Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment: A Case report.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the survival of patients with Epidermal growth factor receptor (EGFR) sensitive mutations in non-small cell lung cancer (NSCLC). CASE SUMMARY: A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment. Secondary pathological tissue biopsy confirmed squamous cell carcinoma (SCC) transformation. Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time, while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC. Notably, EGFR-TKIs resistance includes primary and acquired. Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs, with SCC transformation being relatively rare. Our results provide more detailed results of the patient's diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma. CONCLUSION: Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

A structural optimized fluorescent probe for monitoring hydrogen sulfide in cells and zebrafish.

In this work, we reported a fluorescent probe Fur-SH, a derivative of benzofuranone, which was used to detect H2S in living cells and zebrafish. Based on the three structural characteristics of the probe, the effects of different structural modifications on the optical properties of the fluorophore were compared. Then, the fluorophore Fur-OH was synthesized by modifying diethylamino group with benzofuranone as the main skeleton. With 2,4-dinitrofluorobenzene as the recognition group and diethylamino as the electron donor, the push-pull electron effect occurred with nitro group, which led to fluorescence quenching, and an openable fluorescent probe Fur-SH was formed. The probe Fur-SH (λex = 510 nm; λem = 570 nm) had the advantages of smaller full width at half maxima, rapid response (5 min) and wide pH window. The quantitative properties of the probe were excellent, reaching saturation at 50 equivalents of substrate. The probe Fur-SH showed high sensitivity to H2S, with LOD of 48.9 nM and LOQ of 50 nM. At present, the probe Fur-SH had been applied to fluorescence imaging of MCF-7 cells and zebrafish. By comparing the effects of different structures on the optical properties of fluorophores, this work was expected to be helpful to the development of fluorescent probes in the future.

Comparison of the efficacy of different frequency electroacupuncture in the treatment of polycystic ovary syndrome patients with abdominal obesity. / ä¸åŒé¢‘çŽ‡ç”µé’ˆæ²»ç–—è ¹éƒ¨è‚¥èƒ–åž‹å¤šå›Šåµå·¢ç»¼åˆå¾çš„ç–—æ•ˆæ¯”è¾ƒ.

OBJECTIVES: To compare the effects of 2 Hz continuous wave and 2 Hz/100 Hz dilatational wave setting in electroacupuncture(EA) on ovulation frequency, hormone levels, body fat parameters, quality of life and depression-anxiety level in polycystic ovary syndrome (PCOS) patients with abdominal obesity. METHODS: PCOS patients with abdominal obesity were randomly divided into low-frequency group (n=29) and dilatational wave group (n=29). Patients in both groups were treated with "Tongtiaodaimai" (regulating Dai Meridian) acupuncture therapy, and EA was applied to bilateral Daimai (GB26), Tianshu (ST25), Shenshu (BL23) and Ciliao (BL32). The low-frequency group received EA using a continuous wave at a frequency of 2 Hz, while the dilatational wave group received dilatational wave at a frequency of 2 Hz/100 Hz. Both groups received treatment for 30 min each time, 3 times per week for 12 consecutive weeks. Ovulation frequency was calculated according to the ovulation cycle. The contents of serum anti-Mullerian hormone (AMH) and sex hormone binding globulin (SHBG) were detected with electrochemiluminescence method. Body weight (BW) and waist circumference (WC) were measured, and body mass index (BMI) and waist-height ratio (WHtR) were calculated. PCOS questionnaire (Chi-PCOSQ), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were evaluated. RESULTS: Compared with before treatment, both the low-frequency group and the dilatational wave group showed an increase in ovulation frequency (P<0.01, P<0.05), and a decrease in BW, BMI, WC, WHtR, and SDS score (P<0.01, P<0.05)；the dilatational wave group showed decreased serum AMH contents (P<0.05) and increased serum SHBG contents (P<0.05), the scores related to acne, fatigue, and dysmenorrhea in the Chi-PCOSQ increased (P<0.01, P<0.05). Compared with the low-frequency group, the dilatational wave group showed a reduction (P<0.05) in WC after treatment. CONCLUSIONS: 2 Hz/100 Hz dilatational wave EA is equally effective as 2 Hz low-frequency EA in improving ovulation frequency. In terms of reducing WC in abdominal obesity type PCOS patients, 2 Hz/100 Hz dilatational wave EA is superior to 2 Hz low-frequency EA. 2 Hz/100 Hz dilatational wave EA can decrease serum AMH, increase serum SHBG, and improve symptoms of acne, fatigue, and dysmenorrhea.

NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-ß in endometrial cancer.

OBJECTIVES: NLR family CARD domain containing 5 (NLRC5) could promote major histocompatibility complex class I (MHC-I)-dependent CD8+ T cell-mediated anticancer immunity. In this study, the immunosurveillance role and underlying mechanisms of NLRC5 in endometrial cancer (EC) were characterized. METHODS: CD8+ T cells were separated from healthy women's peripheral blood by using magnetic beads. The effect of NLRC5 and interferon-ß (IFN-ß) on immunosurveillance of EC were examined through a mouse tumor model and a CD8+ T cell-EC cell coculture system after NLRC5 overexpression and IFN-ß overexpression or depletion. The effect of NLRC5 on IFN-ß expression was examined with gain- and loss-of-function experiments. RESULTS: NLRC5 overexpression in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation and migration and promoted EC cell apoptosis and CD8+ T cell proliferation. In vivo, NLRC5 overexpression increased the proportion of CD8+ T cells and inhibited EC progression. Furthermore, IFN-ß overexpression in the EC cell and CD8+ T cell coculture system activated CD8+ T cell proliferation; however, genetic depletion of IFN-ß exerted the opposite effects. In addition, NLRC5 could negatively regulate IFN-ß expression in EC cells. Mechanistically, NLRC5 potentiated the antitumor responses of CD8+ T cells to EC by activating IFN-ß. CONCLUSIONS: Taken together, our findings demonstrated that NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-ß in EC, suggesting that genetically escalated NLRC5 and IFN-ß may act as potential candidates for the clinical translation of adjuvant immunotherapies to patients with EC.

Characteristics and management of vascular compromise after an organ transplantation surgery of the head and neck region: Analysis of 220 submandibular glands with autologous transplantation.

BACKGROUND: Microvascular submandibular gland transplantation (SMGT) for severe dry eye disease (DED) has rarely been reported in the literature. The aim of this study was to report a case series of SMGT with the special focus on monitoring and management of postoperative vascular compromise. METHODS: Using a retrospective single-cohort study design, the investigators enrolled a sample of DED patients undergoing SMGT in a Chinese university hospital during 1999 and 2021. The main outcomes were baseline and surgical data, post-operative manifestations, and surgical results. Descriptive, uni- and bivariate statistics were computed with the significant P < 0.05. RESULTS: During the study period, 220 DED patients (55.9% female) with a mean age of 32.66±14.47 years underwent SMGT. Vascular compromises occurred in 27 grafted glands (12.3%; 22 venous compromises and 5 arterial compromises) at a median of 27 h(range, 3.3 to 288 h) after surgery. Harden texture and swelling of the covering skin flap of the donor indicated venous compromises, while some specific sign was absent for arterial compromise. The accompanying vein of the facial artery (FAV) as a donor's vein was associated with less vascular compromise compared to the anterior facial vein (AFV). Timely reexploration was performed in 25 glands (92.6%), with a salvaged rate of 48%, and more venous compromises were salvaged compared to artery compromises (54.6% vs. 0%, P = 0.047). Temporary hypersecretion on postoperative 2-5 days was noticed in the grafted glands with no or salvaged vascular compromise (Schirmer's test, 35 mm/5 min and 37 mm/5 min, respectively, P = 0.749), while they were absent for the 15 surgically failed grands (Schirmer's test 0 mm/5 min, P<0.001). CONCLUSIONS: Vascular compromise appears to be a common complication of SMGT. Postoperative hypersecretion of the grafted glands may indicate good circulation, and the use of FAV as the donor's vein could help to decrease the risk of vascular compromise.

