OsCM regulates rice defence system in response to UV light supplemented with drought stress.

Studies on plant responses to combined abiotic stresses are very limited, especially in major crop plants. The current study evaluated the response of chorismate mutase overexpressor (OxCM) rice line to combined UV light and drought stress. The experiments were conducted in pots in a growth chamber, and data were assessed for gene expression, antioxidant and hormone regulation, flavonoid accumulation, phenotypic variation, and amino acid accumulation. Wild-type (WT) rice had reduced the growth and vigour, while transgenic rice maintained growth and vigour under combined UV light and drought stress. ROS and lipid peroxidation analysis revealed that chorismate mutase (OsCM) reduced oxidative stress mediated by ROS scavenging and reduced lipid peroxidation. The combined stresses reduced biosynthesis of total flavonoids, kaempferol and quercetin in WT plants, but increased significantly in plants with OxCM. Phytohormone analysis showed that SA was reduced by 50% in WT and 73% in transgenic plants, while ABA was reduced by 22% in WT plants but increased to 129% in transgenic plants. Expression of chorismate mutase regulates phenylalanine biosynthesis, UV light and drought stress-responsive genes, e.g., phenylalanine ammonia lyase (OsPAL), dehydrin (OsDHN), dehydration-responsive element-binding (OsDREB), ras-related protein 7 (OsRab7), ultraviolet-B resistance 8 (OsUVR8), WRKY transcription factor 89 (OsWRKY89) and tryptophan synthase alpha chain (OsTSA). Moreover, OsCM also increases accumulation of free amino acids (aspartic acid, glutamic acid, leucine, tyrosine, phenylalanine and proline) and sodium (Na), potassium (K), and calcium (Ca) ions in response to the combined stresses. Together, these results suggest that chorismate mutase expression induces physiological, biochemical and molecular changes that enhance rice tolerance to combined UV light and drought stresses.

Arterial Spin-Labeling MR Imaging for the Differential Diagnosis of Venous-Predominant AVMs and Developmental Venous Anomalies.

BACKGROUND AND PURPOSE: Venous-predominant AVMs are almost identical in appearance to developmental venous anomalies on conventional MR imaging. Herein, we compared and analyzed arterial spin-labeling findings in patients with developmental venous anomalies or venous-predominant AVMs, using DSA as the criterion standard. MATERIALS AND METHODS: We retrospectively collected patients with either DVAs or venous-predominant AVMs, each available on both DSA and arterial spin-labeling images. Arterial spin-labeling imaging was visually assessed for the presence of hyperintense signal. CBF measured at the most representative section was normalized to the contralateral gray matter. The temporal phase of developmental venous anomalies or venous-predominant AVMs was measured on DSA as a delay between the first appearance of the intracranial artery and the lesion. Correlation between the normalized CBF and the temporal phase was evaluated. RESULTS: Analysis of 15 lesions (13 patients) resulted in categorization into 3 groups: typical venous-predominant AVMs (temporal phase, <2 seconds), intermediate group (temporal phase between 2.5 and 5 seconds), and classic developmental venous anomalies (temporal phase, >10 seconds). Arterial spin-labeling signal was markedly increased in the typical venous-predominant AVM group, while there was no discernible signal in the classic developmental venous anomaly group. In the intermediate group, however, 3 of 6 lesions showed mildly increased arterial spin-labeling signal. The normalized CBF on arterial spin-labeling and the temporal phase on DSA were moderately negatively correlated: r(13) = 0.66, P = .008. CONCLUSIONS: Arterial spin-labeling may predict the presence and amount of arteriovenous shunting in venous-predominant AVMs, and using arterial spin-labeling enables confirmation of typical venous-predominant AVMs without DSA. However, lesions with an intermediate amount of shunting suggest a spectrum of vascular malformations ranging from purely vein-draining developmental venous anomalies to venous-predominant AVMs with overt arteriovenous shunting.

Risk Factors Affecting Complications of Access Site in Vascular Intervention through Common Femoral Artery.

