Relationship between Epidermal Growth Factor Receptor Mutations and Adverse Events in Non-Small Cell Lung Cancer Patients treated with Afatinib.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as afatinib are used for non-small cell lung cancer (NSCLC) and show varying efficacy depending on EGFR gene mutation. Few studies have examined the relationship between EGFR gene mutations and the adverse events of afatinib in NSCLC. This retrospective study included 32 Japanese patients with NSCLC with EGFR gene mutation who were treated with afatinib between May 2014 and August 2018 at Kagawa University Hospital. Among the 32 Japanese patients with NSCLC treated with afatinib, 19 patients were positive for exon 19 deletion mutation (Del 19) and 13 patients were negative for Del 19. The incidence of grade ≥ 2 skin rash was slightly higher in patients positive for Del 19 (42.1% vs. 7.7%, P = 0.050). No significant differences were detected in other adverse events between the two patient groups. Patients positive for Del 19 also showed significantly longer median progression-free survival (288 vs. 84 days, P = 0.049). Our study indicates a higher incidence of skin rash associated with afatinib treatment in Japanese patients with NSCLC positive for Del 19 compared with patients without Del 19. The Del 19 positive patient group also showed better progression-free survival. J. Med. Invest. 68 : 125-128, February, 2021.

An integrated community mental healthcare program to reduce suicidal ideation and improve maternal mental health during the postnatal period: the findings from the Nagano trial.

BACKGROUND: During the perinatal period, suicides are more likely to occur in those with depression and who are not receiving active treatment at the time of death. Suicide is a common outcome in people with suicide ideation. We developed an intervention program taking care of comprehensive perinatal maternal mental healthcare to prevent suicide ideation. We hypothesized that our intervention program could reduce postnatal suicide ideation and improve maternal mental health. METHODS: We performed a controlled trial to examine the usual postnatal care plus a maternal suicide prevention program (the intervention group) compared with usual postnatal care alone, which comprised home visits by public health nurses without mental health screening (the control group) in Nagano city, Japan. In total, 464 women were included; 230 were allocated to the control group and 234 to the intervention group. The intervention had three components: 1) all the women received postnatal mental health screening by public health nurses who completed home visits during the neonatal period, 2) the intervention was administered by a multidisciplinary clinical network, and 3) systematic follow-up sheets were used to better understand bio-psycho-social characteristics of both the mothers and their infants and develop responsive care plans. We measured the participants' mental health at 3-4 months postpartum (T1) and 7-8 months postpartum (T2) using the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: Suicidal ideation was significantly lower in the intervention group compared with the control group at T1 (p = 0.014); however, this significant between-group difference did not continue to T2 (p = 0.111). We measured the intervention effects on maternal mental health using the total score of the EPDS, which was significantly improved in the intervention group compared with the control group at T1. Here, the significant difference continued to T2 (p = 0.049). CONCLUSIONS: Our results indicate that our program may reduce maternal suicidal ideation at 3-4 months postnatally and improve women's mental health during the postnatal periods of 3-4 to 7-8 months. Postnatal maternal mental healthcare, including services to reduce suicide ideation, should be included as an important component of general postnatal care. TRIAL REGISTRATION: Name of registry: A multidisciplinary intervention program for maternal mental health in perinatal periods. UMIN Clinical Trials Registry number: UMIN000033396 . Registration URL: https://upload.umin.ac.jp/cgibin/ctr/ctr_view_reg.cgi?recptno=R000038076 Registration date: July 15, 2018. Registration timing: retrospective.

Consumption of a meal containing refined barley flour bread is associated with a lower postprandial blood glucose concentration after a second meal compared with one containing refined wheat flour bread in healthy Japanese: A randomized control trial.

OBJECTIVE: Foods reducing postprandial hyperglycemia could suppress the postprandial blood glucose response after the next meal (a "second-meal" effect). However, the second-meal effect of refined barley flour bread has not been evaluated. The aim of this study is to determine whether consumption of refined barley flour bread reduces postprandial glucose concentrations after this and the subsequent meal. METHODS: We enrolled 23 healthy young Japanese adults and conducted a randomized, double-blind, placebo-controlled, crossover study. The participants consumed refined barley flour bread containing 2.5 g ß-glucan or refined wheat flour bread in a first meal, then consumed three rice balls as a second meal. Their postprandial blood glucose concentrations were measured 0, 15, 30, 45, 60, 90, and 120 min after both meals. Participants with fasting glucose concentrations above the diagnostic threshold for diabetes were excluded. RESULTS: The blood glucose concentration 30 min after the first meal was significantly lower (P < 0.05) if refined barley flour bread (7.1 ± 1.0 mmol/L) rather than refined wheat flour bread (7.7 ± 1.2 mmol/L) was consumed. Significantly lower glucose concentrations after the second meal measured at 60 (P < 0.05, barley flour bread: 8.7 ± 1.8 mmol/L, wheat flour bread: 9.3 ± 1.7 mmol/L) and 90 min (P < 0.01, barley flour bread: 7.8 ± 1.4 mmol/L, wheat flour bread: 8.8 ± 2.1 mmol/L) were lower in participants who had previously consumed the refined barley flour bread. CONCLUSIONS: Consumption of bread made with refined barley flour lowers postprandial blood glucose concentration after this and a subsequent meal compared with the consumption of refined wheat flour bread in healthy young Japanese adults.

The kick-in system: a novel rapid knock-in strategy.

Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES) cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in" to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2): p.Tyr284Cys (Y284C) and p.Ala306Thr (A306T); both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined phenotyping.

Liganded thyroid hormone receptor-alpha enhances proliferation of pancreatic beta-cells.

Failure of the functional pancreatic beta-cell mass to expand in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is important for beta-cell proliferation in adult animals. In rat pancreatic beta-cell lines (RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T(3)) enhances cell proliferation. This result suggests that T(3) is required for beta-cell proliferation or replication. To identify the role of thyroid hormone receptor alpha (TR(alpha)) in the processes of beta-cell growth and cell cycle regulation, we constructed a recombinant adenovirus vector, AdTR(alpha). Infection with AdTR(alpha) to RIN5F cells increased the expression of cyclin D1 mRNA and protein. Overexpression of the cyclin D1 protein in AdTR(alpha)-infected cells led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway, along with cell cycle progression and cell proliferation following treatment with 100 nM T(3). Conversely, lowering cellular cyclin D1 by small interfering RNA knockdown in AdTR(alpha)-infected cells led to down-regulation of the cyclin D1/CDK/Rb/E2F pathway and inhibited cell proliferation. Furthermore, in immunodeficient mice with streptozotocin-induced diabetes, intrapancreatic injection of AdTR(alpha) led to the restoration of islet function and to an increase in the beta-cell mass. These results support the hypothesis that liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass during postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic strategies that can induce the expansion and regeneration of beta-cells.

Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes.

OBJECTIVE: Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear. RESEARCH DESIGN AND METHODS: Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR. RESULTS: Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells. CONCLUSIONS: These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.

Characterization of halophilic alkaline phosphatase from Halomonas sp. 593, a moderately halophilic bacterium.

A halophilic alkaline phosphatase was highly purified (about 510-fold with about 21% yield) from a moderate halophile, Halomonas sp. 593. The N-terminal 35 amino acid sequence of this enzyme was found to be more acidic than those previously isolated from Vibrio spp., and this enzyme was partially resistant to SDS. Several enzymatic properties demonstrated that it showed higher halophilicity than those enzymes from Vibrio spp.