Regional homogeneity alterations in patients with functional constipation and their associations with gene expression profiles.

Functional constipation, a highly prevalent functional gastrointestinal disorder, often accompanies by mental and psychological disorders. Previous neuroimaging studies have demonstrated brain functional and structural alterations in patients with functional constipation. However, little is known about whether and how regional homogeneity is altered in these patients. Moreover, the potential genetic mechanisms associated with these alterations remain largely unknown. The study included 73 patients with functional constipation and 68 healthy controls, and regional homogeneity comparison was conducted to identify the abnormal spontaneous brain activities in patients with functional constipation. Using Allen Human Brain Atlas, we further investigated gene expression profiles associated with regional homogeneity alterations in functional constipation patients with partial least squares regression analysis applied. Compared with healthy controls, functional constipation patients demonstrated significantly decreased regional homogeneity in both bilateral caudate nucleus, putamen, anterior insula, thalamus and right middle cingulate cortex, supplementary motor area, and increased regional homogeneity in the bilateral orbitofrontal cortex. Genes related to synaptic signaling, central nervous system development, fatty acid metabolism, and immunity were spatially correlated with abnormal regional homogeneity patterns. Our findings showed significant regional homogeneity alterations in functional constipation patients, and the changes may be caused by complex polygenetic and poly-pathway mechanisms, which provides a new perspective on functional constipation's pathophysiology.

Research and application of dual-camera dynamic in-line digital holography using a two-step phase-shifting cepstrum technique.

Due to limits in the properties of digital cameras, in-line digital holography is commonly used to take full advantage of the sampling space of the camera. To realize the dynamic high-resolution measurement of in-line digital holography, dual-camera dynamic in-line digital holography is proposed. By means of a two-step phase-shifting cepstrum algorithm and a dual-camera parallel phase-shifting recording optical path, the complex amplitude of the object wave can be reconstructed without its zero-order and conjugate terms. Meanwhile, a novel spherical wave interference calibration method is also developed for the dual-camera recording system, and image correction is carried out via rotation, translation, and diffraction, with an average error of phase correction of 0.1107 rad. Finally, the feasibility and effectiveness of the proposed technique is well demonstrated by a practical application of dynamic temperature field measurement in a transparent medium.

Risk factors for distal radius fracture in postmenopausal women.

PURPOSE: The aim of this work was to explore the risk factors for distal radius fracture in postmenopausal women. PATIENTS AND METHODS: A total of 611 postmenopausal women with distal radius fractures were included. In all, 173 patients with unstable distal radius fractures were included (unstable fracture group), while there were 438 patients with stable distal radius fractures (stable fracture group). The control group comprised 800 postmenopausal women with no fracture. A questionnaire survey was conducted. RESULTS: Compared with the control group, the 611 postmenopausal women with distal radius fractures had a higher body mass index (BMI). Advanced age and higher BMI were more common in the unstable fracture group than in the stable fracture group (P <0.05). A higher proportion of the 611 postmenopausal women with a distal radius fracture had fallen in the last 12 months than in the control group. Comorbidities and the frequency of falls in the last 12 months were higher in the unstable fracture group than in the stable fracture group (P < 0.05). A higher proportion of the control group was taking calcium supplements, while the proportion taking calcium supplementation in the unstable fracture group was lower than that in the stable fracture group (P < 0.05). Osteoporosis in the two fracture groups (P < 0.05) was significantly higher than in the control group and was the highest in the unstable fracture group (P < 0.05). CONCLUSIONS: In postmenopausal women, obesity, falls, unknown osteoporosis status, and osteoporosis are associated with high risk of distal radius fracture. If comorbidities and advanced age are also present, this group of persons may be at higher risk for unstable distal radius fractures.

Predicting Endothelium-Dependent Diastolic Function (FMD) and Its Correlation with the Degree of Coronary Artery Disease (CAD) and Plaque Vulnerability for Cardiovascular Events.

