Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

GPR39 regulated spinal glycinergic inhibition and mechanical inflammatory pain.

G protein-coupled receptor 39 (GPR39) senses the change of extracellular divalent zinc ion and signals through multiple G proteins to a broad spectrum of downstream effectors. Here, we found that GPR39 was prevalent at inhibitory synapses of spinal cord somatostatin-positive (SOM+) interneurons, a mechanosensitive subpopulation that is critical for the conveyance of mechanical pain. GPR39 complexed specifically with inhibitory glycine receptors (GlyRs) and helped maintain glycinergic transmission in a manner independent of G protein signalings. Targeted knockdown of GPR39 in SOM+ interneurons reduced the glycinergic inhibition and facilitated the excitatory output from SOM+ interneurons to spinoparabrachial neurons that engaged superspinal neural circuits encoding both the sensory discriminative and affective motivational domains of pain experience. Our data showed that pharmacological activation of GPR39 or augmenting GPR39 interaction with GlyRs at the spinal level effectively alleviated the sensory and affective pain induced by complete Freund's adjuvant and implicated GPR39 as a promising therapeutic target for the treatment of inflammatory mechanical pain.

Programmed T cells infiltration into lung metastases with harnessing dendritic cells in cancer immunotherapies by catalytic antigen-capture sponges.

T lymphocytes served as immune surveillance to suppress metastases by physically interacting with cancer cells. Whereas tumor immune privilege and heterogeneity protect immune attack, it limits immune cell infiltration into tumors, especially in invasive metastatic clusters. Here, a catalytic antigen-capture sponge (CAS) containing the catechol-functionalized copper-based metal organic framework (MOF) and chloroquine (CQ) for programming T cells infiltration is reported. The intravenously injected CAS accumulates at the tumor via the folic acid-mediated target and margination effect. In metastases, Fenton-like reaction induced by copper ions of CAS disrupts the intracellular redox potential, i.e., chemodynamic therapy (CDT), thereby reducing glutathione (GSH) levels. Furthermore, CQ helps inhibit autophagy by inducing lysosomal deacidification during CDT. This process leads to the breakdown of self-defense mechanisms, which exacerbates cytotoxicity. The therapies promote the liberation of tumor-associated antigens, such as neoantigens and damage-associated molecular patterns (DAMPs). Subsequently, the catechol groups present on CAS perform as antigen reservoirs and transport the autologous tumor-associated antigens to dendritic cells, resulting in prolonged immune activation. The CAS, which is capable of forming in-situ, serves as an antigen reservoir in CDT-mediated lung metastasis and leads to the accumulation of immune cells in metastatic clusters, thus hindering metastatic tumors.

Reduced expression of APLP2 in spinal GABAergic inhibitory neurons contributed to nerve injury-induced microglial activation and pain sensitization.

The amyloid precursor protein (APP) is critical for the pathogenesis of Alzheimer's disease (AD). The AD patients usually have lower pain sensitivity in addition to cognitive impairments. However, considerably less is known as yet about the role of APP and its two mammalian homologues, amyloid precursor-like protein 1 and 2 (APLP1, APLP2), in spinal processing of nociceptive information. Here we found that all APP family members were present in spinal cord dorsal horn of adult male C57BL/6J mice. Peripheral nerve injury specifically reduced the expression of spinal APLP2 that correlated with neuropathic mechanical allodynia. The loss of APLP2 was confined to inhibitory GABAergic interneurons. Targeted knockdown of APLP2 in GABAergic interneurons of GAD2-Cre mice evoked pain hypersensitivity by means of microglia activation. Our data showed that GABAergic terminals expressed APLP2, a putative cell adhesion protein that interacted with microglia-specific integrin molecule CD11b. Knocking down APLP2 in GAD2-positive neurons to disrupt the trans-cellular interaction led to microglia-dependent pain sensitization. Our data thus revealed an important role of APLP2 for GABAergic interneurons to control microglial activity and pain sensitivity.

Pancreatic ß cell regeneration induced by clinical and preclinical agents.

Diabetes, one of the most common chronic diseases in the modern world, has pancreatic ß cell deficiency as a major part of its pathophysiological mechanism. Pancreatic regeneration is a potential therapeutic strategy for the recovery of ß cell loss. However, endocrine islets have limited regenerative capacity, especially in adult humans. Almost all hypoglycemic drugs can protect ß cells by inhibiting ß cell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress. Several agents, including glucagon-like peptide-1 and γ-aminobutyric acid, have been shown to promote ß cell proliferation, which is considered the main source of the regenerated ß cells in adult rodents, but with less clarity in humans. Pancreatic progenitor cells might exist and be activated under particular circumstances. Artemisinins and γ-aminobutyric acid can induce α-to-ß cell conversion, although some disputes exist. Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion, and pharmacological research into FoxO1 inhibition is ongoing. Other cells, including pancreatic acinar cells, can transdifferentiate into ß cells, and clinical and preclinical strategies are currently underway. In this review, we summarize the clinical and preclinical agents used in different approaches for ß cell regeneration and make some suggestions regarding future perspectives for clinical application.

Heparin-functionalized Pluronic nanoparticles to enhance the antitumor efficacy of sorafenib in gastric cancers.

