Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years ...(1926–1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19‐year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH–DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH–DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin‐embedded intestine from 51 SLE beluga (0–63 years), 4 Cook Inlet (CI) Alaska beluga (0–26 years), and 20 beluga (0–46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light‐to‐dark pink color indicating the presence of PAH–DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H‐scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH–DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH–DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Environ. Mol. Mutagen. 60:29–41, 2019. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
Abstract
The northern Gulf of Mexico has a long history of polycyclic aromatic hydrocarbon (PAH) contamination from anthropogenic activities, natural oil seepages, and the 2010 Deepwater Horizon ...explosion and oil spill. The continental shelf of the same area is a known breeding ground for sperm whales (Physeter macrocephalus). To evaluate PAH-DNA damage, a biomarker for potential cancer risk, we compared skin biopsies collected from Gulf of Mexico sperm whales in 2012 with skin biopsies collected from sperm whales in areas of the Pacific Ocean in 1999–2001. All samples were obtained by crossbow and comprised both epidermis and subcutaneous blubber. To evaluate exposure, 7 carcinogenic PAHs were analyzed in lipids extracted from Pacific Ocean sperm whale blubber, pooled by sex, and location. To evaluate PAH-DNA damage, portions of all tissue samples were formalin-fixed, paraffin-embedded, sectioned, and examined for PAH-DNA adducts by immunohistochemistry (IHC) using an antiserum elicited against benzoapyrene-modified DNA, which crossreacts with several high molecular weight carcinogenic PAHs bound to DNA. The IHC showed widespread epidermal nuclear localization of PAH-DNA adducts in the Gulf of Mexico whales (n = 15) but not in the Pacific Ocean whales (n = 4). A standard semiquantitative scoring system revealed significantly higher PAH-DNA adducts in the Gulf of Mexico whales compared to the whales from the Pacific Ocean study (p = .0002).
The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is ...likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM–DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM–DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3–4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM–DNA adducts were measurable by TAM–DNA chemiluminescence immunoassay. Average TAM–DNA adduct values for the patas uteri (23 adducts/108 nucleotides) were similar to those found in endometrium of the macaques (19 adducts/108 nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/108 nucleotides. To examine TAM–DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM–DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM–DNA adducts/108 nucleotides, whereas unexposed women showed no detectable TAM–DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.
Summary
We examined TAM–DNA adducts in two species of monkeys and in humans treated with TAM. Our data showed that adducts are formed in uterine tissue in monkeys and humans, suggesting a role of TAM genotoxicity in endometrial cancer.
Abstract
Tamoxifen (TAM) is a selective estrogen receptor modulator used worldwide for adjuvant therapy and chemoprevention of breast cancer. However, women receiving TAM therapy have an increased ...risk of endometrial and myometrial cancer, which may be due to genotoxicity and/or estrogen receptor-related mechanisms. It is now accepted that cancer can be both a genetic and an epigenetic disease, with these components participating at all stages of cancer development. DNA methylation at the 5-position of cytosine silences gene expression. Aberrant global DNA 5-methylcytosine (5-mC) levels may produce critical changes in the expression of genes that regulate cell growth and invasiveness. In order to study the effect of TAM exposure on uterine 5-mC levels, we examined uterine tissues taken from aging Erythrocebus patas (patas) and Macaca fascicularis (macaque) monkeys given oral TAM dosing for 3-4 months. In addition, we evaluated endometrial and myometrial samples from breast cancer survivors, who typically receive adjuvant TAM therapy for 5 years. The percentage of 5-mC in DNA was determined by an ELISA that employed a highly-specific 5-mC antibody. Of 5 female patas, 2 were unexposed and 3 were given oral dosing with 1.7 mg TAM/kg bw/day for 3 months. Of 12 female macaques, 6 were unexposed and 6 were given 1.3 mg TAM/kg bw/day for 4 months. Also, uterine tissue was taken at surgery or autopsy from normal-appearing areas and malignant-appearing areas, from women who received 20 mg TAM/day (n=9) and unexposed women (n=6). The patas monkeys given TAM had significantly increased levels of uterine 5-mC compared to the controls (2.9±0.13% vs. 1.9±0.26%, mean ± SE, respectively, p=0.03). However, the macaques showed no significant differences in uterine 5-mC between unexposed and TAM-exposed animals (0.93%±0.1 vs. 1.07%±0.05, mean ± SE, respectively). In human patients, TAM treatment did not alter the global 5-mC levels in either normal-appearing or malignant-appearing endometrium. However, global 5-mC levels in normal-appearing endometrium from the combined TAM-treated and untreated women (n=6) were significantly lower than those found in malignant-appearing uterine tissue from the combined TAM-treated and untreated (n=9) group (0.33%±0.01 vs. 0.70%±0.09, mean ± SE, respectively, p=0.006). Therefore, changes in uterine global DNA 5-mC are not altered consistently within primate species as a result of long-term TAM exposure, suggesting that 5-mC alterations are not major contributors to TAM-induced endometrial cancer. Continuing studies will evaluate 5-mC levels in the promoter regions of specific genes that are modulated in expression level during TAM therapy.
Citation Format: Elena E. Hernandez Ramon, Nancy Si, Mark J. Cline, Charles E. Wood, Ruth Woodward, Miriam C. Poirier. Comparison of global DNA methylation in uterine tissue from different species of monkeys and humans exposed to tamoxifen. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5367. doi:10.1158/1538-7445.AM2013-5367
Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of ...racotumomab as switch maintenance for patients with advanced non-small cell lung cancer (NSCLC).
Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS).
One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively HR, 0.63; 95% confidence interval (CI), 0.46-0.87; P = 0.004. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53-0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times.
Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC.
Background:
The COVID-19 pandemic has caused mental health problems worldwide. The psychopathological implications of COVID-19 in cancer patients have rarely been addressed. Considering the increased ...vulnerability of oncology patients, this issue needs to be addressed to improve the long-term mental health status of these patients.
Methods:
We conducted a prospective study in outpatients under active cancer treatment during the first wave of the COVID-19 pandemic. A semi-structured 24-question survey was designed to measure baseline sociodemographic, psychosocial and COVID-19 exposure characteristics. The Hospital Anxiety and Depression Scale was used to measure psychological symptoms. A descriptive and analytical univariate analysis of the variables studied was performed. We used the
Z
-score to compare different populations (experimental and historical control cohort).
Results:
104 patients were included, the majority of which were women (64.4%), were above 65 years of age (57.7%), had either lung and breast cancer (56.7%), had advanced disease (64%) and were undergoing chemotherapy (63.5%). 51% of them expressed greater fear of cancer than of COVID-19 infection or both.
In relation to HADS, 52.8% of emotional distress, 42.3% of anxiety and 58.6% of depression rates were detected. The main factors related with higher rates of psychological symptomatology were history of previous psychotropic drug consumption and the adoption of additional infection prevention measures because they considered themselves at risk of severe COVID-19 infection (
p
= 0.008;
p
= 0.003 for emotional distress,
p
= 0.026;
p
= 0.004 for anxiety, and
p
= 0.013;
p
= 0.008 for depression). Tumor type, stage, oncologic treatment or rescheduling of cancer treatments were not related to higher levels of psychological symptomatology.
Comparison of our results with another population of similar characteristics was not significant (
Z
score = −1.88;
p
= 0.060).
Conclusions:
We detected high rates of emotional distress during the first wave of the COVID-19 pandemic among cancer patients in active treatment (52.8%). This was higher and clinically relevant than observed in a comparable population (42.5%), although not significant. Cancer itself is the main factor of concern for cancer patients, above and beyond the emotional distress generated by COVID-19 pandemic.
Melon (Cucumis melo), an economically important vegetable crop, belongs to the Cucurbitaceae family which includes several other important crops such as watermelon, cucumber, and pumpkin. It has ...served as a model system for sex determination and vascular biology studies. However, genomic resources currently available for melon are limited.
We constructed eleven full-length enriched and four standard cDNA libraries from fruits, flowers, leaves, roots, cotyledons, and calluses of four different melon genotypes, and generated 71,577 and 22,179 ESTs from full-length enriched and standard cDNA libraries, respectively. These ESTs, together with ~35,000 ESTs available in public domains, were assembled into 24,444 unigenes, which were extensively annotated by comparing their sequences to different protein and functional domain databases, assigning them Gene Ontology (GO) terms, and mapping them onto metabolic pathways. Comparative analysis of melon unigenes and other plant genomes revealed that 75% to 85% of melon unigenes had homologs in other dicot plants, while approximately 70% had homologs in monocot plants. The analysis also identified 6,972 gene families that were conserved across dicot and monocot plants, and 181, 1,192, and 220 gene families specific to fleshy fruit-bearing plants, the Cucurbitaceae family, and melon, respectively. Digital expression analysis identified a total of 175 tissue-specific genes, which provides a valuable gene sequence resource for future genomics and functional studies. Furthermore, we identified 4,068 simple sequence repeats (SSRs) and 3,073 single nucleotide polymorphisms (SNPs) in the melon EST collection. Finally, we obtained a total of 1,382 melon full-length transcripts through the analysis of full-length enriched cDNA clones that were sequenced from both ends. Analysis of these full-length transcripts indicated that sizes of melon 5' and 3' UTRs were similar to those of tomato, but longer than many other dicot plants. Codon usages of melon full-length transcripts were largely similar to those of Arabidopsis coding sequences.
The collection of melon ESTs generated from full-length enriched and standard cDNA libraries is expected to play significant roles in annotating the melon genome. The ESTs and associated analysis results will be useful resources for gene discovery, functional analysis, marker-assisted breeding of melon and closely related species, comparative genomic studies and for gaining insights into gene expression patterns.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Caplacizumab reduces exacerbation and refractoriness in iTTP.•As initial therapy, caplacizumab accelerates response and reduces the need for PEX and hospital stay.
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Immune thrombotic ...thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX.
Small cell lung cancer (SCLC) is commonly classified as either limited or extensive, but the Union for International Cancer Control TNM Classification of Malignant Tumours seventh edition (2009) ...recommended tumor, node, and metastasis (TNM) staging based on analysis of the International Association for the Study of Lung Cancer (IASLC) database.
Survival analyses were performed for clinically and pathologically staged patients presenting with SCLC from 1999 through 2010. Prognosis was compared in relation to the TNM seventh edition staging to serve as validation and analyzed in relation to proposed changes to the T descriptors found in the eighth edition.
There were 5002 patients: 4848 patients with clinical and 582 with pathological stages. Among these, 428 had both. Survival differences were confirmed for T and N categories and maintained in relation to proposed revisions to T descriptors for seventh edition TNM categories and proposed changes in the eighth edition. There were also survival differences, notably at 12 months, in patients with brain-only single-site metastasis (SSM) compared to SSM at other sites, and SSM without a pleural effusion showed a better prognosis than other patients in the M1b category.
We confirm the prognostic value of clinical and pathological TNM staging in patients with SCLC, and recommend continued usage for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. However, for M descriptors, it remains uncertain whether survival differences in patients with SSM in the brain simply reflect better treatment options rather than better survival based on anatomic extent of disease.
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