Objective: This study aims to investigate the correlation between vascular endothelium-dependent diastolic function (FMD) and the degree of coronary artery disease (CAD), plaque vulnerability, and its predictive value for cardiovascular events. Methods: Initially, patients (n=100) who were admitted from January 2020 to January 2021 and intended to undergo percutaneous coronary intervention (PCI) were selected. Further, FMD in all patients was determined before the procedure and divided into a high-FMD group (≥4.2%) and a low-FMD group (<4.2%). Further, the data of two groups, including general information, coronary artery lesions, and plaque fibrous cap, were compared. Finally, the relationship between FMD and the degree of coronary artery lesions and plaque vulnerability was analyzed. Results: No significant differences were observed concerning general information, number of coronary arteries-associated branches, lesion type, involvement of the left main stem (LM), the proportion of chronic occluded lesions (CTO), and lipid pool angle between the low-FMD group and the high-FMD group (P > 0.05). Nevertheless, the degree of stenosis of the lesions in the low-FMD group was significantly higher than in the high-FMD group (P < 0.05). In addition, the thickness of the fibrous cap was considerably lower than that in the high-FMD group (P < 0.05). Moreover, the incidence rate of TCFA was significantly higher than the high-FMD group (P < 0.05). The correlation analysis showed that FMD was significantly negatively correlated with the degree of coronary artery lesion stenosis and TCFA (P < 0.05) and positively correlated with the fibrous cap thickness (P < 0.05). Conclusion: Overall, a negative correlation between FMD and the degree of coronary stenosis, plaque vulnerability, and a high predictive value for post-PCI cardiovascular events suggested that FMD could be a critical diagnostic marker for CAD.

5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression.

Rationale: Serotonin (5-hydroxytryptamine, 5-HT) is generally considered to be involved in colitis-associated cancer (CAC), but previous research has yielded inconsistent results regarding the effect of 5-HT on CAC. 5-HT2B is one of the receptors of 5-HT, and the receptor is expressed in intestinal epithelial cells (IECs). However, the functions of 5-HT2B in CAC remain unclear. Our work demonstrates the variable functions of 5-HT/5-HT2B signaling in the initiation and progression of CAC in mice. Methods: We constructed two types of mutant mice homozygous knockout of Htr2b, the gene encoding 5-HT2B, in IECs (Htr2bΔIEC and Htr2bΔIEC-ER) to study the role of 5-HT2B in AOM/DSS-induced CAC model. Inflammation was measured using the body weight, colon length, and colitis severity score, and by histologic analysis of colon tissues. Tumor severity was assessed by tumor quantity, load, and histologic analysis of colon tumor tissues. Results: In Htr2bΔIEC mice, AOM/DSS induced an enhancement of colitis and tumor severity. This process was due to the inhibition of TGF-ß/SMAD signaling pathway and activation of IL-6/STAT3 signaling pathway. IL-6 antibody treatment reversed the stimulating effect of Htr2b deletion on tumorigenesis. However, tumor severity decreased in Htr2bΔIEC-ER mice injected with tamoxifen on day 48 of AOM/DSS treatment. Knockout Akt1 eliminated the function of 5-HT in promoting tumor cells. Conclusion: Our work elucidates 5-HT/5-HT2B/TGF-ß signaling as a critical tumor suppressing axis during CAC initiation but as a promoter of cancer progression in the late-stage of CAC. Our findings provide a new understanding of the role of 5-HT in the initiation and progression of CAC, offering a new perspective on the long-standing debate on whether the 5-HT signal promotes or inhibits tumors.

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A.

BACKGROUND: Anlotinib resistance is a challenge for advanced non-small cell lung cancer (NSCLC). Understanding the underlying mechanisms against anlotinib resistance is of great importance to improve prognosis and treatment of patients with advanced NSCLC. METHODS: RT-qPCR assay was used to assess the level of miR-136-5p in anlotinib-resistant NSCLC cells and exosomes derived from anlotinib-resistant NSCLC cells. In addition, miR-136-5p level in tumor tissues from patients who exhibited a poor response to anlotinib therapy and patients who were therapy naïve or patients who exhibited a positive response to anlotinib therapy was detected by RT-qPCR assay. RESULTS: In this study, we found that high levels of plasma exosomal miR-136-5p is correlated with clinically poor anlotinib response. In addition, anlotinib-resistant NSCLC cells promoted parental NSCLC cell proliferation via transferring functional miR-136-5p from anlotinib-resistant NSCLC cells to parental NSCLC cells via exosomes. Moreover, exosomal miR-136-5p could endow NSCLC cells with anlotinib resistance by targeting PPP2R2A, leading to the activation of Akt pathway. Furthermore, miR-136-5p antagomir packaging into anlotinib-resistant NSCLC cell-derived exosomes functionally restored NSCLC cell anlotinib sensitivity in vitro. Animal studies showed that A549/anlotinib cell-derived exosomal miR-136-5p agomir promoted A549 cell anlotinib resistance in vivo. CONCLUSION: Collectively, these findings indicated that anlotinib-resistant NSCLC cell-derived exosomal miR-136-5p confers anlotinib resistance in NSCLC cells by targeting PPP2R2A, indicating miR-136-5p may act as a potential biomarker for anlotinib response in NSCLC.

