Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach.

The innate immune system senses viral DNA that enters mammalian cells, or in aberrant situations self-DNA, and triggers type I interferon production. Here we present an integrative approach that combines quantitative proteomics, genomics and small molecule perturbations to identify genes involved in this pathway. We silenced 809 candidate genes, measured the response to dsDNA and connected resulting hits with the known signaling network. We identified ABCF1 as a critical protein that associates with dsDNA and the DNA-sensing components HMGB2 and IFI204. We also found that CDC37 regulates the stability of the signaling molecule TBK1 and that chemical inhibition of the CDC37-HSP90 interaction and several other pathway regulators potently modulates the innate immune response to DNA and retroviral infection.

A WOX homolog disrupted by a transposon led to the loss of spines and contributed to the domestication of lettuce.

The loss of spines is one of the most important domestication traits for lettuce (Lactuca sativa). However, the genetics and regulation of spine development in lettuce remain unclear. We examined the genetics of spines in lettuce using a segregating population derived from a cross between cultivated and wild lettuce (Lactuca serriola). A gene encoding WUSCHEL-related homeobox transcription factor, named as WOX-SPINE1 (WS1), was identified as the candidate gene controlling the spine development in lettuce, and its function on spines was verified. A CACTA transposon was found to be inserted into the first exon of the ws1 allele, knocking out its function and leading to the lack of spines in cultivated lettuce. All lettuce cultivars investigated have the nonfunctional ws1 gene, and a selection sweep was found at the WS1 locus, suggesting its important role in lettuce domestication. The expression levels of WS1 were associated with the density of spines among different accessions of wild lettuce. At least two independent loss-of-function mutations in the ws1 gene caused the loss of spines in wild lettuce. These findings provide new insights into the development of spines and facilitate the exploitation of wild genetic resources in future lettuce breeding programs.

Association of stress hyperglycemia ratio with left ventricular function and microvascular obstruction in patients with ST-segment elevation myocardial infarction: a 3.0 T cardiac magnetic resonance study.

BACKGROUND: Stress hyperglycemia, which is associated with poor prognosis in patients with acute myocardial infarction (AMI), can be determined using the stress hyperglycemia ratio (SHR). Impaired left ventricular function and microvascular obstruction (MVO) diagnosed using cardiac magnetic resonance (CMR) have also been proven to be linked to poor prognosis in patients with AMI and aid in risk stratification. However, there have been no studies on the correlation between fasting SHR and left ventricular function and MVO in patients with acute ST-segment elevation myocardial infarction (ASTEMI). Therefore, this study aimed to investigate the additive effect of fasting SHR on left ventricular function and global deformation in patients with ASTEMI and to explore the association between fasting SHR and MVO. METHODS: Consecutive patients who underwent CMR at index admission (3-7 days) after primary percutaneous coronary intervention (PPCI) were enrolled in this study. Basic clinical, biochemical, and CMR data were obtained and compared among all patients grouped by fasting SHR tertiles: SHR1: SHR < 0.85; SHR2: 0.85 ≤ SHR < 1.01; and SHR3: SHR ≥ 1.01. Spearman's rho (r) was used to assess the relationship between fasting SHR and left ventricular function, myocardial strain, and the extent of MVO. Multivariable linear regression analysis was performed to evaluate the determinants of left ventricular function and myocardial strain impairment in all patients with AMI. Univariable and multivariable regression analyses were performed to investigate the correlation between fasting SHR and the presence and extent of MVO in patients with AMI and those with AMI and diabetes mellitus (DM). RESULTS: A total of 357 patients with ASTEMI were enrolled in this study. Left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI) were significantly lower in SHR2 and SHR3 than in SHR1. Compared with SHR1 and SHR2 groups, left ventricular strain was lower in SHR3, as evidenced by global radial (GRS), global circumferential (GCS), and global longitudinal (GLS) strains. Fasting SHR were negatively correlated with LVEF, LVGFI, and GRS (r = - 0.252; r = - 0.261; and r = - 0.245; all P<0.001) and positively correlated with GCS (r = 0.221) and GLS (r = 0.249; all P <0.001). Multivariable linear regression analysis showed that fasting SHR was an independent determinant of impaired LVEF, LVGFI, GRS, and GLS. Furthermore, multivariable regression analysis after adjusting for covariates signified that fasting SHR was associated with the presence and extent of MVO in patients with AMI and those with AMI and DM. CONCLUSION: Fasting SHR in patients with ASTEMI successfully treated using PPCI is independently associated with impaired cardiac function and MVO. In patients with AMI and DM, fasting SHR is an independent determinant of the presence and extent of MVO.

