Intermedin (adrenomedullin 2) promotes breast cancer metastasis via Src/c-Myc-mediated ribosome production and protein translation.

PURPOSE: Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD, also known as Adrenomedullin 2, ADM2) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. METHODS: Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting, immunoprecipitation, and animal tumor models were used. RESULTS: IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. CONCLUSION: These results suggest that IMD may be a novel target for the treatment of breast cancer.

Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.

BACKGROUND: Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this "sunitinib resistance" remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. METHODS: 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated ß-galactosidase (SA-ß-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of "pre-metastatic niche" which promotes MBC to metastasize to the lungs. RESULTS: We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a "pre-metastatic niche"-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. CONCLUSION: Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib "correctly" playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.

Shade Effects on Peanut Yield Associate with Physiological and Expressional Regulation on Photosynthesis and Sucrose Metabolism.

Intercropping improves land utilization with more crops grown together; however, shorter crops in intercropping experience stress, being shaded by the taller crops. Systematic changes in phenotype, physiology, yield, and gene regulation under shade stress in peanut are largely unknown, although shade responses have been well analyzed in model plants. We exposed peanut plants to simulated 40% and 80% shade for 15 and 30 days at the seedling stage, flowering stage, and both stages. Shade caused the increased elongation growth of the main stem, internode, and leaf, and elongation was positively associated with auxin levels. Shade stress reduced peanut yield. Further comparative RNA-seq analyses revealed expressional changes in many metabolism pathways and common core sets of expressional regulations in all shade treatments. Expressional downregulation of most genes for light-harvesting and photosynthesis agreed with the observed decreased parameters of photosynthesis processes. Other major regulations included expressional downregulation of most core genes in the sucrose and starch metabolism, and growth-promoting genes in plant hormone signal pathways. Together, the results advance our understanding of physiological and molecular regulation in shade avoidance in peanut, which could guide the breeding designing in the intercropping system.

Identifying the Genes Regulated by AtWRKY6 Using Comparative Transcript and Proteomic Analysis under Phosphorus Deficiency.

Phosphorus (P) is an important mineral nutrient for plant growth and development. Overexpressing AtWRKY6 (35S:WRKY6-9) was more sensitive and wrky6 (wrky6-1) was more resistant under low Pi conditions. To better understand the function of AtWRKY6 under low phosphate stress conditions, we applied two-dimensional gel electrophoresis (2-DE) to analyse differentially expressed proteins in the shoots and roots between wild type, 35S:WRKY6-9 and wrky6-1 after phosphorus deficiency treatment for three days. The results showed 88 differentially abundant protein spots, which were identified between the shoots and roots of 35S:WRKY6-9 and wrky6-1 plants. In addition, 59 differentially expressed proteins were identified in the leaves and roots of 35S:WRKY6-9 plants. After analysis, 9 genes with W-box elements in their promoter sequences were identified in the leaves, while 6 genes with W-box elements in their promoter sequences were identified in the roots. A total of 8 genes were identified as potential target genes according to the quantitative PCR (QPCR) and two dimension difference gel electrophoresis, (2D-DIGE) results, including ATP synthase, gln synthetase, nitrilase, 14-3-3 protein, carbonic anhydrases 2, and tryptophan synthase. These results provide important information concerning the AtWRKY6 regulation network and reveal potential vital target genes of AtWRKY6 under low phosphorus stress. two dimension difference gel electrophoresis, 2D-DIGE.

Prevention of propofol injection-related pain using pretreatment transcutaneous electrical acupoint stimulation