In this study, chitosan/heparin immobilized delivery system was developed for the delivery of sorafenib in gastric cancers. The SRF NP was nanosized with spherical outfit and present in the amorphous form. The SRF NP exhibited a sustained release of drug at pH 7.4 conditions and enhanced drug released at pH 5.5 conditions. Flow cytometer analysis showed that cellular uptake of NP increased two-fold after 4h of incubation compared to 1h incubation. The SRF NP showed superior anticancer effect compared to that of free SRF in BGC-823 cancer cells. SRF NP induced a remarkable apoptosis of cancer cells consistent with the cytotoxicity assay. Approximately, ∼ 50% of cell fractions were observed in early apoptosis phase with ∼ 15% of cells in the late apoptosis stage. Consistently, SRF NP exhibited a strong band for caspase-3 and P-53 than compared to free SRF in MGC-823 cancer cells. Importantly, SRF NP showed superior anticancer effect in xenograft tumor model making it a promising delivery vehicle in the treatment of gastric cancers.

Synchronous collision neuroendocrine tumor and rectal adenocarcinoma: a case report.

Collision tumors are thought to arise from the accidental meeting of two independent tumors. Adenocarcinoma is the most common malignant rectal tumor, while neuroendocrine tumor (NET) is relatively rare. Due to the endoscopy and reporting, the overall incidence of NETs was increasing recently but still less than 1 per 100,000. This means that a combination of an adenocarcinoma and NET is a very rare finding and an actual collision of these tumors even more so. We report here a highly unusual case of a 64-year-old woman who had collision tumors composed of a primary rectal adenocarcinoma and NET showing a "side by side" pattern. Resection margins are free of both the tumors. The postoperative course was uneventful. The patient underwent a protocol CT scan at 3 months after surgery, which did not show any recurrence. Both the malignant adenocarcinoma and the NET would make a great influence in the rest lifetime and a follow up will be continued, although the CT did not show any recurrence until now. To the best of our knowledge, this is the first reported case of such an occurrence.

Transthoracic versus abdominal-transhiatal resection for treating Siewert type II/III adenocarcinoma of the esophagogastric junction: a meta-analysis.

Our study aimed to explore the differences in short and long-term outcomes about the transthoracic (TH) and abdominal-transhiatal (TH) approaches for treating esophagogastric junction (AEG). A systematic review of PubMed, EMbase, Cochrane Library, China National Knowledge Infrastructure and CBMdisc was performed. All original articles comparing TH with TA were included in the study. Meta-analysis was conducted using odd ratios (OR) and weighted mean differences (WMDs).Thirteen studies including 2489 patients with adenocarcinoma of the esophagogastric junction, with 1050 patients underwent TA and 1437 patients underwent TH were pooled for this study. There were no significant difference between two approaches concerning duration of operation, blood loss, anastomotic leakage and positive of proximal incisal margin. Lymph node excised also showed no significant differences between two procedures in RCTs while in TA group of Non-RCTs, the number of lymph node dissection is higher. TH approach was associated with a longer length of hospital stay and had higher incidence of respiratory and cardiovascular complications and early postoperative mortality. Overall analysis of 1, 3, 5-year survival showed no significant difference between two approaches. Based on the study, TA approach had a positive impact than TH for AEG with respect to respiratory and cardiovascular complications, hospital stay and early mortality rates. There were no significant differences between the two approaches for long-term survival. Therefore, two surgical approaches are acceptable, and the elders with poor cardiopulmonary function, we recommended TA approach for treating it.

Efficacy and safety of neoadjuvant chemotherapy with modified FOLFOX7 regimen on the treatment of advanced gastric cancer.

BACKGROUND: Gastric cancer is one of the most common types of malignant tumors in China and East Asia and has the highest mortality rate of the malignant gastrointestinal tumors. Neoadjuvant chemotherapy is a systemic or local chemotherapy that is given prior to the local treatment of malignant tumors. Neoadjuvant therapy is currently showing some positive prospects; however, its clinical effects remain controversial. In this study, we used the modified FOLFOX7 (mFOLFOX7) regimen as a neoadjuvant chemotherapy regimen. Perioperative clinical and pathological efficacy, toxicity, effects of surgery, postoperative observation, and prognosis were studied to investigate its clinical efficacy and safety. METHODS: Eighty patients with advanced gastric cancer were treated in our surgery department from 2005 to 2009; 38 of these patients received mFOLFOX7 neoadjuvant chemotherapy, the other 42 patients assigned to the control group. The perioperative effects of mFOLFOX7 chemotherapy, including clinical effects and toxicity, were observed in each patient. RESULTS: After mFOLFOX7 chemotherapy, clinical and pathologic stages decreased in 21.1% and 36.8% of the patients, respectively, but the results were not statistically significant (P = 0.129). The clinical response rate was 50% (19/38). Toxicity was mild; most adverse events were grade I or II and involved no severe infections or deaths. Compared with the control group, the radical resection rate increased (92.1% vs. 85.7%; P = 0.437); surgical effects were completed without an increased incidence of perioperative complications. The 1-, 2-, and 3-year survival rates were 78.70%, 57.40%, and 51.66%, respectively, in the neoadjuvant chemotherapy group and 78.57%, 56.87%, and 43.16%, respectively, in the control group. CONCLUSIONS: The mFOLFOX7 regimen was very effective and well-tolerated as a neoadjuvant chemotherapy for advanced gastric cancer. However, the 1-, 2-, and 3-year survival rates in the mFOLFOX7 group were not significantly different from the control group.

Anti-arthritic effects of magnolol in human interleukin 1ß-stimulated fibroblast-like synoviocytes and in a rat arthritis model.

Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,5'-Diallyl-biphenyl-2,2'-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-κB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1ß-stimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E(2), and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1ß-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo anti-arthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1ß (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5-25 µg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1ß-induced activation of the IKK/IκB/NF-κB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases.

Gangliocytic paraganglioma of the duodenum: a case report.

Gangliocytic paraganglioma of the duodenum is an extremely rare disease. Few cases have been reported in the literature from 1957 to 2010. We reported a 67-year-old man with gangliocytic paraganglioma of the duodenum.