Curcumin inhibits the invasion and migration of pancreatic cancer cells by upregulating TFPI-2 to regulate ERK- and JNK-mediated epithelial-mesenchymal transition.

PURPOSE: Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS: Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS: Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION: Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.

Effects of motor imagery based brain-computer interface on upper limb function and attention in stroke patients with hemiplegia: a randomized controlled trial.

BACKGROUND: Seeking positive and comprehensive rehabilitation methods after stroke is an urgent problem to be solved, which is very important to improve the dysfunction of stroke. The aim of this study was to investigate the effects of motor imagery-based brain-computer interface training (MI-BCI) on upper limb function and attention in stroke patients with hemiplegia. METHODS: Sixty stroke patients with impairment of upper extremity function and decreased attention were randomly assigned to the control group (CR group) or the experimental group (BCI group) in a 1:1 ratio. Patients in the CR group received conventional rehabilitation. Patients in the BCI group received 20 min of MI-BCI training five times a week for 3 weeks (15 sessions) in addition to conventional rehabilitation. The primary outcome measures were the changes in Fugl-Meyer Motor Function Assessment of Upper Extremities (FMA-UE) and Attention Network Test (ANT) from baseline to 3 weeks. RESULTS: About 93% of the patients completed the allocated training. Compared with the CR group, among those in the BCI group, FMA-UE was increased by 8.0 points (95%CI, 5.0 to 10.0; P < 0.001). Alert network response time (32.4ms; 95%CI, 58.4 to 85.6; P < 0.001), orienting network response (5.6ms; 95%CI, 29.8 to 55.8; P = 0.010), and corrects number (8.0; 95%CI, 17.0 to 28.0; P < 0.001) also increased in the BCI group compared with the CR group. Additionally, the executive control network response time (- 105.9ms; 95%CI, - 68.3 to - 23.6; P = 0.002), the total average response time (- 244.8ms; 95%CI, - 155.8 to - 66.2; P = 0.002), and total time (- 122.0ms; 95%CI, - 80.0 to - 35.0; P = 0.001) were reduced in the BCI group compared with the CR group. CONCLUSION: MI-BCI combined with conventional rehabilitation training could better enhance upper limb motor function and attention in stroke patients. This training method may be feasible and suitable for individuals with stroke. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry with Portal Number ChiCTR2100050430(27/08/2021).

Space radiation quality factor for Galactic Cosmic Rays and typical space mission scenarios using a microdosimetric approach.

Space radiation exposure from omnipresent Galactic Cosmic Rays (GCRs) in interplanetary space poses a serious carcinogenic risk to astronauts due to the-limited or absent-protective effect of the Earth's magnetosphere and, in particular, the terrestrial atmosphere. The radiation risk is directly influenced by the quality of the radiation, i.e., its pattern of energy deposition at the micron/DNA scale. For stochastic biological effects, radiation quality is described by the quality factor, [Formula: see text], which can be defined as a function of Linear Energy Transfer (LET) or the microdosimetric lineal energy ([Formula: see text]). In the present work, the average [Formula: see text] of GCR for different mission scenarios was calculated using a modified version of the microdosimetric Theory of Dual Radiation Action (TDRA). NASA's OLTARIS platform was utilized to generate the radiation environment behind different aluminum shielding (0-30 g/cm2) for a typical mission scenario in low-earth orbit (LEO) and in deep space. The microdosimetric lineal energy spectra of ions ([Formula: see text]) in 1 µm liquid water spheres were calculated by a generalized analytical model which considers energy-loss fluctuations and δ-ray transport inside the irradiated medium. The present TDRA-based [Formula: see text]-values for the LEO and deep space missions were found to differ by up to 10% and 14% from the corresponding ICRP-based [Formula: see text]-values and up to 3% and 6% from NASA's [Formula: see text]-model. In addition, they were found to be in good agreement with the [Formula: see text]-values measured in the International Space Station (ISS) and by the Mars Science Laboratory (MSL) Radiation Assessment Detector (RAD) which represent, respectively, a LEO and deep space orbit.

