[Advances in targeted and immune therapies for hepatocellular carcinoma].

Targeted and immunotherapy drugs for hepatocellular carcinoma (HCC) have been rapidly developed. Atezolizumab in combination with bevacizumab has been recommended as the first-line standard of care for unresectable or advanced HCC in several national and international guidelines. The combination therapies with sindilizumab and bevacizumab biosimilar, apatinib and carrilizumab, dulvalizumab and tremelimumab are also recommended as first-line standard regimens for advanced HCC in the guideline of Chinese Society of Clinical Oncology. Local therapy combined with targeted drugs (such as sorafenib and lenvatinib) or immune checkpoint inhibitors can significantly improve outcomes. Therefore, some progress has also been made in the study of single-agent or combination regimens as perioperative neoadjuvant therapy.

[Hepatocellular carcinoma immune microenvironment].

The tumor immune microenvironment (TIME) plays crucial roles in the growth, progression, and therapeutic response of hepatocellular carcinoma(HCC) which is a prototypical inflammation-associated cancer. The efficacy of immunotherapy largely depends on the TIME. Targeting the immune microenvironment is an attractive strategy for the treatment of HCC. This review provides the characteristics of immune microenvironment of HCC,therapeutic approaches based on immune microenvironment,and information on the immune microenvironment underlying the response or resistance of HCC to immunotherapies.

Novel insights into heat tolerance using metabolomic and high-throughput sequencing analysis in dairy cows rumen fluid.

Heat stress influences rumen fermentative processes with effects on the physiology and production of dairy cows. However, the underlying relationship between rumen microbiota and its associated metabolism with heat tolerance in cows have not been extensively described yet. Therefore, the main objective of this study was to investigate differential heat resistance in Holstein cows using rumen bacterial and metabolome analyses. We performed both principal component analysis and membership function analysis to select seven heat-tolerant (HT) and seven heat-sensitive (HS) cows. Under heat stress conditions, the HT cows had a significantly (P < 0.05) higher propionic acid content than the HS cows; while measures of the respiratory rate, acetic, and butyric acid in the HT cows were significantly (P < 0.05) lower compared with the HS cows. Also, the HT cows showed lower (P < 0.01) rectal temperature and acetic acid to propionic acid ratio than the HS group of cows. Omics sequencing revealed that the relative abundances of Muribaculaceae, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, Rikenellaceae_RC9_gut_group, Succiniclasticum, Ruminococcaceae_NK4A214_group and Christensenellaceae_R-7_group were significantly (P < 0.01) higher in the HT cows; whereas Prevotellaceae, Prevotella_1, Ruminococcaceae_UCG-014, and Shuttleworthia were significantly (P < 0.01) lower in HT cows compared to HS cows. Substances mainly involved in carbohydrate metabolism, including glycerol, mannitol, and maltose, showed significantly higher content in the HT cows (P < 0.05) compared to that in the HS cows. Simultaneously, distinct metabolites were significantly correlated with differential bacteria, suggesting that glycerol, mannitol, and maltose could serve as potential biomarkers for determining heat resistance that require further study. Overall, distinct changes in the rumen microbiota and metabolomics in the HT cows may be associated with a better adaptability to heat stress. These findings suggest their use as diagnostic tools of heat tolerance in dairy cattle breeding schemes.

CT presentations of adult and pediatric SARS-CoV-2 patients: A review of early COVID-19 data.

OBJECTIVE: Initial COVID-19 reports described a variety of clinical presentations, but lower respiratory abnormalities are most common and chest CT findings differ between adult and pediatric patients. We aim to summarize early CT findings to inform healthcare providers on the frequency of COVID-19 manifestations specific to adult or pediatric patients, and to determine if the sensitivity of CT justifies its use in these populations. METHODS: PubMed was searched for the presence of the words "CT, imaging, COVID-19" in the title or abstract, and 17 large-scale PubMed and/or Scopus studies and case reports published between January 1, 2020 and April 15, 2020 were selected for data synthesis. RESULTS: Initial CT scans identified ground-glass opacities and bilateral abnormalities as more frequent in adults (74%, n = 698, and 89%, n = 378, respectively) than children (60%, n = 25, and 37%, n = 46). At 14+ days, CT scans evidenced varied degrees of improvement in adults but no resolution until at least 26 days after the onset of flu-like symptoms. In pediatric patients, a third (n = 9) showed additional small nodular GGOs limited to a single lobe 3-5 days after an initial CT scan. CONCLUSION: Early adult CT findings suggest the limited use of CT as a supplemental tool in diagnosing COVID-19 in symptomatic adult patients, with a particular focus on identifying right and left lower lobe abnormalities, GGOs, and interlobular septal thickening. Early pediatric CT findings suggest against the use of CT if RT-PCR is available given its significantly lower sensitivity in this population and radiation exposure.

