Effect of depressive symptoms and HIV exposure on the quality of life of HIV-seropositive and seronegative pregnant women

Introduction: Depression among human immunodeficiency virus (HIV)-seropositive individuals has been associated with reduced quality of life. Objective: To evaluate the effect of depressive symptoms and HIV exposure on mean quality of life scores in HIV-seropositive and HIV-seronegative postpartum women. Methods: A cross-sectional study was conducted with two groups: 80 HIV-seropositive and 80 HIV-seronegative postpartum women. The Edinburgh Postnatal Depression Scale and the World Health Organization Quality of Life short-version scale were used to assess presence of depressive symptoms and quality of life scores. Two-way analysis of variance was used to compare the effects of depressive symptoms, HIV exposure and interaction between depressive symptoms and HIV exposure on mean quality of life scores, with p < 0.05 considered statistically significant. Results: Depressive symptoms were present in 35% (28) of HIV-seropositive and 17.5% (14) of HIV-seronegative participants (p = 0.02). The interaction between depressive symptoms and HIV exposure was not significant for any quality of life domain. The main effect of HIV exposure was also not significant. Depressive symptoms had a negative influence on quality of life scores in all domains (physical health, psychological health, social relationships and environment) (p < 0.001). Conclusion: The quality of life of pregnant women is negatively influenced by the presence of depressive symptoms

Genomic landscape of pleural and peritoneal mesothelioma tumours

BACKGROUND Malignant pleural and peritoneal mesotheliomas are rare malignancies with unacceptable poor prognoses and limited treatment options. The genomic landscape is mainly characterised by the loss of tumour suppressor genes and mutations in DNA repair genes. Currently, data from next-generation sequencing (NGS) of mesothelioma tumours is restricted to a limited number of cases; moreover, data comparing molecular features of mesothelioma from the pleural and peritoneal origin with NGS are lacking. METHODS We analysed 1113 pleural mesothelioma and 355 peritoneal mesothelioma samples. All tumours were sequenced with the FoundationOne® or FoundationOne®CDx assay for detection of substitutions, insertion-deletions, copy-number alterations and selected rearrangements in at least 324 cancer genes. RESULTS This analysis revealed alterations in 19 genes with an overall prevalence of at least 2%. Alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2 occurred with a prevalence of at least 10%. Peritoneal, compared to pleural mesothelioma, was characterised by a lower prevalence of alterations in CDKN2A, CDKN2B and MTAP. Moreover, we could define four distinct subgroups according to alterations in BAP1 and CDKN2A/B. Alterations in Hedgehog pathway-related genes (PTCH1/2 and SUFU) and Hippo pathway-related gene (NF2) as well as KRAS, EGFR, PDGFRA/B, ERBB2 and FGFR3 were detected in both cohorts. CONCLUSION Here, we report the molecular aberrations from the largest cohort of patients with mesothelioma. This analysis identified a proportion of patients with targetable alterations and suggests that molecular profiling can identify new treatment options for patients with mesothelioma

Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma

ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive in vitro to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (n = 257 and n = 241) stained with an engineered ADP-ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high-ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (p < 0.01 each). cyADPR proved to be an independent prognostic factor (p = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (p < 0.01) and worse patient outcome (p < 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (p < 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased ARID1A mutations in ccRCC$^{cyADPR+++/PARP1+}$ compared with ccRCC$^{cyADPR-/PARP1-}$ (31% versus 4%; p < 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations

MTPpilot: An Interactive Software for Visualization of Next-Generation Sequencing Results in Molecular Tumor Boards

PURPOSE Comprehensive targeted next-generation sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards, the detected genomic alterations are often discussed to decide the next treatment options for patients with cancer. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. METHODS We have developed the Molecular Tumor Profiling pilot (MTPpilot) webservice using HTML, PHP, JavaScript, and MySQL to support the clinical discussion of NGS results at molecular tumor boards. RESULTS MTPpilot integrates various public genome, network, and cancer mutation databases with interactive visualization tools to assess the functional impact of mutations and support clinical decision making at tumor boards. CONCLUSION MTPpilot is tailored for discussion of NGS gene panel results at molecular tumor boards. It is freely available as a webservice at MTPpilot

