Assessing Severity of Low Anterior Resection Syndrome After Intersphincteric Resection for Ultralow Rectal Cancer: A Pilot Study Using an Exploratory Instrument.

BACKGROUND: The Delphi consensus identified 8 symptoms and 8 consequences as the highest priorities for defining low anterior resection syndrome. OBJECTIVE: To describe an exploratory scoring instrument correlating the Delphi consensus on low anterior resection syndrome with functional and quality-of-life scores following intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective pilot study. In accordance with the Wexner incontinence score, 5 frequency responses ranging from never (score 0) to always (score 4) were used to measure the severity of symptom- and consequence-specific variables. SETTINGS: Colorectal surgery referral center. PATIENTS: Among 161 eligible patients, 137 participants (85%) completed an electronic self-assessment survey regarding function and quality of life at scheduled follow-up, including 3 to 6, 12, and ≥24 months after ileostomy reversal. MAIN OUTCOME MEASURES: Outcome measures included patient-reported severity of the identified priorities, and their correlation with condition-specific quality of life. RESULTS: The most frequent symptom and consequence were "emptying difficulties" and "dissatisfaction with the bowels," respectively. Aside from "emptying difficulties," the proportions of negative symptom domains increased after reversal. In particular, neither the frequency responses nor the severity scores of "emptying difficulties" differed between groups. The percentages of "always" selection for consequence domains improved at 12-month follow-up, whereas a higher rate was observed at 24 months, except for "toilet dependence" and "dissatisfaction with the bowels." We found significant improvements in the summary score of the Fecal Incontinence Quality-of-Life Scale ( p = 0.04) and our exploratory instrument ( p = 0.009) but not in functional scores measured by traditional questionnaires. Furthermore, the condition-specific quality of life strongly correlated with the Delphi consensus severity score ( rs = -0.73). LIMITATIONS: Single-institution data and limited sample size. CONCLUSIONS: The important priorities identified by the Delphi consensus might enable a comprehensive overview and a better assessment of low anterior resection syndrome after intersphincteric resection. See Video Abstract . EVALE LA GRAVEDAD DEL SNDROME DE RESECCIN ANTERIOR BAJA DESPUS DE LA RESECCIN INTERESFINTRICA PARA EL CNCER DE RECTO ULTRABAJO UN ESTUDIO PILOTO QUE UTILIZA UN INSTRUMENTO EXPLORATORIO: ANTECEDENTES:El consenso Delphi identificó ocho síntomas y ocho consecuencias como las máximas prioridades para definir el síndrome de resección anterior baja.OBJETIVO:Describir un instrumento de puntuación exploratorio que correlaciona el consenso Delphi sobre el síndrome de resección anterior baja con puntuaciones funcionales y de calidad de vida después de la resección interesfinteriana para el cáncer de recto ultrabajo.DISEÑO:Este fue un estudio piloto prospectivo. De acuerdo con la puntuación de incontinencia de Wexner, se utilizaron cinco respuestas de frecuencia que van desde nunca (puntuación 0) hasta siempre (puntuación 4) para medir la gravedad de las variables específicas de los síntomas y las consecuencias.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Entre 161 pacientes elegibles, 137 (85%) participantes completaron una encuesta electrónica de autoevaluación sobre la función y la calidad de vida en el seguimiento programado, incluidos 3 a 6, 12 y ≥ 24 meses después de la reversión de la ileostomía.MEDIDAS PRINCIPALES DE RESULTADO:Las medidas de resultado incluyeron la gravedad de estas prioridades informada por los pacientes, así como su correlación con la calidad de vida específica de la afección.RESULTADOS:El síntoma y la consecuencia más frecuentes fueron "dificultades para vaciar" e "insatisfacción con las deposiciones", respectivamente. Aparte de las "dificultades de vaciado", las proporciones de dominios de síntomas negativos aumentaron después de la reversión. En particular, tanto las respuestas de frecuencia como las puntuaciones de gravedad de las "dificultades para vaciar" no difirieron entre los grupos. Los porcentajes de "opción siempre" para los dominios de consecuencias mejoraron a los 12 meses de seguimiento, mientras que se observó una tasa más alta a los 24 meses después, excepto para "dependencia del baño" e "insatisfacción con los intestinos". Encontramos mejoras significativas en la puntuación resumida de la Escala de calidad de vida de incontinencia fecal ( p = 0,04) y nuestro instrumento exploratorio ( p = 0,009), pero no en las puntuaciones funcionales medidas con los cuestionarios tradicionales. Además, la calidad de vida específica de la condición se correlacionó fuertemente con la puntuación de gravedad del consenso Delphi (rs = -0,73).LIMITACIONES:Datos de una sola institución y tamaño de muestra limitado.CONCLUSIONES:Las importantes prioridades identificadas por el consenso Delphi podrían permitir una visión global y una mejor evaluación del síndrome de resección anterior baja después de la resección interesfintérica. (Traducción-Dr. Yesenia Rojas-Khalil ).