[CT Presentations of Adult and Pediatric SARS-COV-2 Patients: A Review of Early COVID-19 Data]. / Comparación de los hallazgos en la tomografía computarizada de pacientes adultos y pediátricos con COVID-19.

Objective: Initial COVID-19 reports described a variety of clinical presentations, but lower respiratory abnormalities are most common and chest CT findings differ between adult and pediatric patients. We aim to summarize early CT findings to inform healthcare providers on the frequency of COVID-19 manifestations specific to adult or pediatric patients, and to determine if the sensitivity of CT justifies its use in these populations. Methods: PubMed was searched for the presence of the words "CT, imaging, COVID-19" in the title or abstract, and 17 large-scale PubMed and/or Scopus studies and case reports published between January 1, 2020 and April 15, 2020 were selected for data synthesis. Results: Initial CT scans identified ground-glass opacities and bilateral abnormalities as more frequent in adults (74%, n = 698, and 89%, n = 378, respectively) than children (60%, n = 25, and 37%, n = 46). At 14+ days, CT scans evidenced varied degrees of improvement in adults but no resolution until at least 26 days after the onset of flu-like symptoms. In pediatric patients, a third (n = 9) showed additional small nodular GGOs limited to a single lobe 3-5 days after an initial CT scan. Conclusión: Early adult CT findings suggest the limited use of CT as a supplemental tool in diagnosing COVID-19 in symptomatic adult patients, with a particular focus on identifying right and left lower lobe abnormalities, GGOs, and interlobular septal thickening. Early pediatric CT findings suggest against the use of CT if RT-PCR is available given its significantly lower sensitivity in this population and radiation exposure.

Aberrant upregulation of miR-21 in placental tissues of macrosomia.

OBJECTIVE: With China's rapid economic growth in the past 3 decades, an increase in rate of macrosomia has been reported in China. Fetal growth is a result of multiple factors including genetic potential for growth, maternal nutrition, maternal metabolism, endocrine factors and placental perfusion and function. However, the detailed mechanism of how macrosomia happened remains poorly known. Recent studies showed that the expression of a number of microRNAs (miRNAs) in placentas is involved in fetal growth. We hypothesized that aberrant expression of microRNA-21 (miR-21) and microRNA-16 (miR-16) in placenta is associated with macrosomia. STUDY DESIGN: Using quantitative real time PCR, we analyzed the expression level of miR-21 and miR-16 in terminal placentas of macrosomia pregnancies (n=35) and normal controls (n=35). Potential target genes of miRNA were predicted using TargetScan, miRanda and PicTar. Target genes were mapped to KEGG pathways using KEGG Mapper with an in-house Perl script with KEGG Gene IDs. RESULT: MiR-21 showed significant up-regulation in macrosomia (P=0.037). After controlling the potential confounders, multivariable logistic regression analysis suggested the risk of macrosomia increased, multivariable adjusted ORs of macrosomia for those in the highest tertile was 3.931 (95%CI: 1.049-14.736) compared with those in the lowest tertile in terms of miR-21 level. The target genes of miR-21 were involved in eight possible signaling pathways. They were pathways in P53 signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, TGF-beta signaling pathway and PI3K-Akt signaling pathway (P<0.001), Wnt signaling pathway, Jak-STAT signaling pathway and mTOR signaling pathway (P<0.05). CONCLUSION: Our study is the first to investigate the association between placental miRNA expression and macrosomia. Our results indicate that the expression level of miR-21 in placental tissue may be involved in the development of macrosomia.