Effects of repetitive transcranial magnetic stimulation combined with music therapy in non-fluent aphasia after stroke: A randomised controlled study.

BACKGROUND: Although existing studies have shown that both repetitive transcranial magnetic stimulation (rTMS) and music therapy have advantages in the treatment of non-fluent aphasia, the efficacy of the combination of these two methods remains to be investigated. AIMS: To investigate the clinical efficacy of low-frequency rTMS combined with music therapy on language function and depression in patients with non-fluent aphasia after stroke. METHODS & PROCEDURES: A single-blind parallel randomised controlled trial was conducted. Sixty patients (mean duration = 93.78 days) with non-fluent aphasia after stroke were randomly divided into a traditional therapy group (n = 20), a music therapy group (n = 20) and a combined therapy group (n = 20, 1 Hz). The language function and depression were evaluated before and 3 weeks after treatment with the Chinese version of the Western Aphasia Battery scale, Boston Diagnostic Aphasia Examination scale and Stroke Aphasic Depression Questionnaire Hospital Version scale. OUTCOMES & RESULTS: The combined therapy group was significantly better in all outcomes than the traditional therapy group and was significantly better in depression than the music therapy group. The music therapy group was significantly better in repetition and depression than the traditional therapy group. Language improvement was positively correlated with depression improvement. For adverse events, only two patients in the combined therapy group showed slight dizziness during rTMS treatment and their symptoms improved after rest. CONCLUSIONS & IMPLICATIONS: Our preliminary randomised controlled study indicates that low-frequency rTMS combined with music therapy is feasible and safe in improving language function and depression in non-fluent aphasia patients after stroke. WHAT THIS PAPER ADDS: What is already known on this subject Repetitive transcranial magnetic stimulation (rTMS) and music therapy respectively have advantages in the treatment of non-fluent aphasia after stroke, but whether the combination of the two methods is more effective is still unknown. What this paper adds to the existing knowledge This is one of the first randomised control trials to investigate whether the clinical efficacy of low-frequency rTMS combined music therapy for non-fluent aphasia is better. The findings show that low-frequency rTMS combined music therapy is superior to traditional therapy in spontaneous speech, auditory comprehension, repetition, naming, aphasia quotient, functional language level and depression, and superior to music therapy in depression, while music therapy is superior to traditional therapy in repetition and depression. What are the potential or actual clinical implications of this work? Low-frequency rTMS combined music therapy may be a better method for treatment of non-fluent aphasia.

Nomogram for predicting fulminant necrotizing enterocolitis.

BACKGROUND: Fulminant necrotizing enterocolitis (FNEC) is the most serious subtype of NEC and has a high mortality rate and a high incidence of sequelae. Onset prediction can help in the establishment of a customized treatment strategy. This study aimed to develop and evaluate a predictive nomogram for FNEC. METHODS: We conducted a retrospective observation to study the clinical data of neonates diagnosed with NEC (Bell stage ≥ IIB). Neonates were divided into the FNEC and NEC groups. A multivariate logistic regression model was used to construct the nomogram model. The performance of the nomogram was assessed using area under the curve, calibration analysis, and decision curve analysis. RESULTS: A total of 206 neonate cases were included, among which 40 (19.4%) fulfilled the definition of FNEC. The identified predictors were assisted ventilation after NEC onset; shock at NEC onset; feeding volumes before NEC onset; neutrophil counts on the day of NEC onset; and neutrophil, lymphocyte, and monocyte counts on day 1 after NEC onset. The nomogram exhibited good discrimination, with an area under the receiver operating characteristic curve of 0.884 (95% CI 0.825-0.943). The predictive model was well calibrated. Decision curve analysis confirmed the clinical usefulness of this nomogram. CONCLUSION: A nomogram with a potentially effective application was developed to facilitate the individualized prediction of FNEC, with the hope of providing further direction for the early diagnosis of FNEC and timing of intervention.