Study of Helicobacter pylori infection in patients with chronic atrophic gastritis and its relationship with lifestyle habits and dietary nutrient intake: A retrospective analysis.

To explore Helicobacter pylori (Hp) infection status and its relationship with lifestyle habits and dietary factors in patients with chronic atrophic gastritis. Six hundred thirty-eight patients with chronic atrophic gastritis, who were admitted to our hospital from March 2021 to April 2023, were selected for the study. All patients underwent the 13C urea breath test. The relationship between the detection rate of Hp infection and the clinical characteristics, lifestyle habits, and dietary factors of the patients was analyzed. Among the 638 patients with chronic atrophic gastritis, 531 patients were tested positive for Hp infection, the positive rate for Hp infection was approximately 83.23%. Analyzing the clinical characteristics of the patients, it was found that age, family history of gastric cancer, degree of chronic inflammation, degree of glandular atrophy, presence of low-grade dysplasia, and intestinal metaplasia all have an impact on the positive detection rate of patients (P < .05). Analyzing the patients' lifestyle habits, it was found that BMI, smoking history, alcohol consumption, preference for spicy food, dining location, consumption of pickled foods, frequent consumption of grilled/barbecued foods, preference for strong tea, consumption of sweets, and work-related stress had an impact on the positive rate of Hp infection in patients (P < .05). The discovery showed that the levels of total protein, albumin, hemoglobin, cholesterol, and the intake of livestock and poultry meat, seafood, dairy products, vegetables, fruits, and fats have an impact on the positivity rate of Hp infection in patients (P < .05). A multiple logistic regression analysis was performed, and it was found that patients' age, family history of gastric cancer, degree of chronic inflammation, degree of glandular atrophy, presence of low-grade dysplasia, presence of wasting or obesity, history of alcohol consumption, preference for spicy food, dining location, frequent consumption of strong tea, high work pressure, high intake of fish and seafood, low intake of dairy products, low intake of vegetables, low intake of fruits, and low intake of fats all had an impact on the occurrence of Hp infection in patients (P < .05). There is a certain correlation between patients' lifestyle habits, dietary factors, and clinical characteristics with the occurrence of Hp infection. These factors can assist in the prevention of Hp infection.

Conformal sphincteric resection for ultra-low rectal cancer located below the dentate line: A pilot report.

AIM: Sphincter-sparing surgery can be achieved in most cases of low rectal cancer with the development of intersphincteric resection. However, abdominoperineal resection is still inevitable for patients with tumours located below the dentate line. To address this, we have developed a procedure called conformal sphincteric resection (CSR) in which the corresponding part of the subcutaneous portion of the external anal sphincter and the perianal skin on the tumour side is removed to achieve a safe distal resection margin and lateral resection margin while the dentate line and the internal anal sphincter on the tumour-free side are preserved as much as possible, to achieve sphincter preservation without compromising oncological safety and functional acceptability, and to render tumour location no longer a contraindication for sphincter-sparing surgery. This is the first study to describe the concept, indication and surgical procedure of CSR and to report its preliminary surgical, oncological and functional results. METHODS: This is a retrospective, single-centre, single-arm pilot study conducted at Huashan Hospital, Fudan University. Demographic, clinicopathological, oncological and functional follow-up data were collected from 20 consecutive patients with rectal tumours located below the dentate line who underwent laparoscopic CSR by the same surgical team from June 2018 to March 2022. RESULTS: The mean distance of the tumour's lower edge from the anal verge was 13.1 ± 6.0 mm. The mean distal resection margin was 10.6 ± 4.3 mm. All circumferential resection margins were negative. There were no instances of perioperative mortality. The complication rate was 25% but all were Clavien-Dindo Grade I. Among the 20 cases, 17 were diagnosed with adenocarcinoma, one with squamous cell carcinoma and two with adenoma featuring high-grade intraepithelial neoplasia. Pathological TNM staging revealed two, seven, five, five and one case(s) in Stages 0, I, II, III and IV, respectively. The median follow-up period was 20 months (interquartile range 22 months), with no withdrawals. The overall and disease-free survival rates were both 95%. The mean Wexner incontinence score and low anterior resection syndrome score recorded 18 months following diverting ileostomy closure were 6.3 ± 3.8 and 27.3 ± 3.6, respectively. CONCLUSIONS: This study has proposed the CSR procedure for the first time, which is a technically feasible, oncologically safe and functionally acceptable procedure for carefully selected patients with rectal tumours located below the dentate line.

