Recent discoveries on the origins of modern humans from multiple archaic hominin populations and the diversity of human papillomaviruses (HPVs) suggest a complex scenario of virus-host evolution. To ...evaluate the origin of HPV pathogenesis, we estimated the phylogeny, timing, and dispersal of HPV16 variants using a Bayesian Markov Chain Monte Carlo framework. To increase precision, we identified and characterized non-human primate papillomaviruses from New and Old World monkeys to set molecular clock models. We demonstrate specific host niche adaptation of primate papillomaviruses with subsequent coevolution with their primate hosts for at least 40 million years. Analyses of 212 HPV16 complete genomes and 3582 partial sequences estimated ancient divergence of HPV16 variants (between A and BCD lineages) from their most recent common ancestors around half a million years ago, roughly coinciding with the timing of the split between archaic Neanderthals and modern Homo sapiens, and nearly three times longer than divergence times of modern Homo sapiens. HPV16 A lineage variants were significantly underrepresented in present African populations, whereas the A sublineages were highly prevalent in European (A1-3) and Asian (A4) populations, indicative of viral sexual transmission from Neanderthals to modern non-African humans through multiple interbreeding events in the past 80 thousand years. Remarkably, the human leukocyte antigen B*07:02 and C*07:02 alleles associated with increased risk in cervix cancer represent introgressed regions from Neanderthals in present-day Eurasians. The archaic hominin-host-switch model was also supported by other HPV variants. Niche adaptation and virus-host codivergence appear to influence the pathogenesis of papillomaviruses.
Objective To evaluate the health benefits of an exclusively human milk–based diet compared with a diet of both human milk and bovine milk–based products in extremely premature infants. Study design ...Infants fed their own mothers' milk were randomized to 1 of 3 study groups. Groups HM100 and HM40 received pasteurized donor human milk–based human milk fortifier when the enteral intake was 100 and 40 mL/kg/d, respectively, and both groups received pasteurized donor human milk if no mother's milk was available. Group BOV received bovine milk–based human milk fortifier when the enteral intake was 100 mL/kg/d and preterm formula if no mother's milk was available. Outcomes included duration of parenteral nutrition, morbidity, and growth. Results The 3 groups (total n = 207 infants) had similar baseline demographic variables, duration of parenteral nutrition, rates of late-onset sepsis, and growth. The groups receiving an exclusively human milk diet had significantly lower rates of necrotizing enterocolitis (NEC; P = .02) and NEC requiring surgical intervention ( P = .007). Conclusions For extremely premature infants, an exclusively human milk–based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother's milk–based diet that also includes bovine milk–based products.
Technology to restore the ability to communicate in paralyzed persons who cannot speak has the potential to improve autonomy and quality of life. An approach that decodes words and sentences directly ...from the cerebral cortical activity of such patients may represent an advancement over existing methods for assisted communication.
We implanted a subdural, high-density, multielectrode array over the area of the sensorimotor cortex that controls speech in a person with anarthria (the loss of the ability to articulate speech) and spastic quadriparesis caused by a brain-stem stroke. Over the course of 48 sessions, we recorded 22 hours of cortical activity while the participant attempted to say individual words from a vocabulary set of 50 words. We used deep-learning algorithms to create computational models for the detection and classification of words from patterns in the recorded cortical activity. We applied these computational models, as well as a natural-language model that yielded next-word probabilities given the preceding words in a sequence, to decode full sentences as the participant attempted to say them.
We decoded sentences from the participant's cortical activity in real time at a median rate of 15.2 words per minute, with a median word error rate of 25.6%. In post hoc analyses, we detected 98% of the attempts by the participant to produce individual words, and we classified words with 47.1% accuracy using cortical signals that were stable throughout the 81-week study period.
In a person with anarthria and spastic quadriparesis caused by a brain-stem stroke, words and sentences were decoded directly from cortical activity during attempted speech with the use of deep-learning models and a natural-language model. (Funded by Facebook and others; ClinicalTrials.gov number, NCT03698149.).
Purpose
Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression ...in primary cancers from sites with frequent breast metastases remains unclear.
Methods
To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB).
Results
GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers 59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.
Conclusions
GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.
Purpose
Clinical trials showing programmed death (PD)-1–PD-ligand 1 (L1) axis as a promising therapeutic target in melanoma and non-small cell lung cancers have made the pathway a focus of recent ...attention. However, the data regarding PD-L1/PD-1 in breast cancer are inconsistent. Given the heterogeneity of breast cancers, the clinical relevance of PD-L1 and PD-1 tumor infiltrating lymphocytes (TIL) may vary according to subtypes of breast cancer. We aim to investigate PD-L1 expression in a large cohort of breast cancers and analyze its clinico-pathological as well as outcome relationship according to molecular subtypes. Also, we evaluate the relationship of PD-1 TIL and PD-L1 expression with patients’ survival, particularly for breast cancers with high TIL.
