Hyperprogressive disease during PD-1 blockade in patients with advanced pancreatic cancer.

The occurrence of markedly accelerated tumor growth during immunotherapy is considered a new mode of progression called hyperprogressive disease (HPD) and its impact on pancreatic cancer (PC) patients receiving immunotherapy is unknown. In this study, we described and explored the incidence, prognosis and predictors of HPD in patients with advanced PC treated with programmed cell death-1 (PD-1) inhibitors. We retrospectively analyzed clinicopathological data from 104 patients with advanced pancreatic cancer who were treated with PD-1 inhibitors at our institution during 2015-2020 and identified 10 (9.6%) patients with HPD. Overall survival (OS) was significantly poorer in patients with HPD compared to patients with progressive disease (PD) (median OS: 5.6 vs. 3.6 months, p < .01). Clinicopathological factors associated with the occurrence of HPD included smoking, metastatic sites >2, liver metastasis, antibiotic therapy within 21 days before immunotherapy (Abx B21), hemoglobin (Hb) level <110 g/L, and PD-1 inhibitor treatment line >2. Subgroup analysis showed that high levels of CA19-9 at baseline were associated with the development of subsequent HPD (p = .024) and a worse prognosis (mOS:16.2 months vs. 6.1 months, p < .01). Our study demonstrated that HPD may occur in PC patients treated with PD-1 inhibitors and is associated with several clinicopathological characteristics and poor prognosis. The baseline tumor marker CA19-9 may be one of the early predictors of HPD development in PC patients receiving immunotherapy.

A composite indicator of derived neutrophil-lymphocyte ratio and lactate dehydrogenase correlates with outcomes in pancreatic carcinoma patients treated with PD-1 inhibitors.

Background: There are currently no established biomarkers that can predict whether advanced pancreatic carcinoma (PC) patients would benefit from immune checkpoint inhibitors (ICIs). Our study investigated whether the pretreatment composite biomarker of derived neutrophil-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) can be used as a reliable prognostic factor for the survival of PC patients receiving PD-1 inhibitor therapy. Methods: Patients with advanced PC treated with PD-1 inhibitors at a single center from September 2015 to September 2020 were included. The high levels of dNLR (≥3) and LDH (≥250 U/L) were considered to be risk factors. Based on these two risk factors, patients in this study were categorized into two risk groups: the good dNLR-LDH group, without risk factors, and the intermediate/poor dNLR-LDH group, with one to two risk factors. Overall survival (OS) and progression-free survival (PFS) served as this study's primary and secondary endpoints. Cox regression models were used to identify independent prognostic factors for survival benefit. Results: There were 98 patients in our study. The good group included 61 (62.2%) patients and the intermediate/poor group included 37 (37.8%). The overall patients with PC who received immunotherapy had a median OS of 12.1 months, and the good dNLR-LDH group had a significantly longer OS compared with the intermediate/poor dNLR-LDH group (44.2 vs. 6.4 months; p < 0.010); median PFS was 3.7 and 2.5 months (p = 0.010). The number of metastatic sites >2 and immunotherapy as third-line or later was associated with worse PFS, and the line of immunotherapy and the dNLR-LDH indicator were independent prognostic factors for OS, according to multivariate analysis. Conclusion: The pretreatment composite biomarker of dNLR and LDH can be used as a prognostic biomarker in patients with advanced PC treated with PD-1 inhibitors.

A water-soluble fluorescent probe for real-time visualization of γ-glutamyl transpeptidase activity in living cells.

γ-glutamyl transpeptidase (GGT) is a kind of cell-surface enzyme that is overexpressed in many cancer cells. It is of great significance to develop an ideal tool for the diagnosis of GGT-rich cancer cells. Here, we reported a simple-structured but effective imaging probe for the detection of GGT activity. In the presence of GGT, the γ-glutamyl linkage could be cleaved specifically to produce amino-substituted product, resulting in significant fluorescence enhancement at 578 nm. Moreover, we successfully employed the probe to monitor GGT activity in HepG2 cells. We envisaged that such a simple but effective imaging tool could improve the practical applications for bioimaging.

KIF21A regulates breast cancer aggressiveness and is prognostic of patient survival and tumor recurrence.

PURPOSE: Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue. METHODS: The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A. RESULTS: Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence. CONCLUSION: The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.

Effects of tristetraprolin on doxorubicin (adriamycin)-induced experimental kidney injury through inhibiting IL-13/STAT6 signal pathway.

To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of experimental mice were recorded daily. Histological changes were observed using hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, the 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining was used to assess intracellular levels of reactive oxygen species (ROS). TTP and Kim-1 expressions were measured by immunohistochemistry and western blot. The TNF-α, IL-1ß and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected using western blot, respectively. Cell Counting Kit-8 (CCK-8) was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.