Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant ...p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability.
GeneXpert-based testing with Xpert MTB/RIF or Ultra assays is essential for tuberculosis diagnosis. However, testing may be affected by cartridge and staff shortages. More efficient testing ...strategies could help, especially during the coronavirus disease pandemic. We searched the literature to systematically review whether GeneXpert-based testing of pooled sputum samples achieves sensitivity and specificity similar to testing individual samples; this method could potentially save time and preserve the limited supply of cartridges. From 6 publications, we found 2-sample pools using Xpert MTB/RIF had 87.5% and 96.0% sensitivity (average sensitivity 94%; 95% CI 89.0%-98.0%) (2 studies). Four-sample pools averaged 91% sensitivity with Xpert MTB/RIF (2 studies) and 98% with Ultra (2 studies); combining >4 samples resulted in lower sensitivity. Two studies reported that pooling achieved 99%-100% specificity and 27%-31% in cartridge savings. Our results show that pooling may improve efficiency of GeneXpert-based testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration–response (CR) modeling ...applied to data from 2 multiple ascending‐dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to “bridge” pharmacokinetic and safety data between Japanese and non‐Japanese subjects (J‐MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high‐precision measurement technique and evaluated using a linear mixed‐effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was –0.00002 milliseconds per ng/mL (90%CI, –0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8‐fold above exposures expected for the highest planned clinical dose. The model‐predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, –3.49 to 5.78 milliseconds). In neither the J‐MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early‐phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.
Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have ...been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications.
We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa.
We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa.
Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.
Following prolonged hospitalization that included broad-spectrum antibiotic exposure, a strain of
Providencia rettgeri
was cultured from the blood of a patient undergoing extracorporeal membrane ...oxygenation treatment for hypoxic respiratory failure due to COVID-19. The strain was resistant to all antimicrobials tested including the novel siderophore cephalosporin, cefiderocol. Whole genome sequencing detected ten antimicrobial resistance genes, including the metallo-β-lactamase
bla
NDM-1
, the extended-spectrum β-lactamase
bla
PER-1
, and the rare 16S methyltransferase
rmtB2
.
India has a high burden of drug-resistant tuberculosis (DR TB) and many cases go undetected by current drug susceptibility tests (DSTs). This study was conducted to identify rifampicin (RIF) and ...isoniazid (INH) resistance associated genetic mutations undetected by current clinical diagnostics amongst persons with DR TB in Chennai, India. Retrospectively stored 166 DR TB isolates during 2013-2016 were retrieved and cultured in Löwenstein-Jensen medium. Whole genome sequencing (WGS) and MGIT DST for RIF and INH were performed. Discordant genotypic and phenotypic sensitivity results were repeated for confirmation and the discrepant results considered final. Further, drug resistance-conferring mutations identified through WGS were analyzed for their presence as targets in current WHO-recommended molecular diagnostics. WGS detected additional mutations for rifampicin and isoniazid resistance than WHO-endorsed line probe assays. For RIF, WGS was able to identify an additional 10% (15/146) of
mutant isolates associated with borderline rifampicin resistance compared to MGIT DST. WGS could detect additional DR TB cases than commercially available and WHO-endorsed molecular DST tests. WGS results reiterate the importance of the recent WHO revised critical concentrations of current MGIT DST to detect low-level resistance to rifampicin. WGS may help inform effective treatment selection for persons at risk of, or diagnosed with, DR TB.
Background
Thousands of patients annually receive treatment for advanced non‐small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or ...regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision‐making parameters, or clinical progress early in the treatment course predicts regret.
Materials and Methods
Patients receiving systemic treatment for advanced NSCLC completed every 3‐week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS‐QL), including the 3‐Item Global Index (3‐IGI; assessing overall distress, activities, and quality of life QL). A prespecified secondary aim was to determine the frequency of regret evaluated at 3 months after starting treatment. Patients were randomized to usual care or enhanced care (which included use of the DecisionKEYS decision aid).
