Preliminary study of small intestinal manometry on gastrointestinal motility disorders / 中国医师进修杂志

Objective:To investigate the significance of small intestinal manometry in clinical diagnosis and treatment of patients with gastrointestinal motility disorders.Methods:The clinical data of 20 suspected patients with gastrointestinal motility disorders from February 2019 to January 2020 in Shanghai Jiaotong University Affiliated Ninth People′s Hospital were retrospectively analyzed. All patients were performed small intestinal manometry, and the influence on diagnosis and treatment as well as the clinical value of this technique were analyzed.Results:Among the 20 patients, 18 patients successfully accepted small intestinal manometry. Among the 18 patients, 14 patients showed significant motility abnormalities, among which 9 patients showed significant nutritional improvement after treatment and 5 patients were treated with maintaining nutritional support. In 10 patients, small intestinal manometry served as a deciding diagnostic tool, and in 12 patients, major modifications of treatment strategy were made according to results of small intestinal manometry.Conclusions:The small intestinal manometry significantly improves diagnosis and treatment decision in the patients with gastrointestinal motility disorders and shows great value on the clinical practice on this group of patients.

Analysis of 13 cases of enteric dysmotility / 中国医师进修杂志

Objective:To investigate the clinical characters of enteric dysmotility (ED), in order to improve clinical diagnosis and treatment capabilities.Methods:The clinical data of 13 ED patients underwent small intestinal manometry from August 2019 to July 2022 in the Shanghai Jiaotong University Affiliated Ninth People′s Hospital and the Fourth Affiliated Hospital of Nanjing Medical University were retrospectively analyzed, including the clinical manifestation, small intestinal manometry result, treatment and prognosis.Results:Among 13 patients, 1 abnormality was presented in 9 cases, 2 abnormalities presented in 2 cases and 3 abnormalities presented in 2 cases. All 13 cases presented a history of constipation, 5 cases started with constipation and underwent subtotal colectomy. Three patients showed severe chronic abdominal pain with one of them opiate dependence. Eight patients underwent surgical treatment, all of which achieved nutritional improvement and symptom relief.Conclusions:ED is a concisely defined disease with clear diagnostic criteria. The surgery can increase the symptoms of some patients.

Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies / 浙江大学学报·医学版

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.

The impact of lipids on the cancer-immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Erratum: Author correction to 'Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA' Acta Pharmaceutica Sinica B 13 (2023) 2585-2600

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].

Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

Clinical study of modified Renshen decoction plus routine western medicine on patients of chronic congestive heart failure / 国际中医中药杂志

Objective To evaluate the effect of modified Renshen decoction plus routine western medicine on chronic congestive heart failure. Methods The selected 75 candidate patients were divided into control group with 37 patients and treatment group with 38 patients. The patients of control group received routine western medicine and treatment group received modified Renshen decoction plus routine western medicine. After 2 weeks of treatment, the effect of both group were evaluated with indictors of clinical heart function, BNP and traditional Chinese syndrome. Results There were significantly statistical difference, of total effective ratio of clinical heart function (χ2=4.343, P<0.05)between the treatment group (92.1%,35/38)and control group (73.0%, 27/37), and of total effective ratio of traditional Chinese syndrome (χ2=4.649, P<0.05) between the treatment group (94.7%, 36/38) and control group (73.0%, 27/37). The BNP levels of both group decreased significantly (P<0.05), and the significant statistical difference between two groups was also observed 1477.1 ± 316.7 pg/ml vs. 2256.9 ± 521.3 pg/ml; t=7.853, P<0.01). Conclusions The Modified Renshen decoction plus routine western medicine could improve chronic congestive heart failure patients' the heart function, reduce BNP and attenuate the symptoms.

Effects of invigorating spleen and eliminating dampness granules on CGRP in rat D-IBS model / 重庆医学

Objective To observe the effectof Invigorating Spleen and Eliminating DampnesGranuleon calcitonin gene related peptide(CGRP) in ramodelof diarrhepredominanirritable bowel syndrome (D-IBS) .Method60 Wistaratwere ran-domly divided into the control group(n=10) and the constructing model group (n=50) .Then ,the constructing model group warandomly re-divided into the model group (n= 10) ,positive control group (n= 10) ,invigorating spleen and eliminating dampnesGranulelow ,middle and high dose groups(n=10 each) .The D-Ibramodel waestablished by the restrainstresstimulation and gavage of folium sennae decoction fo2 week.The expression of CGRP in small intestinal mucosal membrane in each group wadetected by the immunohistochemical method .ResultIn the model group ,the CGRP positive arewadecreased ,which showed the statistical difference compared with the control group (P＜0 .05);the CGRP positive arein varioutreatmengroupwaincreased ,which showed the statistical difference compared with the model group (P＜0 .05);in the invigorating spleen and e-liminating dampnesgranulemiddle and low dose group,the CGRP positive arewaincreased with the statistical difference com-pared with the positive control group (P＜0 .05) ,while withouthe statistical difference compared with the invigorating spleen and eliminating dampnesgranulehigh dose group (P＞0 .05) .Conclusion Invigorating spleen and eliminating dampnesgranulea-chievethe therapeutical effecby increasing the level of CGRP in local intestinal tissue .

Effect of JPHSKL on the quantity of 5-Hydroxytryptamine of colonic mucosa of diarrhea-predominant irritable bowel syndrome rats / 重庆医学

Objective To observe the effect of Jian Pi Hua Shi Ke Li(JPHSKL) on IBS‐D ,gastrointestinal peptide hormones of rats 5‐HT ,and explore the therapeutic mechanism .Methods 60 clean‐level Wistar rats were used in the experiment .The rats were randomly divided into normal group ,model group ,JPHS low ,middle ,high and Deshute group(10 rats in each group) .Used gavage senna and restraint stress to establish D‐IBS rat model .The drug contrations of JPHSKL low ,midle ,high group were 1 .5 ,2 .5 ,4 .0 g/mL ,3 mg/mol in Deshute group .Once each day ,for 2 weeks ,the other groups were nomol group without any treatment and mod‐el group which building successful .Immunohistochemical SABC method to observe 5‐HT level of colonic specimens .Results The 5‐HT level in colonic tissue of the rats in IBS‐D model were obviously higher than the nomal group(P0 .05) .Conclusion JPHSKL can im‐prove gastrointestinal function of IBS‐D model rats ,effect mechanism is relating to decrease the level of 5‐HT in colonic mucosa .

Endovascular treatment of inferior vena cava syndrome / 中国微创外科杂志

Objective To investigate the curative effect of endovascular treatment for inferior vena cava syndrome(IVCS).Methods A total of 17 cases of inferior vena cava syndrome was treated by endovascular dilatation and self-expandable metallic stent placement between June 2002 and November 2004.Routine anticoagulation therapy was given after the procedure.Results The pressure gradient across the inferior vena cava was reduced from 16.8?4.3 mmHg preoperatively to 2.6?0.6 mmHg postoperatively(t=13.280,P=0.001).The IVCS symptom scores were decreased from 4.4?1.6 preoperatively to 2.1?1.7 postoperatively(t=6.880,P=0.010).Symptoms of edema on lower limbs,scrotal or pubic dropsy,ascites,and anasarca subsided at 1～4 days after procedure.Conclusions Endovascular treatment of inferior vena cava syndrome is effective and reliable.