EGFR T790M Mutation: A Double Role in Lung Cancer Cell Survival?

Abstract:Even though lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance is almost inevitable after a progression-free period of approximately 10 months. A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Nevertheless, several lines of evidence indicate that the T790M mutation confers growth advantage to cancer cells, and it was shown that mice expressing tetracycline-inducible EGFR transgenes harboring the T790M mutation develop lung tumors. Thus, T790M mutation seems to play a double role in the survival of lung cancer cells. Several second-generation EGFR-TKIs are currently being developed to overcome the acquired resistance caused by the T790M mutation. MET (met proto-oncogene) amplification or activation of IGF1R are reported as alternative mechanisms for acquired resistance to EGFR-TKIs. Clarification of the pathways leading to acquired resistance is essential to maximize the efficacy of EGFR-TKI therapy for patients with lung cancer

Weather Divide in Winter Season in Japan Analyzed by AMeDAS Data

The distribution of weather divides in Japanese winters was identified using 30-year data of the Automated Meteorological Data Acquisition System (AMeDAS) operated by the Japan Meteorological Agency. Two kinds of weather divide were defined, one is a cloudy weather divide(CWD) determined by the high-frequency grids of large gradients in the sunshine duration distribution, and the other is a precipitation area border(PAB) where the edge of daily precipitation areas frequently appeared. The CWD appeared continuously in eastern Japan along the Pacific backbone ranges, but it was discontinuous in the central mountain ranges and western Japan. The CWD also appeared in Pacific coastal areas, such as east ofKamikouchi, south of the Kii Peninsula, and southeast of Shikoku Sanchi. The PAB overlapped with the CWD distribution in eastern Japan, and it was enhanced throughout the Sekigahara-Tamba Kochi and Chugoku Sanchi areas, but the CWD in pacific coastal areas was not associated with the PAB. Most of the weather divides were caused by the winter monsoon pressure pattern, and some PABs in northwestern Tohoku and Hokkaido areas occurred with passing pacific coastal extratropical cyclones. The distribution of the weather divides in cold-winter years was dependent on the dominance of Satoyuki/Yamayuki weather patterns, and weather divides became unclear in warm winters

Prevention of Hepatocellular Carcinoma Development Associated with Chronic Hepatitis by Anti-Fas Ligand Antibody Therapy

A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellular carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined. Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development

Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)-high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3-dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE-low primary tumors (vs NE-high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high, P = 0.004) tumors. TIM3 expression was significantly increased in NE-low (vs NE-high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies

Association of melanocortin 1 receptor gene (MC1R) polymorphisms with skin reflectance and freckles in Japanese.

Most studies on the genetic basis of human skin pigmentation have focused on people of European ancestry and only a few studies have focused on Asian populations. We investigated the association of skin reflectance and freckling with genetic variants of melanocortin 1 receptor (MC1R) gene in Japanese. DNA samples were obtained from a total of 653 Japanese individuals (ages 19-40 years) residing in Okinawa; skin reflectance was measured using a spectrophotometer and freckling status was determined for each individual. Lightness index (L*) and freckling status were not correlated with age, body mass index or ancestry (Ryukyuan or Main Islanders of Japan). Among the 10 nonsynonymous variants that were identified by direct sequencing of the coding region of MC1R, two variants--R163Q and V92M--with the derived allele frequencies of 78.6 and 5.5%, respectively, were most common. Multiple regression analysis showed that the 163Q allele and the presence of nonsynonymous rare variants (allele frequencies <5%) were significantly associated with an increase in sex-standardized skin lightness (L* of CIELAB (CIE 1976 (L*a*b*) color space)) of the inner upper arm. Relative to the 92V allele, the 92M allele was significantly associated with increased odds of freckling. This is the first study to show an association between the 163Q allele and skin reflectance values; this association indicated that light-toned skin may have been subjected to positive selection in East Asian people

コレステロール負荷時におけるキノア蛋白質のコレステロール上昇抑制効果

キノアより蛋白質画分(QPro)を取得した。マウスに0.5%コレステロールを含む食餌を基本とし,これにQProを0%(コントロール群),2.5%および5.0%添加(QPro添加群)して4週間経口投与した。QPro添加群とコントロール群間で食事摂取量,体重増加に有意差を認めなかった。QPro添加群では血清と肝臓の総コレステロールの上昇を有意に抑制した。QPro添加群の糞中胆汁酸量は14日目でコントロール群に比べ増加した。肝臓におけるHMG-CoA reductaseの発現は,コントロール群に比べQPro添加群で有意に減少した。これらの結果より,キノア蛋白質画分の血清および肝臓コレステロールの上昇抑制作用は,糞中への胆汁酸排泄の促進およびコレステロール合成系酵素の抑制にあると推察した。We extracted protein fraction (QPro) from quinoa seeds. Mice were fed on 0.5% cholesterol diet, containing 0% (control), 2.5% and 5.0% of QPro respectively (2.5% QPro and 5.0% QPro) for 4 weeks. Neither of the diets with additional QPro showed a significant difference between food intake and body weight gain. The QPro additional diet significantly prevented the increase in plasma and liver total cholesterol levels. Excretion of bile acids in the QPro groups was higher than in the control group by the 14th day. Expression of mRNA of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver, a key enzyme for cholesterol biosynthesis, was suppressed by the QPro diet. These results suggest that the prevention of increases in plasma and liver cholesterol levels in mice fed the QPro diet can be ascribed to the promotion of fecal excretion of bile acid and to suppress the expression of the cholesterol synthesis enzyme

Recent Advances in Cancer Immunotherapy

The strategy to use the immune system to fight cancer is not a novel concept; in 1891, Coley reported the treatment of three cases of sarcoma by inoculation with erysipelas [...