Clinical outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision in locally advanced rectal cancer with mesorectal fascia involvement.

PURPOSE: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. MATERIALS AND METHODS: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of ≤50.4 Gy were defined as the non-boost group, while ≥54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. RESULTS: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). CONCLUSION: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed.

Dose-Escalated Radiotherapy for Primary Tracheobronchial Adenoid Cystic Carcinoma.

Primary tracheobronchial adenoid cystic carcinoma (ACC) is a rare malignancy, so the optimal radiotherapy (RT) dose remains unestablished. We aimed to evaluate the effectiveness of dose-escalated RT for primary tracheobronchial ACC. We retrospectively reviewed 48 patients who had undergone definitive or postoperative RT. Patients classified into the low- and high-dose groups received RT doses <70.0 and ≥70.0 Gy in EQD2, respectively. The primary endpoint was freedom from local progression (FFLP) and overall survival (OS). Throughout the follow-up period, seven patients (14.6%) experienced local progression, while 31 (64.6%) exhibited distant metastasis, most commonly in the lungs. In total, the 5-year FFLP and OS rates were 85.7 and 84.7%, respectively. Multivariate analysis revealed that regional lymph node metastasis at diagnosis and receipt of definitive RT were associated with poorer OS. In the subgroup analysis, the definitive RT group had a 5-year FFLP rate of 33.3 and 78.2% in the low- and high-dose groups (p = 0.065), whereas 5-year OS rates were 66.7 and 79.0%, respectively (p = 0.022). Four patients (8.3%) experienced Grade 3 toxicity with tracheal or main bronchus stenosis. Dose-escalated RT with conventional fractionation may be effective in patients with tracheobronchial ACC, especially for a definitive aim.

A novel GPR119 agonist DA-1241 preserves pancreatic function via the suppression of ER stress and increased PDX1 expression.

DA-1241 is a novel small molecule G protein-coupled receptor 119 (GPR119) agonist in early clinical development for type 2 diabetic patients. This study aimed to elucidate the pharmacological characteristics of DA-1241 for its hypoglycemic action. DA-1241 potently and selectively activated GPR119 with enhanced maximum efficacy. DA-1241 increased intracellular cAMP in HIT-T15 insulinoma cells (EC50, 14.7 nM) and increased insulin secretion (EC50, 22.3 nM) in association with enhanced human insulin promoter activity. Accordingly, postprandial plasma insulin levels were increased in mice after single oral administration of DA-1241. Postprandial glucose excursion was significantly reduced by single oral administration of DA-1241 in wild-type mice but not in GPR119 knockout mice. GLP-1 secretion was increased by DA-1241 treatment in mice. Thus, upon combined sitagliptin and DA-1241 treatment in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice, plasma active GLP-1 levels were synergistically increased. Accordingly, blood glucose and triglyceride levels were significantly lowered both by DA-1241 and sitagliptin alone and in combination. Immunohistochemical analysis revealed that ß-cell mass with reduced PDX1 levels in the islets from HFD/STZ diabetic mice was significantly preserved by DA-1241, whereas increased glucagon and BiP levels were significantly suppressed. In HIT-T15 insulinoma cells subjected to ER stress, decreased cell viability was significantly rescued by treatment with DA-1241. Additionally, increased apoptosis was largely attenuated by DA-1241 by inhibiting BiP and CHOP expression through suppression of p38 MAPK. In conclusion, these studies provide evidence that DA-1241 can be a promising antidiabetic drug by potentially preserving pancreatic functions through suppressing ER stress and increasing PDX1 expression.

Comparative study on four amylosucrases from Bifidobacterium species.

Amylosucrase (ASase) is α-glucan-producing enzyme. Four putative ASase genes (bdas, blas, bpas, and btas) were cloned from Bifidobacterium sp. and expressed in Escherichia coli. All ASases from Bifidobacterium sp. (BAS) displayed typical ASase properties with slightly different characteristics. Among the BASs studied, BdAS and BpAS showed maximal enzyme activities at 35 and 30 °C, respectively, whereas BlAS and BtAS were maximally active at higher temperatures, i.e., 45 and 50 °C, respectively. BpAS exhibited optimum pH under slightly basic conditions (pH 8.0), while BdAS, BlAS, and BtAS preferred weakly acidic conditions (pH 5.0-6.0). All BASs showed higher isomerization activities. Particularly, BlAS produced more trehalulose than turanose. Although polymerization was the highest for BtAS, BtAS synthesized α-1, 4-glucans with a lower degree of polymerization than that of the other BASs. The versatile properties of the BASs described could contribute to the efficient production of highly valuable biomaterials for the agriculture, food, and pharmaceutical industries.

Antitumor Activity of Rivoceranib Against Canine Mammary Gland Tumor Cell Lines.

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.

Additive effects of evogliptin in combination with pioglitazone on fasting glucose control through direct and indirect hepatic effects in diabetic mice.