A case report of Trousseau syndrome.

RATIONALE: In 1865, Trousseau first discovered pulmonary embolism caused by multiple venous thrombosis in patients with gastric cancer, and later all clinical manifestations of malignant patients during pathogenesis due to abnormal coagulation and fibrinolysis were referred to collectively as Trousseau syndrome. Trousseau syndrome is not a benign thrombophlebitis, and when diagnosed it requires immediate treatment. The survival rate over 1 year is only 12%. Stroke in cancer patients has distinct characteristics different from conventional stroke and has higher mortality. PATIENT CONCERNS: A 54-year-old female presented to the Department of Otolaryngology with recurrent right nasal bleeding for 4 days. After surgery, the patient experienced 7 different cerebral infarction courses. Finally died of brain herniation. DIAGNOSIS: The specific abnormal laboratory index is the increase of D-dimer, suggesting the hypercoagulation state. The patient developed multiple cerebral infarction, myocardial injury, renal infarction, splenic infarction, and lower extremity arterial thrombosis, and finally was diagnosed Trousseau syndrome. INTERVENTIONS: In the treatment, aspirin and atorvastatin were selected, but it did not work very well. D-dimer were high, we used low molecular weight heparin, and D-dimer decreased significantly. OUTCOMES: Finally the patient died of brain herniation. CONCLUSION: The raise of D-dimer and typical magnetic resonance imaging manifestation which provides a greater basis for diagnosis. The specific abnormal laboratory index is the increase of D-dimer, which provides direction for treatment and helps to evaluate treatment effect.

Pattern-recognition receptors in endometriosis: A narrative review.

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane-bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis-associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, targeting PRRs and their new synthetic ligands may provide new therapeutic options for treating endometriosis.

METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer.

BACKGROUND: N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism. METHODS: We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8+ T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC. RESULTS: METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8+ T-cell proliferation, and in vivo, METTL3 overexpression increased CD8+ T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2). CONCLUSIONS: Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.

Myocardial Perfusion Imaging by Cardiovascular Magnetic Resonance: Research Progress and Current Implementation.

Cardiovascular diseases pose a significant health and economic burden worldwide, with coronary artery disease still recognized as a major problem. It is closely associated with hypertension, diabetes, obesity, smoking, lack of exercise, poor diet, and excessive alcohol consumption, which may lead to macro- and microvascular abnormalities in the heart. Coronary artery stenosis reduces the local supply of oxygen and nutrients to the myocardium and results in reduced levels of myocardial perfusion, which can lead to more severe conditions and irreversible damage to myocardial tissues. Therefore, accurate evaluation of myocardial perfusion abnormalities in patients with these risk factors is critical. As technology advances, magnetic resonance myocardial perfusion imaging has become more accurate at evaluating the myocardial microcirculation and has shown a powerful ability to detect myocardial ischemia. The purpose of this review is to summarize the principle, research progress of acquisition and analysis, and clinical implementation of cardiovascular magnetic resonance (CMR) myocardial perfusion imaging.

A highly chromogenic selective Rhodamine-chloride-based fluorescence probe activated by cysteine and application in living cells and zebrafish.

Cysteine (Cys), one of the biological thiols, which plays critical roles in biological system regulating the balance of redox homeostasis. In order to monitor the level of Cys in the living cells and organisms, a chromogenic fluorescence probe Rhocl-Cys based on Rhodamine chloride exhibiting the preferable performance of fluorescence turn-on response reacting with Cys was presented. Rhocl-Cys responded rapidly to Cys within 20 min, and had stable fluorescence intensity within pH 6.0-10.0, high selectivity towards Cys and the anti-inference capability with a low detection limit of 0.80 µM. In particular, Rhocl-Cys could qualitatively and quantitatively monitor the level of endogenous and exogenous Cys in living cells and successfully apply to zebrafish detecting Cys. Therefore, these results might further provide the basis exploring the role of Cys in biological system and facilitate as clinical diagnostic molecular tools.

NLRC5 Might Promote Endometrial Cancer Progression by Inducing PD-L1 Expression.