Contribuição dos alimentos ultraprocessados no consumo alimentar diário de mulheres soropositivas e soronegativas para o HIV durante a gestação

Objective To assess the daily dietary intake and energy contribution of ultraprocessed foods among women who are positive and negative for the human immunodeficiency virus (HIV) during pregnancy. Methods This case–control study included 77 HIV-positive and 79 HIV-negative puerperal women between 2015 and 2016. The socioeconomic and maternal demographic data were assessed, and a food frequency questionnaire (FFQ) adapted for pregnant women was applied. The Fisher exact test and the Mann-Whitney test were applied to detect differences between the groups. Linear regression was used to assess the associations between the intake of ultra-processed food and energy, macro- and micronutrients, with values of p < 0.05 considered significant. Results The HIV-positive group was older (p < 0.001) and had lower income (p ¼ 0.016) and level of schooling (p < 0.001) than the HIV-negative group. Both groups presented similar average food intake: 4,082.99 Kcal/day and 4,369.24 Kcal/day for the HIV-positive and HIV-negative women respectively (p ¼ 0.258).The HIV-positive group consumed less protein (p ¼ 0.048), carbohydrates (p ¼ 0.028) and calcium (p ¼ 0.001), andmore total fats (p ¼ 0.003). Ultra-processed foods accounted for 39.80% and 40.10% of the HIV-positive and HIV-negative groups’ caloric intake respectively (p ¼ 0.893). The intake of these foods was associated with a higher consumption of carbohydrates (p < 0.001), trans fat (p ¼ 0.013) and sodium (p < 0.001), as well as lower protein (p < 0.001) and fiber intake (p ¼ 0.022). Conclusion These findings demonstrate that the energy consumption and ultraprocessed food intake were similar in both groups, which reinforces the trend toward a high intake of ultra-processed food in the general population. The intake of ultraprocessed food was positively associated with the consumption of carbohydrates, trans fat and sodium, and negatively associated with the consumption of protein and fiberObjetivo Avaliar o consumo alimentar diário e a contribuição dos alimentos ultraprocessados na dieta de gestantes soropositivas e soronegativas para o vírus da imunodeficiência humana (HIV). Métodos Estudo de caso–controle com 77 puérperas soropositivas e 79 soronegativas entre 2015 e 2016. Analisaram-se dados socioeconômicos e demográficos maternos, e aplicou-se um questionário de frequência alimentar (QFA) adaptado para gestantes. Utilizou-se o teste exato de Fisher e o teste de Mann-Whitney para detectar diferenças entre os grupos. A regressão linear avaliou a associação entre o consumo de ultraprocessados e de energia, macro e micronutrientes. Valores de p < 0,05 foram considerados significativos. Resultados O grupo de puérperas soropositivas foi mais velho (p < 0,001), com menor renda familiar (p ¼ 0,016) e escolaridade (p < 0,001) quando comparado com o grupo das soronegativas. Ambos os grupos apresentaram médias de consumo semelhantes, com 4.082,99 Kcal/dia entre as puérperas soropositivas e 4.369,24 kcal/dia entre as soronegativas (p ¼ 0,258). Observou-se que as puérperas soropositivas consumiam menos proteínas (p ¼ 0,048), carboidratos (p ¼ 0,028) e cálcio (p ¼ 0,001), e mais gorduras totais (p ¼ 0,003). Os ultraprocessados corresponderam a 39,80% das calorias entre as soropositivas, e a 40,10% entre as soronegativas (p ¼ 0,893). O consumo destes alimentos esteve associado a um maior consumo de carboidratos (p < 0,001), gordura trans (p ¼ 0,013) e sódio (p < 0,001), e a um menor consumo de proteínas (p < 0,001) e fibras (p ¼ 0,022). Conclusão Esses achados demonstram que o consumo de energia e de alimentos ultraprocessados foram semelhantes nos dois grupos, o que reforça a tendência ao consumo elevado de alimentos ultraprocessados na população geral. O consumo de alimentos ultraprocessados foi positivamente associado ao consumo de carboidratos, gorduras trans e sódio, e negativamente associado ao consumo de proteínas e fibras

