The history of chromosomal instability in genome doubled tumors.

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.

Accumulation of ß-aminoisobutyric acid mediates hyperalgesia in ovariectomized mice through Mas-related G protein-coupled receptor D signaling.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

Accumulation of advanced oxidation protein products contributes to age-related impairment of gap junction intercellular communication in osteocytes of male mice.

AIMS: Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes' GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes' GJIC in aged male mice and its mechanism. METHODS: Changes in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks. RESULTS: The AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes' GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo. CONCLUSION: Our study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing. Cite this article: Bone Joint Res 2022;11(7):413-425.

Interference with miR-210 Alleviated Renal Injury in Septic Rats by Inhibiting JAK-STAT Pathway.

Pediatric sepsis has become the leading cause of death in pediatric intensive care units (PICU). The regulation of target genes may be the key to the treatment of pediatric sepsis. The expression of miR-210 in rat serum was detected by RT-qPCR. The serum BUN, Scr, and CysC were detected by an automatic biochemical analyzer. The expression of inflammatory factors was detected by ELISA. The apoptosis level of the cells was detected by TUNEL staining. The expression of apoptotic proteins Bcl2, Bax, Cleaved caspase3, caspase3, and JAK/STAT3 pathway-related proteins were detected by western blot. The expression of miR-210 was abnormally elevated in sepsis pups. Interfering with the expression of miR-210 in rats could reduce the degree of renal injury and inhibit the inflammatory response in sepsis pups. In addition, interference with miR-210 could inhibit the apoptosis level of renal tissue cells, and the expression of apoptosis-related proteins was also significantly decreased. During this process, we found that after interfering with the expression of miR-210, the expression of the JAK/STAT pathway was inhibited. Then, pathway agonist SC-39100 can reverse the inhibitory effects of interfering with miR-210 on renal tissue damage, inflammatory response, and apoptosis. Interference with miR-210 alleviated renal injury in septic rats by inhibiting JAK-STAT pathway.

Protein-protein interaction network with machine learning models and multiomics data reveal potential neurodegenerative disease-related proteins.

Research of protein-protein interaction in several model organisms is accumulating since the development of high-throughput experimental technologies and computational methods. The protein-protein interaction network (PPIN) is able to examine biological processes in a systematic manner and has already been used to predict potential disease-related proteins or drug targets. Based on the topological characteristics of the PPIN, we investigated the application of the random forest classification algorithm to predict proteins that may cause neurodegenerative disease, a set of pathological changes featured by protein malfunction. By integrating multiomics data, we further showed the validity of our machine learning model and narrowed down the prediction results to several hub proteins that play essential roles in the PPIN. The novel insights into neurodegeneration pathogenesis brought by this computational study can indicate promising directions for future experimental research.

Fructus mume Protects Against Cigarette Smoke Induced Chronic Cough Guinea Pig.

Fructus mume was recorded in the Chinese Pharmacopoeia and traditional Chinese medical books for chronic cough, but the effect and related constituents are still unknown. Thus, we investigated the protect effects and the relevant constituents of F. mume in a guinea pig model with chronic cough induced by cigarette smoke (CS). The organic acids and polysaccharides in F. mume were detected by high performance liquid chromatography, gel permeation chromatography, and gas chromatography-mass spectrometry. The guinea pigs were orally administrated with vehicle or the water extract of Fructus mume (FW) during the 14 days of CS exposure. Citric acid induced coughs were automatically measured by Buxco system. The differential cells in bronchoalveolar lavage fluid (BALF) and histopathological changes in lung tissue were assessed by hematoxylin and eosin staining. The tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) levels in lung tissue were detected via enzyme-linked immunosorbent assay. The mucus productions in tracheas were determined with Alcian blue-periodic acid Schiff staining. The results suggested relatively high concentration of citric acid, chlorogenic acid, and neochlorogenic acid in F. mume, and high proportion of galactose and glucose and lower molecular weight of polysaccharides. Administration of FW significantly reduced the cough frequency, decreased inflammatory cells in BALF and lung tissue, and attenuated the thickening of airway epithelium and submucosa compared with CS-exposure group. Moreover, the overproduction of TNF-α and IL-8 in lung tissues, and mucus in central airways of CS-induced guinea pigs was markedly inhibited by FW. The extract could also protect against CS exposure-induced chronic cough in guinea pigs by reducing coughs, airways inflammation, and mucus overproduction.