Aims: The NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5 (NLRC5) was dysregulated in endometrial cancer (EC). However, the potential regulatory mechanisms of NLRC5 in EC remained unclear. We aimed to explore whether NLRC5 could regulate the programmed cell death protein ligand 1 (PD-L1) in EC. We also investigated the related molecular which led to the inactivation of NLRC5 in EC. Methods: The expressions of NLRC5 and PD-L1 in endometrium tissue microarray were detected by immunohistochemistry. Pearson's correlation analysis was performed to detect the expression correlation between NLRC5 and PD-L1. Immunofluorescence staining, western blotting, and quantitative real-time PCR (qRT-PCR) were used to detect the role of NLRC5 in PD-L1 in EC cell lines. The somatic mutation in EC patients was detected by whole-exome sequencing (WGS). Results: NLRC5 was downregulated in the endometrium of EC patients when compared to those in the normal endometrium. The level of PD-L1 in the endometrium of EC patients was higher when compared to those in the normal endometrium. There was a negative expression correlation between NLRC5 and PD-L1. NLRC5 could promote the expression of PD-L1 in EC cell lines. The mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Conclusion: NLRC5 could inhibit the activation of PD-L1 in EC. Mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Future study should investigate the mechanism of NLRC5 in PD-L1, as well as the mechanism of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK in NLRC5.

LncRNA GATA3-AS1 promoted invasion and migration in human endometrial carcinoma by regulating the miR-361/ARRB2 axis.

Endometrial carcinoma (EC) is a kind of fatal female malignancy. lncRNA GATA3-AS1 has been identified as an oncogene in various cancers. However, the functions and mechanisms of GATA3-AS1 in EC remain to be explored. Human EC tissues and four EC cell lines were used. Western blotting and quantitative real-time PCR (qRT-PCR) were used to evaluate the expression of GATA3-AS1, miR-361, and ARRB2. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to validate the interaction among GATA3-AS1, miR-361, and ARRB2. Flow cytometry, colony formation assay, scratch assay, and transwell assay were used to examine the cell apoptosis, proliferation, migration, and invasion of EC cells, respectively. In vivo tumor growth was monitored in nude mice. GATA3-AS1 and ARRB2 were upregulated while miR-361 was downregulated in human EC tissues and EC cells. GATA3-AS1 knockdown constrained cell proliferation, invasion, migration, and EMT while promoting the apoptosis of EC cells by upregulating miR-361. GATA3-AS1 negatively regulated miR-361 expression. ARRB2 was the direct target of miR-361 and could activate the Src/Akt pathway. In vivo, GATA3-AS1 knockdown suppressed tumor progression by upregulating the miR-361 expression. lncRNA GATA3-AS1 promoted EC invasion and migration by the miR-361/ARRB2 axis, which indicated that GATA3-AS1 might be a promising therapeutic option for advanced EC progression. KEY MESSAGES: GATA3-AS1 knockdown suppressed EC proliferation, invasion, and migration. GATA3-AS1 directly inhibited miR-361 as a ceRNA. MiR-361 knockdown reversed the tumor suppressive effect caused by GATA3-AS1 knockdown. MiR-361 bound to ARRB2 directly and suppressed its expression. The GATA3-AS1/miR-361/ARRB2 axis regulated EC cell proliferation, invasion, and migration.

Submandibular Gland Transplantation vs Minor Salivary Glands Transplantation for Treatment of Dry Eye: A Retrospective Cohort Study.