Does anastomotic leakage after intersphincteric resection for ultralow rectal cancer influence long-term outcomes? A retrospective observational study.

PURPOSE: To determine whether anastomotic leakage (AL) following intersphincteric resection (ISR) for ultralow rectal cancer (uLRC) is associated with long-term negative outcomes. METHODS: Between June 2011 and January 2022, 236 consecutive patients who underwent ISR with diverting ileostomy for uLRC were included. The primary outcome was long-term clinical consequences of AL, including chronic stricture, stoma reversal, and oncological and functional results. RESULTS: Forty-one (17.4%) patients developed symptomatic AL, whereas only two (0.8%) required re-laparotomy due to severe leakage. Patients with leaks had a significantly increased incidence of chronic stricture (29.3% vs. 8.7%, P = 0.001) and stoma non-reversal (34.1% vs. 4.6%, P < 0.0001) than controls. The severe consequences were particularly common in patients with anastomotic separation, resulting in 60% of those presenting with chronic stricture and 50% ending up with stoma non-reversal. After a median follow-up of 59 (range, 7-139) months, AL did not compromise long-term oncological outcomes, including tumor recurrence (9.8% vs. 5.6%, P = 0.3), 5-year disease-free, and overall survival (73.4% vs. 74.8% and 85.1% vs. 85.4%, P = 0.56 and P = 0.55). A total of 149 patients with bowel continuity who completed self-assessment questionnaires were enrolled for functional evaluation. The median follow-up was 24 (range, 12-94) months after ileostomy reversal, and functional results were comparable between patients with and without leaks. CONCLUSION: AL is an unfortunate reality for patients who underwent ISR for uLRC, but the rate of severe leakage is limited. Leaks contribute to possible adverse impacts on chronic stricture and stoma non-reversal, especially for patients with anastomotic separation. However, long-term oncological and functional results may not be compromised. TRIAL REGISTRATION: Chictr.org.cn identifier: ChiCTR-ONC-15007506 and ChiCTR2100051614.

Thermal ablation of hepatic hemangioma: A multi-center experience with long-term outcomes.

BACKGROUND: Thermal ablation, currently used extensively for liver tumors, also has been applied. successfully to hepatic hemangioma; however, it is still considered experimental because previous studies have comprised small sample sizes with short follow-up periods. PURPOSE: We aimed to investigate the effectiveness, safety, and long-term outcomes of thermal ablation for hepatic hemangioma. MATERIALS AND METHODS: From October 2011 to February 2021, the data of 357 patients with 378 hepatic hemangiomas treated by thermal ablation at six hospitals were analyzed in this retrospective study. The technical success, safety, and long-term follow-up results were analyzed. RESULTS: A total of 252 patients (mean age, 49.2 ± 10.5 years) with 273 subcapsular hemangiomas underwent laparoscopic thermal ablation, whereas 105 patients with 105 hemangiomas located in the liver parenchyma underwent CT-guided percutaneous ablation. Of the 378 hepatic hemangiomas (5.0-21.2 cm), 369 lesions were subjected to one session of ablation, while 9 lesions were subjected to two sessions of ablation. Technical success was achieved in 100.0% of cases. Complete ablation was achieved in 361 of 378 hemangiomas (95.5%), while 17 hemangiomas (4.5%) were incompletely ablated, showing subtle enhancement at the peripheral rim. The major complication rate was 2.0% (7/357). The median follow-up period was 67 months (range, 12-124 months). Of the 224 patients with hemangioma-related symptoms, 216 demonstrated complete disappearance of symptoms (96.4%), while 8 were ameliorated (3.6%). Ablated lesion shrinkage was progressive, and 11.4% of hemangiomas almost completely disappeared over time (P < 0.01). CONCLUSION: With a reasonable ablation strategy and comprehensive treatment measurements, thermal ablation could be a safe, feasible, and effective treatment option for hepatic hemangioma.

CircEPS15, as a sponge of MIR24-3p ameliorates neuronal damage in Parkinson disease through boosting PINK1-PRKN-mediated mitophagy.

Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, circEPS15 was selected for further research. Low expression of circEPS15 was found in PD patients and there was a negative positive correlation between the circEPS15 level and severity of PD motor symptoms, while overexpression of circEPS15 protected DA neurons against neurotoxin-induced PD-like neurodegeneration in vitro and in vivo. Mechanistically, circEPS15 acted as a MIR24-3p sponge to promote the stable expression of target gene PINK1, thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, circEPS15 rescued DA neuronal degeneration through the MIR24-3p-PINK1 axis-mediated improvement of mitochondrial function. This study reveals that circEPS15 exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD.Abbreviations: AAV: adeno-associated virus; DA: dopaminergic; FISH: fluorescence in situ hybridizations; HPLC: high-performance liquid chromatography; H-Y stage: Hohen-Yahr stage; LDH: lactate dehydrogenase; MMP: mitochondrial membrane potential; MPTP/p: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid; NC: negative control; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PBS: phosphate-buffered saline; ROS: reactive oxygen species; SNpc: substantia nigra pars compacta; TEM: transmission electron microscopy; UPDRS: Unified Parkinson's Disease Rating Scale-motor score.

Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease.

Alanine-serine-cysteine transporter 2 (ASCT2) is reported to participate in the progression of tumors and metabolic diseases. It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasome-triggered neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate. It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate drug for PD treatment.

Quality of Life and Functional Outcomes After Intersphincteric Resection for Ultralow Rectal Cancer: A Prospective Observational Study.

BACKGROUND: Intersphincteric resection is the ultimate sphincter-preserving surgical technique for ultralow rectal cancer, but quality-of-life changes after surgery remain unclear. It is also unknown which questionnaire has better associations with functional results for capturing clinical variation in quality of life. OBJECTIVE: This study aimed to assess change in the quality of life and its correlation with functional outcomes among patients undergoing intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective, observational, single-center study. SETTINGS: Colorectal surgery referral center. PATIENTS: Patients with ultralow rectal cancer who underwent intersphincteric resection were included. MAIN OUTCOME MEASURES: The primary outcomes were quality-of-life and functional results at 3 to 6, 12, and 24 months after ileostomy closure using validated questionnaires. The secondary outcome was the relationship between quality of life and neorectal function. RESULTS: A total of 102 patients (62.7% men) completed follow-up surveys. Wexner incontinence score and Kirwan's incontinence score significantly improved at 12 months after ileostomy reversal, but such improvement in low anterior resection syndrome score was proved until 24 months later ( p = 0.01). Condition-specific quality-of-life domains improved over time, with significant changes in lifestyle ( p = 0.02) and coping/behavior ( p = 0.01), as well as the summary score of Fecal Incontinence Quality of Life ( p = 0.02) and visual analog scale score ( p < 0.001). Among health-related quality-of-life domains, the subscale scores did not differ significantly. The functional systems scores were significantly correlated with all the domains of condition-specific quality-of-life but only a few health-related quality-of-life domains. Only weak to moderate associations with the functional outcomes were observed for both quality-of-life questionnaires. LIMITATIONS: Single-center data and limited sample size. CONCLUSIONS: Although low anterior resection syndrome persists for years after intersphincteric resection, condition-specific quality of life and functional outcomes improve over time. Compared to health-related quality-of-life questionnaires, condition-specific quality-of-life instruments might be preferable to evaluate changes in quality-of-life after surgery. See Video Abstract at http://links.lww.com/DCR/C130 . CALIDAD DE VIDA Y RESULTADOS FUNCIONALES DESPUS DE UNA RESECCIN INTERESFINTRICA EN CASO DE CNCER RECTAL ULTRABAJO ESTUDIO PROSPECTIVO OBSERVACIONAL: ANTECEDENTES:La resección inter-esfintérica es la última técnica quirúrgica conservadora de esfínteres en casos de cáncer rectal ultrabajo, pero los cambios en la calidad de vida después de la cirugía siguen sin estar claros. Se desconoce también, qué tipo de cuestionario tiene mejor asociación con los resultados funcionales para así captar las variaciones clínicas en la calidad de vida.OBJETIVO:Evaluar el cambio en la calidad de vida y su correlación con los resultados funcionales durante el período postoperatorio en pacientes sometidos a resección interesfintérica por cáncer de recto ultrabajo.DISEÑO:Estudio prospectivo, observacional y de un solo centro.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Se incluyeron pacientes con cáncer de recto ultra bajo que se sometieron a resección interesfintérica con el cierre de la ileostomía.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la calidad de vida y los resultados funcionales a los 3-6, 12 y 24 meses después del cierre de la ileostomía utilizando cuestionarios validados. El resultado secundario fue la relación entre la calidad de vida y la función del néorecto.RESULTADOS:Un total de 102 pacientes (62,7% hombres) completaron las encuestas de seguimiento. La puntuación de incontinencia de Wexner y la puntuación de incontinencia de Kirwan mejoraron significativamente a los 12 meses después del cierre de la ileostomía, pero dicha mejoría en la puntuación del síndrome de resección anterior baja se demostró solo hasta 24 meses después ( p = 0,01). Las condiciones en el dominio de la calidad de vida específicos mejoraron con el tiempo, con cambios significativos en el estilo de vida ( p = 0,02) y el afrontamiento/comportamiento ( p = 0,01), así como la puntuación general de la calidad de vida y de la incontinencia fecal ( p = 0,02), puntuación de la escala analógica visual ( p < 0,001). Entre los dominios de la calidad de vida relacionada con la salud, las puntuaciones de las sub-escalas no difirieron significativamente. Las puntuaciones de los sistemas funcionales se correlacionaron significativamente con todos los dominios de la calidad de vida específica de la nueva condición, pero solo con pocos dominios de calidad de vida relacionados con la salud. Solo se observaron asociaciones débiles a moderadas con los resultados funcionales para ambos cuestionarios de calidad de vida.LIMITACIONES:Datos de un solo centro y tamaño de muestra limitado.CONCLUSIONES:Aunque el síndrome de resección anterior baja persiste durante años después de la resección interesfintérica, la calidad de vida específica de la nueva condición y los resultados funcionales mejoran con el tiempo. En comparación con los cuestionarios de calidad de vida relacionados con la salud, los instrumentos de calidad de vida específicos de la nueva condición pueden ser preferibles para evaluar los cambios en la calidad de vida después de la cirugía. Consulte Video Resumen en http://links.lww.com/DCR/C130 . (Traducción-Dr. Xavier Delgadillo ).

Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway.

Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates' efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC50 values of 1.97, 1.84, and 2.03 µM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg-1 ·d-1, i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.

Neuroprotective effects of a lead compound from coral via modulation of the orphan nuclear receptor Nurr1.

AIMS: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds. METHODS: The lead compounds with neuroprotective effects were screened by H2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes. RESULTS: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways. CONCLUSION: Lead compounds from marine corals exerted significant neuroprotective effects， which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease.

Mitochondrial glutamine transporter SLC1A5_var, a potential target to suppress astrocyte reactivity in Parkinson's Disease.

SLC1A5 variant (SLC1A5_var) is identified as a mitochondrial glutamine transporter in cancer cells recently. However, the role of SLC1A5_var in Parkinson's disease (PD) is completely unknown. Here, we found the significant downregulation of SLC1A5_var in astrocytes and midbrain of mice treated with MPTP/MPP+ and LPS. Importantly, overexpression of SLC1A5_var ameliorated but knockdown of SLC1A5_var exacerbated MPTP/MPP+- and LPS-induced mitochondrial dysfunction. Consequently, SLC1A5_var provided beneficial effects on PD pathology including improvement of PD-like motor symptoms and rescue of dopaminergic (DA) neuron degeneration through maintaining mitochondrial energy metabolism. Moreover, SLC1A5_var reduced astrocyte reactivity via inhibition of A1 astrocyte conversion. Further investigation demonstrated that SLC1A5_var restrained the secretion of astrocytic pro-inflammatory cytokines by blunting TLR4-mediated downstream pathways. This is the first study to prove that astrocytic SLC1A5_var inhibits neuroinflammation, and rescues the loss of DA neurons and motor symptoms involved in PD progression, which provides a novel target for PD treatment.

ß-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between ß-arrestin2 and STAT3 in mouse model of depression.

BACKGROUND: Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. METHODS: We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/ß-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the ß-arrestin2 knockout mice or administrating the ß-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the ß-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. RESULTS: Drd2-biased ß-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of ß-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic ß-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/ß-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. CONCLUSIONS: Drd2/ß-arrestin2 pathway is a potential therapeutic target for depression and ß-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

Anatomic resection versus radiofrequency ablation with an ablative margin ≥ 1.0 cm for solitary small hepatocellular carcinoma measuring ≤ 3 cm: Comparison of long-term outcomes using propensity score matching analysis.