ENO1 Promotes OSCC Migration and Invasion by Orchestrating IL-6 Secretion from Macrophages via a Positive Feedback Loop.

Oral squamous cell carcinoma (OSCC) has a five-year survival rate of less than 50% due to its susceptibility to invasion and metastasis. Crosstalk between tumor cells and macrophages has been proven to play a critical role in tumor cell migration and invasion. However, the specific mechanisms by which tumor cells interact with macrophages have not been fully elucidated. This study sought to investigate the regulatory mechanism of tumor cell-derived alpha-enolase (ENO1) in the interaction between tumor cells and macrophages during OSCC progression. Small interfering RNA (siRNA) transfection and recombinant human ENO1 (rhENO1) stimulation were used to interfere with the interaction between tumor cells and macrophages. Our results showed that ENO1 was expressed higher in CAL27 cells than in HaCaT cells and regulated lactic acid release in CAL27 cells. Conditioned medium of macrophages (Macro-CM) significantly up-regulated the ENO1 mRNA expression and protein secretion in CAL27 cells. ENO1 promoted the migration and invasion of tumor cells by facilitating the epithelial-mesenchymal transition (EMT) through macrophages. ENO1 orchestrated the IL-6 secretion of macrophages via tumor cell-derived lactic acid and the paracrine ENO1/Toll-like receptor (TLR4) signaling pathway. In turn, IL-6 promoted the migration and invasion of tumor cells. Collectively, ENO1 promotes tumor cell migration and invasion by orchestrating IL-6 secretion of macrophages via a dual mechanism, thus forming a positive feedback loop to promote OSCC progression. ENO1 might be a promising therapeutic target which is expected to control OSCC progression.

The effect of music therapy on language recovery in patients with aphasia after stroke: a systematic review and meta-analysis.

OBJECTIVE: The aim of this meta-analysis was to evaluate the evidence on the effectiveness of music therapy in the recovery of language function in post-stroke aphasia, compared with conventional therapy or no therapy. METHODS: We searched studies that explored the effect of music therapy on language function in post-stroke aphasia and published in PubMed, Embase, the Cochrane Library, Web of Science, CINAHL, ProQuest Digital Dissertations, and ClinicalTrials.gov from inception to March 2021. Six reviewers independently screened out eligible studies, extracted data, and evaluated the methodological quality. Results were pooled using mean difference (MD) with 95% confidence interval (CI). Heterogeneity was assessed by the chi-square test and I2 statistic. RESULTS: Six studies were included in this meta-analysis involving 115 patients. The methodological quality of these studies ranged from poor to excellent. There was significant mean difference in functional communication for post-stroke aphasia by 1.45 (95% CI: 0.24, 2.65; P = 0.02, from poor to excellent evidence), in repetition by 6.49 (95% CI: 0.97, 12.00; P = 0.02, from acceptable to excellent evidence), and in naming by 11.44 (95% CI: 1.63, 21.26; P = 0.02, from acceptable to excellent evidence). But there was no significant difference in comprehension for post-stroke aphasia by 7.21 (95% CI: - 10.88, 25.29; P = 0.43, from acceptable to excellent evidence). CONCLUSIONS: Music therapy can improve functional communication, repetition, and naming in patients with post-stroke aphasia, but did not significantly improve comprehension. TRIAL REGISTRATION: CRD42021251526.

Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection.

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.

Relationship between thyroid disorders and uterine fibroids among reproductive-age women.