BACKGROUNDS: Traditionally, vascular interventions have been performed through the femoral artery. AIMS: The purpose of this study was to evaluate risk factors affecting access-site complications in patients with hepatocellular carcinoma or peripheral arterial disease in lower extremity who underwent vascular intervention by accessing the common femoral artery (CFA). PATIENTS AND METHODS: From December 2015 to November 2018, 287 patients underwent transarterial chemoembolization (TACE) or peripheral vascular intervention with ultrasound (US)-guided CFA access. Standard 18-gauge (G) access was used in 127 patients and Micropuncture® 21-G needles in 160 patients. Most access sites were managed with vascular closure devices and several were managed with manual compression. Within 24 hours after the procedure, all patients underwent US to evaluate the puncture site. RESULTS: Access-site complications occurred in 55 of 287 patients: 34 hematomas (11.9%), 20 pseudoaneurysms (7.0%), and 1 dissection (0.4%). In the crude model, risk factors related to access-site complications were the usage of 18-G needles (OR, 2.18; 95% CI, 1.17-4.07; P = 0.014), smoking (OR, 2.23; 95% CI, 1.16-4.27; P = 0.016), and approach route (OR, 3.23; 95% CI, 1.33-7.82; P = 0.009). Needle size (OR, 2.13; 95% CI, 1.10-4.12; P = 0.025) was the only factor associated with access-site complications in the adjusted model. CONCLUSION: Needle profile was the only factor associated with access-site complications in this study. Therefore, a needle with a smaller profile than an 18-G needle will reduce the incidence of complications at the access site.

Tumor immune microenvironment is influenced by frameshift mutations and tumor mutational burden in gastric cancer.

PURPOSE: Immunoscore can effectively predict prognosis in patients with colon cancer; however, its clinical application is limited. We modified the Immunoscore and created a tumor immune microenvironment (TIM) classification system for gastric carcinoma. Unlike previous studies that used small sample sizes or focused on particular immune-cell subtypes, our simplified system enables pathologists to classify gastric carcinomas intuitively using H&E-stained sections. METHODS: Samples from 326 patients with advanced gastric carcinoma were reviewed and analyzed by pathologists using simple determination and digital image analysis. Comprehensive results of cancer-panel sequencing, Epstein-Barr‒virus (EBV) status, and PD-L1, HER2, ATM, PTEN, MET, FGFR2, and EGFR immunohistochemistry were evaluated with respect to the TIM class. RESULTS: The TIM was classified as "hot" (n = 22), "immunosuppressed" (n = 178), "excluded" (n = 83), or "cold" (n = 43). TIM category was significantly associated with numbers of frameshift mutations (P < 0.001) and high tumor mutational burden (P < 0.004), and predicted overall survival. It was also significantly associated with age, histological type, degree of fibrosis, PD-L1 expression, loss of ATM and PTEN expression (P < 0.001), sex, EBV positivity, and HER2 overexpression (P < 0.04). "Hot" tumors were frequent in PD-L1 expressing and EBV-positive samples, and in those with ATM and PTEN loss. "Excluded" tumors were frequent in HER2-positive cases, whereas "cold" tumors were more frequent in younger patients with poorly cohesive histology and high fibrosis levels. CONCLUSIONS: TIM classification system for gastric carcinoma has prognostic significance and results in classes that are associated with molecular characteristics.

Immune response to hepatitis B vaccination and factors associated with poor immune response among healthcare workers.

BACKGROUND: Hepatitis B virus (HBV) infection is a major global health problem, and healthcare workers (HCWs) are at high risk for HBV infection. Current guidelines strongly recommend immunization and screening for high-risk groups. AIMS: We evaluated immunization and screening for HBV vaccination, assessed post-vaccination immune status of HCW's and characterized potential risk factors associated with poor immune response. MATERIALS AND METHODS: From January 2010 to December 2018, we retrospectively analyzed comprehensive health checkup data for a total of 303 HCWs who received an HBV vaccination. After vaccination, HBV surface antibody (anti-HBs) titers were collected and the distribution of immune response types was determined. Risk factors for poor immune responses were identified using logistic regression. RESULTS: A total of 213 HCWs were analyzed after exclusion based on the exclusion criteria. In total, 28 (13.2%) HCWs had anti-HBs titers <100 mIU/mL (hyporesponsive/nonresponsive groups), and 185 (86.8%) had anti-HBs titers ≥100 mIU/mL (hyperresponsive group). Follow-up observations found that 75% (21/28) of the hyporesponsive/nonresponsive groups did not have increased anti-HBs titers or did not maintain an increased response. A multivariate analysis showed that HBV antibody titers at the time of employment were a significant risk factor (OR, 6.12; CI, 1.34-27.93; P = 0.019). CONCLUSIONS: More attention should be paid to groups that are hyporesponsive/nonresponsive after vaccination and to those with low anti-HBs titers at the beginning of employment. HCWs can be further protected from HBV if their results are discussed at postvaccination follow-ups.

