Dysregulation of microRNAs has been reported to be involved in the progression of human colorectal cancers (CRCs). Loss of the adenomatous polyposis coli (APC) gene is a common initiating event in CRCs. PTEN inactivation by mutation or allelic loss also occurs in CRCs. miR‑135b was reported to be upregulated in CRCs and its overexpression was due to APC/β‑catenin and PTEN/PI3K pathway deregulation. APC was proven to be a target of miR‑135b and forms a feedback loop with miR‑135b. In the present study, we found that ubiquitin‑specific peptidase 13 (USP13) was a target of miR‑135b. miR‑135b downregulated the expression of USP13, and reduced the stability of PTEN. miR‑135b promoted cell proliferation and glycolysis that could be reversed by the overexpression of USP13 or PTEN. Moreover, knockdown of USP13 upregulated the levels of endogenous miR‑135b, but not those in CRC cells with PTEN mutation. The results showed positive feedback loops between miR‑135b and PTEN inactivation in CRCs.
Purpose While TIGIT has been propelled as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials. Therefore, patient stratification is critical for this therapy, which could benefit from a whole-body, non-invasive, and quantitative evaluation of TIGIT expression in cancers. In this study, a 68 Ga-labeled D-peptide antagonist, 68 Ga-GP12, was developed and validated for PET imaging of TIGIT expression in vitro, in vivo , and in an exploratory human study. Methods The D-enantiomer peptide antagonists were modified and radiolabeled with 68 Ga. In vitro binding assays were performed in human peripheral blood mononuclear cells (PBMCs) to assess their affinity and specificity. The imaging capacity, biodistribution, pharmacokinetics, and radiation dosimetry were investigated. Flow cytometry, autoradiography, and immunohistochemical staining were used to confirm the expression of TIGIT. The safety and potential of 68 Ga-GP12 for PET/CT imaging of TIGIT expression were evaluated in NSCLC patients. Results 68 Ga-labeled D-peptides were conveniently produced with high radiochemical yields, radiochemical purities and molar activities. In vitro binding assays demonstrated 68 Ga-GP12 has high affinity and specificity for TIGIT with a K D of 37.28 nM. In vivo and ex vivo studies demonstrated the capacity of 68 Ga-GP12 for PET imaging of TIGIT expression with high tumor uptake of 4.22 ± 0.68 %ID/g and the tumor-to-muscle ratio of 12.94 ± 2.64 at 60 min post-injection. In NSCLC patients, primary and metastatic lesions found in 68 Ga-GP12 PET images were comparable to that in 18 F-FDG PET images. Moreover, tracer uptake in primary and metastatic lesions and intra-tumoral distribution in the large tumor were inhomogenous, indicating the heterogeneity of TIGIT expression. Conclusion 68 Ga-GP12 is a promising radiotracer for PET imaging of TIGIT expression in cancers , indicating its potential as a potential companion diagnostic for anti-TIGIT therapies. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05672-x.
Background: Pharmacotherapy constitutes the first-line treatment for depression. However, its clinical use is hindered by several limitations, such as time lag, side effects, and narrow therapeutic windows. Nanotechnology can be employed to shorten the onset time by ensuring permeation across the blood brain barrier (BBB) to precisely deliver more therapeutic agents; unfortunately, formidable challenges owing to the intrinsic shortcomings of commercial drugs remain. Results: Based on the extraordinary capability of monoamines to regulate the neuronal environment, we engineer a network nanocapsule for delivering serotonin (5-hydroxytryptamine, 5-HT) and catalase (CAT) to the brain parenchyma for synergistic antidepression therapy. The nanoantidepressants are fabricated by the formation of 5-HT covalent bonds and simultaneous payload CAT, following by surface modifications using human serum albumin and rabies virus glycoprotein. The virus-inspired nanocapsules benefit from the surface-modifying strategies and exhibit pronounced BBB penetration. Once nanocapsules reach the brain parenchyma, the mildly acidic conditions trigger the release of 5-HT from the sacrificial nanocapsule. Releasing 5-HT further positively regulate moods, relieving depressive symptoms. Meanwhile, cargo CAT alleviates neuroinflammation and enhances therapeutic efficacy of 5-HT. Conclusion: Altogether, the results offer detailed information encouraging the rational designing of nanoantidepressants and highlighting the potential of nanotechnology in mental health disorder therapies.
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