A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and ...sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in its progression to a more aggressive disease. These coactivators interact with ...nuclear receptors and other transcription factors to boost transcription of multiple genes, which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial–mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high-throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs are synthesized that incorporate the addition of F atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5–50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress the growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells, respectively, SI-10 and SI-12 effectively inhibited the progression of breast cancer lung metastasis. These results demonstrate that SI-10 and SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.
•The Khorana score VTE risk assessment model has not been validated in patients with uterine cancer.•Patients with uterine cancer undergoing chemotherapy had a VTE rate of 6.5%.•Uterine cancer ...patients that had a VTE during treatment had a non-statistically significant higher average Khorana score.•A high Khorana score is a poor predictor of VTE in patients with uterine cancer undergoing chemotherapy.
Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a validated tool to assess risk of VTE in cancer patients. The purpose of this study is to determine if the Khorana score can be used as a risk stratification tool for VTE in patients with uterine cancer undergoing chemotherapy.
A retrospective cohort study of patients with newly diagnosed uterine cancer receiving chemotherapy over a 4-year period was conducted. The patients were stratified based on their Khorana score as well as their chemotherapy sequence, neoadjuvant or definitive versus adjuvant.
A total of 276 patients were included: 40 received neoadjuvant or definitive, 236 adjuvant chemotherapy. Most patients had advanced stage disease (64.5%). 18 (6.5%) patients developed VTE within 180 days of initiating chemotherapy. High Khorana score was associated with a non-significant increase in VTE (K ≥ 2 OR 1.17, CI 0.40–3.39, K ≥ 3 OR 1.69, CI 0.61–4.69) but had poor predictive accuracy based on area under the curve (K ≥ 2 0.51, K ≥ 3 0.55). The VTE rate was higher in the neoadjuvant/definitive chemotherapy group to adjuvant (12.5% vs 5.5%, p = 0.11). While the former group had a higher average Khorana score (2.35 vs 1.93, p = 0.0048), this was not predictive of VTE.
While validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in patients with uterine cancer. The use of the Khorana score to guide routine thromboprophylaxis in these patients should be used with caution and further investigation is warranted.
In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for the targeted degradation of proteins with short half-lives. The covalent attachment of ubiquitin to lysine residues of ...targeted proteins is a signal for the recognition and rapid degradation by the proteasome, a large multi-subunit protease. In this report, we demonstrate that the human estrogen receptor (ER) protein is rapidly degraded in mammalian cells in an estradiol-dependent manner. The treatment of mammalian cells with the proteasome inhibitor MG132 inhibits activity of the proteasome and blocks ER degradation, suggesting that ER protein is turned over through the ubiquitin-proteasome pathway. In addition, we show that in vitro ER degradation depends on ubiquitin-activating E1 enzyme (UBA) and ubiquitin-conjugating E2 enzymes (UBCs), and the proteasome inhibitors MG132 and lactacystin block ER protein degradation in vitro. Furthermore, the UBA/UBCs and proteasome inhibitors promote the accumulation of higher molecular weight forms of ER. The UBA and UBCs, which promote ER degradation in vitro, have no significant effect on human progesterone receptor and human thyroid hormone receptor β proteins.
We have discovered a mutant loblolly pine (Pinus taeda L.) in which expression of the gene encoding cinnamyl alcohol dehydrogenase (CAD; EC 1.1.1.195) is severely reduced. The products of CAD, ...cinnamyl alcohols, are the precursors of lignin, a major cell wall polymer of plant vascular tissues. Lignin composition in this mutant shows dramatic modifications, including increased incorporation of the substrate of CAD (coniferaldehyde), indicating that CAD may modulate lignin composition in pine. The recessive cad-n1 allele, which causes this phenotype, was discovered in a tree heterozygous for this mutant allele. It is inherited as a simple Mendelian locus that maps to the same genomic region as the cad locus. In mutant plants, CAD activity and abundance of rod RNA transcript are low, and free CAD substrate accumulates to a high level. The wood of the mutant is brown, whereas the wood in wild types is nearly white. The wood phenotype resembles that of brown midrib (bm) mutants and some transgenic plants in which xylem is red-brown due to a reduction in CAD activity. However, unlike transgenics with reduced CAD, the pine mutant has decreased lignin content. Wood in which the composition of lignin varies beyond previous expectations still provides vascular function and mechanical support
Postoperative chemical meningitis mimics bacterial meningitis, complicating the diagnosis until results of cerebrospinal fluid (CSF) cultures can be obtained. We analyzed clinical and laboratory data ...from a series of 1146 patients to identify findings that could exclude bacterial meningitis.
We reviewed the charts of patients who developed meningitis after cerebellopontine angle surgery. Lumbar puncture data from asymptomatic postoperative patients were our control.
Clinical symptoms, CSF profiles, and serum white blood cell (WBC) counts were compared between patients with chemical meningitis, bacterial meningitis, and asymptomatic patients.
The incidence of meningitis in our series of 1146 patients was 4.54 percent; 0.87 percent was culture-proven bacterial meningitis. The patients with bacterial meningitis had significantly higher CSF and serum WBC counts, and lower CSF glucose. The major difference between asymptomatic patients and those with chemical meningitis was the significantly lower ratio of CSF WBCs to red blood cells (RBCs) in asymptomatic patients.