A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Plant growth-promoting endophytic bacteria augment growth and salinity tolerance in rice plants.

Salt stress negatively affects growth and development of plants. However, it is hypothesized that plant growth-promoting endophytic bacteria can greatly alleviate the adverse effects of salinity and can promote growth and development of plants. In the present research, we aimed to isolate endophytic bacteria from halotolerant plants and evaluate their capacity for promoting crop plant growth. The bacterial endophytes were isolated from selected plants inhabiting sand dunes at Pohang beach, screened for plant growth-promoting traits and applied to rice seedlings under salt stress (NaCl; 150 mm). Out of 59 endophytic bacterial isolates, only six isolates, i.e. Curtobacterium oceanosedimentum SAK1, Curtobacterium luteum SAK2, Enterobacter ludwigii SAK5, Bacillus cereus SA1, Micrococcus yunnanensis SA2, Enterobacter tabaci SA3, resulted in a significant increase in the growth of Waito-C rice. The cultural filtrates of bacterial endophytes were tested for phytohormones, including indole-3-acetic acid, gibberellins and organic acids. Inoculation of the selected strains considerably reduced the amount of endogenous ABA in rice plants under NaCl stress, however, they increased GSH and sugar content. Similarly, these strains augmented the expression of flavin monooxygenase (OsYUCCA1) and auxin efflux carrier (OsPIN1) genes under salt stress. In conclusion, the pragmatic application of the above selected bacterial strains alleviated the adverse effects of NaCl stress and enhanced rice growth attributes by producing various phytohormones.

Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer.

BACKGROUND: Heat shock protein 90 (HSP90) possesses two major isoforms - HSP90α and HSP90ß. They have essential roles in the protection against stressful conditions. They are also important for the re-establishment of cellular homeostasis. We investigated the clinical significance of HSP90α and HSP90ß expression in patients with gastric cancer (GC). METHODS: HSP90α and HSP90ß expression levels were examined immunohistochemically in surgical specimens obtained from 186 GC patients. The correlations between their expression levels and clinicopathological parameters including patient survival were analyzed. RESULTS: The frequencies of larger tumor size (maximum diameter ≥4 cm) and more prominent tumor invasion (≥pT3) in the high intensity HSP90α expression group were 73.4% and 68.8% higher, respectively, than those in the low intensity group (both P = 0.001). High HSP90α expression level was also significantly associated with lymphatic invasion, lymph node metastasis, and advanced stage (TNM stage ≥III) disease (P = 0.047, P = 0.046, and P = 0.004, respectively). Patients with high HSP90α expression levels demonstrated significantly worse survival than those with low HSP90α expression levels (P = 0.047). In contrast, survival did not differ significantly according to the intensity of HSP90ß expression. CONCLUSIONS: Our results showed that HSP90α overexpression might be associated with disease progression and poorer survival in patients with GC. Therefore, HSP90α could be used as possible biomarker for the prognosis of GC.

Phase lag entropy as a hypnotic depth indicator during propofol sedation.

Phase lag entropy, an electro-encephalography-based hypnotic depth indicator, calculates diversity in temporal patterns of phase relationship. We compared the performance of phase lag entropy with the bispectral index™ in 30 patients scheduled for elective surgery. We initiated a target-controlled infusion of propofol using the Schnider model, and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation scale every 30 s with each stepwise increase in the effect-site propofol concentration. Phase lag entropy and bispectral index values were recorded. The correlation coefficient and prediction probability between phase lag entropy or bispectral index and the sedation level or effect-site propofol concentration were analysed. We calculated baseline variabilities of phase lag entropy and bispectral index. In addition, we applied a non-linear mixed-effects model to obtain the pharmacodynamic relationships among the effect-site propofol concentration, phase lag entropy or bispectral index and sedation level. As sedation increased, phase lag entropy and bispectral index both decreased. The prediction probability values of phase lag entropy and bispectral index for sedation levels were 0.697 and 0.700 (p = 0.261) and for the effect-site concentration of propofol were 0.646 and 0.630 (p = 0.091), respectively. Baseline variability in phase lag entropy and bispectral index was 3.3 and 5.7, respectively. The predicted propofol concentrations, using the Schnider pharmacokinetic model, producing a 50% probability of moderate and deep sedation were 1.96 and 3.01 µg.ml-1 , respectively. Phase lag entropy was found to be useful as a hypnotic depth indicator in patients receiving propofol sedation.

PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer.

This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using in situ hybridization and MSI status was performed using PCR and MLH1 IHC. The PD-L1 segment was associated with increased T-cell infiltrates, while the MSI-high segment was enriched for PD-L1, CD3, and CD8. Multivariate analysis confirmed PD-L1 positivity, high CD3 and high CD8 as independent prognostic factors for both disease-free survival and overall survival (all p < 0.05). Patients with MSI-high tumours had better overall survival by both univariate and multivariate analysis. The ATM-low and HER2-high subgroups differed markedly in their immune profile; the ATM-low subgroups enriched for MSI, PD-L1 positivity and CD8 + T-cells, while the HER2 segment was enriched for MSS, with no enrichment for immune markers. Hence, we demonstrate a molecular profiling approach that can divide GC into four molecular subgroups, namely ATM-low, HER2-high, PD-L1 positive and MSI-high with differing levels of immune infiltrates and prognostic significance which may help to stratify patients for response to targeted therapies.

Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer.

BACKGROUND: Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. PATIENTS AND METHODS: Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. RESULTS: In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (APhigh), and this was used to define the APhigh tertile of the second cohort (13 APhigh of 37). APhigh tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the APhigh group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099-0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. CONCLUSION: A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT#02589496.

Clinicopathological features and outcome of type 3 gastric neuroendocrine tumours.

BACKGROUND: With the widespread use of endoscopy, small and low-grade type 3 gastric neuroendocrine tumours (NETs) are increasingly being detected. The clinicopathological features, biological behaviour and appropriate treatment strategy for these NETs remain unclear. METHODS: Patients with biopsy-proven gastric NET and a normal fasting serum gastrin level were identified from a prospectively maintained database. Clinicopathological features and long-term outcome of local resection for type 3 NETs were reviewed retrospectively and compared according to tumour grade. RESULTS: Some 32 patients with type 3 gastric NETs were included (25 patients with NET grade G1, 5 with G2 and 2 with G3). Pathological tumour size was 2·0 cm or less in 30 patients. All tumours were well differentiated, even G3 lesions, and all tumours but one were confined to the submucosal layer. G1 NETs were significantly smaller and had a significantly lower lymphovascular invasion rate than G2 and G3 NETs. Twenty-two patients with a G1 NET without lymphovascular invasion were treated with wedge or endoscopic resection. After a median follow-up of 59 (range 6-102) months, no patient with a G1 NET of 1·5 cm or smaller developed recurrence and one patient with a G1 NET larger than 1·5 cm had recurrence in a perigastric lymph node. Among seven patients with a G2 or G3 NET, two had lymph node metastasis and one had liver metastases. CONCLUSION: Low-grade type 3 gastric NET has non-aggressive features and a favourable prognosis. Wedge or endoscopic resection may be a valid option for patients with type 3 gastric G1 NET no larger than 1·5 cm without lymphovascular invasion.

Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes.