Uterine fibroids and thyroid nodules, both of which are crucially affected by estrogen, are common diseases among reproductive-age women. However, little attention has been paid to the association between the two diseases. This retrospective case-control study aimed to assess the relationships among thyroid nodules, thyroid function and uterine fibroids in China. We reviewed the electronic records of 853 reproductive-age women who attended health check-ups at the Second Affiliated Hospital of Wenzhou Medical University from July 1st, 2017, to June 30th, 2018. All subjects received transvaginal pelvic ultrasound, thyroid ultrasound, thyroid function, and other laboratory tests. We found that the prevalence of thyroid nodules in subjects with uterine fibroids was remarkably higher than that in subjects without fibroids. The proportion of thyroid nodules ≥1 cm in subjects with uterine fibroids was significantly higher than that in subjects without fibroids. Women with thyroid nodules had a higher proportion of multiple uterine fibroids than women without thyroid nodules. Among the parameters of thyroid function, the only statistically significant parameter was total triiodothyronine, i.e., women with uterine fibroids had lower total triiodothyronine levels than unaffected controls; however, the total triiodothyronine levels were within the normal ranges. Moreover, no significant difference was noted in thyroid hormone status between subjects with and without uterine fibroids. Our findings suggest that thyroid nodules are positively correlated with uterine fibroids among reproductive-age women in China. Further studies are needed to confirm this association and fully understand the common pathogenetic mechanism underlying the association between uterine fibroids and thyroid nodules.

SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats.

BACKGROUND: Diabetic patients are more sensitive to myocardial ischemic injury than non-diabetic patients. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase making the heart more resistant to ischemic injury. As SIRT1 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of SIRT1 in the diabetic heart may overcome its increased susceptibility to ischemic injury. METHODS: Male Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin once to induce diabetes. Diabetic rats received injections of adenoviral vectors encoding SIRT1 (Ad-SIRT1) at five myocardial sites. Four days after adenoviral injection, the rats were subjected to myocardial ischemia and reperfusion (MI/R). Outcome measures included left ventricular function, infarct size, cellular death and oxidative stress. RESULTS: Delivery of Ad-SIRT1 into the hearts of diabetic rats markedly increased SIRT1 expression. Up-regulation of SIRT1 in diabetic hearts improved cardiac function and reduced infarct size to the extent as in non-diabetic animals following MI/R, which was associated with reduced serum creatine kinase-MB, lactate dehydrogenase activities and cardiomyocyte apoptosis. Moreover, Ad-SIRT1 reduced the increase in the superoxide generation and malonaldialdehyde content and simultaneously increased the antioxidant capability. Furthermore, Ad-SIRT1 increased eNOS phosphorylation and reduced eNOS acetylation in diabetic hearts. NOS inhibitor L-NAME inhibited SIRT1-enhanced eNOS phosphorylation, and blunted SIRT1-mediated anti-apoptotic and anti-oxidative effects and cardioprotection. CONCLUSIONS: Overexpression of SIRT1 reduces diabetes-exacerbated MI/R injury and oxidative stress via activating eNOS in diabetic rats. The findings suggest SIRT1 may be a promising novel therapeutic target for diabetic cardiac complications.

Paper-based cell impedance sensor and its application for cytotoxic evaluation.

Disposable analytical devices for developing sensitive and label-free monitoring of cancerous cells would be attractive for cancer research. Here, paper-based electroanalytical devices based on impedance spectrometry were applied for the study of K562 cells and the toxic effect of anticancer drugs. The proposed device integrating gold nanorods modified ITO electrodes could provide a biocompatible surface for immobilization of living cells maintaining their bioactivity. The impedance results exhibited good correlation to the logarithmic value of cell numbers ranging from 7.5 × 10(2) to 3.9 × 10(6) cells mL(-1) with a detection limit of 500 cells mL(-1). Furthermore, this strategy was used to evaluate the cytotoxic effects of arsenic trioxide and cyclophosphamide. Results obtained by the impedimetric method correlate well with the conventional cell viability assay. Cells exposed to drugs exhibited a prominent reduction of impedance data, showing an inverse dose-dependent relationship. This simple, cost-effective and portable paper-based electrochemical analytical device could provide a new impedance platform for applications in monitoring cell behavior, pharmacological studies and toxicological analyses.