Patients with mild CSF leukocytosis and normal CSF glucose without high serum WBC counts or focal neurological deficits may be treated for chemical meningitis.
While early epidemiologic studies ascribed increases in the incidence of human papillomavirus-associated oropharyngeal cancers to middle-aged patients, recent analyses have demonstrated an increasing ...median age of diagnosis. Treatment of patients older than 70 years is controversial as their inclusion in the practice-defining clinical trials has been limited and the survival benefit conferred by chemotherapy may be outweighed by treatment toxic effects.
To assess the oncologic outcomes of older adults with human papillomavirus-associated oropharyngeal cancer who underwent upfront transoral robotic surgery and pathologic characteristics-guided adjuvant therapy in a large cohort of patients with close follow-up.
A retrospective cohort analysis was conducted in a tertiary care academic medical center between January 1, 2010, and December 30, 2017. Patients aged 70 years or older at time of diagnosis with biopsy-proven and surgically resectable p16-positive oropharyngeal cancers were included. Data analysis was conducted from March 1 to June 1, 2020.
Transoral robotic surgery oropharyngeal resection and neck dissection with pathologic characteristic-guided adjuvant therapy.
Three-year estimates of disease-specific survival, overall survival, and disease-free survival, as well as rates of adjuvant therapy (radiotherapy and chemoradiotherapy) and perioperative complications.
Seventy-seven patients were included (median age, 73.0; interquartile range, 71.0-76.0; range, 70-89 years); of these, 58 were men (75.3%). Perioperative mortality was 1.3% and the rate of oropharyngeal hemorrhage was 2.6%. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy. The median length of follow-up was 39.6 (range, 0.1-96.2) months, and the 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for disease-specific survival, 90.0% (95% CI, 79.4%-95.0%) for overall survival, and 84.3% (95% CI, 73.4%-91.0%) for disease-free survival.
The findings of this cohort study suggest that transoral robotic surgery and pathologic characteristic-guided adjuvant therapy can provide beneficial survival outcomes, infrequent perioperative mortality, and, for most carefully selected older adults, obviate the need for chemotherapy.
This Tropospheric Ozone Assessment Report (TOAR) on the current state of knowledge of ozone metrics of relevance to vegetation (TOAR-Vegetation) reports on present-day global distribution of ozone at ...over 3300 vegetated sites and the long-term trends at nearly 1200 sites. TOAR-Vegetation focusses on three metrics over vegetation-relevant time-periods across major world climatic zones: M12, the mean ozone during 08:00–19:59; AOT40, the accumulation of hourly mean ozone values over 40 ppb during daylight hours, and W126 with stronger weighting to higher hourly mean values, accumulated during 08:00–19:59.
Although the density of measurement stations is highly variable across regions, in general, the highest ozone values (mean, 2010–14) are in mid-latitudes of the northern hemisphere, including southern USA, the Mediterranean basin, northern India, north, north-west and east China, the Republic of Korea and Japan. The lowest metric values reported are in Australia, New Zealand, southern parts of South America and some northern parts of Europe, Canada and the USA. Regional-scale assessments showed, for example, significantly higher AOT40 and W126 values in East Asia (EAS) than Europe (EUR) in wheat growing areas (p < 0.05), but not in rice growing areas. In NAM, the dominant trend during 1995–2014 was a significant decrease in ozone, whilst in EUR it was no change and in EAS it was a significant increase.
TOAR-Vegetation provides recommendations to facilitate a more complete global assessment of ozone impacts on vegetation in the future, including: an increase in monitoring of ozone and collation of field evidence of the damaging effects on vegetation; an investigation of the effects on peri-urban agriculture and in mountain/upland areas; inclusion of additional pollutant, meteorological and inlet height data in the TOAR dataset; where not already in existence, establishing new region-specific thresholds for vegetation damage and an innovative integration of observations and modelling including stomatal uptake of the pollutant.
Purpose Computed tomography (CT) is a fast and ubiquitous tool to evaluate intra-abdominal organs and diagnose appendicitis. However, traditional CT reporting does not necessarily capture the degree ...of uncertainty and indeterminate findings are still common. The purpose of this study was to evaluate the reproducibility of a standardized CT reporting system for appendicitis across a large population and the system′s impact on radiologists′ certainty in diagnosing appendicitis. Methods Using a previously described standardized reporting system, eight radiologists retrospectively evaluated CT scans, blinded to all clinical information, in a stratified random sample of 237 patients from a larger cohort of patients imaged for possible appendicitis (2010–2014). Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to evaluate the diagnostic performance of readers for identifying appendicitis. Two-thirds of these scans were randomly selected to be independently read by a second reader, using the original CT reports to balance the number of positive, negative and indeterminate exams across all readers. Inter-reader agreement was evaluated. Results There were 113 patients with appendicitis (mean age 38, 67% male). Using the standardized report, radiologists were highly accurate at identifying appendicitis (AUC=0.968, 95%CI confidence interval: 0.95, 0.99. Inter-reader agreement was >80% for most objective findings, and certainty in diagnosing appendicitis was high and reproducible (AUC=0.955 and AUC=0.936 for the first and second readers, respectively). Conclusions Using a standardized reporting system resulted in high reproducibility of objective CT findings for appendicitis and achieved high diagnostic accuracy in an at-risk population. Predictive tools based on this reporting system may further improve communication about certainty in diagnosis and guide patient management, especially when CT findings are indeterminate.
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