PURPOSE: To compare the long-term outcomes of anatomic resection (AR) and radiofrequency ablation (RFA) with an ablative margin (AM) of ≥ 1.0 cm as first-line treatment for solitary hepatocellular carcinoma measuring ≤ 3 cm. METHODS: Two hundred and fifty-one patients who underwent AR (n = 156) or RFA (ablative margin ≥ 1.0 cm, n = 95) at any of 6 tertiary hospitals from 2009 to 2018 were enrolled. Propensity score matched analysis (PSM) were used to compare overall survival (OS), recurrence-free survival (RFS), and perioperative outcomes. Univariate and multivariate analyses were performed to identify prognostic factors associated with RFS and OS. RESULTS: PSM created 67 patient-pairs. After 96 months of follow-up, RFA with an ablative margin ≥ 1.0 cm and AR showed comparable 1-year, 3-year, 5-year, and 8-year OS rates before (P = 0.580) and after (P = 0.640) PSM. However, RFS was better at 1, 3, 5, and 8 years after AR before (P = 0.0036) and after (P = 0.017) PSM. The operation time and postoperative hospital stay were significantly longer in the AR group than in the RFA group before and after PSM (P < 0.05). Multivariate analysis identified age and type of treatment to be independent prognostic factors for RFS and age and hepatitis C to be associated with OS. CONCLUSIONS: Long-term OS was not significantly different between AR and RFA with an AM ≥ 1.0 cm in patients with a solitary hepatocellular carcinoma measuring ≤ 3 cm; but, RFS appeared to be better after AR than after RFA. However, RFA was associated with fewer perioperative complications and a shorter postoperative hospital stay.

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/ß-arrestin2 pathway.

BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to directly bind with 5-HT2B receptor (5-HT2BR), but the precise mechanisms, whereby fluoxetine confers the anti-depressive actions via 5-HT2BR is not fully understood. Although neuroinflammation-induced A1 astrocytes are involved in neurodegenerative diseases, the role of A1 astrocyte in the pathogenesis and treatment of major depressive disorder (MDD) remains unclear. METHODS: Mice were subjected to chronic mild stress (CMS) for 6 weeks and subsequently treated with fluoxetine for 4 weeks. The depressive-like and anxiety-like behaviors and the activation of A1 reactive astrocyte in hippocampus and cortex of mice were measured. Primary astrocytes were stimulated with A1 cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1α and C1q), activated (LPS) microglia-conditioned medium (MCM) or IL-6 for 24 h and the expression of A1-special and A2-special markers were determined using RT-qPCR and western blot. The role of 5-HT2BR in the effects of fluoxetine on A1 reactive astrocyte was measured using 5-HT2BR inhibitor and siRNA in vitro and AAVs in vivo. The functions of downstream signaling Gq protein and ß-arrestins in the effects of fluoxetine on the activation of A1 astrocyte were determined using pharmacological inhibitor and genetic knockout, respectively. RESULTS: In this study, we found that fluoxetine inhibited the activation of A1 reactive astrocyte and reduced the abnormal behaviors in CMS mice, as well as ameliorated A1 astrocyte reactivity under three different stimulators in primary astrocytes. We also showed that astrocytic 5-HT2BR was required in the inhibitory effects of fluoxetine on A1 reactive astrocyte in MDD in vivo and in vitro. We further found that the functions of fluoxetine in the activation of A1 astrocyte were independent of either Gq protein or ß-arrestin1 in vitro. ß-arrestin2 pathway was the downstream signaling of astrocytic 5-HT2BR mediated the inhibitory effects of fluoxetine on A1 astrocyte reactivity in primary astrocytes and CMS mice, as well as the improved roles of fluoxetine in behavioral impairments of CMS mice. CONCLUSIONS: These data demonstrate that fluoxetine restricts reactive A1 astrocyte via astrocytic 5-HT2BR/ß-arrestin2 pathway in a mouse model of MDD and provide a novel therapeutic avenue for MDD.

Cumulative Incidence and Risk Factors of Permanent Stoma After Intersphincteric Resection for Ultralow Rectal Cancer.

