Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers. Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%–91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%–96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0–26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naïve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P = 0.006). Conclusions: In a population largely naïve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.
Evolutionary shifts in extant mustelid (Mustelidae: Carnivora) cranial shape, body size and body shape coincide with the Mid-Miocene Climate Transition

Environmental changes can lead to evolutionary shifts in phenotypic traits, which in turn facilitate the exploitation of novel adaptive landscapes and lineage diversification. The global cooling, increased aridity and expansion of open grasslands during the past 50 Myr are prime examples of new adaptive landscapes that spurred lineage and ecomorphological diversity of several mammalian lineages such as rodents and large herbivorous megafauna. However, whether these environmental changes facilitated evolutionary shifts in small- to mid-sized predator morphology is unknown. Here, I used a complete cranial and body morphological dataset to examine the timing of evolutionary shifts in cranial shape, body size and body shape within extant mustelids (martens, otters, polecats and weasels) during the climatic and environmental changes of the Cenozoic. I found that evolutionary shifts in all three traits occurred within extant mustelid subclades just after the onset of the Mid-Miocene Climate Transition. These mustelid subclades first shifted towards more elongate body plans followed by concurrent shifts towards smaller body sizes and more robust crania. I hypothesize that these cranial and body morphological shifts enabled mustelids to exploit novel adaptive zones associated with the climatic and environmental changes of the Mid to Late Miocene, which facilitated significant increases in clade carrying capacity.
Physiological and Perceptual Responses to Aerobic Exercise With and Without Blood Flow Restriction

Abstract Silva, JCG, Domingos-Gomes, JR, Freitas, EDS, Neto, GR, Aniceto, RR, Bemben, MG, Lima-dos-Santos, A, and Cirilo-Sousa, MS. Physiological and perceptual responses to aerobic exercise with and without blood flow restriction. J Strength Cond Res 35(9): 2479–2485, 2021—Although previous studies have demonstrated the potential benefits of aerobic exercise (AE) with blood flow restriction (BFR), these findings have been limited by the approaches used to determine the occlusive pressure. In addition, the physiological and perceptual responses of AE with BFR compared to high-intensity interval exercise (HIIE) remain unclear. Thus, we investigated the physiological and perceptual responses to AE with and without BFR, and HIIE. Twenty-two men were randomly assigned to 4 experimental conditions: AE (40% of maximal oxygen consumption [V˙o2peak]), AE with 50% of BFR (AE-BFR: 40% VV˙o2peak), HIIE (80% V˙o2peak), and a no exercise control condition (CON: 50% of BFR). Each exercise bout lasted 18 minutes, during which oxygen consumption (V˙o2), heart rate (HR), and ratings of perceived exertion (RPE) were measured at rest and at every 3 minutes during exercise. Ratings of discomfort before and after each trial. The HIIE condition induced the greatest increases in V˙o2 and HR (p < 0.05), whereas AE-BFR was significantly (p < 0.05) greater than AE and CON. HIIE and AE-BFR also elicited the greatest (p < 0.05), but similar (p > 0.05), increases in RPE during exercise, although AE-BFR was significantly greater than HIIE immediately after exercise (p < 0.05). AE-BFR and HIIE also induced similar levels of discomfort after exercise (p > 0.05). In conclusion, HIIE induced the greatest increases in V˙o2 and HR, although the perceptual responses were essentially the same compared with AE-BFR. However, albeit inferior to HIIE, V˙o2 was greater during AE-BFR compared with AE, indicating that this training method may be used to replace HIIE and still significantly elevate V˙o2.
Assessment of dietary exposure to aflatoxin B1 from corn arepas in Colombia

ABSTRACT The aim of this research was to evaluate dietary exposure to aflatoxin B1 (AFB1) in corn arepas in Colombia. In addition, in this study an assessment considering compliance to the maximum level of AFB1 (4 µg kg−1) for this food was conducted. AFB1 concentration data in corn arepas were obtained from 168 samples. The samples were collected from factories in 16 departments in Colombia. AFB1 was quantified by High-Performance Liquid Chromatography with a fluorescence detector. Consumption data and body weight (b.w.) were measured from the 2005 Colombian National Survey of Nutritional Status. Probabilistic estimates were made by Monte Carlo simulation of dietary exposure and margin of exposure (MOE) segmented by age group. The results showed that 27% of corn arepa samples were contaminated with AFB1, with an average concentration of 15.1 µg kg−1 and a maximum value of 111.1 µg kg−1. The stochastic dietary exposure assessment showed that the age group most exposed was children between 4 and 8 years old (10.014 ng (kg b.w. day)−1). In addition, the MOE values for all age groups were lower than 10,000, indicating a potential risk for consumers. However, in the scenario where AFB1 concentration level complies with the maximum limit of 4 µg kg−1 AFB1, the level of concern could be reduced for the adult population between 14 and 64 years old because the MOE value is above 10,000.
Immobilized Luminescent Bacteria for the Detection of Mycotoxins under Discrete and Flow-Through Conditions

