BACKGROUND: Investigating novel therapeutic strategies for colorectal cancer (CRC) is imperative. However, there is limited research on the use of drugs to target peripheral blood immune cells in this context. To address this gap, we performed a two-sample Mendelian randomization (MR) analysis to identify potential therapeutic targets for CRC.
METHODS: We applied two-sample MR to identify the causal relationship between peripheral blood immune cells and CRC. GWAS data were obtained from the IEU OPEN GWAS project. Based on the implications from the MR results, we conducted a comprehensive database search and genetic analysis to explore potential underlying mechanisms. We predicted miRNAs for each gene and employed extensive research for potential therapeutic applications.
RESULTS: We have identified causal associations between two peripheral immune cells and colorectal cancer. Activated & resting Treg %CD4 + cell was positively associated with the risks of CRC, while DN (CD4-CD8-) %leukocyte cell exhibited a protective role in tumor progression. NEK7 (NIMA related kinase 7) and LHX9 (LIM homeobox 9) expressed in Treg cells were positively associated with CRC risks and may play a vital role in carcinogenesis.
CONCLUSIONS: This study identified causal relationship between peripheral immune cell and CRC. Treg and DN T cells were implicated to own promoting and inhibiting effects on CRC progression respectively. NEK7 and LHX9 in Treg cells were identified as potential biotarget for antitumor therapies.

UNASSIGNED: Inflammatory bowel disease is an incurable group of recurrent inflammatory diseases of the intestine. Mendelian randomization has been utilized in the development of drugs for disease treatment, including the therapeutic targets for IBD that are identified through drug-targeted MR.
UNASSIGNED: Two-sample MR was employed to explore the cause-and-effect relationship between multiple genes and IBD and its subtypes ulcerative colitis and Crohn\'s disease, and replication MR was utilized to validate this causality. Summary data-based Mendelian randomization analysis was performed to enhance the robustness of the outcomes, while Bayesian co-localization provided strong evidential support. Finally, the value of potential therapeutic target applications was determined by using the estimation of druggability.
UNASSIGNED: With our investigation, we identified target genes associated with the risk of IBD and its subtypes UC and CD. These include the genes GPBAR1, IL1RL1, PRKCB, and PNMT, which are associated with IBD risk, IL1RL1, with a protective effect against CD risk, and GPX1, GPBAR1, and PNMT, which are involved in UC risk.
UNASSIGNED: In a word, this study identified several potential therapeutic targets associated with the risk of IBD and its subtypes, offering new insights into the development of therapeutic agents for IBD.

UNASSIGNED: Rheumatoid arthritis (RA) is a systemic autoimmune disease. Its pathogenesis has not yet been clarified, so it is urgent to explore therapeutic targets. Here, we clarified the role of HDAC6 in the mechanism of action of RA through mediating chaperone-mediated autophagy (CMA) to provide a clinical treatment of RA.
UNASSIGNED: We used rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis mice (CIA mice) as models of RA and pharmacological inhibitors as well as genetic interference with adeno-associated viruses to reduce the expression of HDAC6. We explored the influence of CAY10603 on RA-FLS proliferation and inflammation, as well as the expression of proteins related to the CMA signaling pathway. CIA model was constructed using DBA/1J mice. Arthritis symptoms in CIA mice were evaluated, and the expression and localization of CMA-related proteins in mouse ankle joints were examined.
UNASSIGNED: CAY10603 inhibited proliferation as well as the level of the molecular chaperone autophagy in RA-FLS. HDAC6 shRNA significantly reduced the clinical signs of arthritis in CIA mice, as did the expression of HDAC6 in the serum and ankle synovial tissues of CIA mice. Finally, it significantly inhibited the level of Hsc70 and LAMP-2A, which are involved in the CMA signaling pathway, in ankle joint tissues.
UNASSIGNED: Downregulation of HDAC6 may inhibit CMA and thereby ameliorate RA.

BACKGROUND: The efficacy of washed microbiota transplantation (WMT) in terms of refractory functional constipation (FC)-related therapeutic targets and influencing factors have not been elucidated. This study aimed to assess the efficacy and influencing factors of WMT in treating refractory FC-related therapeutic targets.
METHODS: The clinical data of patients diagnosed with refractory FC and received with WMT were retrospectively collected. The therapeutic targets included straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, manual maneuvers, and decreased stool frequency. Each target was recorded as 1 (yes) or 0 (no). All patients were followed up for approximately 24 weeks from the end of the first course of WMT. The primary outcomes were the improvement rates for the individual therapeutic targets and the overall response in respect of the therapeutic targets decreased by 2 at weeks 4, 8, and 24. The secondary outcomes were the clinical remission rate (i.e., the proportion of patients with an average of 3 or more spontaneous complete bowel movements per week), clinical improvement rate (i.e., the proportion of patients with an average increase of 1 or more SCBMs/week or patients with remission), stool frequency, Wexner constipation score, Bristol Stool Form Scale (BSFS) score, and adverse events. The factors influencing the efficacy were also analyzed.
RESULTS: Overall, 63 patients with 112 WMT courses were enrolled. The improvement rates at weeks 8 and 24 were 45.6% and 35.0%, 42.9% and 38.6%, 45.0% and 35.7%, 55.6% and 44.4%, and 60.9% and 50.0%, respectively, for straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, and decreased stool frequency. The overall response rates were 49.2%, 50.8%, and 42.9%, respectively, at weeks 4, 8, and 24. The rates of clinical remission and clinical improvement were 54.0% and 68.3%, respectively, at weeks 4. The stool frequency, BSFS score, and Wexner constipation score tended to improve post-WMT. Only 22 mild adverse events were observed during the 112 WMT courses and the follow-up. The number of WMT courses was identified to be the independent factor influencing the efficacy.
CONCLUSIONS: WMT is efficacious in improving refractory FC-related therapeutic targets. The effectiveness of WMT in the management of FC is enhanced with the administration of multiple courses.