Background/aim: This study aimed to study the effect of pretreatment transcutaneous electrical acupoint stimulation (TEAS) in preventing propofol injection-related pain. Materials and methods: A total of 360 patients who were to undergo elective hysteroscopy surgery were randomly divided into the following three groups of 120 patients each: control (Group C), sham TEAS (Group F), and TEAS (Group T). Patients in Group C did not undergo any treatment before surgery; 30 min before the induction of anesthesia, patients in Groups F and T underwent electrical stimulation of the bilateral LI4-PC6 acupoint. Patients in Group F were subjected to 'feeling flow', while those in Group T were subjected to 'tolerance flow.' The stimulation frequency was 2/100 Hz and the duration of stimulation was 30 min. After the induction of anesthesia, propofol injection-related pain scores, hemodynamic parameters, and adverse reactions were recorded. Results: Of the 360 patients, 324 completed the study. There were significant differences among the groups in terms of the incidence of moderate-to-severe pain. In terms of the four-point scaling method, the end of the radial vein, the cubital vein, and the 'back of the hand' vein differed significantly among the three groups (P = 0.05). Finally, using a numerical rating scale, a significant difference was observed among the three groups in terms of the pain scores in the different veins. Conclusions: Pretreatment TEAS effectively reduces the incidence and severity of propofol injection-related pain, the incidence of postoperative nausea and vomiting, and patient postoperative pain scores.

Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway.

AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R.

AKI after conditional and kidney-specific knockdown of stanniocalcin-1.

Stanniocalcin-1 is an intracrine protein; it binds to the cell surface, is internalized to the mitochondria, and diminishes superoxide generation through induction of uncoupling proteins. In vitro, stanniocalcin-1 inhibits macrophages and preserves endothelial barrier function, and transgenic overexpression of stanniocalcin-1 in mice protects against ischemia-reperfusion kidney injury. We sought to determine the kidney phenotype after kidney endothelium-specific expression of stanniocalcin-1 small hairpin RNA (shRNA). We generated transgenic mice that express stanniocalcin-1 shRNA or scrambled shRNA upon removal of a floxed reporter (phosphoglycerate kinase-driven enhanced green fluorescent protein) and used ultrasound microbubbles to deliver tyrosine kinase receptor-2 promoter-driven Cre to the kidney to permit kidney endothelium-specific shRNA expression. Stanniocalcin-1 mRNA and protein were expressed throughout the kidney in wild-type mice. Delivery of tyrosine kinase receptor-2 promoter-driven Cre to stanniocalcin-1 shRNA transgenic kidneys diminished the expression of stanniocalcin-1 mRNA and protein throughout the kidneys. Stanniocalcin-1 mRNA and protein expression did not change in similarly treated scrambled shRNA transgenic kidneys, and we observed no Cre protein expression in cultured and tyrosine kinase receptor-2 promoter-driven Cre-transfected proximal tubule cells, suggesting that knockdown of stanniocalcin-1 in epithelial cells in vivo may result from stanniocalcin-1 shRNA transfer from endothelial cells to epithelial cells. Kidney-specific knockdown of stanniocalcin-1 led to severe proximal tubule injury characterized by vacuolization, decreased uncoupling of protein-2 expression, greater generation of superoxide, activation of the unfolded protein response, initiation of autophagy, cell apoptosis, and kidney failure. Our observations suggest that stanniocalcin-1 is critical for tubular epithelial survival under physiologic conditions.

In vivo histological evaluation of fractional ablative microplasma radio frequency technology using a roller tip: an animal study.

The aim of the present study is to investigate the histological characteristics associated with microplasma radio frequency (MPRF) technology in an animal study using different treatment parameters. Two white piglets, aged 6 months, received MPRF treatment using a roller tip; the treatment site was located on the dorsal skin. Four groups of parameters were adopted regarding the performance of the treatment at four zones on the dorsum. Immediately, at 7 days and at 1, 3, and 6 months posttreatment, we observed the healing process and obtained specimens from each treatment zone. Hematoxylin and eosin and Masson stainings of histological sections were performed to assess the degree of tissue injury, the heat effect, the healing process, and neocollagenesis. Heat shock protein (HSP) was also detected using immunohistochemistry. The roller tip generated a fractional treatment, which had a general trend involving an increase in depth and width with increasing pulse energy and decreasing sliding speed. During the wound healing process, dermal neocollagenesis was stimulated, remodeled, and matured gradually. The expression of HSP47 and HPS72 was elevated in the dermis surrounding the microlesions after treatment; it peaked at 1 month posttreatment and became diffuse in the dermis. MPRF is a promising fractional skin resurfacing technique. The roller tip can be used with low risk in the entire treatment zone with rapid healing. An appropriate treatment regimen should be chosen to guarantee therapeutic efficacy and safety.