Due to very limited preclinical reports, pharmacodynamic interactions between dipeptidyl peptidase 4 (DPP4) inhibitors and peroxisome proliferator-activated receptor γ (PPARγ) agonists are not conclusive yet. This study aimed to evaluate the pharmacological responses from adding evogliptin, a DPP4 inhibitor, to pioglitazone, a PPARγ agonist, in diabetic db/db mice after a 2-week treatment. This combination led to further decrease in both fasting and fed blood glucose levels compared to evogliptin alone (P < 0.05), but combination effects were more dramatic in fasting glucose levels (P < 0.05 vs. each treatment alone). Of note, plasma glucagon and high-molecular-weight (HMW) form of adiponectin were also further altered by the combination (P < 0.05 vs. each treatment alone). In line with these results, hepatic gluconeogenic gene expression was normalized by this combination. However, although evogliptin or pioglitazone directly suppressed glucose output in HepG2 hepatocytes, their combination did not further reduce hepatic glucose output. By contrast, glucose utilization of HepG2 cells was synergistically enhanced by this combination regardless of insulin presence (P < 0.05 vs. each treatment alone). These results suggest that the combination of evogliptin and pioglitazone is more efficacious in fasting glucose control through systemic alterations such as decreasing glucagon and increasing adiponectin, and through enhancing glucose utilization. To our knowledge, this is the first report regarding the significant combination effects of DPP4 inhibitors plus PPARγ agonists on plasma HMW adiponectin and hepatic glucose utilization. Our findings provide insight that the evogliptin and pioglitazone combination therapy may be more beneficial in type 2 diabetic patients characterized by exaggerated glucagon dysregulation.

Immunostimulatory effect of pepsin enzymatic extract from Porphyra yezoensis on murine splenocytes.

BACKGROUND: Porphyra yezoensis is a red alga consumed mainly in Korea, Japan, and China for food. This study researches the immunological effect of pepsin extract of P. yezoensis (PPEE) on murine splenocytes. RESULTS: PPEE was not toxic on murine splenocytes and dramatically increased the proliferation of splenocytes compared with untreated control. Flow cytometry assay performed to sum up the effect of PPEE (31.3 and 62.5 µg mL-1 ) on major immune cells revealed that PPEE had no effect on the function of CD3e+ CD4+ T-helper cells, CD3e+ CD8+ T-cytotoxic cells, or CD44+ CD62L- effector T cells in splenocytes compared with untreated control. More importantly, CD45+ CD11b+ macrophage and dendritic cell populations and Ly-6C+ Ly-6G+ macrophages/monocytes in splenocytes were activated by PPEE treatment compared with untreated control. Further experiments showed that PPEE treatment increased the secretion of macrophage-derived cytokines such as interleukin-1ß, tumor necrosis factor-α, and interleukin-12, and macrophage-activating cytokines interferon-γ and interleukin-10 compared with untreated control. CONCLUSION: Taken together, these results suggest that PPEE has an immune stimulatory effect on macrophages, dendritic cells, and memory T cells. This property signifies the potential medicinal value of PPEE in clinical implications for immune-compromised diseases. © 2017 Society of Chemical Industry.

Silencing of voltage-gated potassium channel KV9.3 inhibits proliferation in human colon and lung carcinoma cells.

Voltage-gated potassium (Kv) channels are known to be involved in cancer development and cancer cell proliferation. KV9.3, an electronically silent subunit, forms heterotetramers with KV2.1 in excitable cells and modulates its electrophysiological properties. However, the role of KV9.3 alone in non-excitable cancer cells has not been studied. Here, we evaluated the effect of silencing KV9.3 on cancer cell proliferation in HCT15 colon carcinoma cells and A549 lung adenocarcinoma cells. We confirmed the expression of KV9.3 mRNA in HCT15 and A549 cells and showed that silencing KV9.3 using small interfering RNA caused G0/G1 cell cycle arrest and alterations in cell cycle regulatory proteins in both HCT15 and A549 cells without affecting apoptosis. Also, stable knockdown of KV9.3 expression using short-hairpin RNA inhibited tumor growth in SCID mouse xenograft model. Using a bioinformatics approach, we identified Sp1 binding sites in the promoter region of the gene encoding KV9.3. We further found that Sp1 bound to this region and showed that the Sp1 inhibitor, mithramycin A, induced a concentration-dependent decrease in KV9.3 expression. Taken together, these data suggest that knockdown of KV9.3 inhibits proliferation in colon carcinoma and lung adenocarcinoma cell lines and may be regulated by Sp1.

Attentional bias towards emotional facial expressions in survivors of dating violence.

This study identified components of attentional bias (e.g. attentional vigilance, attentional avoidance and difficulty with disengagement) that are critical characteristics of survivors of dating violence (DV). Eye movements were recorded to obtain accurate and continuous information regarding attention. DV survivors with high post-traumatic stress symptoms (DV-High PTSS group; n = 20) and low post-traumatic stress symptoms (DV-Low PTSS group; n = 22) and participants who had never experienced DV (NDV group; n = 21) were shown screens displaying emotional (angry, fearful and happy) faces paired with neutral faces and negative (angry and fearful) faces paired with happy faces for 10 s. The results indicate that the DV-High PTSS group spent longer dwelling on angry faces over time compared with the DV-Low PTSS and NDV groups. This result implies that the DV-High PTSS group focused on specific trauma-related stimuli but does not provide evidence of an attentional bias towards threatening stimuli in general.

Attentional bias to violent images in survivors of dating violence.

This study investigated the time-course characteristics of attentional bias, such as vigilance and maintenance, towards violent stimuli in dating violence (DV) survivors. DV survivors with PTSD symptoms (DV-PTSD group; n=14), DV survivors without PTSD symptoms (Trauma Control group; n=14), and individuals who were never exposed to dating violence (NDV group; n=15) viewed slides that presented four categories of images (violent, dysphoric, positive, and neutral) per slide, for ten seconds. Our results revealed that the DV-PTSD group spent more time on violent stimuli than did the Trauma Control or NDV groups. The DV survivors, both with and without PTSD symptoms, spent more time on dysphoric stimuli and less time on happy stimuli than did the NDV group. In addition to the effects of PTSD, researchers should also be considering the effects of simple traumatic exposure.