Two cytokine signaling molecules co-operate to promote axonal transport and growth.

The neuropoietic cytokines and their cytoplasmic signaling molecules contribute to axotomy-induced events in the nerve cell body that are beneficial to axonal regeneration. Previous studies have revealed a paradox in that, in vivo, suppressor of cytokine signaling (SOCS3) is induced in axotomized primary sensory neurons which are in a growth mode but, in vitro, SOCS3 strongly inhibits neurite growth from the same neurons. The present studies in cell lines with immuno-precipitation and western blotting, and Förstner resonance energy transfer showed that SOCS3 binds to the C terminus of C-Jun N-terminal kinase-interacting protein-1 (JIP1), increases its serine phosphorylation, and increases its binding to kinesin. Axonal transport was studied in vitro in adult rat primary sensory neurons by analyses of recovery of fluorescence after photobleaching and of the velocity and direction of movement of organelles. Over-expression of SOCS3 in addition to JIP1 had two consequences. First, recovery of fluorescence after photobleaching was more rapid and, second, JIP1-containing organelles moved more quickly and more frequently in retrograde direction. With respect to neurite outgrowth, SOCS3 alone was, as expected, strongly inhibitory but, in the presence of excess JIP1 augmented the stimulatory activity of the latter. The observations indicate that interactions between JIP1 and SOCS3 influence favorably axonal transport and growth in vitro.

Short and long term analysis of heart rate variations in spontaneously hypertensive rats: effects of DSP-4 administration.

The purpose of this study was to investigate whether or not central noradrenergic neurons were involved in the time structure of circadian variation of heart rate (HR) in hypertension. We used spontaneously hypertensive rats (SHR(Izm)) and normotensive controls (Wistar Kyoto rats, WKY(Izm)). We selectively destroyed the noradrenergic neurons in the central nervous system (CNS) by administering noradrenergic neurotoxin, N-(2-chloroethy)-N-ethyl-2-bromobenzylamine (DSP4). Frequency domain measures of variation of HR (VHR) were obtained using the maximum entropy method. The 24-h time frame in VHR is usually dominant in both SHR(Izm) and WKY(Izm). Fourteen days after the administering of DSP4, the mean 24-h systolic arterial pressure (SAP) remained higher in SHR(Izm) than in WKY(Izm). After chemical lesion, ultradian rhythms (12-, 8-, 6-, and 4-h periods) in VHR became more remarkable in both SHR(Izm) and WKY(Izm) than before chemical lesion. Before chemical lesion, an inverse relationship existed between frequency and power spectral density in VHR, demonstrating 1/f(beta) characteristics. The slope of 1/f(beta) in VHR did not differ between SHR(Izm) and WKY(Izm). After the chemical lesion it did not also differ from that of each strain in control period (before lesion). Therefore, the noradrenergic neurons may not affect the time structure of HR in SHR(Izm) and WKY(Izm) for short-term time analysis. However, the intact noradrenergic neurons in CNS may be important to keep normal cardiac autonomic function in SHR(Izm) for long-term analysis.

Analysis of interaction of spinal and supraspinal reflex pathways involved in physiological tremor.

A model of feedback type in which physiological tremor are produced by both muscular skeletal system and reflex action is described. Analysis of this model shows that the interaction between the spinal and the supraspinal reflex pathways is important in responsible for low and high frequency oscillations of physiological tremor. Particularly the effect of gain ratio of the two pathways is studied in order to examine the role for the two reflex pathways in controlling neuromuscular oscillations. The existence of a critical point of the gain ratio at which one oscillating frequency transitions to two ones is predicted theoretically. A shift of the critical point with variations of weight load is found and suggests a changeable correlation relation between the spinal and the supraspinal pathways due to loading conditions. Our computations for physiological tremor demonstrate the results that the high frequency component of about 25 Hz is produced by the muscle-spinal reflex loop, and the low frequency component of about 10 Hz originates from the central nervous system or from supraspinal reflex loop. Several relations derived in this study are described, and they can be compared with experimental observations. Our model sheds considerable light on the details of the possible mechanism for physiological tremor. In addition, a possibility arising from our study is that the tremulous oscillation associated with some pathological states, say Parkinson's disease, may arise from modified gains in one or more of the reflex pathways.