BACKGROUND: A permanent stoma is an unintended consequence that cannot be avoided completely after intersphincteric resection for ultralow rectal cancer. Unfortunately, its incidence and risk factors have been poorly defined. OBJECTIVE: The objective was to determine the cumulative incidence and risk factors of permanent stoma after intersphincteric resection for ultralow rectal cancer. DESIGN: This study was a retrospective analysis of prospectively collected data. SETTINGS: This study was conducted at a colorectal surgery referral center. PATIENTS: A total of 185 consecutive patients who underwent intersphincteric resection with diverting ileostomy from 2011 to 2019 were included. MAIN OUTCOME MEASURES: The primary outcome was the incidence of and risk factors for the permanent stoma. The secondary outcome included differences in stoma formation between patients with partial, subtotal, and total intersphincteric resection. RESULTS: After a median follow-up of 40 months (range, 6-107 months), 26 of 185 patients eventually required a permanent stoma, accounting for a 5-year cumulative incidence of 17.4%. The causes of permanent stoma were anastomotic morbidity (46.2%, 12/26), local recurrence (19.2%, 5/26), distant metastasis (19.2%, 5/26), fecal incontinence (3.8%, 1/26), perioperative mortality (3.8%, 1/26), patients' refusal (3.8%, 1/26), and poor general condition (3.8%, 1/26). Although the incidence of permanent stoma was significantly different between the intersphincteric resection groups (partial vs subtotal vs total: 8.3% vs 20% vs 25.8%, p = 0.02), it was not an independent predictor of stoma formation. Multivariate analysis demonstrated that anastomotic leakage (OR = 5.29; p = 0.001) and anastomotic stricture (OR = 5.13; p = 0.002) were independently predictive of permanent stoma. LIMITATIONS: This study was limited by its retrospective nature and single-center data. CONCLUSIONS: The 5-year cumulative incidence of permanent stoma was 17.4%. Anastomotic complications were identified as risk factors. Patients should be informed of the risks and benefits when contemplating the ultimate sphincter-sparing surgery. It might be preferable to decrease the probability of permanent stoma by further minimizing anastomotic complications. See Video Abstract at http://links.lww.com/DCR/B704. INCIDENCIA ACUMULADA Y FACTORES DE RIESGO DE ESTOMA PERMANENTE DESPUS DE UNA RESECCIN INTERESFNTRICA EN CNCER RECTAL ULTRA BAJO: ANTECEDENTES:La necesidad de efectuar un estoma permanente es la consecuencia no intencional e inevitable por completo después de una resección interesfintérica en presencia de un cáncer rectal ultra bajo. Desafortunadamente, la incidencia y los factores de riesgo se han definido en una forma limitada.OBJETIVO:El objetivo fue determinar la incidencia acumulada y los factores de riesgo para la necesidad de efectuar un estoma permanente después de la resección intersfintérica de un cáncer rectal ultra bajo.DISEÑO:El presente estudio es un análisis retrospectivo de la información obtenida.ESCENARIO:Centro de referencia de cirugía colo-rectal.PACIENTES:Se incluyeron un total de 185 pacientes consecutivos que se sometieron a resección intersfintérica de un cáncer rectal ultra bajo con ileostomía de derivación de 2011 a 2019.MEDICION DE RESULTADOS:El resultado principal fue la identificación de la incidencia y los factores de riesgo para la presencia de un estoma permanente. En forma secundaria se describieron los resultados de las diferentes técnicas de la formación de un estoma entre los pacientes con resección interesfintérica parcial, subtotal o total.RESULTADOS:Posterior a una media de seguimiento de cuarenta meses (rango de 6 a 107), 26 de 185 pacientes requirieron en forma eventual un estoma permanente, lo que equivale a una incidencia acumulada a cinco años de 17.4 %. Las causas para dejar un estoma permanente fueron morbilidad de la anastomosis (46.2%, 12/26), recurrencia local (19.2%, 5/26), metástasis a distancia (19.2%, 5/26), incontinencia fecal (3.8%, 1/26), mortalidad perioperatoria (3.8%, 1/26), rechazo del paciente (3.8%, 1/26), y malas condiciones generales (3.8%, 1/26). Aunque la incidencia de un estoma permanente fue significativamente diferente entre los grupos de resección interesfintérica (parcial vs subtotal vs total: 8.3% vs 20% vs 25.8%, p = 0.02), no se consideró un factor predictor independiente para la formación de estoma. En el análisis multivariado se demostró que la fuga anatomótica (OR = 5.29; p = 0.001) y la estenosis anastomótica (OR = 5.13; p = 0.002) fueron factores independientes para predecir la necesidad de un estoma permanente.LIMITACIONES:La naturaleza retrospectiva del estudio y la información proveniente de un solo centro.CONCLUSIONES:La incidencia acumulada a cinco años de estoma permantente fue de 17.4%. Se consideran a las complicaciones anastomóticas como factores de riesgo. Los pacientes deberán ser informados de los riesgos y beneficios cuando se considere la posibilidad de efectuar una cirugía preservadora de esfínteres finalmente. Puede ser preferible disminuir la probabilidad de dejar un estoma permanente tratando de minimizar la posibilidad de complicaciones de la anastomosis. Consulte Video Resumen en http://links.lww.com/DCR/B704.

Kir6.2 is essential to maintain neurite features by modulating PM20D1-reduced mitochondrial ATP generation.