[Effect of assisted anesthesia of auricular point magnetic sticking on postoperative recovery of gynecological surgery].

OBJECTIVE: To explore an optimum method on postoperative recovery of general-anesthesia gynecological laparoscopic surgery. METHODS: One hundred and twenty cases of gynecological laparoscopic surgery were randomly divided into three groups, 40 cases in each one. The sensitive points of bilateral Shenmen (TF4), Zigong (TF2), Wei (CO4), Dachang (CO7) and so on were selected in all three groups one night before the surgery. The sticking with magnetic beads was applied in the group A. The magnetic beads were in-pair stuck at front-back corresponding location of both ears in the group B. The same-appearance plaster was put at the corresponding acupoints in the group C. The intubation anesthesia was applied in all three groups and postoperative recovery of gynecological laparoscopic surgery was observed. RESULTS: The postoperative visual analogue scale (VAS) was (1.77 +/- 1.65) in the group A and (1.80 +/- 1.96) in the group B, which was both lower than (2.62 +/- 1.46) in the group C (both P < 0.01). The occurrence rate of nausea and vomiting was 25.0% (9/36) in the group A and 20.0% (8/40) in the group B, which was both lower than 50.0% (19/38) in the group C (both P < 0.01). The recovery of borborygmus on postoperative 1st and 3rd day in the group A and B was faster than that in the group C (both P < 0.05), while time of fart and defecation in the group A and B was earlier than that in the group C (both P < 0.05). The score of state-trait anxiety inventory in the group A and B was lower than that in the group C (both P < 0.05), but the differences of each item between the group A and B were not obvious (both P > 0.05). CONCLUSION: The auricular point sticking could support analgesia of general-anesthesia gynecological laparoscopic surgery, which could relieve anxiety mood, reduce occurrence of nausea and vomiting and improve function of stomach and intestine to benefit postoperative recovery. However, the effect of in-pair sticking of auricular point with magnetic beads at front-back acupoints was not obviously strengthened.

[Observation on the anesthesia effect of general anesthesia assisted by auricular-plaster therapy in gynecological surgery].

OBJECTIVE: To observe the impacts on anesthetic dosage and postoperative pain under general anesthesia assisted by auricular-plaster therapy. METHODS: One hundred and twenty cases of gynecological laparoscopic surgery were randomized into three groups, 40 cases in each one. In auricular point group A, the magnetic beads were stick on the auricular points which were Shenmen (TF4), Lung (fei, CO14), Spleen (pi,CO13), Stomach (wei, CO4), Large Intestine (dachang, CO7), Adrenal (shenshangxian, TG2 (P)), Endocrine (neifenmi, CO18), Uterus and Pelvic Cavity(penqiang, TF5) etc. In auricular point group B, the magnetic beads were stick on the preauricular points and the corresponding retroauricular points of the ears. In a placebo group, the plasters of the same appearance were stick on the corresponding auricular points of the ears. The anesthetic method was same in three groups and the anesthesia effect were assessed and compared among the three groups. RESULTS: In surgery, the dosage of sufentanil, the narcotic analgesic was (22.08 +/- 7.11) microg in auricular point group A and was (20.19 +/- 7.21) microg in auricular point group B, which were reduced as compared with (26.13 +/- 9.04) microg in the placebo group (both P < 0.05). The difference in the dosage of propofol, the anesthetic was not significant statistically among three groups (P > 0.05). On the 1st day after surgery, the score of pain visual analogue scale (VAS) was (1.77 +/- 1.65) in auricular point group A and was (1.80 +/- 1.96) in auricular point group B, which were reduced as compared with (2.62 +/- 1.46) in the placebo group (both P < 0.05). Before surgery, the serum beta-endorphin (beta-EP) was (198.8 +/- 124.1) pg/mL in auricular point group A and was (207.2 +/-102.7) pg/mL in auricular point group B, which were higher apparently as compared with (143.6 +/- 87.1) pg/mL in the placebo group (both P < 0.05). The differences in the above indices were not significant statistically between the two auricular point groups. CONCLUSION: The auricular-plaster therapy reduces the dosage of anesthetic, alleviates postoperative pain and acts on tranquilization and analgesia. The effect is not intensified apparently in the treatment for the magnetic beads sticking on both preauricular points and the corresponding retroauricular points of the ears.