A biosensitive element in the form of bacterial Photobacterium phosphoreum cells immobilized in poly(vinyl alcohol) cryogel was tested for the determination of different mycotoxins under discrete and flow-through analysis conditions. The immobilized bioluminescent cells made it possible to quantify the presence of Ochratoxin A, Sterigmatocystin, Zearalenone, and Deoxynivalenon in aqueous media in a wide range of their concentrations (0.017–56 mg/L, 0.010–33 mg/L, 0.009–14 mg/L, and 0.026–177 mg/L, respectively) via measuring the quenching of cell luminescence. The flow conditions allowed the analysis sensitivity to be improved by an order of magnitude in terms of detected concentrations. Using the immobilized luminescent bacterial cells, we have shown the possibility of evaluating the efficiency of the mycotoxins’ hydrolysis under the action of enzymes. In this way, a 94 ± 4.5% efficiency of Zearalenone hydrolysis with hexahistidine-containing organophosphorus hydrolase for 1h-long treatment of the mycotoxin solution (100 mg/L) was shown.
Interorganelle Trafficking of Ceramide Is Regulated by Phosphorylation-dependent Cooperativity between the PH and START Domains of CERT*

The synthesis and transport of lipids are essential events for membrane biogenesis. However, little is known about how intracellular trafficking of lipids is regulated. Ceramide is synthesized at the endoplasmic reticulum (ER) and transported by the ceramide transfer protein CERT to the Golgi apparatus, where it is converted to sphingomyelin. CERT has a phosphoinositide-binding pleckstrin homology (PH) domain for Golgi-targeting and a lipid transfer START domain for intermembrane transfer of ceramide. We here show that CERT receives multiple phosphorylations at a serine-repeat motif, a possibe site for casein kinase I, and that the phosphorylation down-regulates the ER-to-Golgi transport of ceramide. In vitro assays show that the phosphorylation induces an autoinhibitory interaction between the PH and START domains and consequently inactivates both the phosphoinositide binding and ceramide transfer activities of CERT. Loss of sphingomyelin and cholesterol from cells causes dephosphorylation of CERT to activate it. The cooperative control of functionally distinct domains of CERT is a novel molecular event to regulate the intracellular trafficking of ceramide.
Risperidone, olanzapine and quetiapine in the treatment of behavioral and psychological symptoms in patients with Alzheimer's disease: Preliminary findings from a naturalistic, retrospective study

Abstract The objectives of this retrospective, naturalistic study were to provide preliminary data on the effects of 6 months treatment with risperidone, olanzapine and quetiapine on behavioral disturbances, within a sample of outpatients with mild to moderate Alzheimer's disease, and on predictors of response. Between July 2005 and December 2005, data were collected from 58 consecutive outpatients with a DSM‐IV‐TR diagnosis of Alzheimer's disease with behavioral disturbances, who received a 6‐month treatment with risperidone, olanzapine or quetiapine. Primary outcome measures were Neuropsychiatric Inventory (NPI) total score and its items forming the basic core of behavioral disturbances in Alzheimer's disease: delusions, hallucinations and agitation/aggressiveness. Secondary outcome measures were Mini‐Mental State Examination (MMSE), Activities of Daily Living, Instrumental Activities of Daily Living and Clinical Insight Rating scale. Correlations between baseline MMSE score and improvements in behavioral disturbances were investigated. At 6 months mean NPI total score had fallen 43.5% in the risperidone group, 45.6% in the olanzapine group and 33.3% in the quetiapine group, with no significant between‐group differences. Global cognitive function showed no significant change from baseline to end‐point. Incidence of adverse events was low. A significant correlation was found between MMSE score and NPI total score and NPI item agitation decreases. Risperidone, olanzapine and quetiapine produced significant improvements in behavioral disturbances and were well tolerated. No significant differences emerged among treatments. The preliminary results also suggest that baseline cognitive function might influence treatment response.
Insane in the Membrane: Glial Extracellular Vesicles Transmit Polyomaviruses

