Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors.

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy.

A new therapy strategy for relapsing patients who have received trastuzumab treatment urgently needs to be explored. HER2-specific chimeric antigen receptor (CAR)-expressing NK cells are being rapidly developed for solid tumor therapy, as they have many advantages over HER2-CAR-T cells. Endogenous soluble PD-1 (sPD-1) from the PD-1 extracellular domain blocks PD-1/PD-L1 interaction to promote cancer immunology. Herein, we engineered a new HER2-CAR-NK cell that co-expresses sPD-1 (designed as sPD-1-CAR-NK cells) and assessed its cytotoxic activities toward various cancer cells, activation of immunity and sPD-1 release in vitro and in mouse models bearing breast cancer cells with high HER2 expression, with or without trastuzumab resistance. We demonstrated that sPD-1-CAR-NK cells were able to release bioactive sPD-1, thereby enhancing the cytolytic activities of HER2-CAR-NK cells against HER2 and PD-L1 highly expressing target cells accompanied by increases in the secretion of perforin, granzyme B and IFN-γ. In vivo, sPD-1-CAR-NK cells had superior immunological anticancer efficacy compared to HER2-CAR-NK cells, and they had advantages over HER2-CAR-NK cells in the intraperitoneal injection of sPD-1. Moreover, the infiltration and activation of NK and T cells into tumor tissue were increased in mice with sPD-1-CAR-NK cells. There was no significant change in the body temperature, organ tissue and body weight in all groups except for the group with the PD-1 injection. Together, these data indicate that HER2-specific sPD-1-CAR-NK cells can transport sPD-1 into cancer tissues with high HER2 expression, further improving the efficacy of HER-CAR-NK cells without obvious side effects. sPD-1-CAR-NK is a promising cytotherapeutic agent for patients bearing HER2-positive breast cancer, including those with trastuzumab resistance.

Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation.

Lactate accumulation in the tumor microenvironment was shown to be closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase A (LDHA) has been pursued as a potential novel antitumor strategy. However, only a few potent LDHA inhibitors have been developed and most of them did not show potent antitumor effects in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05. ML-05 inhibited cellular lactate production and tumor cell proliferation, which was associated with inhibition of ATP production and induction of reactive oxygen species and G1 phase arrest. In a mouse B16F10 melanoma model, intratumoral injection of ML-05 significantly reduced lactate production, inhibited tumor growth, and released antitumor immune response of T cell subsets (Th1 and GMZB+ CD8 T cells) in the tumor microenvironment. Moreover, ML-05 treatment combined with programmed cell death-1 Ab or stimulator of interferon genes protein (STING) could sensitize the antitumor activity in B16F10 melanoma model. Collectively, we developed a novel potent LDHA inhibitor, ML-05, that elicited profound antitumor activity when injected locally, and was associated with the activation of antitumor immunity. In addition, ML-05 could sensitize immunotherapies, which suggests great translational value.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Anti-inflammatory germacrane-type sesquiterpene lactones from Vernonia sylvatica.

Nine new germacranolides, sylvaticalides A-H (1-9), and three known analogues (10-12) were isolated from the aerial part of Vernonia sylvatica. Their structures were established using comprehensive spectroscopic analysis, including high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and 1D and 2D nuclear magnetic resonance (NMR) spectra. Their absolute configurations were determined by X-ray diffraction experiments. The anti-inflammatory activities of all isolated compounds were assessed by evaluating their inhibitory effects on the nuclear factor kappa B (NF-κB) pathway, which was activated by lipopolysaccharide (LPS)-stimulated human THP1-Dual cells, and the interferon-stimulated gene (ISG) pathway, activated by STING agonist MSA-2 in the same cell model. Compounds 1, 2 and 6 showed inhibitory effects on the NF-κB and ISG signaling pathways, with IC50 values ranging from 4.12 to 10.57 µmol·L-1.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects.

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.

GV-971 attenuates the progression of neuromyelitis optica in murine models and reverses alterations in gut microbiota and associated peripheral abnormalities.

