Background
Diffuse-type gastric cancers (DGC) typically have a poor prognosis related to their invasion and metastasis, in which the epithelial–mesenchymal transition (EMT) is the initiation step. ...ULK2 plays a role in the autophagy initiation, which might provide a survival advantage in cancer cells. Although knock-down of
ULK2
reportedly induces autophagy and EMT in a lung cancer cell line, the mechanism of EMT via the down-regulation of
ULK2
, as well as its clinical significance, remains yet unclear. The present study, therefore, aims at clarifying this mechanism and its clinical significance in gastric cancers.
Methods
We examined
ULK2
mRNA expression in gastric cancer tissues and normal gastric tissues of healthy people. The effects of knock-downed
ULK2
were examined in two gastric cancer cells, which were investigated in terms of their gene expression changes by the mRNA microarray.
Results
ULK2 was strongly expressed in intestinal-type cancers but was scarcely expressed in DGC by immunohistochemical staining. Furthermore, we found that
ULK2
was methylated in DGC and was unmethylated in corresponding adjacent normal tissues. Then, we validated whether knock-down of
ULK2
could induce autophagy, cell migration, and EMT in NUGC3 and MKN45 cells. Using mRNA microarray analysis, we confirmed that knock-down of
ULK2
changed expressions of oncogenic genes associated with cell migration and EMT. Autophagy inhibitor suppressed cell migration and EMT induced by knock-down of
ULK2
in NUGC3 and MKN45.
Conclusion
Methylation silencing of
ULK2
could induce cell migration and EMT by means of autophagy induction, causing transformation to poorly differentiated cancers.
Abstract Purpose Ambiguity tolerance specific to the clinical context – in contrast to ambiguity tolerance as a personality trait – may vary with experience and has received considerable attention. ...Although this tolerance appears to be related to burnout and work engagement, few studies have examined this association among physicians. Thus, we aimed to examine the relationships between clinical context-specific ambiguity tolerance, burnout, and work engagement among physicians in Japan. Methods We conducted a nationwide cross-sectional study in Japan. We invited family physicians from 14 family medicine residency programs and physicians with specialties other than family medicine from monitors of an Internet survey company to participate in the study. We measured ambiguity tolerance in the clinical context using the Japanese version of the Tolerance of Ambiguity in Medical Students and Doctors (J-TAMSAD) scale, burnout using the Japanese version of the Burnout Assessment Scale (BAT-J), and work engagement using the Utrecht Work Engagement Scale (UWES). We performed a multivariable linear regression analysis to determine whether the J-TAMSAD scale score was associated with the BAT-J and UWES scores. Results 383 respondents were included in the analysis. After adjustment for possible confounders, clinical context-specific ambiguity tolerance showed a dose-dependent negative association with burnout (adjusted mean difference -0.39, 95% confidence interval (CI) -0.56 to -0.22 for the highest J-TAMSAD score quartile compared with the lowest). Ambiguity tolerance in the clinical context also showed a dose-dependent positive association with work engagement (adjusted mean difference 0.83, 95% CI 0.49 to 1.16 for the highest J-TAMSAD score quartile compared with the lowest). Conclusions Our study showed that tolerance for ambiguity in the clinical context was negatively associated with burnout, and positively associated with work engagement. These findings will be useful in developing interventions aimed at preventing burnout and promoting work engagement among physicians.
Focal seizures, characterized by excessive electrical excitation in a brain region, present diagnostic challenges due to diverse manifestations, particularly with non-motor symptoms. Here, we present ...a 69-year-old Japanese woman experiencing unexplained recurrent episodes of sweating, chills, and shivering. Despite exhaustive investigations that identified no abnormalities, her symptoms remained unalleviated by symptomatic treatments. The episodic nature of her presentations subsequently prompted a clinical suspicion of seizures, leading to further neurological evaluations. Magnetic resonance imaging (MRI) of the brain and electroencephalography (EEG) revealed chronic ischemic changes in the cerebral white matter and intermittent sharp and slow wave bursts in the frontal regions. These findings led to a diagnosis of focal seizures manifesting as autonomic symptoms. The patient's symptoms were successfully treated with carbamazepine. This case illustrates the importance of considering non-motor focal seizures in patients with episodic symptoms, even when routine tests show no abnormalities.
