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Over the past decade, remarkable advances have been witnessed in the development of small-molecule probes. These molecular tools have been widely applied for interrogating proteins, pathways and drug–target interactions in preclinical research. While novel structures and designs are commonly explored in probe development, the clinical translation of small-molecule probes remains limited, primarily due to safety and regulatory considerations. Recent synergistic developments – interfacing novel chemical probes with complementary analytical technologies – have introduced and expedited diverse biomedical opportunities to molecularly characterize targeted drug interactions directly in the human body or through accessible clinical specimens (e.g., blood and ascites fluid). These integrated developments thus offer unprecedented opportunities for drug development, disease diagnostics and treatment monitoring. In this review, we discuss recent advances in the structure and design of small-molecule probes with novel functionalities and the integrated development with imaging, proteomics and other emerging technologies. We further highlight recent applications of integrated small-molecule technologies for the molecular analysis of drug–target interactions, including translational applications and emerging opportunities for whole-body imaging, tissue-based measurement and blood-based analysis. [ABSTRACT FROM AUTHOR]

Glioblastomas shed large quantities of small, membrane-bound microvesicles into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating microvesicles directly from blood samples of patients with glioblastoma. Microvesicles, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate glioblastoma multiforme (GBM) microvesicles from nontumor host cell--derived microvesicles. We also show that circulating GBM microvesicles can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials., Many cancers shed materials into the peripheral circulation such as circulating tumor cells (CTCs) (1) and soluble proteins (2), (3), which are being exploited as surrogate markers of tumor staging [...]

Introduction: Recent studies have suggested that alternative lengthening of telomeres (ALT) is associated with metastasis and poor survival in pancreatic neuroendocrine tumors (PanNETs). This study evaluated whether this association is applicable to Chinese patients as well as the potential somatic mutations associated with ALT. Methods: We assessed the prevalence of ALT by performing telomere-specific fluorescence in situ hybridization and analyzed DAXX/ATRX expression using immunohistochemistry in 112 Chinese patients with PanNETs to evaluate the association between ALT and clinical outcomes. A subset of the noninsulinoma samples (28/60) was subjected to Sanger sequencing and targeted sequencing. Results: The ALT-positive phenotype was identified in 23.2% (26/112) of the samples. The clinicopathologic factors significantly associated with progression in the noninsulinoma (n = 60) cohort were the female sex (p = 0.006), Ki-67 index (p < 0.001), World Health Organization grade (p = 0.031), and ALT positivity (p = 0.013). Patients with ALT-positive PanNETs had significantly shorter progression-free survival than those with ALT-negative PanNETs in the entire cohort (p < 0.001), noninsulinoma subgroup (p = 0.01), and G2 subgroup (p = 0.001). ALT-positive samples frequently harbored somatic mutations in DAXX, ATRX, MEN1, SETBP1, PRKDC, and GNAS.Conclusions: We confirmed that ALT positivity is an effective risk predictor, especially in the noninsulinoma and G2 subgroups. ALT is also related to somatic mutations in MEN1, SETBP1, PRKDC, and GNAS, in addition to DAXX and ATRX. [ABSTRACT FROM AUTHOR]

High-grade appendiceal mucinous neoplasm (HAMN) has been separated from appendiceal adenocarcinoma recently as an independent entity and categorized into appendiceal mucinous neoplasms. These neoplasms demonstrate distinct histological characteristics, including architectures and appendiceal mural changes similar to low-grade appendiceal mucinous neoplasm but with high-grade cytology, and no infiltrative invasion. Overt mucinous feature are not evident in some cases as the high-grade neoplastic epithelium may show intracytoplasmic mucin reduction. Occasionally, the neoplastic epithelial cells show florid proliferation and tubulovillous configuration and may be misdiagnosed as appendiceal tubulovillous adenoma. We report the case of a 67-year-old woman with appendicular dilatation and luminal mucin. She underwent an ileocecoectomy. The appendiceal lesion was found histologically to be a HAMN, which closely resembled appendiceal tubulovillous adenoma. The tumor cells demonstrated wild-type p53 expression and mismatch repair proficiency by immunochemistry. Molecular testing showed 1 KRAS mutation, 2 PIK3CA mutations, and 1 BRCA2, EP300, TGFBR2, CHD4, CREBBP, FANCC, PKHD1 mutation each in the tumor. The patient was followed up for 1 year with no evidence of disease. [ABSTRACT FROM AUTHOR]