Effect of assisted anesthesia of auricular point magnetic sticking on postoperative recovery of gynecological surgery / 中国针灸

<p><b>OBJECTIVE</b>To explore an optimum method on postoperative recovery of general-anesthesia gynecological laparoscopic surgery.</p><p><b>METHODS</b>One hundred and twenty cases of gynecological laparoscopic surgery were randomly divided into three groups, 40 cases in each one. The sensitive points of bilateral Shenmen (TF4), Zigong (TF2), Wei (CO4), Dachang (CO7) and so on were selected in all three groups one night before the surgery. The sticking with magnetic beads was applied in the group A. The magnetic beads were in-pair stuck at front-back corresponding location of both ears in the group B. The same-appearance plaster was put at the corresponding acupoints in the group C. The intubation anesthesia was applied in all three groups and postoperative recovery of gynecological laparoscopic surgery was observed.</p><p><b>RESULTS</b>The postoperative visual analogue scale (VAS) was (1.77 +/- 1.65) in the group A and (1.80 +/- 1.96) in the group B, which was both lower than (2.62 +/- 1.46) in the group C (both P < 0.01). The occurrence rate of nausea and vomiting was 25.0% (9/36) in the group A and 20.0% (8/40) in the group B, which was both lower than 50.0% (19/38) in the group C (both P < 0.01). The recovery of borborygmus on postoperative 1st and 3rd day in the group A and B was faster than that in the group C (both P < 0.05), while time of fart and defecation in the group A and B was earlier than that in the group C (both P < 0.05). The score of state-trait anxiety inventory in the group A and B was lower than that in the group C (both P < 0.05), but the differences of each item between the group A and B were not obvious (both P > 0.05).</p><p><b>CONCLUSION</b>The auricular point sticking could support analgesia of general-anesthesia gynecological laparoscopic surgery, which could relieve anxiety mood, reduce occurrence of nausea and vomiting and improve function of stomach and intestine to benefit postoperative recovery. However, the effect of in-pair sticking of auricular point with magnetic beads at front-back acupoints was not obviously strengthened.</p>

Observation on the anesthesia effect of general anesthesia assisted by auricular-plaster therapy in gynecological surgery / 中国针灸

<p><b>OBJECTIVE</b>To observe the impacts on anesthetic dosage and postoperative pain under general anesthesia assisted by auricular-plaster therapy.</p><p><b>METHODS</b>One hundred and twenty cases of gynecological laparoscopic surgery were randomized into three groups, 40 cases in each one. In auricular point group A, the magnetic beads were stick on the auricular points which were Shenmen (TF4), Lung (fei, CO14), Spleen (pi,CO13), Stomach (wei, CO4), Large Intestine (dachang, CO7), Adrenal (shenshangxian, TG2 (P)), Endocrine (neifenmi, CO18), Uterus and Pelvic Cavity(penqiang, TF5) etc. In auricular point group B, the magnetic beads were stick on the preauricular points and the corresponding retroauricular points of the ears. In a placebo group, the plasters of the same appearance were stick on the corresponding auricular points of the ears. The anesthetic method was same in three groups and the anesthesia effect were assessed and compared among the three groups.</p><p><b>RESULTS</b>In surgery, the dosage of sufentanil, the narcotic analgesic was (22.08 +/- 7.11) microg in auricular point group A and was (20.19 +/- 7.21) microg in auricular point group B, which were reduced as compared with (26.13 +/- 9.04) microg in the placebo group (both P < 0.05). The difference in the dosage of propofol, the anesthetic was not significant statistically among three groups (P > 0.05). On the 1st day after surgery, the score of pain visual analogue scale (VAS) was (1.77 +/- 1.65) in auricular point group A and was (1.80 +/- 1.96) in auricular point group B, which were reduced as compared with (2.62 +/- 1.46) in the placebo group (both P < 0.05). Before surgery, the serum beta-endorphin (beta-EP) was (198.8 +/- 124.1) pg/mL in auricular point group A and was (207.2 +/-102.7) pg/mL in auricular point group B, which were higher apparently as compared with (143.6 +/- 87.1) pg/mL in the placebo group (both P < 0.05). The differences in the above indices were not significant statistically between the two auricular point groups.</p><p><b>CONCLUSION</b>The auricular-plaster therapy reduces the dosage of anesthetic, alleviates postoperative pain and acts on tranquilization and analgesia. The effect is not intensified apparently in the treatment for the magnetic beads sticking on both preauricular points and the corresponding retroauricular points of the ears.</p>