Results
Of 164 patients entered, 160 received treatment and 142 were evaluable for regret. In total, 11.5% of patients and 9% of their supporters expressed regret. Baseline characteristics did not predict regret; regret was rarely expressed by those who had a less than 20% decline or improvement in the 3‐IGI PRO score after two treatment cycles. In contrast, when asked if they would make the same decision again, only 1% not having a 20% 3‐IGI decline expressed regret, versus 14% with a 3‐IGI decline (p = .01).
Conclusion
The majority of patients having regret were identified early using the PRO 3‐IGI of the eLCSS‐QL measure. Identifying patients at risk for regret allows for interventions, including frank discussions of progress and goals early in the treatment course, which could address regret in patients and their supporters.
Implications for Practice
This report documents prospectively, for the first time, the incidence of treatment‐related regret in patients with advanced lung cancer and outlines that risk of regret is associated with patient‐determined worsening health status early in the course of treatment. Identifying patients at risk for regret early in treatment (before the third cycle of treatment) appears to be crucial. Counseling at that time should include a discussion of consideration of treatment change and the reason for this change.
Considering that most patients are unlikely to have a major response treatment for advanced non‐small cell lung cancer, efforts should be made to avoid or reduce patient regret associated with treatment decision making. This article focuses on frequency of regret, prospectively evaluated in patients at 3 months after starting systemic treatment for advanced lung cancer.
COVID-19 stay-at-home orders enacted in New Orleans, LA on March 16, 2020, may have caused changes in the way young men interacted with sex partners.
An online substudy was conducted (May 21, 2020 to ...June 9, 2020) among Black men who have sex with women, 18 years and older, and who had previously enrolled in the parent study Check It (May 17, 2017 to March 6, 2020) to assess changes in sexual behavior during the stay-at-home orders.
Among 111 participants, from enrollment in Check It to during stay-at-home orders, recent vaginal sex declined from 96.4% to 47.8% (P < 0.0001), reports of multiple female sex partners declined from 45.0% to 14.4% (P < 0.0001), and sexual abstinence increased from 3.6% to 38.7% (P < 0.0001). Among those who did have vaginal sex, condomless sex rates did not change between enrollment in Check It and the substudy (64.5% vs 67.9%, P = 0.68). During stay-at-home orders oral sex, virtual sex, and pornography viewing were 40.5%, 42.3%, and 76.6%, respectively. Some (17.1%) acquired a new sex partner during stay-at-home orders, and 44.1% left their home to meet a partner for sex. Only 27.9% had seen information about safe sex during the pandemic. Income was diminished for 62.2% and 23.4% moved away from New Orleans when stay-at-home orders were enacted.
Although there was an overall reduction in physical sex, half of participants reported physical sex, with many leaving their home to have sex during stay-at-home orders and many not using condoms. Others adopted sexual abstinence, increased virtual sex, and/or pornography viewing, which may have protected them from both sexually transmitted infections and COVID-19.
SUMMARY
Evolutionary developmental biology (evo‐devo) has undergone dramatic transformations since its emergence as a distinct discipline. This paper aims to highlight the scope, power, and future ...promise of evo‐devo to transform and unify diverse aspects of biology. We articulate key questions at the core of eleven biological disciplines—from Evolution, Development, Paleontology, and Neurobiology to Cellular and Molecular Biology, Quantitative Genetics, Human Diseases, Ecology, Agriculture and Science Education, and lastly, Evolutionary Developmental Biology itself—and discuss why evo‐devo is uniquely situated to substantially improve our ability to find meaningful answers to these fundamental questions. We posit that the tools, concepts, and ways of thinking developed by evo‐devo have profound potential to advance, integrate, and unify biological sciences as well as inform policy decisions and illuminate science education. We look to the next generation of evolutionary developmental biologists to help shape this process as we confront the scientific challenges of the 21st century.
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