NEAT 1 knockdown enhances the sensitivity of human non-small-cell lung cancer cells to anlotinib.

Anlotinib treatment of non-small cell lung cancer (NSCLC) is hindered by drug insensitivity. Downregulation of long non-coding RNA (lncRNA) NEAT1 can suppress the proliferation and invasion by NSCLC cells. This study explored the role of the combination of anlotinib with NEAT1 knockdown on NSCLC progression. A549 and NCI-H1975 cells were used to evaluate the effect of anlotinib with NEAT 1 knockdown on NSCLC cells in vitro. The proliferation, invasion, migration, and apoptosis of NSCLC cells were evaluated with CCK-8 assays, EdU staining, Transwell assays, and flow cytometry. The antitumor effect of anlotinib with NEAT 1 knockdown was further explored in a mouse xenograft model. NEAT 1 knockdown enhanced the inhibitory effect of anlotinib on NSCLC cell proliferation, migration, and invasion. NEAT 1 knockdown also increased the pro-apoptotic and cytotoxic effects of anlotinib through downregulation of the Wnt/ß-catenin signaling pathway. The inhibitory effect of anlotinib on tumor growth was boosted in the presence of NEAT 1 knockdown in vivo. NEAT 1 knockdown promoted NSCLC cell sensitivity to anlotinib in vitro and in vivo. Thus, combined treatment of anlotinib with NEAT 1 knockdown may provide a new combined therapeutic approach for NSCLC patients.

Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer.

PURPOSE: This study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. MATERIALS AND METHODS: Lewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed. RESULTS: For the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen-specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved. CONCLUSION: Our results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

Spies in the minority game.

We study the effects of the existence of another type of agents, called spies, in the minority game (MG). Unlike the normal agents in the MG, the spies do not carry any strategy. Instead, they decide their action by scouting some normal agents and take the minority action of the spied group. For a few spies and when there is useful information in the normal agents' actions, the spies can avoid the crowd effect of the normal agents and win more readily. When information becomes less useful and when more spies are present, the spies' crowd effect hurts the success rate of the spies themselves, and the normal agents could have a higher success rate than the spies. More spies actually assist more normal agents to win, as the spies also provide more winning quotas. This leads to a nonmonotonic behavior in the total success rate of the population as a function of the fraction of spies.

Targeted deletion of the MLC1f/3f downstream enhancer results in precocious MLC expression and mesoderm ablation.

The expression of skeletal muscle contractile proteins is tightly regulated during embryonic development. In the mouse, the myosin light chain (MLC) 1f/3f gene locus is not activated until E9.5, exclusively in skeletal muscle precursor cells. A potent enhancer downstream of the MLC1f/3f locus confers correct temporal and spatial activation of linked reporter gene in transgenic mouse embryos. To examine roles of the MLC downstream enhancer (MLCE) in its native context of the MLC1f/3f gene locus, we eliminated a 1.5-kb DNA segment containing the enhancer from the mouse genome by targeted deletion, leaving no exogenous sequences at the deletion site. Mouse embryos homozygous for the MLCE deletion were smaller and developmentally delayed, formed no mesoderm by E7.5, and were resorbed almost completely at E8.5. In situ hybridization and RT-PCR analyses of affected mutant embryos at E7.5 revealed ectopic MLC transcripts, whose products would be predicted to interfere with a variety of nonmuscle cell functions determining differentiation of mesoderm. These results suggest that the MLC downstream enhancer and its flanking sequences include negative regulatory elements which block precocious activation of MLC expression in mesodermal precursors during a critical window of development, as well as positive elements which subsequently permit tissue-restricted MLC transcription in differentiating skeletal muscles.