitivity.
RESUMEN
Introduction: Tumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment. Methods and Results: Here, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent manner in vitro. Notably, an intermediate dose best induced immunogenic cell death and the expression of immune-activating markers without maximizing expression of markers associated with immune suppression. Bone marrow-derived dendritic cells exposed to ovalbumin-expressing melanoma treated with intermediate doxorubicin dose became activated and best presented tumor antigen. In a murine melanoma model, both the doxorubicin dose and delivery location (systemic infusion versus local administration) affected the expression of these markers on live tumor cells. Particularly, local release of doxorubicin from a hydrogel increased calreticulin expression on tumor cells without inducing immune-suppressive markers, in a manner dependent on the loaded dose. Doxorubicin exposure also altered the expression of immune-interacting markers in patient-derived melanoma cells. Conclusions: Together, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00742-y.
RESUMEN
Herniation of small bowel through defects in the gastro-intestinal mesentery is a rare cause of acute bowel obstruction. Its possible presence must be borne in mind if the clinical condition of the patient suggests bowel obstruction, despite the absence of external herniae and in the absence of any history of previous abdominal surgery. Early operation is essential, and three cases of the condition are now reported. The relevant literature is reviewed.