An investigation of stretch reflex in physiological tremor.

This paper describes a theoretical consideration on muscle stretch reflex in physiological tremor (abbreviated as tremor). In making a model, the function of rostro-caudal homonymous motoneurone pool as well as the interaction between spinal cord mechanism and supraspinal system is investigated. The known physiology of the neuromuscular oscillations is used to evaluate the responses of a set of differential equation that represents lumped system dynamics underlying the stretch reflex process of tremor. According to the model, the stretch reflex along with the mechanics of limb is behaving as a filter. With sharp resonant peaks and without the need of any external inputs, the filter selects oscillators and sustains tremulous movement. These reflex features, especially the findings of an existence of two sharp resonant centers, are particular valuable in an explanation of the two spectral peaks observed in tremor. It is demonstrated that (1) the two peaks of tremor, which vibrate at 10 Hz and 20 Hz, largely depend on the coupling lambda between spinal and supraspinal system, i.e., lambda leads to "spontaneous symmetry breaking" producing a peak doubling; (2) the two peaks are attributable to two decoupled states found in our model. The pea with 10 Hz is attributed to the state Z+ (t) describing an average state of spinal+supraspinal system, while the one with 20 Hz denotes the state Z-(t) which presents a relative movement of spinal and supraspinal system. With regarding to the nature of tremor under various conditions such as loading, fatigue, and pseudo-gravity, this paper discusses the possible connections of lambda to these experimental environments. Also, this paper argues that representation of stretch reflex by the decoupled states is more essential than other traditional representations used in approaching to tremor phenomena.

Monitoring accumulative fatigue of finger by autoregressive modeling of physiological tremor.

In this study, block data structured autoregressive (AR) method is used to evaluate fatigue, based on physiological tremor during and after loading a weight mass on the index finger. The temporal changes in the prediction coefficients and the reflection coefficients are determined. AR spectral estimation with the ninth-order is obtained and presented in graphical form. The results indicate that the first prediction coefficient a1 can be used to characterize the state of fatigue of finger muscle and the other prediction coefficients do not show any tendency for the finger load. The coefficient a1 can be applied to monitor the accumulative fatigue induced by the weight loading for a duration of time.

Physiological tremor under pseudo-fraction gravity.

The effect of pseudo-fraction gravity on physiological tremor of the human finger (finger tremor) has been examined experimentally by immersing an index finger into water at different immersion levels. The pseudo-fraction gravity, gamma G, was established by water buoyancy at immersion level omega, G being gravitation acceleration and gamma between zero and unit. The nature of variations of finger tremor under the influence of gamma G is estimated based on FFT spectral analysis. It is illustrated that with a decrease in gamma, or equivalently an increase in omega, two dominant peaks remaining approximately constant in frequencies around 10Hz and 20Hz are found, while peak amplitude is decreased rapidly for higher peak and slowly for lower one. Theoretically the effect of pseudo-fraction gravity is analyzed in terms of a specific model for finger tremor. The experimental results presented in this paper are predicted rather well by two resonant modes which occurred in our model system. It is possible to conclude that the model, which is characterized by a pair of antagonistic muscles and two reflex pathways, provides an adequate quantitative description of finger tremor.

Effects of weight load on physiological tremor: the AR representation.

The propriety of the autoregressive (AR) method as a means of processing the signals of physiological tremor of human finger (finger tremor) was investigated. Application of the Akaike's criterion demonstrated that the 15-th order AR model was required to describe the recordings of finger tremor. According to Burg's algorithm, both AR spectrum and AR parameters were estimated to study the effects of various weight loads on finger tremor. It was found that, (1) the amplitude of AR spectrum was apparently enhanced by adding the load; (2) the first prediction coefficient (a1) and the first reflection coefficient (rho 1) significantly declined by increasing the weight loads. The results were compared with the calculations from FFT (Fast Fourier Transform) and autocorrelation function. Simple physical interpretation of the AR parameters (i.e. a1 and rho 1) was discussed in relation with system's resonant modes.