PURPOSE: To compare submandibular gland (SMG) transplantation with minor salivary gland (MSG) transplantation for the treatment of different dry eye diseases (DED). DESIGN: Retrospective clinical cohort study. METHODS: A total of 73 refractory DED eyes were divided into 3 groups. Group A comprised 35 end-stage DED eyes that underwent SMG transplantation. Group B comprised 20 end-stage DED eyes with MSG transplantation. Group C comprised 18 non-end-stage DED eyes with MSG transplantation. Schirmer test (ST), tear break-up time (TBUT), corneal fluorescein staining (FL), and best-corrected visual acuity (BCVA) were measured before and after surgery. RESULTS: Hospital length of stay, length of operation, and hospital fee were significantly higher in group A than in group B or C. Eyes in group A showed the most severe DED disease, with preoperative ST, TBUT, FL, and BCVA of 0.36 mm per 5 minutes, 0.03 seconds, 10.97, and 0.11, respectively, which improved significantly to 20.23 mm per 5minutes, 1.74 seconds, 7.58, and 0.2 at >2-year follow-up. Group B had similar baseline data, and significant but limited improvement only in the ST (0.55 mm per 5 minutes to 3.79 mm per 5 minutes) and FL (11.10 to 9.58) after the operation. Group C had better baseline ST, TBUT, FL, and BCVA of 0.89 mm per 5min, 3.49 seconds, 1.83, and 0.81, respectively, which improved significantly (except for BCVA) to 9.35 mm per 5min, 9.08 s, 0.53, and 0.89 after MSG transplantation. CONCLUSION: SMG transplantation could be recommended to treat end-stage refractory DED. MSG transplantation may provide satisfying results for refractory DED with relatively less severe impairment of the eye.

Blockade of Microglial Activation in Hypothalamic Paraventricular Nucleus Improves High Salt-Induced Hypertension.

BACKGROUND: It has been shown that activated microglia in brain releasing proinflammatory cytokines (PICs) contribute to the progression of cardiovascular diseases. In this study, we tested the hypothesis that microglial activation in hypothalamic paraventricular nucleus (PVN), induced by high-salt diet, increases the oxidative stress via releasing PICs and promotes sympathoexcitation and development of hypertension. METHODS: High-salt diet was given to male Dahl salt-sensitive rats to induce hypertension. Those rats were bilaterally implanted with cannula for PVN infusion of minocycline, a selective microglial activation blocker, or artificial cerebrospinal fluid for 4 weeks. RESULTS: High-salt diet elevated mean arterial pressure of Dahl salt-sensitive rats. Meanwhile, elevations of renal sympathetic nerve activity and central prostaglandin E2, as well as increase of plasma norepinephrine, were observed in those hypertensive rats. Tumor necrosis factor-α, interleukin-1ß (IL-1ß), and IL-6 increased in the PVN of those rats, associated with a significant activation of microglia and prominent disruption of redox balance, which was demonstrated by higher superoxide and NAD(P)H oxidase 2 (NOX-2) and NAD(P)H oxidase 4 (NOX-4), and lower Cu/Zn superoxide dismutase in PVN. PVN infusion of minocycline attenuated all hypertension-related alterations described above. CONCLUSION: This study indicates that high salt leads to microglial activation within PVN of hypertensive rats, and those activated PVN microglia release PICs and trigger the production of reactive oxygen species, which contributes to sympathoexcitation and development of hypertension. Blockade of PVN microglial activation inhibits inflammation and oxidative stress, therefore attenuating the development of hypertension induced by high-salt diet.

Use of saliva flow rate measurement in minor salivary glands autotransplantation for treatment of severe dry eye disease.

AIMS: To use minor salivary glands' flow rate (MSGFR) measurement in minor salivary glands (MSGs) autotransplantation for the treatment of severe dry eye disease (DED). METHODS: MSGs autotransplantations were performed in 18 eyes (17 patients) with severe DED. MSGFR were measured before operation. The upper or lower lip with higher MSGFR was selected as the donor site. Buccal mucosa was the back-up in cases labial MSGs showing markedly decreased MSGFRs. Two pieces of salivary lobules with the covering mucosa were harvested and transplanted to the recipient beds prepared in both upper and lower lids. RESULTS: The donor sites included lower lip in 12 eyes, upper lip in 5 eyes and buccal mucosa in 1 eye. Postoperative follow-up confirmed viable grafts in all cases. The overall subjective relief rate of DED symptoms was 58.8%, with Schirmer test values increasing from 0 mm to 4 mm (p<0.05). The mean preoperative MSGFR was 1.7 (range: 0.9-3.3) µL/min/cm2. ROC analysis indicated an outstanding discrimination power for preoperative MSGFR to predicate postoperative relief of DED symptoms (area under the curve (AUC)=0.948, p<0.01). The maximum sensitivity (100%) and specificity (72.7%) were reached at a cut-off of 1.785 µL/min/cm2. Patients with preoperative MSGFR >1.785 µL/min/cm2 showed greater improvement of Schirmer test values after surgery than those with MSGFR ≤1.785 µL/min/cm2 (p<0.05). CONCLUSION: MSGs transplantation proved to be useful for treating severe DED. The amount of postoperative lubrication and the treatment effect were positively correlated with preoperative MSGFR. MSGFR measurement and donor-site selection should be critical steps before the operation.