OBJECTIVE: To evaluate the achievement of low-density lipoprotein cholesterol (LDLc) goals established by the 2019 European Guidelines for the Management of Dyslipidemias and 2021 Cardiovascular Disease Prevention Guidelines, describe the lipid-lowering treatment received, analyze the achievement of goals according to the lipid-lowering treatment received and study the factors associated with therapeutic success.
METHODS: Observational study that included 185 patients of both sexes aged 18 or over undergoing lipid-lowering treatment for primary or secondary prevention, attended at the Lipid Unit.
RESULTS: 62.1% of the patients had a very high cardiovascular risk (CVR) according to the 2019 guidelines, and 60.5% according to the 2021 guidelines. Of the total cases, 22.7% achieved adequate control of LDLc according to the 2019 guidelines and 20% according to the 2021 guidelines. 47.6% of the patients received very high intensity lipid-lowering treatment, and 14.1% received extremely high intensity lipid-lowering treatment. 76% of subjects with very high CVR on extremely high intensity lipid-lowering treatment achieved the therapeutic objectives of both guides. In the multivariate analysis, factors associated with therapeutic success were the presence of arteriosclerotic cardiovascular disease, the intensity of lipid-lowering treatment, diabetes mellitus, and low to moderate alcohol consumption.
CONCLUSIONS: Dyslipidemia control is improvable. High or extremely high intensity lipid-lowering treatments can contribute to optimizing control of patients with higher CVR.

Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

OBJECTIVE: To elucidate the mechanism underlying how Ureaplasma urealyticum (UU) affects sperm quality and identify a therapeutic target.
METHODS: In this prospective observational study, the differences in and relationships among semen volume, pH, viscosity, liquefaction time, sperm concentration, sperm motility [progressive motility (PR)], and seminal polymorphonuclear (PMN) elastase were analyzed in 198 normal semen samples (control group) and 198 UU-infected semen samples (observation group). The UU-infected samples were treated and the above parameters were compared between the two groups.
RESULTS: The semen volume, viscosity, liquefaction time, and seminal PMN elastase were significantly higher in the observation than control group, but the pH and PR were significantly lower. In the observation group, the pH and PR were significantly higher after than before treatment, whereas the semen volume, PMN elastase, viscosity, and liquefaction time were lower. UU was closely related to semen volume, pH, viscosity, liquefaction time, sperm motility (PR), and PMN elastase. PMN elastase had significant negative effects on semen pH and sperm motility (PR) but positive effects on viscosity and liquefaction time.
CONCLUSIONS: UU might induce PMN elastase to increase the liquefaction time and viscosity of semen, eventually decreasing PR. PMN elastase might be a therapeutic target of UU.

Recent studies have revealed that circRNAs can affect tumor DNA damage and repair, apoptosis, proliferation, and invasion and influence the transport of intratumor substances by acting as miRNA sponges and transcriptional regulators and binding to proteins in a variety of ways. However, research on the role of circRNAs in cancer radiotherapy and chemoresistance is still in its early stages. Chemotherapy is a common approach to oncology treatment, but the development of tumor resistance limits the overall clinical efficacy of chemotherapy for cancer patients. The current study suggests that circRNAs have a facilitative or inhibitory effect on the development of resistance to conventional chemotherapy in a variety of tumors, suggesting that circRNAs may serve as a new direction for the study of antitumor drug resistance. In this review, we will briefly discuss the biological features of circRNAs and summarize the recent progression of the involvement of circRNAs in the development and pathogenesis of cancer chemoresistance.

(1) Background: The aim of this dynamic-LC/MS-human-serum-proteomic-study was to identify potential proteins-candidates for biomarkers of acute ischemic stroke, their changes during acute phase of stroke and to define potential novel drug-targets. (2) Methods: A total of 32 patients (29-80 years) with acute ischemic stroke were enrolled to the study. The control group constituted 29 demographically-matched volunteers. Subjects with stroke presented clinical symptoms lasting no longer than 24 h, confirmed by neurological-examination and/or new cerebral ischemia visualized in the CT scans (computed tomography). The analysis of plasma proteome was performed using LC-MS (liquid chromatography-mass spectrometry). (3) Results: Ten proteins with significantly different serum concentrations between groups volunteers were: complement-factor-B, apolipoprotein-A-I, fibronectin, alpha-2-HS-glycoprotein, alpha-1B-glycoprotein, heat-shock-cognate-71kDa protein/heat-shock-related-70kDa-protein-2, thymidine phosphorylase-2, cytoplasmic-tryptophan-tRNA-ligase, ficolin-2, beta-Ala-His-dipeptidase. (4) Conclusions: This is the first dynamic LC-MS study performed on a clinical model which differentiates serum proteome of patients in acute phase of ischemic stroke in time series and compares to control group. Listed proteins should be considered as risk factors, markers of ischemic stroke or potential therapeutic targets. Further clinical validation might define their exact role in differential diagnostics, monitoring the course of the ischemic stroke or specifying them as novel drug targets.

[This corrects the article DOI: 10.3389/fvets.2021.652224.].