Methods and results
Immunohistochemical analysis of PD-L1 on tissue arrays for 1091 breast cancer patients and PD-1 TIL on 97 whole sections was performed. Associations of PD-L1 with luminal cancers (
p
< 0.001) and features associated with that subtype lower histologic grade, absence of necrosis, ER, PR, and AR expression (
p
< 0.001) were observed. However, in HER2+ breast cancers, PD-L1 was an independent poor prognostic indicator (DFS: HR = 1.866,
p
= 0.001; OS: HR = 1.517,
p
= 0.036). Interestingly, HER2+ cancers showed a lower PD-1 TIL level compared to the other high TIL cases (
p
= 0.011). Cases with low PD-TIL but high PD-L1 expression showed the worst survival. This could be indicative of an active immune suppression by PD-L1 expression.
Conclusions
Our data showed the relevance of PD-L1 expression in HER2+ breast cancer. A combined evaluation of PD-L1 and PD-1 TIL in the prognosis of breast cancer might also be of value in treatment prediction.
Burns are a serious injury that requires optimal nutritional support. This review discusses the nutritional care for adults and children with major burns. A burned patient's metabolism is greatly ...accelerated with increased requirements for energy, carbohydrates, proteins, fats, vitamins, minerals, and antioxidants. Early nutrition by parenteral and enteral feedings is vital. Careful assessment of the nutritional state of the burn patient is also important to reduce infection, recovery time, and long-term sequelae.
The latest ASCO/CAP guideline has recommended to report oestrogen receptor (ER) low cases (ER
; 1-10%) as "ER low positive category", prompting us to compare the clinicopathologic features, ...biomarkers, survival and treatment of the ER
cases with other subgroups (ER negative (ER
) and ER high (ER
)). ER
cases revealed more similar clinicopathologic and biomarker profiles (including younger age, larger tumour, high proliferation, HER2 and basal markers expression) to ER
than ER
cancers. The ER
cases receiving hormonal therapy showed a similarly poor outcome as ER
cancers. However, majority of ER
cases were downstaged to stage I in the 8th AJCC pathological prognostic staging, highlighting a risk of potential under treatment. Overall, our data highlighted the differences of ER
from other ER
cases and their management should be considered separately.
Fusion of vesicles into target membranes during many types of regulated exocytosis requires both SNARE-complex proteins and fusogenic lipids, such as phosphatidic acid. Mitochondrial fusion is less ...well understood but distinct, as it is mediated instead by the protein Mitofusin (Mfn). Here, we identify an ancestral member of the phospholipase D (PLD) superfamily of lipid-modifying enzymes that is required for mitochondrial fusion. Mitochondrial PLD (MitoPLD) targets to the external face of mitochondria and promotes trans-mitochondrial membrane adherence in a Mfn-dependent manner by hydrolysing cardiolipin to generate phosphatidic acid. These findings reveal that although mitochondrial fusion and regulated exocytic fusion are mediated by distinct sets of protein machinery, the underlying processes are unexpectedly linked by the generation of a common fusogenic lipid. Moreover, our findings suggest a novel basis for the mitochondrial fragmentation observed during apoptosis.
A novel vapor-generation technique is described for mercury determination in aqueous solutions. Without need for a chemical reducing agent, dissolved mercury species are converted to volatile Hg ...vapor in a solution cathode glow discharge. The generated Hg vapor is then transported to an inductively coupled plasma for determination by atomic emission spectrometry. Mercury vapor is readily generated from a background electrolyte containing 0.1 M HNO 3. Vapor generation efficiency was found to be higher by a factor of 2-3 in the presence of low molecular weight organic acids (formic or acetic acids) or alcohols (ethanol). Optimal conditions for discharge-induced vapor generation and reduced interference from concomitant inorganic ions were also identified. However, the presence of chloride ion reduces the efficiency of Hg-vapor generation. In the continuous sample introduction mode, the detection limit was found to be 0.7 microg L (-1), and repeatability was 1.2% RSD ( n = 11) for a 20 microg L (-1) standard. In comparison with other vapor generation methods, it offers several advantages: First, it is applicable to both inorganic and organic Hg determination; organic mercury (thiomersal) can be directly transformed into volatile Hg species without the need for prior oxidation. Second, the vapor-generation efficiency is high; the efficiency (with formic acid as a promoter) is superior to that of conventional SnCl 2-HCl reduction. Third, the vapor generation is extremely rapid and therefore is easy to couple with flow injection. The method is sensitive and simple in operation, requires no auxiliary reagents, and serves as a useful alternative to conventional vapor generation for ultratrace Hg determination.
The solution-cathode glow discharge (SCGD) is an optical emission source for atomic spectrometry comprised of a moderate-power atmospheric-pressure DC glow discharge sustained directly upon the ...surface of an electrically conductive solution. The SCGD boasts a simple, inexpensive design and has demonstrated detection limits similar to those of more conventional excitation sources used in atomic spectrometry. Although the analytical performance of the SCGD as an optical emission source is well characterized, the mechanism through which the discharge atomizes and excites analyte from the sample solution remains a point of debate. The current paper presents visual observations of the SCGD from a variety of imaging techniques. The implications of the images regarding the mechanism of analyte solution-to-plasma transport and excitation in the SCGD are discussed.
► Droplets appear to be ejected from the surface of the discharge. ► Droplets are drawn downward toward the cathodic solution. ► Hot spots appear on the solution surface in the presence of the discharge. ► Optical emission is particularly strong in the region of the hot spots.
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