Given the unknown biologic antecedents before aortic aneurysm rupture, the purpose of this study was to establish a reproducible model of aortic aneurysm rupture.
We fed 7-week-old apolipoprotein E ...deficient mice a high-fat diet for 4 weeks and osmotic infusion pumps containing Angiotensin II were implanted. Angiotensin II was delivered continuously for 4 weeks at either 1,000 ng/kg/min (n = 25) or 2,000 ng/kg/min (n = 29). A third group (n = 14) were given Angiotensin II at 2,000 ng/kg/min and 0.2% β-aminopropionitrile dissolved in drinking water. Surviving mice were killed 28 days after pump placement, aortic diameters were measured, and molecular analyses were performed.
Survival at 28 days was significantly different among groups with 80% survival in the 1,000 ng/kg/min group, 52% in the 2,000 ng/kg/min group, and only 14% in the Angiotensin II/β-aminopropionitrile group (P = .0001). Concordantly, rupture rates were statistically different among groups (8% versus 38% versus 79%, P < .0001). Rates of abdominal aortic aneurysm were 48%, 55%, and 93%, respectively, with statistically higher rates in the Angiotensin II/β-aminopropionitrile group compared with both the 1,000 ng and 2,000 ng Angiotensin II groups (P = .006 and P = .0165, respectively). Rates of thoracic aortic aneurysm formation were 12%, 52%, and 79% in the 3 groups with a statistically higher rate in the Angiotensin II/β-aminopropionitrile group compared with 1,000 ng group (P < .0001).
A reproducible model of aortic aneurysm rupture was developed with a high incidence of abdominal and thoracic aortic aneurysm. This model should enable further studies investigating the pathogenesis of aortic rupture, as well as allow for targeted strategies to prevent human aortic aneurysm rupture.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Antibody‐mediated rejection (AbAR) is increasingly recognized in the renal allograft population, and successful therapeutic regimens have been developed to prevent and treat AbAR, enabling excellent ...outcomes even in patients highly sensitized to the donor prior to transplant. It has become critical to develop standardized criteria for the pathological diagnosis of AbAR. This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001. This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation.
Full text
Available for:
BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
23.
Featured Cover Konstorum, Anna; Mohanty, Subhasis; Zhao, Yujiao ...
Aging cell,
February 2023, Volume:
22, Issue:
2
Journal Article
Peer reviewed
Open access
Cover legend: The cover image is based on the Research Article Platelet response to infl uenza vaccination refl ects effects of aging by Anna Konstorum et al., https://doi.org/10.1111/acel.13749. ...Image Credit: Hannah Wang
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
One of the tasks required of most statistics researchers and academic faculty is to publish their innovative ideas in the peer‐reviewed literature. In this paper, we provide guidance about the ...different stages of the process as experienced authors and offer advice from those who hold the decision about the success or failure of these papers, namely the editors of applied statistics journals. The paper is organized into four sections focusing on the different stages of publishing: (1) Planning what to write about, where to submit and how to organize the paper; (2) The process of writing the paper; (3) Interpreting and responding to peer‐reviews from the journal editors and referees to prepare for resubmission; and (4) General comments about the publication process, including collaboration and mentoring. Each section starts with fundamentals provided by the moderators (C.A.C. and L.L.) on key aspects to consider on each topic and then is followed with discussion from some current and past editors of impactful journals in the field of applied statistics. Our hope is that this collection of insights may help accelerate learning about the process for young researchers and help all researchers to understand some of the important often‐unspoken aspects of the process.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We recently characterized gene expression patterns in gastrointestinal stromal tumors (GISTs) using cDNA microarrays, and found that the gene
FLJ10261
(
DOG1
, discovered on GIST-1), encoding a ...hypothetical protein, was specifically expressed in GISTs. The immunoreactivity of a rabbit antiserum to synthetic DOG1 peptides was assessed on two soft tissue tumor microarrays. The tissue microarrays included 587 soft tissue tumors, with 149 GISTs, including 127 GIST cases for which the
KIT
and
PDGFRA
mutation status was known. Immunoreactivity for DOG1 was found in 136 of 139 (97.8%) of scorable GISTs. All seven GIST cases with a
PDGFRA
mutation were DOG1-positive, while most of these failed to react for KIT. The immunohistochemical findings were confirmed with
in situ
hybridization probes for
DOG1
,
KIT
, and
PDGFRA
. Other neoplasms in the differential diagnosis of GIST, including desmoid fibromatosis (0 of 17) and Schwannoma (0 of 3), were immunonegative for DOG1. Only 4 of 438 non-GIST cases were immunoreactive for DOG1. DOG1, a protein of unknown function, is expressed strongly on the cell surface of GISTs and is rarely expressed in other soft tissue tumors. Reactivity for DOG1 may aid in the diagnosis of GISTs, including
PDGFRA
mutants that fail to express KIT antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Somatic mutations, often translocations or single nucleotide variations, are pathognomonic for certain types of cancers and are increasingly of clinical importance for diagnosis and prediction of ...response to therapy. Conventional clinical assays only evaluate 1 mutation at a time, and targeted tests are often constrained to identify only the most common mutations. Genome-wide or transcriptome-wide high-throughput sequencing (HTS) of clinical samples offers an opportunity to evaluate for all clinically significant mutations with a single test. Recently a “desktop version” of HTS has become available, but most of the experience to date is based on data obtained from high-quality DNA from frozen specimens. In this study, we demonstrate, as a proof of principle, that translocations in sarcomas can be diagnosed from formalin-fixed paraffin-embedded (FFPE) tissue with desktop HTS. Using the first generation MiSeq platform, full transcriptome sequencing was performed on FFPE material from archival blocks of 3 synovial sarcomas, 3 myxoid liposarcomas, 2 Ewing sarcomas, and 1 clear cell sarcoma. Mapping the reads to the “sarcomatome” (all known 83 genes involved in translocations and mutations in sarcoma) and using a novel algorithm for ranking fusion candidates, the pathognomonic fusions and the exact breakpoints were identified in all cases of synovial sarcoma, myxoid liposarcoma, and clear cell sarcoma. The Ewing sarcoma fusion gene was detectable in FFPE material only with a sequencing platform that generates greater sequencing depth. The results show that a single transcriptome HTS assay, from FFPE, has the potential to replace conventional molecular diagnostic techniques for the evaluation of clinically relevant mutations in cancer.
Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before ...cystectomy for muscle-invasive bladder cancer. This study sought to compare the ability of GC and ddMVAC to achieve pathologic response; and to evaluate the benefit of switching regimens after 1 or 2 cycles of the other.
Patients aged ≥ 18 with muscle-invasive bladder cancer (≥ cT2) and who had received either GC or ddMVAC as neoadjuvant chemotherapy followed by cystectomy were retrospectively evaluated using the electronic medical record. Patients who received 1 or 2 cycles of one regimen followed by several cycles of the other regimen before cystectomy were classified as switch therapy patients. This study assessed the rates of pathologic complete response (pCR) and any degree of downstaging.
Among 109 patients who received GC or ddMVAC, 7 (21%) of 33 ddMVAC patients demonstrated pCR, and 19 (25%) of 76 GC patients demonstrated pCR (odds ratio, 1.24; 95% confidence interval, 0.46-3.31; P = .67). Downstaging rates were 39% for ddMVAC and 50% for GC (P = .31). Thirty-three of 36 patients aged ≥ 70 years received GC (P < .001). Four of 7 patients treated with switch therapy showed downstaging, and 2 of 7 experienced pCR.
There was no difference in pCR rates between GC and ddMVAC, and patients were most often able to receive 3 or 4 cycles of treatment. Switch therapy may be of benefit in patients whose disease has a poor initial response.
Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before cystectomy for muscle-invasive bladder cancer. We retrospectively evaluated 109 patients who received GC or ddMVAC, or GC and ddMVAC (switch therapy). We did not find a difference in response rates for patients treated with GC or ddMVAC, but 4 of 7 patients treated with GC followed by ddMVAC as switch therapy had downstaged disease, and 2 experienced complete response. These findings support the use of GC or ddMVAC based on patient-specific factors; switch therapy may be an option for patients with poor initial response to a single regimen.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 ...and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.
Many soft tissue tumors recapitulate features of normal connective tissue. We hypothesize that different types of fibroblastic tumors are representative of different populations of fibroblastic cells ...or different activation states of these cells. We examined two tumors with fibroblastic features, solitary fibrous tumor (SFT) and desmoid-type fibromatosis (DTF), by DNA microarray analysis and found that they have very different expression profiles, including significant differences in their patterns of expression of extracellular matrix genes and growth factors. Using immunohistochemistry and in situ hybridization on a tissue microarray, we found that genes specific for these two tumors have mutually specific expression in the stroma of nonneoplastic tissues. We defined a set of 786 gene spots whose pattern of expression distinguishes SFT from DTF. In an analysis of DNA microarray gene expression data from 295 previously published breast carcinomas, we found that expression of this gene set defined two groups of breast carcinomas with significant differences in overall survival. One of the groups had a favorable outcome and was defined by the expression of DTF genes. The other group of tumors had a poor prognosis and showed variable expression of genes enriched for SFT type. Our findings suggest that the host stromal response varies significantly among carcinomas and that gene expression patterns characteristic of soft tissue tumors can be used to discover new markers for normal connective tissue cells.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Male gender is a well-established risk factor for abdominal aortic aneurysm (AAA), whereas estrogen is hypothesized to play a protective role. Although rupture rates are higher in women, these ...reasons remain unknown. In the present study, we sought to determine if female mice are protected from AAA rupture.
Apolipoprotein E–deficient male and female mice (aged 7 wk; n = 25 per group) were infused with angiotensin II (AngII; 2000 ng/kg/min) plus β-aminopropionitrile (BAPN) in the drinking water for 28 d to test the effects of gender on AAA rupture. Separately, a second group of male apolipoprotein E–deficient mice underwent AngII infusion + BAPN while being fed high-fat phytoestrogen free or a high-fat phytoestrogen diet to assess effects of phytoestrogens on rupture. In a third group, female mice either underwent oophorectomy or sham operation 4 wk before infusion of AngII and BAPN to further test the effects of female hormones on AA rupture. Surviving mice abdominal aorta were collected for histology, cytokine array, and gelatin zymography on postoperative day 28.
Female mice had decreased AAA rupture rates (16% versus 46%; P = 0.029). Female mice expressed fewer elastin breaks (P = 0.0079) and decreased smooth muscle cell degradation (P = 0.0057). Multiple cytokines were also decreased in the female group. Gelatin zymography demonstrated significantly decreased pro-matrix metalloproteinase 2 in female mice (P = 0.001). Male mice fed a high dose phytoestrogen diet failed to decrease AAA rupture. Female mice undergoing oophorectomy did not have accelerated aortic rupture.
These data are the first to attempt to tease out hormonal effects on AAA rupture and the possible role of gender in rupture.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