Melasma-like hyperpigmentation induced by intense pulsed light treatment in Chinese individuals.

BACKGROUND: Symmetric melasma-like hyperpigmentation (MLH) has been identified in several patients following intense pulsed laser (IPL) treatment sessions. These patients exhibited no typical signs of melasma prior to IPL therapy. OBJECTIVES: To investigate the incidence of MLH in Chinese patients receiving IPL treatment and to discuss potential causative factors for this condition and potential preventive measures. METHODS: 675 patients with skin types III-IV who were treated with IPL were retrospectively studied. RESULTS: MLH was noted in 20 cases (20/675, 2.96%) within 3 months following IPL treatment session. All the patients had a pigmentary disorder prior to their IPL treatment s, the most common being photoaging or the presence of freckles. The lesions seen in 14 of the 20 cases (14/20, 70%) were multiple pigmented lesions along a wide distribution of the skin with undefined borders. Six of the cases had a strong post-treatment local reaction which also may have contributed to the MLH. In 2 cases, the original skin concern became worse following the IPL therapy and may have been a reason for the formation of MLH. In 6 cases, we noted that these individuals were not regular users of sunscreen post-therapy, despite our recommendations, which also may have contributed to the formation of their MLH. CONCLUSIONS: The adverse event and formation of IPL-induced MLH seen in Chinese individuals does have a relationship to a primary pigmentary lesion(s) and trend toward melasma prior to the IPL therapy. The IPL parameters chosen should be suitable for the skin condition being treated and should follow the recommendations of the manufacturer's default settings prior to undertaking the treatments. Post-therapy skin care and the use of appropriate sun protection are also important factors in preventing MLH.

Comparison of Different Intraocular Lens Power Calculation Formulas in Eyes with Primary Angle Closure.

PURPOSE: To compare the accuracy of six intraocular lens power calculation formulas, Barrett Universal Ⅱ (BU Ⅱ), Haigis, Hoffer QST, HolladayⅠ, Kane and SRK/T, in eyes with primary angle closure disease (PACD). SETTING: Xiamen University Affiliated Xiamen Eye center, Xiamen, Fujian, China. DESIGN: Prospective case series. METHODS: Patients diagnosed with PACD and cataract and met the indication for cataract surgery were enrolled in the study. Six intraocular lens power calculation formulas were used to calculate refractive diopter. Percentage of eyes with prediction error (PE) within ±0.50D, and the median absolute prediction error (MedAE) were compared to determine the accuracy of different formulas in PACD patients. Subgroup analysis was performed according to axial length (AL). The accuracy of Barrett Universal Ⅱ was compared between PACD patients and age-related cataract patients. RESULTS: 105 patients (105 eyes) with PACD and 35 patients (35 eyes) with age-related cataract were enrolled in the study. Haigis, Kane and Barrett Universal Ⅱ formula achieved a comparable outcome and outperformed over the other three formulas in PACD patients. Subgroup analysis showed that the group with long AL has lower values of MedAE. PE was significantly positively correlated with AL and negatively correlated with relative lens position (RLP) when calculated use Barrett Universal Ⅱ and Kane. CONCLUSIONS: Haigis, Kane and Barrett Universal Ⅱ formula achieved a comparable outcome and outperformed over the other three formulas in PACD patients.

A new modality for fractional CO2 laser resurfacing for acne scars in Asians.