Ethyl cinnamate derivatives as promising high-efficient acaricides against Psoroptes cuniculi: synthesis, bioactivity and structure-activity relationship.

This paper reported the synthesis, structure-activity relationship (SAR) and acaricidal activity in vitro against Psoroptes cuniculi, a mange mite, of 25 ethyl cinnamate derivatives. All target compounds were synthesized and elucidated by means of MS, (1)H- and (13)C-NMR analysis. The results showed that 24 out of 25 tested compounds at 1.0 mg/mL demonstrated acaricidal activity in varying degrees. Among them, 6, 15, 26, 27 and 30 showed significant activity with median lethal concentration values (LC50) of 89.3, 119.0, 39.2, 29.8 and 41.2 µg/mL, respectively, which were 2.1- to 8.3-fold the activity of ivermectin (LC50=247.4 µg/mL), a standard drug in the treatment of Psoroptes cuniculi. Compared with ivermectin, with a median lethal time value (LT50) of 8.9 h, 27 and 30 showed smaller LT50 values of 7.9 and 1.3 h, respectively, whereas 6, 15 and 26 showed slightly larger LT50 values of 10.6, 11.0 and 10.4 h at 4.5 µmol/mL. SARs showed that the presence of o-NO2 or m-NO2 on the benzene ring significantly improved the activity, whereas the introduction of a hydroxy, methoxy, acetoxy, methylenedioxy, bromo or chloro group reduced the activity. (E)-Cinnamates were more effective than their (Z)-isomer. Nevertheless, the carbon-carbon double bond in the acrylic ester moiety was proven not to be essential to improve the activity of cinnamic acid esters. Thus, the results strongly indicate that cinnamate derivatives, especially their dihydro derivatives, should be promising candidates or lead compounds for the development of novel acaricides for the effective control of animal or human acariasis.

Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

A novel and rare diverticulum-like adenomyosis: A case report.

INTRODUCTION: Cystic adenomyosis is a rare variant of adenomyosis, with only 90 reported cases found in the literature so far. Diverticulum-like adenomyosis is even more uncommon, with only one documented case to date. CASE PRESENTATION: We report the case of a 42-year-old asymptomatic woman who had an incidental finding of a parauterine cyst on an abdominal computed tomography scan. B-ultrasonography also revealed an endometriotic cyst. Further MRI revealed a cystic lesion measuring 7.6 × 6.1 × 7.7 cm that communicated with the uterine cavity through a tiny channel. The fluid in the cyst showed high signal intensity on T1-weighted image (T1WI), and the cyst wall showed a marked low signal intensity on T2-weighted image (T2WI). No other masses were found on either side. After obtaining informed consent, we performed a laparoscopic exploration on the patient, where it became apparent that the 7.6 × 6.1 × 7.7 cm cystic mass was located on the left uterine isthmus-the excised lesion contained chocolate-like fluid within a thickened wall. Pathological examination revealed typical endometrial glands and interstitial tissues in the cystic wall. DISCUSSION: Cystic adenomyosis is a rare benign lesion in women of reproductive age that is known to cause hypermenorrhea, dysmenorrhea, and abnormal uterine bleeding. Our case represents the second documented case of diverticulum-like adenomyosis. However, the patient in our case did not exhibit abnormal uterine bleeding or dysmenorrhea. One possible explanation for this finding is that the sinus tract was too small to cause blood influx into the uterine cavity. CONCLUSION: Our case report provides valuable insights for clinicians to better understand this uncommon disease and reduce the incidence of misdiagnosis.

The therapeutic effect of transcranial direct current stimulation combined with cognitive training on patients with unilateral neglect after stroke.