Clinical and histopathologic characteristics of submandibular gland in Stevens-Johnson syndrome: A comparative study.

OBJECTIVE: The objective of this study was to investigate the clinical manifestations and pathologic appearances of the submandibular gland (SMG) in Stevens-Johnson syndrome (SJS). STUDY DESIGN: Patients with autologous transplantation of SMG for treatment of severe dry eye between March 1998 and May 2018 were divided into the SJS group (70 cases) and non-SJS group (50 cases) according to the history of SJS. The SMG weight and computed tomography volume and salivary flow rate were measured. The concentration index and secretion index were estimated using scintigraphy with technetium-99m-pertechnetate. Histopathology studies of SMG tissues were conducted, and the acini parameters were measured using a digital image analyzer. RESULTS: A decreased computed tomography volume and weight was observed in 48.57% the SJS group and 2% in the non-SJS group (P < .01). The rest whole, acid-stimulated whole, and SMG rest salivary flow rates decreased in the SJS group (P < .05). The normal SMG concentration index (37.5% vs 96.67%, P < .001) and secretion index (35% vs 96.67%, P < .001) rates were lower in the SJS group than in the non-SJS group. The glandular parenchyma was reduced, the acinar space was widened, and the fat content was increased in the SJS group. CONCLUSION: SMG atrophic and degenerative changes occurred in the SJS group, with a decrease in salivary secretion function in more than half of the patients.

Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension.

The incidence rate and mortality of hypertension increase every year. Hypothalamic paraventricular nucleus (PVN) plays a critical role on the pathophysiology of hypertension. It has been demonstrated that the imbalance of neurotransmitters including norepinephrine (NE), glutamate (Glu) and γ-aminobutyric acid (GABA) are closely related to sympathetic overactivity and pathogenesis of hypertension. N-methyl-D-aspartate receptor (NMDAR), consisting of GluN1 and GluN2 subunits, is considered to be a glutamate-gated ion channel, which binds to Glu, and activates neuronal activity. Studies have found that the synthesis of respiratory chain enzyme complex was affected and mitochondrial function was impaired in spontaneously hypertensive rats (SHR), further indicating that mitochondria is associated with hypertension. Nuclear respiratory factor 1 (Nrf1) is a transcription factor that modulates mitochondrial respiratory chain and is related to GluN1, GluN2A, and GluN2B promoters. However, the brain mechanisms underlying PVN Nrf1 modulating sympathoexcitation and blood pressure during the development of hypertension remains unclear. In this study, an adeno-associated virus (AAV) vector carrying the shRNA targeting rat Nrf1 gene (shNrf1) was injected into bilateral PVN of male rats underwent two kidneys and one clip to explore the role of Nrf1 in mediating the development of hypertension and sympathoexcitation. Administration of shNrf1 knocked down the expression of Nrf1 and reduced the expression of excitatory neurotransmitters, increased the expression of inhibitory neurotransmitters, and reduced the production of reactive oxygen species (ROS), and attenuated sympathoexcitation and hypertension. The results indicate that knocking down Nrf1 suppresses sympathoexcitation in hypertension by reducing PVN transcription of NMDAR subunits (GluN1, GluN2A, and GluN2B), rebalancing PVN excitatory and inhibitory neurotransmitters, inhibiting PVN neuronal activity and oxidative stress, and attenuating sympathetic activity.