Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder that predisposes patients to cutaneous tumors, pulmonary cysts with recurrent spontaneous pneumothoraces, and a variety of renal ...neoplasms including hybrid oncocytic and chromophobe renal cell carcinomas. There has been much debate regarding the genetic link with the occurrence of colorectal cancer and other colonic anomalies. Associations between BHD and intestinal adenomatous polyposis and sigmoid diverticulosis have been described in the literature, but there have been no prior reports of appendiceal diverticulosis in patients with BHD. Here, we present a 40-year-old female patient with a known family history of BHD, who was found to have diverticulosis of the appendix and pulmonary blebs on computed tomography upon routine screening for renal and pulmonary abnormalities, suggesting additional focus be given to the gastrointestinal tract (including the appendix) at the time of CT assessment.
Mesenchymal chondrosarcoma is a rare and aggressive chondrogenic neoplasm arising from the bone or the soft tissue. Mesenchymal chondrosarcomas develop outside the osseous structures in about ...one-third of cases, and the majority of these occur in the meninges and the brain parenchyma. Intramuscular extraskeletal mesenchymal chondrosarcoma (EMC) is exceedingly rare, with very few cases reported in the literature. Although mesenchymal chondrosarcoma has a high potential for metastasis, there have been no reports of pulmonary metastasis from an EMC of intramuscular origin. Here, we describe a patient who came to our facility with a history of progressively worsening left lower extremity pain and swelling, and was found to have pathology-proven EMC originating in the left adductor magnus, with complete workup demonstrating multiple bilateral pulmonary metastases in addition to a possible metastatic focus in the right adrenal gland discovered during the interval surveillance period.
Anaplastic Large Cell Lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive Anaplastic Lymphoma Kinase (ALK) fusion protein. ALK inhibitors such as crizotinib provide ...alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq data derived from ALK inhibitor relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.
Beneficial bacteria promise to promote the health and productivity of farmed fish species. However, the impact on host physiology is largely strain-dependent, and studies on Arctic char (
Salvelinus ...alpinus
), a commercially farmed salmonid species, are lacking. In this study, 10 candidate probiotic strains were subjected to
in vitro
assays, small-scale growth trials, and behavioral analysis with juvenile Arctic char to examine the impact of probiotic supplementation on fish growth, behavior and the gut microbiome. Most strains showed high tolerance to gastric juice and fish bile acid, as well as high auto-aggregation activity, which are important probiotic characteristics. However, they neither markedly altered the core gut microbiome, which was dominated by three bacterial species, nor detectably colonized the gut environment after the 4-week probiotic treatment. Despite a lack of long-term colonization, the presence of the bacterial strains showed either beneficial or detrimental effects on the host through growth rate enhancement or reduction, as well as changes in fish motility under confinement. This study offers insights into the effect of bacterial strains on a salmonid host and highlights three strains,
Carnobacterium divergens
V41,
Pediococcus acidilactici
ASG16, and
Lactiplantibacillus plantarum
ISCAR-07436, for future research into growth promotion of salmonid fish through probiotic supplementation.
The t(9;22) translocation that forms the Philadelphia chromosome of chronic myelogenous leukemia (CML) also forms a fusion gene,
BCR-ABL
. The new gene encodes an abnormal tyrosine kinase, which ...causes the leukemia. Imatinib mesylate inhibits the function of the BCR-ABL protein and can induce remission of CML. This large trial found that imatinib induced cytogenetic and hematologic responses in most patients in whom standard therapy with interferon alfa had failed.
This large trial found that imatinib induced cytogenetic and hematologic responses in most patients after interferon alfa had failed.
Chronic myelogenous leukemia (CML) accounts for about 20 percent of newly diagnosed cases of leukemia in adults.
1
,
2
The course of the disease is characteristically triphasic: a chronic phase lasting three to six years is followed by transformation to accelerated and then blast phases of short duration.
1
–
6
The cause of CML is the translocation of regions of the
BCR
and
ABL
genes to form a
BCR-ABL
fusion gene.
1
,
7
–
12
In at least 90 percent of cases, this event is a reciprocal translocation termed t(9;22), which forms the Philadelphia (Ph) chromosome.
7
,
8
The product of the
BCR-ABL
gene, the . . .
Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to ...uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.
Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide ...alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance–specific relapse.
•Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL.•In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.
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