Evaluation of plasma biomarkers to predict major adverse kidney events in hospitalized patients with COVID-19

RATIONALE & OBJECTIVE: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers. EXPOSURE: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization. OUTCOME: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days. ANALYTICAL APPROACH: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index. RESULTS: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively. LIMITATIONS: No control group of hospitalized patients without COVID-19. CONCLUSIONS: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes. PLAIN-LANGUAGE SUMMARY: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes

A microfluidic-based filtration system to enrich for bone marrow disseminated tumor cells from breast cancer patients

Disseminated tumors cells (DTCs) present in the bone marrow (BM) are believed to be the progenitors of distant metastatic spread, a major cause of mortality in breast cancer patients. To better understand the behavior and therapeutic vulnerabilities of these rare cell populations, unbiased methods for selective cell enrichment are required. In this study, we have evaluated a microfluidic-based filtration system (ParsortixR, Angle PLC), previously demonstrated for use in circulating tumor cell (CTC) capture, to capture BM DTCs. Performance using BM samples was also compared directly to enrichment of CTCs in the peripheral blood (PB) from both metastatic and non-metastatic breast cancer patients. Although the non-specific capture of BM immune cells was significant, the device could routinely achieve significant cytoreduction of BM and PB WBCs and at least 1,000-fold enrichment of DTCs, based on labeled tumor cell spike-in experiments. Detection of previously characterized DTC-associated gene expression biomarkers was greatly enhanced by the enrichment method, as demonstrated by droplet digital PCR assay. Cells eluted from the device were viable and suitable for single cell RNA sequencing experiments. DTCs in enriched BM samples comprised up to 5% of the total cell population, allowing for effective single cell and population-based transcriptional profiling of these rare cells. Use of the Parsortix instrument will be an effective approach to enrich for rare BM DTCs in order to better understand their diverse molecular phenotypes and develop approaches to eradicate these cells to prevent distant disease development in breast cancer patients

Portrayal of women in television and women’s magazines: perception of college students

Present study was conducted on girl students of undergraduate arts stream in the age group of 17-21 years in district Ludhiana. Questionnaire as a tool of data collection was used to collect information from three hundred girl students of three colleges. The image of women in television and magazines as perceived by the young respondents has been analyzed. Respondents felt that both television and magazines portray realistic image of women. More respondents with rural background perceived positive portrayal of women on Television as it presents a real picture, while majority of the respondents from urban background admitted negative portrayal of women. Similarly, results show that respondents younger in the age were more under the influence of television characters because they treat them to be real. They start feeling that whatever is being shown on television is real. A good majority of the respondents with rural background showed interest in magazine reading as compared to the respondents with urban background. A considerable proportion of the respondents irrespective of their background, were satisfied with the text and language used in women magazine

Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy.MethodsClinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1-MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations.ResultsA total of 3 women and 4 men with NF1-MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [NF1], ROS proto-oncogene 1 [ROS1], tumor protein p53 [TP53], and tyrosine kinase 2 [TYK2]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), another neural crest-derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (<7%). In the current series, recurrent TYK2 mutations were identified in 2 cases of NF1-MPNST (30% of cases), whereas TYK2 protein overexpression was observed in 60% of MPNST cases using an independently generated tissue microarray, regardless of NF1 status.ConclusionsClinical genomic analysis of the current series of NF1-MPNST cases found that TYK2 is a new gene mutated in MPNST. Future work will focus on examining the utility of TYK2 expression as a biomarker and therapeutic target for these cancers. Cancer 2017;123:1194-1201. © 2016 American Cancer Society

Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth

Abstract Background Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk. Results The Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling. Conclusions We identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants

Whole exome sequencing reveals the maintained polyclonal nature from primary to metastatic malignant peripheral nerve sheath tumor in two patients with NF1.

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with high metastatic rates and poor overall patient survival. There are currently no effective therapies, underscoring the pressing need to define the molecular etiologies that underlie MPNST progression. The aim of this study was to examine clonal progression and identify the molecular events critical for MPNST spread.MethodsIn two patients with temporally and spatially distinct metastatic lesions, we employed whole exome sequencing (WES) to elucidate the genetic events of clonal progression, thus identifying the molecular events critical for MPNST spread.ResultsFirst, we demonstrated shared clonal origins for the metastatic lesions relative to the primary tumors, which were maintained throughout the course of MPNST progression, supporting the conclusion that cancer cells with metastatic potential already exist in the primary neoplasm. Second, we discovered TRIM23, a member of the Tripartite Motif family of proteins, as a regulator of MPNST lung metastatic spread in vivo.ConclusionsThe ability to track the genomic evolution from primary to metastatic MPNST offers new insights into the sequence of genetic events required for tumor progression and has identified TRIM23 as a novel target for future study in this rare cancer

Whole exome sequencing reveals the maintained polyclonal nature from primary to metastatic malignant peripheral nerve sheath tumor in two patients with NF1

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with high metastatic rates and poor overall patient survival. There are currently no effective therapies, underscoring the pressing need to define the molecular etiologies that underlie MPNST progression. The aim of this study was to examine clonal progression and identify the molecular events critical for MPNST spread. METHODS: In two patients with temporally and spatially distinct metastatic lesions, we employed whole exome sequencing (WES) to elucidate the genetic events of clonal progression, thus identifying the molecular events critical for MPNST spread. RESULTS: First, we demonstrated shared clonal origins for the metastatic lesions relative to the primary tumors, which were maintained throughout the course of MPNST progression, supporting the conclusion that cancer cells with metastatic potential already exist in the primary neoplasm. Second, we discovered TRIM23, a member of the Tripartite Motif family of proteins, as a regulator of MPNST lung metastatic spread in vivo. CONCLUSIONS: The ability to track the genomic evolution from primary to metastatic MPNST offers new insights into the sequence of genetic events required for tumor progression and has identified TRIM23 as a novel target for future study in this rare cancer