BACKGROUND: Euglycaemic ketoacidosis has been reported after sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. However, the degree of ketonaemia and its metabolic effects have not been well investigated. Our study examined the degree of ketonaemia induced by SGLT2 inhibition and its association with metabolic profiles in type 2 diabetes mellitus (T2DM). METHODS: Biochemical parameters, including insulin, glucagon, free fatty acid (FFA), ß-hydroxybutyrate (BHB) and acetoacetate (ACA) levels, were measured in 119 T2DM patients after dapagliflozin treatment for>3 months, and compared with a matched control group. RESULTS: Levels of total ketones, BHB and ACA were significantly higher in the dapagliflozin group than in the control group: 283.7±311.0 vs 119.8±143.8µmol/L; 188.3±226.6 vs 78.0±106.7µmol/L; and 94.1±91.3 vs 41.8±39.1µmol/L, respectively (all P<0.001). After dapagliflozin treatment, BHB was higher than the upper limit of normal (>440µmol/L) in 13 (10.9%) patients who had no relevant symptoms. BHB level after dapagliflozin treatment correlated positively with HbA1c (r=0.280), FFA levels (r=0.596) and QUICKI (r=0.238), and negatively with BMI (r=-0.222), insulin-to-glucagon ratio (r=-0.199) and HOMA-IR (r=-0.205; all P<0.05). On multivariable linear regression analysis, QUICKI was independently associated with BHB level. CONCLUSION: Ketone levels were higher in T2DM patients treated with dapagliflozin than in controls, but with no clinical symptoms or signs of ketonaemia. Low-grade ketonaemia after dapagliflozin treatment may also be associated with improved insulin sensitivity.

HLA-A*02:687, a novel allele identified by sequence-based typing in cord blood from a Korean woman.

A*02:687 showed one nucleotide difference with A*02:01:01:01 resulting in an amino acid change.

Navigation programs, are they helpful for perioperative care with thyroid cancer patients?

The purpose of this study was to develop and evaluate a navigation program for patients with thyroid cancer. The navigation program was developed following an analysis of the unmet needs of patients who underwent surgery for thyroid cancer. Ninety-nine patients in the control group received usual care, and 95 in the navigation group were managed with a navigation program during the perioperative period. The effectiveness of the navigation program was assessed by administering a questionnaire to both groups. Overall satisfaction scores were significantly higher in the navigation than in the control group (p = .025), as were satisfaction scores on the continuity of information (p < .001), the continuity of management (p = .002), the continuity of relationships with healthcare providers (p<.001), and patient empowerment (p < .001). The newly developed navigation program for patients with thyroid cancer was effective in raising satisfaction levels and in actively managing the disease during the perioperative period.

Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition.

Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Patients and methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition. Results: NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line. Conclusions: RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.

Sarcopenia as a Predictor of Future Cognitive Impairment in Older Adults.

OBJECTIVES: We investigated the association between the indices of sarcopenia and future risk of cognitive impairment in older adults. DESIGN: Community-based prospective cohort study. SETTING: Community. PARTICIPANTS: A total of 297 participants aged ≥65 years without cognitive impairment at baseline (mean age, 71.9 ± 6.6 years; men:women, 158:139) and who underwent cognitive evaluation at the 5-year follow-up. MEASUREMENTS: Sarcopenia parameters including appendicular lean mass (ALM), handgrip strength, and the Short Physical Performance Battery (SPPB) score at baseline were compared according to the later progression of mild cognitive impairment (MCI) and/or dementia. The operational criteria suggested by the Foundation for the National Institutes of Health Sarcopenia Project were used. We performed multivariate logistic regression analysis to identify the independent indicators of the progression of cognitive impairment. RESULTS: Among the 297 participants, 242 (81.5%) remained cognitively normal (nonprogression group), whereas 55 (18.5%) showed progression of cognitive impairment (50 subjects (16.8%) to MCI and 5 subjects (1.7%) to dementia) (progression group). Compared with the nonprogression group, subjects in the progression group were older, had a lower educational level, and had lower physical function as assessed by the SPPB; a higher percentage were depressed. Other baseline markers of sarcopenia, including the ALM-to-body mass index ratio and handgrip strength did not differ significantly between the groups. The association between a low SPPB score (<9) and progression of cognitive impairment was maintained after adjustment for conventional risk factors for cognitive impairment (hazard ratio 2.222, 95% confidence interval 1.047-4.716, P = 0.038). CONCLUSION: Decreased physical performance, as assessed by the SPPB, but not other markers of sarcopenia, was independently associated with the risk of later cognitive impairment in older adults.

HLA-A*33:102, a novel allele identified by sequence-based typing in cord blood from a Korean woman.

The new allele A*33:102 showed two nucleotide differences with A*33:03:01 in exon 3.

Novel strategy for a bispecific antibody: induction of dual target internalization and degradation.

Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.