Extracellular vesicles (EVs) are major vehicles for transporting viruses en bloc among hosts. While RNA viruses make up the great majority of transmission by EVs, in a recent article in mBio (mBio 10:e00379-19, 2019, https://mbio.asm.org/content/10/2/e00379-19.long), Morris-Love and colleagues revealed that a double-stranded DNA (dsDNA) virus, JC polyomavirus (JCPyV), a major cause of progressive multifocal leukoencephalopathy (PML), can be released from and transmitted to other glia in EVs. ABSTRACT Extracellular vesicles (EVs) are major vehicles for transporting viruses en bloc among hosts. While RNA viruses make up the great majority of transmission by EVs, in a recent article in mBio (mBio 10:e00379-19, 2019, https://mbio.asm.org/content/10/2/e00379-19.long), Morris-Love and colleagues revealed that a double-stranded DNA (dsDNA) virus, JC polyomavirus (JCPyV), a major cause of progressive multifocal leukoencephalopathy (PML), can be released from and transmitted to other glia in EVs. This mode of transmission appears to be highly infectious, independent of the free virus attachment and entry receptors LSTc and 5-HT2, and protected from neutralizing antibodies. This novel form of JCPyV transmission may potentially explain its dissemination into the central nervous system (CNS) and its increased virulence.
Predicting anaemia and transfusion dependency in severe alloimmune haemolytic disease of the fetus and newborn in the first 3 months after birth

Infants with haemolytic disease of the fetus and newborn (HDFN) often require erythrocyte transfusions in the first 3 months of life. We aimed to evaluate the incidence, timing and potential predictors of transfusion‐dependent anaemia. An observational cohort of 298 term and near‐term infants with severe HDFN treated with or without intrauterine transfusion (IUT) was evaluated. Transfusions were administered to 88% (169/193) of infants with IUT and 60% (63/105) without IUT. The following potential predictors were associated with less anaemia: K compared to D immunisation [odds ratio (OR) 0·13, 95% confidence interval (CI): 0·03–0·55], higher reticulocyte count at birth [per 10 parts per thousand (‰) higher, OR 0·99, CI: 0·97–1·00] and exchange transfusion (OR 0·11, 95% CI: 0·03–0·50). Without IUT, these variables were: lower reticulocyte count at birth (per 10‰ lower, OR 1·02, 95% CI: 1·00–1·03), lower maximum bilirubin after birth (per 10 μmol/l lower, OR 1·01, 95% CI: 1·01–1·02) and exchange transfusion (OR 0·07, 95% CI: 0·01–0·20). In conclusion, potential predictors for anaemia in infants with severe HDFN varied between infants treated with and without IUT and are useful for selecting subgroups of infants at increased risk of anaemia.
Nurses' knowledge about palliative care in Southeast Iran

Abstract Objective: Palliative care requires nurses to be knowledgeable about different aspects of the care that they provide for dying patients. This study, therefore, was conducted to examine oncology and intensive care nurses' knowledge about palliative care in Southeast Iran. Method: Using the Palliative Care Quiz for Nursing (PCQN), 140 oncology and intensive care unit (ICU) nurses' knowledge about palliative care in three hospitals supervised by Kerman University of Medical Sciences was assessed. Results: In PCQN, the mean score was 7.59 (SD: 2.28). The most correct answers were in the category of management of pain and other symptoms (46.07%). The lowest correct answers were in the category of psychosocial and spiritual care (19.3%). Significance of results: These findings suggest that nurses' knowledge about palliative care can be improved by establishing specific palliative care units to focus on end-of-life care. This establishment requires incorporation of an end-of-life nursing education curriculum into undergraduate nursing studies.
Decadal trends in the ocean carbon sink

Significance The ocean and land absorb anthropogenic CO2 from industrial fossil-fuel emissions and land-use changes, helping to buffer climate change. Here, we compare decadal variability of ocean CO2 uptake using three independent methods and find that the ocean could be responsible for as much as 40% of the observed decadal variability of CO2 accumulation in the atmosphere. The remaining variability is due to variability in the accumulation of carbon in the terrestrial biosphere. Models capture these variations, but not as strongly as the observations, implying that CO2 uptake by the land and ocean is more sensitive to climate variability than currently thought. Models must capture this sensitivity to provide accurate climate predictions. Measurements show large decadal variability in the rate of CO2 accumulation in the atmosphere that is not driven by CO2 emissions. The decade of the 1990s experienced enhanced carbon accumulation in the atmosphere relative to emissions, while in the 2000s, the atmospheric growth rate slowed, even though emissions grew rapidly. These variations are driven by natural sources and sinks of CO2 due to the ocean and the terrestrial biosphere. In this study, we compare three independent methods for estimating oceanic CO2 uptake and find that the ocean carbon sink could be responsible for up to 40% of the observed decadal variability in atmospheric CO2 accumulation. Data-based estimates of the ocean carbon sink from pCO2 mapping methods and decadal ocean inverse models generally agree on the magnitude and sign of decadal variability in the ocean CO2 sink at both global and regional scales. Simulations with ocean biogeochemical models confirm that climate variability drove the observed decadal trends in ocean CO2 uptake, but also demonstrate that the sensitivity of ocean CO2 uptake to climate variability may be too weak in models. Furthermore, all estimates point toward coherent decadal variability in the oceanic and terrestrial CO2 sinks, and this variability is not well-matched by current global vegetation models. Reconciling these differences will help to constrain the sensitivity of oceanic and terrestrial CO2 uptake to climate variability and lead to improved climate projections and decadal climate predictions.
Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer

Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of non-CSC tumor cells, CSCs are often drug-resistant, leading to tumor recurrence and metastasis. The heterogeneity of CSCs is the main challenge in developing CSC-targeting therapy; therefore, we and other investigators have focused on developing novel therapeutic strategies that combine conventional chemotherapy with inhibitors of CSC-regulating pathways. Encouraging preclinical findings have suggested that CSC pathway blockade can indeed enhance cellular sensitivity to non-targeted conventional therapy, and this work has led to several ongoing clinical trials of CSC pathway inhibitors. Our studies in bladder cancer and lung adenocarcinoma have demonstrated a crucial role of YAP1, a transcriptional regulator of genes that promote cell survival and proliferation, in regulating CSC phenotypes. Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features. In this review, we summarize the therapeutic strategies for targeting CSCs in several cancers and discuss the potential and challenges of the approach.
Regulation of Ribosomal Proteins on Viral Infection

Ribosomal proteins (RPs), in conjunction with rRNA, are major components of ribosomes involved in the cellular process of protein biosynthesis, known as “translation”. The viruses, as the small infectious pathogens with limited genomes, must recruit a variety of host factors to survive and propagate, including RPs. At present, more and more information is available on the functional relationship between RPs and virus infection. This review focuses on advancements in my own understanding of critical roles of RPs in the life cycle of viruses. Various RPs interact with viral mRNA and proteins to participate in viral protein biosynthesis and regulate the replication and infection of virus in host cells. Most interactions are essential for viral translation and replication, which promote viral infection and accumulation, whereas the minority represents the defense signaling of host cells by activating immune pathway against virus. RPs provide a new platform for antiviral therapy development, however, at present, antiviral therapeutics with RPs involving in virus infection as targets is limited, and exploring antiviral strategy based on RPs will be the guides for further study.
Moderate-to-Vigorous-Intensity Physical Activity Observed in People With Diabetes-Related Foot Ulcers Over a One-Week Period

Background: Regular moderate-to-vigorous-intensity physical activity results in health benefits in people with diabetes. No study has observed the moderate-to-vigorous-intensity physical activity typically performed by people with diabetes-related foot ulcers (DFU) in their everyday free-living environments. We observed the bouts, and accumulated time, spent doing moderate-to-vigorous-intensity physical activity in cases with DFU compared with diabetes-related peripheral neuropathy (DPN) and diabetes (DM) controls over a one-week period. Methods: This was a secondary analysis of a cross-sectional case-control study. Participants wore a multisensor device for >5 days (>22 hours per day). Primary outcomes included the number, duration (minutes) and intensity (metabolic equivalent tasks [METs]) of bouts of moderate-to-vigorous-intensity physical activity (defined as at least >3 METs for >10 consecutive minutes). Secondary outcomes included the total accumulated times spent doing moderate-to-vigorous-intensity physical activity (>3 METs) and doing sedentary-intensity activity (<1.5 METs). DFU subgroups with minor amputations and nonremovable offloading devices were also analyzed. Results: Overall, 15 DM, 23 DPN, and 27 DFU participants were included. All groups recorded similar low median daily numbers (0.33, 0.29, 0.25 numbers, respectively), duration (15, 17, 14 minutes), and intensity of daily bouts of moderate-to-vigorous-intensity physical activity (4.1, 4.3, 3.9 METs) (all, P > .1). Median accumulated daily time spent doing moderate-to-vigorous-intensity physical activity was also similar (40, 37, 36 minutes; P > .8). Those with DFU had more mean accumulated daily time spent doing sedentary-intensity activity (796 minutes) compared to DPN (720 minutes; P < .05), but not compared to DM (728 minutes; P < .08). DFU subgroups with minor amputations had more median accumulated daily time spent doing moderate-to-vigorous-intensity physical activity (66, 28 minutes; P < .05) and less mean time doing sedentary-intensity activity (745, 837; P < .05) than those without amputations. Conclusions: People with DFU performed similar low numbers of daily bouts of moderate-to-vigorous-intensity physical activity to controls, but spend more time doing sedentary-intensity activities. Interventions that gradually increase the moderate-to-vigorous-intensity physical activity in people with DFU should be investigated.