Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer.

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.

A new Covid-19 diagnosis strategy using a modified KNN classifier.

Covid-19 is a very dangerous disease as a result of the rapid and unprecedented spread of any previous disease. It is truly a crisis that threatens the world since its first appearance in December 2019 until our time. Due to the lack of a vaccine that has proved sufficiently effective so far, the rapid and more accurate diagnosis of this disease is extremely necessary to enable the medical staff to identify infected cases and isolate them from the rest to prevent further loss of life. In this paper, Covid-19 diagnostic strategy (CDS) as a new classification strategy that consists of two basic phases: Feature selection phase (FSP) and diagnosis phase (DP) has been introduced. During the first phase called FSP, the best set of features in laboratory test findings for Covid-19 patients will be selected using enhanced gray wolf optimization (EGWO). EGWO combines both types of selection techniques called wrapper and filter. Accordingly, EGWO includes two stages called filter stage (FS) and wrapper stage (WS). While FS uses many different filter methods, WS uses a wrapper method called binary gray wolf optimization (BGWO). The second phase called DP aims to give fast and more accurate diagnosis using a hybrid diagnosis methodology (HDM) based on the selected features from FSP. In fact, the HDM consists of two phases called weighting patient phase (WP2) and diagnostic patient phase (DP2). WP2 aims to calculate the belonging degree of each patient in the testing dataset to class category using naïve Bayes (NB) as a weight method. On the other hand, K-nearest neighbor (KNN) will be used in DP2 based on the weights of patients in the testing dataset as a new training dataset to give rapid and more accurate detection. The suggested CDS outperforms other strategies according to accuracy, precision, recall (or sensitivity) and F-measure calculations that are equal to 99%, 88%, 90% and 91%, respectively, as showed in experimental results.

Effects of awake-prone positioning on oxygenation and physiological outcomes in non-intubated patients with COVID-19: A randomized controlled trial.

BACKGROUND: Prone positioning is a well-known supportive approach for increasing oxygenation and reducing mortality in non-COVID-19 patients with moderate to severe acute respiratory distress syndrome. However, studies highlighting the effects of proning in patients with COVID-19 are limited. AIM: To investigate the effects of awake-prone positioning (APP) on oxygenation and physiological outcomes in non-intubated patients with COVID-19. STUDY DESIGN: A randomized controlled trial was carried out with two parallel groups at 1:1 ratio. Adult awake non-intubated patients with confirmed COVID-19, non-rebreathing face mask or continuous positive airway pressure, PaO2 /FiO2 ratio ≤150 mmHg were randomly assigned to the APP group or control group. The control group was subjected to conventional positioning interventions. Outcome measures were PaO2 /FiO2 ratio, ROX index, PaO2 , PaCO2 , SaO2 , respiratory rate, blood pressure, and shock index. These parameters were recorded immediately before positioning, 10 min after patient positioning, and 1 h after patient positioning. RESULTS: Of 115 patients assessed for eligibility, 82 were randomized to the APP group or control group (41 patients in each group). The use of APP for non-intubated patients with COVID-19 resulted in statistically significant improvements in oxygenation parameters, that is, SpO2 , PaO2 /FiO2 , ROX index, PaO2 , and SaO2 , at the three study time points (p = .000, .007, .000, .011, and .000 respectively). The SpO2 was increased to 92.15 ± 2.735 mmHg for the APP group versus 88.17 ± 4.847 for the control group after 1 h of patients' positioning. The PaO2 /FiO2 ratio increased in the APP group before proning compared with 1 h after proning (79.95 ± 22.508 vs. 98.91 ± 34.44) respectively. APP improved the SpO2 , PaO2 /FiO2 , ROX index, PaO2 , and SaO2 values for the APP group, representing an increase of 5.85%, 23.71%, 30.79%, 22.59%, and 5.26%, respectively. CONCLUSION: Awake proning in non-intubated patients with COVID-19 showed marked improvement in oxygenation and physiological parameters. RELEVANCE TO CLINICAL PRACTICE: This study provides evidence for critical care nurses to implement APP in non-intubated patients with COVID-19 to improve oxygenation and physiological parameters, as it was tolerated by most of the patients without serious adverse events.

Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue.

Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time.

HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma.

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC. SIGNIFICANCE: This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.

Establishment of a human embryonic stem cell line with homozygous TP53 R248W mutant by TALEN mediated gene editing.

Genetic mutations in TP53 contribute to multiple human cancers. Here we report the generation of a H1-p53(R248W/R248W) human embryonic stem cell line harboring a homozygous TP53 R248W mutation created by TALEN-mediated precise gene editing. The H1-p53(R248W/R248W) cell line maintains a normal karyotype, robust pluripotency gene expression, and the potential to differentiate to the three germ layers.

A homozygous p53 R282W mutant human embryonic stem cell line generated using TALEN-mediated precise gene editing.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers. Many hot-spot mutations of TP53 confer novel functions not found in wild-type p53 and contribute to tumor development and progression. We report on the generation of a H1 human embryonic stem cell line carrying a homozygous TP53 R282W mutation using TALEN-mediated genome editing. The generated cell line demonstrates normal karyotype, maintains a pluripotent state, and is capable of generating a teratoma in vivo containing tissues from all three germ layers.