Coherent anti-Stokes Raman scattering imaging of lipids in cancer metastasis

<p>Abstract</p> <p>Background</p> <p>Lipid-rich tumours have been associated with increased cancer metastasis and aggressive clinical behaviours. Nonetheless, pathologists cannot classify lipid-rich tumours as a clinically distinctive form of carcinoma due to a lack of mechanistic understanding on the roles of lipids in cancer development.</p> <p>Methods</p> <p>Coherent anti-Stokes Raman scattering (CARS) microscopy is employed to study cancer cell behaviours in excess lipid environments <it>in vivo </it>and <it>in vitro</it>. The impacts of a high fat diet on cancer development are evaluated in a Balb/c mice cancer model. Intravital flow cytometry and histology are employed to enumerate cancer cell escape to the bloodstream and metastasis to lung tissues, respectively. Cancer cell motility and tissue invasion capability are also evaluated in excess lipid environments.</p> <p>Results</p> <p>CARS imaging reveals intracellular lipid accumulation is induced by excess free fatty acids (FFAs). Excess FFAs incorporation onto cancer cell membrane induces membrane phase separation, reduces cell-cell contact, increases surface adhesion, and promotes tissue invasion. Increased plasma FFAs level and visceral adiposity are associated with early rise in circulating tumour cells and increased lung metastasis. Furthermore, CARS imaging reveals FFAs-induced lipid accumulation in primary, circulating, and metastasized cancer cells.</p> <p>Conclusion</p> <p>Lipid-rich tumours are linked to cancer metastasis through FFAs-induced physical perturbations on cancer cell membrane. Most importantly, the revelation of lipid-rich circulating tumour cells suggests possible development of CARS intravital flow cytometry for label-free detection of early-stage cancer metastasis.</p

A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

Cancer: evolutionary, genetic and epigenetic aspects

There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy

2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group

The International Liaison Committee on Resuscitation initiated a continuous review of new, peer-reviewed published cardiopulmonary resuscitation science. This is the fifth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; a more comprehensive review was done in 2020. This latest summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation task force science experts. Topics covered by systematic reviews in this summary include resuscitation topics of video-based dispatch systems; head-up cardiopulmonary resuscitation; early coronary angiography after return of spontaneous circulation; cardiopulmonary resuscitation in the prone patient; cord management at birth for preterm and term infants; devices for administering positive-pressure ventilation at birth; family presence during neonatal resuscitation; self-directed, digitally based basic life support education and training in adults and children; coronavirus disease 2019 infection risk to rescuers from patients in cardiac arrest; and first aid topics, including cooling with water for thermal burns, oral rehydration for exertional dehydration, pediatric tourniquet use, and methods of tick removal. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, according to the Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations or good practice statements. Insights into the deliberations of the task forces are provided in Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces listed priority knowledge gaps for further research

T-piece resuscitator or self-inflating bag during neonatal resuscitation: a scoping review.

BACKGROUND:To identify the evidence for administering positive pressure ventilation (PPV) to infants at birth by either T-piece resuscitator (TPR) or self-inflating bag (SIB), and to determine whether a full systematic review (SR) is warranted. METHODS:Guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for scoping reviews, eligible studies included peer-reviewed human studies, prospectively or retrospectively comparing a TPR vs. SIB for administering PPV at birth. Databases searched were OVID Medline, PubMed, Embase and the Cochrane Central Register of Controlled Trials. Review Manager software was used for the data analysis. RESULTS:Following electronic literature search and review, data from four eligible studies (3 RCT and 1 observational study), enrolling a total of 2889 patients, were included. Studies differed regarding the investigated populations, reported outcomes and came from different geographical areas. In particular for preterm infants, use of TPR for providing PPV may improve survival, result in fewer intubations at birth and decrease the incidence of bronchopulmonary dysplasia. CONCLUSIONS:This scoping review identified two new studies with substantive new evidence, pointing towards improved survival, decreased bronchopulmonary dysplasia and fewer intubations at birth, in particular among preterm infants treated with TPR. Full SR of the literature is advised. IMPACT:This scoping review identified studies comparing TPR vs. SIB for respiratory support of newborn infants previously not included in the International Liaison Committee on Resuscitation (ILCOR) recommendations.Our review found substantive new evidence highlighting that device choice may impact the outcomes of compromised newborn infants'.This scoping review stipulates the need for full SR and updated meta-analysis of studies investigating supportive equipment for stabilizing infants at birth in order to inform ILCOR treatment recommendations

Devices for administering ventilation at birth: a systematic review

CONTEXT: Positive pressure ventilation (PPV) is the most important intervention during neonatal resuscitation. OBJECTIVE: To compare T-piece resuscitators (TPRs), self-inflating bags (SIBs), and flow-inflating bags for newborns receiving PPV during delivery room resuscitation. DATA SOURCES: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, and trial registries (inception to December 2020). STUDY SELECTION: Randomized, quasi-randomized, interrupted time series, controlled before-and-after, and cohort studies were included without language restrictions. DATA EXTRACTION: Two researchers independently extracted data, assessed the risk of bias, and evaluated the certainty of evidence. The primary outcome was in-hospital mortality. When appropriate, data were pooled by using fixed-effect models. RESULTS: Meta-analysis of 4 randomized controlled trials (1247 patients) revealed no significant difference between TPR and SIB for in-hospital mortality (risk ratio 0.74; 95% confidence interval [CI] 0.40 to 1.34). Resuscitation with a TPR resulted in a shorter duration of PPV (mean difference −19.8 seconds; 95% CI −27.7 to −12.0 seconds) and lower risk of bronchopulmonary dysplasia (risk ratio 0.64; 95% CI 0.43 to 0.95; number needed to treat 32). No differences in clinically relevant outcomes were found in 2 randomized controlled trials used to compare SIBs with and without positive end-expiratory pressure valves. No studies used to evaluate flow-inflating bags were found. LIMITATIONS: Certainty of evidence was very low or low for most outcomes. CONCLUSIONS: Resuscitation with a TPR compared with an SIB reduces the duration of PPV and risk of bronchopulmonary dysplasia. A strong recommendation cannot be made because of the low certainty of evidence. There is insufficient evidence to determine the effectiveness of positive end-expiratory pressure valves when used with SIBs.</p