Since fractional photothermolysis was first introduced in 2004, it has become a very popular procedure, especially with more and more ablative fractional laser systems and treatments. Fractional ablative laser has been shown to be very effective; however, it does not reach the efficacy of conventional ablative laser treatments in most instances. In an attempt order to make the fractional CO2 laser treatment more efficacious and safe, we combined both the conventional CO2 laser and the fractional CO2 laser to treat acne scars. We report our experience with this new modality. A total of 44 Chinese patients with facial acne scars and skin type IV were included in this study. Each patient received a minimum of two treatment sessions. For each laser session, both the conventional CO2 laser treatment and the DeepFX laser treatment were focused on treating the scar areas only. Following this technique, the more superficialf ActiveFX fractional CO2 laser was performed to the entire face. The efficacy of the procedure was evaluated 3 months after the final laser treatment. The improvement in acne scars and the overall skin texture change were assessed by photographic evaluation using the following scales: ≤25 % (mild), 26-50 % (moderate), 51-75 % (marked), and >75 % (excellent). Side effects from this therapy were mild to moderate. Two cases of HSV outbreak were noted; they were treated and resolved without adverse sequelae. Post-laser erythema was resolved within 1 month in one half of the patients. Prolonged erythema (≤3 months) was noted in 12(27 %) cases. Temporary post-inflammatory hyperpigmentation (PIH; ≤1 month) was seen in approximately 50 % of the patients. PIH (≤3 months) was noted in four cases (9 %). Sixty-four percent of the patients (28/44) had an improvement of between 51 and 75 % after more than two sessions of the combination of laser treatments. The average overall improvement was 52.50 % (±12.25 %). Three patients achieved improvement of >75 %. This new modality of ablative conventional CO2 laser therapy with fractional CO2 laser resurfacing was shown to be safe and efficacious in the treatment of acne scars in Asian patients. It did not increase the risk of PIH compared to other reports of laser therapy and PIH. It is the hope that future study with combination therapy will further enhance the clinical results and thus lessen potential adverse events.

[Effect of transcutaneous acupoint electrical stimulation on stress in brain surgery with propofol target controlled infusion general anesthesia].

OBJECTIVE: To study the effect of transcutaneous acupoint electrical stimulation (TAES) on stress who received propofol target controlled infusion (TCI) general anesthesia in brain surgery. METHODS: Totally 40 neurosurgical patients of I-II grade (ASA grading) in our hospital were randomly divided into the TAES group (T group) and the control group (C group), 20 in each group. All patients received intravenous anesthesia by propofol TCI. The TAES intervention was adopted in those of C group. Electrodes were only applied to corresponding acupoints without electric stimulation. The arterial blood was withdrawn before TAES (T0), before anesthesia (T1), before cutting (T2), at 60 min after encephalic incision (T3), immediately after incisions suture (T4), at about 10 min after removing tracheal catheters (T5) to detect beta-endorphin (beta-EP), cortisol (COR), adrenalin (E), blood sugar (Glu). The heart rate (HR) and mean arterial pressure (MAP) were recorded. The total time of surgery, anesthesia, total infusion amount, blood lost amount, and urine amount were recorded. RESULTS: In both groups, HR, MAP, COR, and E at T2 were lower than at T0 significantly (P < 0.05). beta-EP in group C at T2 was lower than at T0 significantly (P < 0.05). HR, MAP, COR in group C at T3 were higher than at T0 significantly (P < 0.05). HR, MAP, E, and Glu in group C at T4 and T5 were higher than at T0 significantly (P < 0.05). beta-EP in group T at T1 and T3 were higher than at T0 significantly (P < 0.05). HR, COR, E, Glu, and beta-EP in group T at T4 and T5 were higher than at T0 significantly (P < 0.05). Between groups, comparing with the time point T0, the amplitude of variation of MAP, COR, and E at T2 in group C were significantly less (P < 0.05); the amplitude of variation of HR, MAP, and COR at T3 in group C were less significantly, when compared with the time point T0 (P < 0.05); the amplitude of variation of HR, MAP, COR, E, and Glu at T4 and T5 in group C were less significantly, when compared with the time point T0 (P < 0.05). When comparing the two groups, the amplitude of variation of beta-EP at time points of T1, T3, T4, and T5 in group T were larger than at T0 in group C (P < 0.05). CONCLUSION: TAES could reduce stress and stabilize the internal environment when used in brain surgery with propofol TCI general anesthesia.