Kir6.2, a pore-forming subunit of the ATP-sensitive potassium (KATP) channels, regulates the functions of metabolically active tissues and acts as an ideal therapeutic target for multiple diseases. Previous studies have been conducted on peripheral kir6.2, but its precise physiological roles in the central nervous system (CNS) have rarely been revealed. In the current study, we evaluated the neurophenotypes and neuroethology of kir6.2 knockout (kir6.2-/-) mice. We demonstrated the beneficial effects of kir6.2 on maintaining the morphology of mesencephalic neurons and controlling the motor coordination of mice. The mechanisms underlying the abnormal neurological features of kir6.2 deficiency were analyzed by RNA sequencing (RNA-seq). Pm20d1, a gene encoding PM20D1 secretase that promotes the generation of endogenous mitochondria uncouplers in vivo, was dramatically upregulated in the midbrain of kir6.2-/- mice. Further investigations verified that PM20D1-induced increase of N-acyl amino acids (N-AAAs) from circulating fatty acids and amino acids promoted mitochondrial impairments and cut down the ATP generation, which mediated the morphological defects of the mesencephalic neurons and thus led to the behavioral impairments of kir6.2 knockout mice. This study is the first evidence to demonstrate the roles of kir6.2 in the morphological maintenance of neurite and motor coordination control of mice, which extends our understanding of kir6.2/KATP channels in regulating the neurophysiological function.

Variation in rectoanal inhibitory reflex after laparoscopic intersphincteric resection for ultralow rectal cancer.

AIM: The aim was to evaluate the physiological variation in rectoanal inhibitory reflex (RAIR) after laparoscopic intersphincteric resection (Lap-ISR) for ultralow rectal cancer. METHOD: This was a retrospective study that included 56 patients who underwent Lap-ISR from a prospectively collected database. The RAIR was examined preoperatively and up to 12 months after ileostomy closure. The primary outcome included physiological variation in RAIR and its difference between partial, subtotal and total ISR. The secondary outcome was its correlation with functional outcome. RESULTS: The reflex was present in 95% (53/56) of patients preoperatively, in 36% (20/56) before ileostomy closure, in 48% (27/56) at 3-6 months and in 61% (34/56) at 12 months after ileostomy closure. The elicited volume of RAIR was significantly increased at 12 months after ileostomy closure than at baseline (P = 0.005), but its duration and amplitude did not differ significantly. There was no significant difference in the reflex recovery between the ISR groups (partial vs. subtotal vs. total: 65% vs. 63% vs. 44%, P = 0.61). At 12 months after ileostomy closure, the RAIR-present group had favourable functional results and patient satisfaction (P < 0.05). Major faecal incontinence was found in 82% of patients in the RAIR-absent group. CONCLUSION: The RAIR is abolished in the majority of patients after Lap-ISR, but a time-dependent recovery could be observed in more than half of the patients. The reflex recovery is not influenced by the resection grade of the internal sphincter. However, persistent loss of the RAIR correlates with worse continence.

Enrichment of phospholipids using magnetic Fe3O4/TiO2 nanoparticles for quantitative detection at single cell levels by electrospray ionization mass spectrometry.

Quantitative detection of phospholipids at the single cell level remains in challenge. Herein, the TiO2-coated Fe3O4 nanoparticles were synthesized to selectively enrich trace phospholipids from single cell, which were then eluted using 1.5% ammonia/methanol (w/w) for sensitive detection by electrospray ionization mass spectrometry. Under the optimal experimental conditions, eighteen phospholipids in single cell samples were detected and identified by MS/MS experiments. The limit-of-detections (LODs) were 0.012 µg/L for phosphatidylcholine (PC, 34:1) and 0.014 µg/L for phosphatidylcholine (PC, 36:2) in PBS matrix, with the linear range of 0.05-50 µg/L (R2 ≥ 0.999). The recovery rates of 94.90-104.00% were obtained, with the relative standard deviations (RSDs ≤ 6.90%). Quantitative determination of PC in real unicellular samples was also achieved, with the concentration of 1.82-2.11 µg/L for PC(34:1) and 1.25-1.65 µg/L for PC(36:2) in six types of single cell, opening up possibilities for quantitative analysis of trace compounds in complex bio-samples. A set of 6 types of tumor cells were analyzed and further differentiated by the partial least squares-discriminant analysis (PLS-DA). Conclusively, a facile method for the direct quantification of phospholipids in single cell samples has been developed, showing potential applications for advanced investigation of phosphorylated substance at the single cell level.

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection.

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.