Background
The profiles of genetic and epigenetic alterations in cancer-related pathways are considered to be useful for selection of patients likely to respond to specific drugs, including ...molecular-targeted and epigenetic drugs. In this study, we aimed to characterize such profiles in gastric cancers (GCs).
Methods
Genetic alterations of 55 cancer-related genes were analyzed by a benchtop next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes.
Results
The WNT pathway was activated by mutations of
CTNNB1
in 2 GCs and potentially by aberrant methylation of its negative regulators, such as
DKK3
,
NKD1
, and
SFRP1
, in 49 GCs. The AKT/mTOR pathway was activated by mutations of
PIK3CA
and
PTPN11
in 4 GCs. The MAPK pathway was activated by mutations and gene amplifications of
ERBB2
,
FLT3
, and
KRAS
in 11 GCs. Cell-cycle regulation was affected by aberrant methylation of
CDKN2A
and
CHFR
in 13 GCs. Mismatch repair was affected by a mutation of
MLH1
in 1 GC and by aberrant methylation of
MLH1
in 2 GCs. The p53 pathway was inactivated by mutations of
TP53
in 19 GCs and potentially by aberrant methylation of its downstream genes in 38 GCs. Cell adhesion was affected by mutations of
CDH1
in 2 GCs.
Conclusions
Genes involved in cancer-related pathways were more frequently affected by epigenetic alterations than by genetic alterations. The profiles of genetic and epigenetic alterations are expected to be useful for selection of the patients who are likely to benefit from specific drugs.
The need to engage medical students in understanding the social and environmental determinants of health in disparate communities is increasing. However, previous reviews have noted the limited ...community diagnosis programs and program evaluation. Given the feasibility of the programs, it is expected to be widely available online. Therefore, this study used a realist approach to identify learning patterns through an online community diagnosis program, namely context (C), mechanism (M), and outcomes (O) patterns.
A 2-week general medicine clinical practice program was conducted for 4
- and 5
-year medical students at a medical university in Japan. The program included a one-hour zoom-based lecture, feedback for students on their presentations on community diagnosis, and a structural report on community diagnosis. We developed the program based on variation theory, which views discernment and variation in situations having time, space, and social dimensions as core learning. The students' reflections on their learning through the program were thematically analyzed through CMO perspectives. The realist approach used in the online diagnosis program evaluation allows us to explore, test, and refine what mechanisms work under what conditions (context) and with what interventions (including opportunities and resources), from which we can describe iteratively explainable results.
First, the medical students, who spent most of their time in the limited residential areas they lived in, discovered the characteristics of their own community by discovery learning and comparison among peers. Second, they increased their intrinsic interest in the community by discerning specific issues in their familiar community through community diagnosis. Third, they valued community diagnosis by identifying relationships between local data on health issues under their learning responsibility. Fourth, they become more flexible in their thinking and created new knowledge that would fit the local community, and their reflection on themselves was encouraged.
In this online community diagnosis program, medical students learned about the community through four types of learning patterns. Medical students may develop an understanding of community with interest using variation theory as a program development perspective and cognitive flexibility theory surrounding the essential ambiguity and abstraction of community.
Background
Helicobacter pylori
(
HP
) infection potently induces aberrant DNA methylation in gastric mucosae, and its accumulation is associated with gastric cancer risk. Cross-sectional analysis of ...methylation levels (fraction of methylated DNA molecules) and temporal analysis of methylation incidence suggested that methylation levels decrease after
HP
infection discontinues. We aimed to demonstrate the decrease in methylation levels.