Comparison of calling pipelines for whole genome sequencing: an empirical study demonstrating the importance of mapping and alignment

Rapid advances in high-throughput DNA sequencing technologies have enabled the conduct of whole genome sequencing (WGS) studies, and several bioinformatics pipelines have become available. The aim of this study was the comparison of 6 WGS data pre-processing pipelines, involving two mapping and alignment approaches (GATK utilizing BWA-MEM2 2.2.1, and DRAGEN 3.8.4) and three variant calling pipelines (GATK 4.2.4.1, DRAGEN 3.8.4 and DeepVariant 1.1.0). We sequenced one genome in a bottle (GIAB) sample 70 times in different runs, and one GIAB trio in triplicate. The truth set of the GIABs was used for comparison, and performance was assessed by computation time, F1 score, precision, and recall. In the mapping and alignment step, the DRAGEN pipeline was faster than the GATK with BWA-MEM2 pipeline. DRAGEN showed systematically higher F1 score, precision, and recall values than GATK for single nucleotide variations (SNVs) and Indels in simple-to-map, complex-to-map, coding and non-coding regions. In the variant calling step, DRAGEN was fastest. In terms of accuracy, DRAGEN and DeepVariant performed similarly and both superior to GATK, with slight advantages for DRAGEN for Indels and for DeepVariant for SNVs. The DRAGEN pipeline showed the lowest Mendelian inheritance error fraction for the GIAB trios. Mapping and alignment played a key role in variant calling of WGS, with the DRAGEN outperforming GATK

Molecular and immunophenotypic characterization of SMARCB1 (INI1) - deficient intrathoracic Neoplasms

The switch/sucrose-non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeling complex that plays important roles in DNA repair, transcription and cell differentiation. This complex consists of multiple subunits and is of particular interest in thoracic malignancies due to frequent subunit alteration of SMARCA4 (BRG1). Much less is known about SMARCB1 (INI1) deficient intrathoracic neoplasms, which are rare, often misclassified and understudied. In a retrospective analysis of 1479 intrathoracic malignant neoplasms using immunohistochemistry for INI1 (SMARCB1) on tissue micro arrays (TMA) and a search through our hospital sarcoma database, we identified in total nine intrathoracic, INI1 deficient cases (n = 9). We characterized these cases further by additional immunohistochemistry, broad targeted genomic analysis, methylation profiling and correlated them with clinical and radiological data. This showed that genomic SMARCB1 together with tumor suppressor alterations drive tumorigenesis in some of these cases, rather than epigenetic changes such as DNA methylation. A proper diagnostic classification, however, remains challenging. Intrathoracic tumors with loss or alteration of SMARCB1 (INI1) are highly aggressive and remain often underdiagnosed due to their rarity, which leads to false diagnostic interpretations. A better understanding of these tumors and proper diagnosis is important for better patient care as clinical trials and more targeted therapeutic options are emerging

ERBB2‐amplified lobular breast carcinoma exhibits concomitant CDK12 co‐amplification associated with poor prognostic features

Most invasive lobular breast carcinomas (ILBCs) are luminal‐type carcinomas with an HER2‐negative phenotype (ERBB2 or HER2 un‐amplified) and CDH1 mutations. Rare variants include ERBB2‐amplified subtypes associated with an unfavorable prognosis and less response to anti‐HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2‐amplified ILBC and compared these characteristics with ERBB2‐unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin‐embedded formalin‐fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast‐specific markers was tested by immunohistochemistry (IHC). Hybrid capture‐based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2‐amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2‐unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2‐positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2‐amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2‐amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2‐unamplified ILBC. CDK12/ERBB2 co‐amplification may explain the poor prognosis and therapy resistance of ERBB2‐amplified ILBC