AIMS: Growing evidence suggests that an imbalanced gut microbiota composition plays a crucial role in the development of neuromyelitis optica spectrum disorders (NMOSD), an inflammatory demyelinating disease primarily affecting the optic nerves and central nervous system (CNS). In light of this, we explored the potential therapeutic benefits of GV-971 in NMOSD. GV-971 is a drug used for treating mild-to-moderate Alzheimer's disease, which targets the gut-brain axis and reduces neuroinflammation. METHODS: To evaluate GV-971's effects, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model to establish NMOSD animal models. This was achieved by injecting NMO-IgG into aged mice (11 months old) or using NMO-IgG along with complement injection and microbubble-enhanced low-frequency ultrasound (MELFUS) techniques in young mice (7 weeks old). We assessed the impact of GV-971 on incidence rate, clinical scores, body weight, and survival, with methylprednisolone serving as a positive control. In NMOSD models of young mice, we analyzed spinal cord samples through H&E staining, immunohistochemistry, and Luxol Fast Blue staining. Fecal samples collected at different time points underwent 16S rRNA gene sequencing, while plasma samples were analyzed using cytokine array and untargeted metabolomics analysis. RESULTS: Our findings indicated that GV-971 significantly reduced the incidence of NMOSD, alleviated symptoms, and prolonged survival in NMOSD mouse models. The NMOSD model exhibited substantial neuroinflammation and injury, accompanied by imbalances in gut microbiota, peripheral inflammation, and metabolic disorders, suggesting a potentially vicious cycle that accelerates disease pathogenesis. Notably, GV-971 effectively reduces neuroinflammation and injury, and restores gut microbiota composition, as well as ameliorates peripheral inflammation and metabolic disorders. CONCLUSIONS: GV-971 attenuates the progression of NMOSD in murine models and reduces neuroinflammation and injury, likely through its effects on remodeling gut microbiota and peripheral inflammation and metabolic disorders.

Integrated multi-omics analysis reveals gut microbiota dysbiosis and systemic disturbance in major depressive disorder.

Major depressive disorder (MDD) involves systemic changes in peripheral blood and gut microbiota, but the current understanding is incomplete. Herein, we conducted a multi-omics analysis of fecal and blood samples obtained from an observational cohort including MDD patients (n = 99) and healthy control (HC, n = 50). 16S rRNA sequencing of gut microbiota showed structural alterations in MDD, as characterized by increased Enterococcus. Metagenomics sequencing of gut microbiota showed substantial functional alterations including upregulation in the superpathway of the glyoxylate cycle and fatty acid degradation and downregulation in various metabolic pathways in MDD. Plasma metabolomics revealed decreased amino acids and bile acids, together with increased sphingolipids and cholesterol esters in MDD. Notably, metabolites involved in arginine and proline metabolism were decreased while sphingolipid metabolic pathway were increased. Mass cytometry analysis of blood immune cell subtypes showed rises in proinflammatory immune subsets and declines in anti-inflammatory immune subsets in MDD. Furthermore, our findings revealed disease severity-related factors of MDD. Interestingly, we classified MDD into two immune subtypes that were highly correlated with disease relapse. Moreover, we established discriminative signatures that differentiate MDD from HC. These findings contribute to a comprehensive understanding of the MDD pathogenesis and provide valuable resources for the discovery of biomarkers.

Grb14 as an independent good prognosis factor for breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: Growth factor receptor-binding protein 14, a new member of noncatalytic adaptor proteins family, has been shown to be upregulated in breast cancer. We investigated the prognostic value of growth factor receptor-binding protein 14 expression in breast cancer patients treated with neoadjuvant chemotherapy. METHODS: Primary breast cancer specimens were taken from locally advanced breast cancer patients in a Phase II clinical trial of neoadjuvant chemotherapy and the expression pattern of growth factor receptor-binding protein 14 was determined by immunohistochemistry. Kaplan-Meier analysis and Cox regression model were used to assess disease-free and overall survival, according to the expression of growth factor receptor-binding protein 14 in tumor cells. RESULTS: Our result showed that growth factor receptor-binding protein 14 was highly expressed in 23.1% of breast cancer sections, and high expression of growth factor receptor-binding protein 14 was significantly associated with better disease-free (P = 0.016, hazard ratio 0.07, 95% confidence interval 0.06-0.08) and overall survival (P = 0.004, hazard ratio 0.02, 95% confidence interval 0.02-0.03), compared with the low-expression group. Multivariate analysis indicated that high expression of growth factor receptor-binding protein 14 was an independent good prognostic factor for both disease-free (P = 0.04, hazard ratio 0.37, 95% confidence interval 0.14-0.98) and overall survival (P = 0.03, hazard ratio 0.11, 95% confidence interval 0.10-0.82). CONCLUSIONS: High expression of growth factor receptor-binding protein 14 in breast cancer cells may help to identify low-risk patients for additional therapies after neoadjuvant chemotherapy.

Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9.

Curcumin, a principal component of turmeric (Curcuma longa), has potential therapeutic activities against breast cancer through multiple signaling pathways. Increasing evidence indicates that curcumin reverses chemo-resistance and sensitizes cancer cells to chemotherapy and targeted therapy in breast cancer. To date, few studies have explored its potential antiproliferation effects and resistance reversal in antiestrogen-resistant breast cancer. In this study, we therefore investigated the efficacy of curcumin alone and in combination with tamoxifen in the established antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. We discovered that curcumin treatment displayed anti-proliferative and pro-apoptotic activities and induced cell cycle arrest at G2/M phase. Of note, the combination of curcumin and tamoxifen resulted in a synergistic survival inhibition in MCF-7/LCC2 and MCF-7/LCC9 cells. Moreover, we found that curcumin targeted multiple signals involved in growth maintenance and resistance acquisition in endocrine resistant cells. In our cell models, curcumin could suppress expression of pro-growth and anti-apoptosis molecules, induce inactivation of NF-κB, Src and Akt/mTOR pathways and downregulate the key epigenetic modifier EZH2. The above findings suggested that curcumin alone and combinations of curcumin with endocrine therapy may be of therapeutic benefit for endocrine-resistant breast cancer.

Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway.

The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA), produced by the modified Escherichia coli Nissle 1917, shows high antitumor activity and effectively reduces the systemic effects of the "off-target" caused by the activation of the STING pathway. In this study, we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro. We developed 2 engineered strains, CIBT4523 and CIBT4712, for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth. Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels, it had lower antitumor activity than CIBT4523 in an allograft tumor model, which might be related to the stability of the surviving bacteria in the tumor tissue. CIBT4523 exhibited complete tumor regression, prolonged survival of mice, and rejection of rechallenged tumors, thus, offering new possibilities for more effective tumor therapy. We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity.

Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer.

The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8+ cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.

Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth.

Controllable activation of the innate immune adapter protein - stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential "on-target off-tumor" toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.

SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer.

Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20-25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-ß1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-ß1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.

Oligomannurarate sulfate sensitizes cancer cells to doxorubicin by inhibiting atypical activation of NF-κB via targeting of Mre11.

Aberrant regulation of nuclear factor kappa B (NF-κB) transcription factor is involved in cancer development, progression and resistance to chemotherapy. JG3, a marine-derived oligomannurarate sulfate, was reported as a heparanase and NF-κB inhibitor to significantly block tumor growth and metastasis in various animal models. However, the detailed functional mechanism remains unclear. Here, we report that JG3 inhibits NF-κB activation by specifically antagonizing the doxorubicin-triggered Ataxia-telangiectasia-mutated kinase (ATM) and the sequential MEK/ERK/p90Rsk/IKK signaling pathway but does not interfere with TNF-α-mediated NF-κB activation. This selective inactivation of the specific NF-κB cascade is attributed to the binding capacity of JG3 for Mre11, a major sensor of DNA double-strand breaks (DSB). Based on this selective mechanism, JG3 showed synergistic effect with doxorubicin in a panel of tumor cells and did not affect immune system function as shown in the in vivo delayed-type hypersensitivity (DTH) and hemolysis assays. All these highlight the clinical potential of JG3 as a favorable sensitizer in cancer therapy. In addition, identification of Mre11 as a potential target in the development of NF-κB inhibitors provides a platform for the further development of effective anticancer agents.

Chronic Kidney Disease and Cognitive Impairment: The Kidney-Brain Axis.

