Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study

Background: The main forms of mercury (Hg) exposure in the general population are methylmercury (MeHg) from seafood, inorganic mercury (I-Hg) from food, and mercury vapor (Hg0) from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg) in the tissues was evaluated. Methods: Samples of blood, brain (occipital lobe cortex), pituitary, thyroid, abdominal muscle and toenails were collected at autopsy of 30 deceased individuals, age from 47 to 91 years of age. Concentrations of total-Hg and I-Hg in blood and brain cortex were determined by cold vapor atomic fluorescence spectrometry and total-Hg in other tissues by sector field inductively coupled plasma-mass spectrometry (ICP-SFMS). Results: The median concentrations of MeHg (total-Hg minus I-Hg) and I-Hg in blood were 2.2 and 1.0 μg/L, and in occipital lobe cortex 4 and 5 μg/kg, respectively. There was a significant correlation between MeHg in blood and occipital cortex. Also, total-Hg in toenails correlated with MeHg in both blood and occipital lobe. I-Hg in both blood and occipital cortex, as well as total-Hg in pituitary and thyroid were strongly associated with the number of dental amalgam surfaces at the time of death. Conclusion: In a fish-eating population, intake of MeHg via the diet has a marked impact on the MeHg concentration in the brain, while exposure to dental amalgam restorations increases the I-Hg concentrations in the brain. Discrimination between mercury species is necessary to evaluate the impact on Hg in the brain of various sources of exposure, in particular, dental amalgam exposure

Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.publishedVersio

Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study

Abstract Background The main forms of mercury (Hg) exposure in the general population are methylmercury (MeHg) from seafood, inorganic mercury (I-Hg) from food, and mercury vapor (Hg0) from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg) in the tissues was evaluated. Methods Samples of blood, brain (occipital lobe cortex), pituitary, thyroid, abdominal muscle and toenails were collected at autopsy of 30 deceased individuals, age from 47 to 91 years of age. Concentrations of total-Hg and I-Hg in blood and brain cortex were determined by cold vapor atomic fluorescence spectrometry and total-Hg in other tissues by sector field inductively coupled plasma-mass spectrometry (ICP-SFMS). Results The median concentrations of MeHg (total-Hg minus I-Hg) and I-Hg in blood were 2.2 and 1.0 μg/L, and in occipital lobe cortex 4 and 5 μg/kg, respectively. There was a significant correlation between MeHg in blood and occipital cortex. Also, total-Hg in toenails correlated with MeHg in both blood and occipital lobe. I-Hg in both blood and occipital cortex, as well as total-Hg in pituitary and thyroid were strongly associated with the number of dental amalgam surfaces at the time of death. Conclusion In a fish-eating population, intake of MeHg via the diet has a marked impact on the MeHg concentration in the brain, while exposure to dental amalgam restorations increases the I-Hg concentrations in the brain. Discrimination between mercury species is necessary to evaluate the impact on Hg in the brain of various sources of exposure, in particular, dental amalgam exposure.</p

MRI‐based radiomic signatures for pretreatment prognostication in cervical cancer

Abstract Background Accurate pretherapeutic prognostication is important for tailoring treatment in cervical cancer (CC). Purpose To investigate whether pretreatment MRI‐based radiomic signatures predict disease‐specific survival (DSS) in CC. Study Type Retrospective. Population CC patients (n = 133) allocated into training(T) (nT = 89)/validation(V) (nV = 44) cohorts. Field Strength/Sequence T2‐weighted imaging (T2WI) and diffusion‐weighted imaging (DWI) at 1.5T or 3.0T. Assessment Radiomic features from segmented tumors were extracted from T2WI and DWI (high b‐value DWI and apparent diffusion coefficient (ADC) maps). Statistical Tests Radiomic signatures for prediction of DSS from T2WI (T2rad) and T2WI with DWI (T2 + DWIrad) were constructed by least absolute shrinkage and selection operator (LASSO) Cox regression. Area under time‐dependent receiver operating characteristics curves (AUC) were used to evaluate and compare the prognostic performance of the radiomic signatures, MRI‐derived maximum tumor size ≤/> 4 cm (MAXsize), and 2018 International Federation of Gynecology and Obstetrics (FIGO) stage (I–II/III–IV). Survival was analyzed using Cox model estimating hazard ratios (HR) and Kaplan–Meier method with log‐rank tests. Results The radiomic signatures T2rad and T2 + DWIrad yielded AUCT/AUCV of 0.80/0.62 and 0.81/0.75, respectively, for predicting 5‐year DSS. Both signatures yielded better or equal prognostic performance to that of MAXsize (AUCT/AUCV: 0.69/0.65) and FIGO (AUCT/AUCV: 0.77/0.64) and were significant predictors of DSS after adjusting for FIGO (HRT/HRV for T2rad: 4.0/2.5 and T2 + DWIrad: 4.8/2.1). Adding T2rad and T2 + DWIrad to FIGO significantly improved DSS prediction compared to FIGO alone in cohort(T) (AUCT 0.86 and 0.88 vs. 0.77), and FIGO with T2 + DWIrad tended to the same in cohort(V) (AUCV 0.75 vs. 0.64, p = 0.07). High radiomic score for T2 + DWIrad was significantly associated with reduced DSS in both cohorts. Data Conclusion Radiomic signatures from T2WI and T2WI with DWI may provide added value for pretreatment risk assessment and for guiding tailored treatment strategies in CC