From bench to bedside: the history and progress of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with snRNP biogenesis machinery.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-specific gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identified a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the final snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the first characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.

Influence of Pilocarpine Eyedrops on the Ocular Biometric Parameters and Intraocular Lens Power Calculation.

Objective: To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power calculation in patients with primary angle-closure glaucoma (PACG). Methods: Twenty-two PACG patients and fifteen normal subjects were enrolled. Ocular biometric parameters including the axial length (AL), anterior chamber depth (ACD), lens thickness (LT), mean keratometry (Km), and white-to-white distance (WTW) were measured by using a Lenstar LS 900 device before and at least 30 minutes after instillation of 2% pilocarpine eyedrops. Lens position (LP) was calculated, and the IOL power prediction based on the ocular biometric parameters was performed using the Barrett Universal II, Haigis, Hoffer Q, Holladay I, or SRK/T formulas before and after pilocarpine application. Results: In both PACG and normal groups, pilocarpine eyedrops induced a slight but statistically significant increase in the mean AL (0.01 mm for both groups) and mean LT (0.02 mm and 0.03 mm, respectively) but a significant decrease in the mean ACD (0.03 mm and 0.05 mm, respectively) and mean LP (0.02 mm and 0.04 mm, respectively). No significant changes in the mean Km and WTW were noticed in both groups. In addition, the IOL power calculation revealed insignificant changes before and after the pilocarpine instillation in both groups, regardless of the formula used. Conclusions: Pilocarpine eyedrops can induce slight changes in the ocular biometric parameters including the AL, ACD, LT, and LP. However, these parameter changes will not result in a significant difference in IOL power estimation.

Intermedin (adrenomedullin 2) plays a protective role in sepsis by regulating T- and B-cell proliferation and activity.

BACKGROUND: Sepsis is the major cause of death in intensive care units. We previously found that intermedin (IMD), a calcitonin family peptide, can protect against sepsis by dynamically repairing vascular endothelial junctions and can ameliorate the inflammatory response by inhibiting the infiltration of macrophages in peripheral tissues. The effects of IMD on inflammatory and immune responses indicate that IMD may play a role in immunity. However, whether IMD affects immune cell development, differentiation and response to infection remains unclear. METHODS: IMD-knockout (Adm2-/-) mice were generated in our previous work. Wild-type and IMD-KO mice were subjected to sham or cecal ligation and puncture (CLP) surgery, and bone marrow cells were obtained for RNA sequencing (RNA-Seq) analysis. The RNA-Seq results were verified by real-time RT-PCR. The effect of IMD KO or IMD rescue on the septic mice was explored using mild and severe infection models induced by CLP surgery at different levels of severity, and the survival outcomes were analyzed using Kaplan-Meier curves and the log-rank test. The mechanism underlying the effects of IMD in T/B cell proliferation and differentiation were investigated by PCR, Western blot (WB), and cell proliferation assays and flow cytometry analysis. RESULTS: RNA-Seq showed that IMD-KO mice exhibited a primary immunosuppression phenotype characterized by a marked decrease in the expression of T- and B-cell function-related genes. This immunosuppression made the IMD-KO mice vulnerable to pathogenic invasion, and even mild infection killed nearly half of the IMD-KO mice. Supplementation with the IMD peptide restored the expression of T/B-cell-related genes and significantly reduced the mortality rate of the IMD-KO mice. IMD is likely to directly promote T- and B-cell proliferation through ERK1/2 phosphorylation, stimulate T-cell differentiation via Ilr7/Rag1/2-controled T cell receptor (TCR) recombination, and activate B cells via Pax5, a transcription factor that activates at least 170 genes needed for B-cell functions. CONCLUSION: Together with previous findings, our results indicate that IMD may play a protective role in sepsis via three mechanisms: protecting the vascular endothelium, reducing the inflammatory response, and activating T/B-cell proliferation and differentiation. Our study may provide the first identification of IMD as a calcitonin peptide that plays an important role in the adaptive immune response by activating T/B cells and provides translational opportunities for the design of immunotherapies for sepsis and other diseases associated with primary immunodeficiency.