BACKGROUND: Unilateral neglect (UN) is a frequent cognitive disability following a stroke. Additional research is needed to determine the most effective cognitive rehabilitation techniques. OBJECTIVE: Based on the unilateral neglect neural network, we aim to explore the effect of a new model of transcranial direct current stimulation (tDCS) combined with cognitive training on stroke patients with unilateral neglect. METHODS: Thirty stroke patients with UN after stroke were randomly divided into three groups. All patients received cognitive training for UN and transcranial direct current stimulation with an anode placed on the corresponding part of the right hemisphere for 2 weeks. Treatment group A received multi-site tDCS from the inferior parietal lobule, middle temporal gyrus to prefrontal lobe. Group B received single-site tDCS of the inferior parietal lobule. The improvement of UN symptoms was evaluated by the scores of the Deviation index and Behavioral Inattention Test conventional tests. RESULTS: All groups showed improvements in all tests, and the scores of the treatment groups were statistically significant compared with the control group. CONCLUSION: Both single-site tDCS and multi-site tDCS have therapeutic effects on UN after stroke, and the difference in the therapeutic effects of the two modes still needs to be further explored.

Integrated analysis identities Rho GTPases related molecular map in patients with gastric carcinoma.

The intricate involvement of Rho GTPases in a multitude of human malignancies and their diverse array of biological functions has garnered substantial attention within the scientific community. However, their expression pattern and potential role in gastric cancer (GC) remain unclear. In this study, we successfully identified two distinct subtypes associated with Rho GTPase-related gene (RGG) through consensus clustering analysis, which exhibited significant disparities in overall survival and the tumor microenvironment. Subsequently, an extensively validated risk model termed RGGscore was meticulously constructed to prognosticate the outcomes of GC patients. This model was further assessed and validated using an external cohort. Notably, the high RGGscore group was indicative of a poorer prognosis. Univariate and multivariate Cox regression analyses unveiled the RGGscore as an autonomous prognostic indicator for GC patients. Subsequent external validation, utilizing two cohorts of patients who underwent immunotherapy, demonstrated a significant correlation between a low RGGscore and improved response to immunotherapy. Additionally, the expression levels of three genes associated with RGGscore were examined using qRT-PCR. Taken together, a pioneering RGGscore model has been successfully established, showcasing its potential efficacy in offering valuable therapeutic guidance for GC.

Analysis of the Risk Factors of Breast Cancer-Related Lymphedema and Construction and Evaluation of a Prediction Model.

Objective: The occurrence of breast cancer-related lymphedema (BCRL) in postoperative breast cancer survivors is described and the independent risk factors of BCRL are analyzed. A BCRL nomogram prediction model is constructed, and its effectiveness is evaluated to screen out high-risk patients with BCRL. Methods: A univariate analysis was carried out to determine the risk factors possibly related to BCRL, and a logistic regression analysis was utilized to determine the independent risk factors related to BCRL. A BCRL nomogram prediction model was built, and a nomogram was drawn by R software v4.1.0. The area under the curve (AUC) of the receiver operating characteristic (ROC) and the Hosmer-Lemeshow test were used to evaluate the efficacy of the constructed model to assess its clinical application value. Results: The risk factors independently associated with BCRL were body mass index (BMI), handedness on the operation side, no BCRL-related rehabilitation plan, axillary lymph node dissection (ALND), taxane-based chemotherapy, and radiotherapy (all p < 0.05). The BCRL nomogram prediction model was built on this basis, and the results of the efficacy evaluation showed a good fit: AUC = 0.952 (95% confidence interval: 0.930-0.973) for the ROC and χ2 = 6.963, p = 0.540 for the Hosmer-Lemeshow test. Conclusions: The risk factors for BCRL included higher BMI, handedness on the operation side, no BCRL-related rehabilitation plan, ALND, taxane-based chemotherapy, and radiotherapy. In addition, the BCRL nomogram prediction model accurately calculated the risk of possible BCRL among breast cancer survivors and effectively screened for high-risk patients with BCRL. Therefore, this prediction model can provide a basis for rehabilitation physicians and therapists to formulate early and individualized prevention and treatment programs.