A 10-gene prognostic signature points to LIMCH1 and HLA-DQB1 as important players in aggressive cervical cancer disease

Background: Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. Methods: Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. Results: Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). Conclusions: This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment

Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer

A Selective Biomarker Panel Increases the Reproducibility and the Accuracy in Endometrial Biopsy Diagnosis

Grading and histologic typing of endometrial cancer in biopsy material has a direct impact on the decision to perform lymphadenectomy and/or omentectomy in many cancer centers. Endometrial biopsies are among the most common general surgical pathology specimens. Multiple studies have shown that biopsy diagnosis suffers from a lack of reproducibility. Although many biomarkers have been proposed, none have been demonstrated to improve the diagnosis in the biopsy setting. In this study, 70 biopsies with endometrial carcinoma were supplemented with a biomarker panel consisting of ER, PR, P53, and DNA ploidy. A representative H&E slide was scanned digitally and made available to 12 gynecologic pathologists in 4 Nordic countries: Finland, Denmark, Sweden, and Norway. Reviewers diagnosed the cases both before and after being provided with the biomarker results. The interobserver percent agreement and Cohen κ improved from 75.8% (κ=0.52, moderate) to 84% (κ=0.68, substantial) with inclusion of the biomarker panel. Agreement with the subsequent hysterectomy diagnosis also improved from 83.6% (κ=0.67) to 88.7% (κ=0.77). There was no statistical improvement between a reflex (84% agreement) and a reflective testing algorithm (82.9% agreement), suggesting that the selective use of biomarkers is appropriate. Difficult cases were almost exclusively high-grade tumors. Finally, a statistical model indicated that only P53 and DNA ploidy, in conjunction with an H&E review, had an impact on the decision to upgrade or downgrade cases

Contrasting Monosymptomatic Patients with Hallucinations and Delusions in First-Episode Psychosis Patients: A Five-Year Longitudinal Follow-Up Study

Objectives: This thesis explores different symptom profiles found in First Episode Psychosis (FEP) patients assessed at several points of time over a ten year period. Earlier studies have focused predominantly on groups of symptoms rather than individual symptoms when describing course of illness and outcome, and long-term studies of symptom development in epidemiological FEP samples assessed multiples times are lacking. By studying individual symptoms longitudinally from the onset of illness we aimed to gain more knowledge about symptom development and the relationship between symptoms and outcome variables that are known to be affected in psychotic disorders. The aim of the study was threefold: 1) to identify a group of patients with delusions only and a group with hallucinations only, and examine if the groups differed with regard to demographics, clinical variables and outcome measures, and in particular suicidality, 2) to assess the prevalence of apathy ten years after the first psychotic episode, and to explore the association between apathy and general functioning, and between apathy and quality of life, and 3) to identify different flat affect (FA) symptom profiles based on longitudinal symptom trajectories and assess the prevalence and correlates of these trajectories, to assess predictors of enduring FA, and to explore the longitudinal relationship between FA and social functioning. Methods: Three-hundred-and-one first episode, non organic psychosis patients were included in the TIPS Study (Early Treatment and Intervention in Psychosis) and followed over a ten year period. Patients were assessed at baseline, three months, and one, two, five and ten year follow-up with an extensive battery of instruments including measures of demographics, duration of untreated psychosis (DUP), premorbid function (PAS), diagnosis (SCID), symptom measures (PANSS, AES, CDSS), measures of functioning (GAF, SCLFS), suicidality and quality of life (L-QoLI). The relationship of the symptoms of interest, namely hallucinations and delusions (PANSS P1 and P3, respectively), apathy (AES-SApathy and PANSS N2+N4) and flat affect (PANSS N1), to the above measures were assessed with t-test, correlation and regression analyses. Results: Sub-groups of patients with hallucinations only and delusions only can be identified in a five year follow-up study, and the groups differed on multiple variables. Most importantly, the hallucination only group scored higher on measures of suicidality, and insight might be a possible mediator of suicidality in this group. Apathy was found to be a common symptom ten years after the first psychotic episode, affecting 30 % of the sample. Proxy-measures of apathy indicated that this symptom declined in the follow-up period. Clinical apathy was strongly related to poorer functioning and to poorer subjective quality of life in patients ten years after the first psychotic episode. Five different FA trajectory groups were identified. FA was more fluctuant than expected, and only 5 % of the sample experienced enduring FA. Furthermore, FA was related to poorer functional outcome measures, in particular to objective social functioning, both premorbidly and throughout the ten year follow-up period. Conclusions: By looking at individual symptoms rather than groups of symptoms it was possible to shed light on patients with symptom profiles that previously have received limited attention, and to learn more about the long-term development of the individual symptoms. Combined, the findings highlight the importance of looking at symptoms separately in order to both better understand the longitudinal association between symptoms, and to gain knowledge of how individual symptom profiles affect outcome measures including suicidality, quality of life, and social functioning