Methods
Thirty-five patients with
HP
infection who had undergone curative endoscopic resection and 11 healthy volunteers were recruited. Methylation levels were quantified by real-time methylation-specific PCR. Histology was evaluated according to the updated Sydney System.
Results
In the 20 patients with successful eradication, the
FLNc
methylation level, along with infiltration of inflammatory cells, decreased from 0.6 to 0.4% at 6 weeks (
P
= 0.049) and remained low at 1 year. The
THBD
methylation level (30.1%) remained high at 6 weeks, but decreased to 19.0% at 1 year (
P
= 0.0032). Nine healthy volunteers with successful eradication tended to show a decrease of both
FLNc
and
THBD
at 6 weeks. However, the methylation levels after the decrease were still higher than those of healthy individuals without
HP
infection. In the 15 patients with persistent infection, the methylation levels remained the same. Before eradication, the
THBD
methylation level correlated with the degree of inflammatory cell infiltration (
P
<
0.05).
Conclusions
Methylation levels in gastric mucosae decreased to certain levels after
HP
eradication in profiles unique to individual markers. Involvement of chronic inflammation in methylation induction was suggested.
Background
Gastric cancer risk can be accurately predicted by measuring the methylation level of a single marker gene in gastric mucosa. However, the mechanism is still uncertain. We hypothesized ...that the methylation level measured reflects methylation alterations in the entire genome (methylation burden), induced by
Helicobacter pylori
(
H. pylori
) infection, and thus cancer risk.
Methods
Gastric mucosa of 15 healthy volunteers without
H. pylori
infection (G1), 98 people with atrophic gastritis (G2), and 133 patients with gastric cancer (G3) after
H. pylori
eradication were collected. Methylation burden of an individual was obtained by microarray analysis as an inverse of the correlation coefficient between the methylation levels of 265,552 genomic regions in the person’s gastric mucosa and those in an entirely healthy mucosa.
Results
The methylation burden significantly increased in the order of G1 (n = 4), G2 (n = 18), and G3 (n = 19) and was well correlated with the methylation level of a single marker gene (r = 0.91 for
miR124a-3
). The average methylation levels of nine driver genes tended to increase according to the risk levels (
P
= 0.08 between G2 vs G3) and was also correlated with the methylation level of a single marker gene (r = 0.94). Analysis of more samples (14 G1, 97 G2, and 131 G3 samples) yielded significant increases of the average methylation levels between risk groups.
Conclusions
The methylation level of a single marker gene reflects the methylation burden, which includes driver gene methylation, and thus accurately predicts cancer risk.
Caliciviruses are contagious pathogens of humans and various animals. They are the most common cause of viral gastroenteritis in humans, and can cause lethal diseases in domestic animals such as ...cats, rabbits and immunocompromised mice. In this study, we conducted cytopathic effect-based screening of 2080 selected compounds from our in-house library to find antiviral compounds against three culturable caliciviruses: feline calicivirus, murine norovirus (MNV) and porcine sapovirus (PoSaV). We identified active six compounds, of which two compounds, both related to theaflavins, showed broad antiviral activities against all three caliciviruses; three compounds (abamectin, a mixture of avermectin B1a and B1b; avermectin B1a; and (-)-epigallocatechin gallate hydrate) were effective against PoSaV only; and a heterocyclic carboxamide derivative (BFTC) specifically inhibited MNV infectivity in cell cultures. Further studies of the antiviral mechanism and structure-activity relationship of theaflavins suggested the following: (1) theaflavins worked before the viral entry step; (2) the effect of theaflavins was time- and concentration-dependent; and (3) the hydroxyl groups of the benzocycloheptenone ring were probably important for the anti-calicivirus activity of theaflavins. Theaflavins could be used for the calicivirus research, and as potential disinfectants and antiviral reagents to prevent and control calicivirus infections in animals and humans.
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