Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients.

BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).

Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway.

OBJECTIVE: This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats. METHODS: The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA. RESULTS: APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05). CONCLUSION: EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP. Please cite this article as: Ding YY, Xu F, Wang YF, Han LL, Huang SQ, Zhao S, Ma LL, Zhang TH, Zhao WJ, Chen XD. Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway. J Integr Med. 2023; 21(5): 496-508.

Modified Tong Xie Yao Fang relieves solitary rectal ulcer syndrome: A case report.

BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a rare rectal disorder characterized by bloody mucus in the stool, difficulty in defecation, pain, and anal swelling. To date, the etiology of this syndrome remains not well understood and the diagnosis is frequently confused with other disorders, making treatment a clinical challenge. CASE SUMMARY: A 50-year-old woman presented to our hospital with a 40-d history of bloody mucus in the stool and anal swelling. SRUS was suspected. Rectoscopy revealed a large, severe ulcerous lesion. Histologically, the lesion was characterized as chronic ulcer without clear tumor cells, and the final diagnosis of SRUS was made. The patient was treated with Chinese medicine therapy, with administration of Tong Xie Yao Fang. After 3 wk of treatment, the symptoms improved significantly. At 2-mo follow-up, rectoscopy in a local hospital showed healed ulcer scars without obvious protrusion 3 cm from the anal verge. CONCLUSION: Chinese medicine therapy represents a potential treatment of SRUS with predominant rectal bleeding, mucinous discharge, and anal swelling pain.

Targeting RyR2 with a phosphorylation site-specific nanobody reverses dysfunction of failing cardiomyocytes in rats.

Chronic PKA phosphorylation of ryanodine receptor 2 (RyR2) has been shown to increase diastolic sarcoplasmic reticulum (SR) Ca2+ leakage and lead to cardiac dysfunction. We hypothesize that intracellular gene delivery of an RyR2-targeting phosphorylation site-specific nanobody could preserve the contractility of the failing myocardium. In the present study, we acquired RyR2-specific nanobodies from a phage display library that were variable domains of Camelidae heavy chain-only antibodies. One of the nanobodies, AR185, inhibited RyR2 phosphorylation in vitro and was chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)9-mediated cardiac expression of AR185 to combat postischemic heart failure (HF). AAV gene delivery elevated the intracellular expression of the AR185 protein in a rat model of ischemic HF, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of SR calcium leaks, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited the PKA-mediated phosphorylation of RyR2 in failing cardiomyocytes. Our results provide preclinical experimental evidence that the cardiac expression of RyR2 nanobodies with AAV9 vectors is a promising therapeutic strategy for HF.-Li, T., Shen, Y., Lin, F., Fu, W., Liu, S., Wang, C., Liang, J., Fan, X., Ye, X., Tang, Y., Ding, M., Yang, Y., Lei, C., Hu, S. Targeting RyR2 with a phosphorylation site-specific nanobody reverses dysfunction of failing cardiomyocytes in rats.

[Screening genes related to 'black' character in wu-ding chicken by delta differential display].

The 'black' character is a cardinal character of black chicken that is very important to the medical value and economical value of black chicken. The study compared gene expression between black chicken and non-black chicken by delta differential display method, and obtained twenty-nine expressed sequence tags(ESTs) by extraction, amplification, purification, northern blotting, cloning and sequencing of gel-embedded DNA. Of twenty-nine ESTs, eight ESTs have high similarity rate with known gene in chicken-beta-trepomyosin gene, cardiac myosin alkali light chain gene, insertionally activated c-Ha-ras oncogene, fra-2 oncogene, 16S rRNA gene and mitochondrion genome sequence, respectively, with similarity rate 97%,100%, 98%, 98%, 98%, 99%, 99% and 97%. Five ESTs have high similarity rate with human TTN gene, human phosphoglucomutase 5 gene, human or mouse signal recongnition particle 54 kD gene, human or mouse ribonuclease/angiogenin inhibitor gene, respectively, with similarity rate 82%, 82%, 87%, 99% and 99%. Their homologous genes in chicken are still not cloned. Thirteen ESTs are novel gene fragments. Of thirteen ESTs, nine ESTs have high similarity with ESTs in database. Four ESTs have not high similarity with any EST in database. The results of gene expression analysis show that one known gene (insertionally activated c-Ha-ras oncogene) fragment and one novel gene fragment are expressed in all non-black chicken and are not expressed in all black chicken, and that one known gene (signal recongnition particle 54 kD gene) fragment is expressed in all black chicken and is not expressed in all non-black chicken. According to these results, we conclude that the expression of insertionally activated c-Ha-ras oncogene, signal recongnition particle 54 kD gene and one novel gene are related to the 'black' character in chicken.