Background: Cognitive impairment, increasingly recognized as a major social burden, is commonly found in chronic kidney disease (CKD) patients. Summary: Vascular damage, uremic toxicity, oxidative stress, and peripheral/central inflammation induced by CKD might be involved in brain lesions and ultimately result in cognitive decline. Uncovering the pathophysiology of CKD-associated cognitive impairment is important for early diagnosis and prevention, which undoubtedly prompts innovative pharmacological treatments. Key Messages: Here, we sequentially review the current understanding and advances in the epidemiology, risk factors, and pathological mechanisms of cognitive impairment in CKD. Furthermore, we summarize the currently available therapeutic strategies for cognitive impairment in CKD.

Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration.

The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-κB signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development.

Withaphysalins from Medicinal and Edible Physalis minima and Their Anti-inflammatory Activities.

Physalis minima is a medicinal and edible plant in China. In this study, 22 new withaphysalins, including a novel 1(10 → 6)abeo-14ß-hydroxy one (1) and other 15 unusual 14ß-hydroxy ones (3-4, 6-17, 19), were isolated from the whole herbs of P. minima together with two known analogues (23-24). Their structures were established by extensive analysis of high-resolution electrospray ionization mass spectrometry, IR, and 1D and 2D NMR spectroscopic data. Their absolute configurations were determined by electronic circular dichroism (ECD) spectra and single-crystal X-ray crystallographic analyses, together with DFT NMR calculations. All isolated compounds were evaluated for their anti-inflammatory activity via measuring the colorimetric reporter of the secreted embryonic alkaline phosphatase gene driven by an IFN-ß minimal promoter fused to five copies of the NF-κB consensus transcriptional response element and three copies of the c-Rel binding site in LPS-stimulated human THP1-Dual cells. Compounds 2, 5, 6, 9, 10, 11, and 20 showed significant anti-inflammatory effects with IC50 values in the range of 3.01-13.39 µM. Among them, compounds 2 and 10 showed better anti-inflammatory effects to inhibit the secretion of IL-6, IL-1ß, and TNF-α in LPS-stimulated THP1-Dual cells.

Integrated Module of Multidimensional Omics for Peripheral Biomarkers (iMORE) in patients with major depressive disorder: rationale and design of a prospective multicentre cohort study.

INTRODUCTION: Major depressive disorder (MDD) represents a worldwide burden on healthcare and the response to antidepressants remains limited. Systems biology approaches have been used to explore the precision therapy. However, no reliable biomarker clinically exists for prognostic prediction at present. The objectives of the Integrated Module of Multidimensional Omics for Peripheral Biomarkers (iMORE) study are to predict the efficacy of antidepressants by integrating multidimensional omics and performing validation in a real-world setting. As secondary aims, a series of potential biomarkers are explored for biological subtypes. METHODS AND ANALYSIS: iMore is an observational cohort study in patients with MDD with a multistage design in China. The study is performed by three mental health centres comprising an observation phase and a validation phase. A total of 200 patients with MDD and 100 healthy controls were enrolled. The protocol-specified antidepressants are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Clinical visits (baseline, 4 and 8 weeks) include psychiatric rating scales for symptom assessment and biospecimen collection for multiomics analysis. Participants are divided into responders and non-responders based on treatment response (>50% reduction in Montgomery-Asberg Depression Rating Scale). Antidepressants' responses are predicted and biomarkers are explored using supervised learning approach by integration of metabolites, cytokines, gut microbiomes and immunophenotypic cells. The accuracy of the prediction models constructed is verified in an independent validation phase. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of Shanghai Mental Health Center (approval number 2020-87). All participants need to sign a written consent for the study entry. Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04518592.

Novel Sphingosine Kinase 1 Inhibitor Suppresses Growth of Solid Tumor and Inhibits the Lung Metastasis of Triple-Negative Breast Cancer.

Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer via the SphK1/S1P signaling pathway. However, exploration of SphK1 inhibitor therapeutic applications has been hampered by the poor pharmacokinetic properties of these SphK1 inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel SphK1 inhibitors. The novel compound 28 selectively inhibits SphK1 and exhibits higher anti-proliferative activity compared to the positive compound PF-543 in various cancer cells, which is associated with the induction of G0/G1 phase arrest and apoptosis; besides, it could also inhibit the cell migration. Further, compound 28 can suppress in vivo growth of both colon tumor and triple-negative breast tumor and inhibits the lung metastasis of triple-negative breast cancer with higher potency compared with that of PF-543. Collectively, compound 28 represents a promising lead compound for the treatment of solid tumor and the metastasis.