The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-specific gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identified a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the final snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the first characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.

Transcutaneous electrical acupoint stimulation in adult patients receiving gastrectomy/colorectal resection: A randomized controlled trial.

BACKGROUND: Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear. AIM: To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection. METHODS: Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound. RESULTS: In total, 441 patients were randomized; 405 patients (58.4 ± 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups (P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups (P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 ± 1.2) than in the sham stimulation group (1.7 ± 1.1; P = 0.04). Surgical complications did not differ among the four groups. CONCLUSION: TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.

Overexpression of stanniocalcin-1 inhibits reactive oxygen species and renal ischemia/reperfusion injury in mice.

Reactive oxygen species, endothelial dysfunction, inflammation, and mitogen-activated protein kinases have important roles in the pathogenesis of ischemia/reperfusion kidney injury. Stanniocalcin-1 (STC1) suppresses superoxide generation in many systems through the induction of mitochondrial uncoupling proteins and blocks the cytokine-induced rise in endothelial permeability. Here we tested whether transgenic overexpression of STC1 protects from bilateral ischemia/reperfusion kidney injury. This injury in wild-type mice caused a halving of the creatinine clearance; severe tubular vacuolization and cast formation; increased infiltration of macrophages and T cells; higher vascular permeability; greater production of superoxide and hydrogen peroxide; and higher ratio of activated extracellular regulated kinase/activated Jun-N-terminal kinase and p38, all compared to sham-treated controls. Mice transgenic for human STC1 expression, however, had resistance to equivalent ischemia/reperfusion injury indicated as no significant change from controls in any of these parameters. Tubular epithelial cells in transgenic mice expressed higher mitochondrial uncoupling protein 2 and lower superoxide generation. Pre-treatment of transgenic mice with paraquat, a generator of reactive oxygen species, before injury restored the susceptibility to ischemia/reperfusion kidney injury, suggesting that STC1 protects by an anti-oxidant mechanism. Thus, STC1 may be a therapeutic target for ischemia/reperfusion kidney injury.

Clinical Study on the Combination of Transcutaneous Electrical Acupoint Stimulation and Lidocaine for Preventing Propofol Injection Pain.

Purpose: Propofol is a widely used intravenous anesthetic in clinical practice. Lidocaine pretreatment is currently the most commonly used method to reduce the pain of propofol injection. However, propofol injection pain has not been eliminated and its incidence remains high. Transcutaneous electrical acupoint stimulation is a green therapy that combines transcutaneous electrical nerve stimulation therapy with the traditional acupuncture therapy of our motherland. This study investigated the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) combined with lidocaine in preventing propofol injection pain and determined whether it can reduce postoperative complications and promote rapid postoperative recovery of patients. Patients and Methods: A total of 220 women scheduled to undergo hysteroscopic surgery were enrolled in the study. The included patients were randomly divided into four groups of 55 patients each: normal saline group (group K), lidocaine group (group L), TEAS group (group T), and lidocaine + TEAS group (group L + T). Patients in group K received 2 mL saline (0.9% NaCl) pre-injection before anesthesia induction. Group L received 40 mg lidocaine pre-injection (2 mL of 2% lidocaine) before anesthesia induction. Group T received 30 min of transcutaneous electrical stimulation at bilateral election Hegu, Neiguan, and 2 mL saline pre-injections before anesthesia induction. Group L + T received TEAS and lidocaine pre-injection. Results: The VAS scores and the four-point verbal rating scale of propofol injection were significantly different among the four groups. The prevalence of nausea, vomiting, abdominal pain, and abdominal distension after surgery among the four groups were statistically different. The bleeding days after surgery were significantly different among the four groups. Conclusion: TEAS combined with lidocaine pre-injection reduced the incidence of propofol injection pain and significantly reduced patients' pain levels compared with single lidocaine pre-injection. TEAS can also reduce the incidence of postoperative nausea and vomiting, abdominal pain, and abdominal distension, shorten postoperative bleeding days, and accelerate the postoperative recovery of patients.