Advances, breakthroughs, and challenges in gastric cancer surgery.

Gastric cancer (GC) remains a substantial health burden worldwide, ranking fifth in incidence and third in mortality among all cancer types. Surgeons have persistently attempted to address this growing burden through surgical management of GC encompassing various aspects of surgery, including advances in surgical techniques and tools for minimally invasive surgery, novel technology for real-time image-guided surgery, and function-preserving and oncometabolic surgeries, aimed at improving patients' quality of life. The current perspective discusses the five most critical dimensions of the recent technical improvements and conceptual changes in GC surgery. We recommend further exploration of long-term benefits of these advancements, identification of breakthrough solutions to address current challenges, and delivery of the best quality of care.

EGFR Tyrosine Kinase Inhibitor Lazertinib Activates a Subset of Mouse Sensory Neurons Via TRPA1.

Lazertinib (JNJ-73841937, YH25448) is a mutant-selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor targeting both the T790M and activating mutation while sparing wild-type epidermal growth factor receptor. Paresthesia is one of the most common adverse events seen with lazertinib treatment, suggesting that lazertinib could affect the sensory nervous system. However, the mechanism of action for this paresthesia remains unclear. In this study, we investigated whether and how lazertinib affects peripheral sensory neurons. Through Fura-2-based calcium imaging and whole-cell patch clamp recording in primary-cultured dorsal root ganglion (DRG) neurons from adult mice, we found that application of lazertinib elicits spontaneous calcium responses in a subset of small-to-medium-sized neurons. Moreover, lazertinib induced spontaneous firings and hyperexcitability in a subset of transient receptor potential vanilloid 1-lineage DRG neurons and sensitized transient receptor potential ankyrin 1 (TRPA1) response, while sparing transient receptor potential vanilloid 1 response. Lazertinib-responsive neurons were also responsive to capsaicin, further supporting that lazertinib selectively activates nociceptive neurons. Lazertinib-induced calcium responses were pharmacologically blocked with HC-030031 (TRPA1 antagonist) and MDL-12330A (adenylyl cyclase inhibitor), suggesting that lazertinib activates sensory neurons through indirect activation of TRPA1. However, unlike vincristine which produces peripheral neuropathy by axonal degeneration, lazertinib did not cause neurite fragmentation in cultured DRG neurons. Finally, intraplantar injection of lazertinib induced TRPA1-dependent pain-like behaviors in vivo. Collectively, our data suggest a direct effect of lazertinib on nociceptive sensory neurons via TRPA1 selective mechanisms, which could be a putative mechanism of lazertinib-induced sensory abnormalities in clinical patients. PERSPECTIVE: This article presents a TRPA1-dependent, lazertinib-induced activation of mouse sensory neurons in vitro and lazertinib-induced pain-like behaviors in vivo. The same mechanisms may underlie the clinical condition, suggesting that TRPA1 could be a potential therapeutic target to manage lazertinib-induced paresthesia.

VITAS, a sensitive in vivo selection assay to discover enzymes producing antiviral natural products.

To discover new broad-spectrum antiviral nucleotide analogues from natural resources or through protein engineering, we have developed a sensitive in vivo selection assay named Viral polymerase-Inhibition Toxin-Associated Selection (VITAS). We show that the assay works with enzymes from three Kingdoms of life.

Silent Speech Recognition with Strain Sensors and Deep Learning Analysis of Directional Facial Muscle Movement.

Silent communication based on biosignals from facial muscle requires accurate detection of its directional movement and thus optimally positioning minimum numbers of sensors for higher accuracy of speech recognition with a minimal person-to-person variation. So far, previous approaches based on electromyogram or pressure sensors are ineffective in detecting the directional movement of facial muscles. Therefore, in this study, high-performance strain sensors are used for separately detecting x- and y-axis strain. Directional strain distribution data of facial muscle is obtained by applying three-dimensional digital image correlation. Deep learning analysis is utilized for identifying optimal positions of directional strain sensors. The recognition system with four directional strain sensors conformably attached to the face shows silent vowel recognition with 85.24% accuracy and even 76.95% for completely nonobserved subjects. These results show that detection of the directional strain distribution at the optimal facial points will be the key enabling technology for highly accurate silent speech recognition.

The Nature of Noradrenergic Volume Transmission From Locus Coeruleus to Brainstem Mesencephalic Trigeminal Sensory Neurons.

Noradrenergic neurons in the locus coeruleus (LC) release noradrenaline (NA) that acts via volume transmission to activate extrasynaptic G-protein coupled receptors (GPCRs) in target cells throughout the brain. As the closest projection, the dorsal LC laterally adjoins the mesencephalic trigeminal nucleus (MTN), in which proprioceptive primary sensory neurons innervating muscle spindles of jaw-closing muscles are exceptionally located. MTN neurons express α2-adrenergic receptors (α2-ARs) and display hyperpolarization-activated cyclic nucleotide-gated (HCN) currents (Ihs), which is downregulated by α2-AR activation. To quantify the activity-dependent outcome of volume transmission of NA from LC to MTN, we investigated how direct LC activation inhibits Ih in MTN neurons by performing dual whole-cell recordings from LC and MTN neurons. Repetition of 20 Hz spike-train evoked with 1-s current-pulse in LC neurons every 30 s resulted in a gradual decrease in Ih evoked every 30 s, revealing a Hill-type relationship between the number of spike-trains in LC neurons and the degree of Ih inhibition in MTN neurons. On the other hand, when microstimulation was applied in LC every 30 s, an LC neuron repeatedly displayed a transient higher-frequency firing followed by a tonic firing at 5-10 Hz for 30 s. This subsequently caused a similar Hill-type inhibition of Ih in the simultaneously recorded MTN neuron, but with a smaller Hill coefficient, suggesting a lower signal transduction efficacy. In contrast, 20 Hz activity induced by a 1-s pulse applied every 5-10 s caused only a transient facilitation of Ih inhibition followed by a forced termination of Ih inhibition. Thus, the three modes of LC activities modulated the volume transmission to activate α2-adrenergic GPCR to differentially inhibit Ih in MTN neurons.

Vasomotor symptoms and carotid artery intima-media thickness among Korean midlife women.

OBJECTIVES: To evaluate the association between vasomotor symptoms (VMS) and carotid intima-media thickness (CIMT) in Korean midlife women. STUDY DESIGN: This cross-sectional study included 918 Korean women aged 45-65 years who attended their routine health checkup at a single institution between 2013 and 2016. MAIN OUTCOME MEASURES: All participants' results on the Menopause Rating Scale were used to assess the VMS. Severe and very severe VMS were combined into severe VMS. CIMT and blood flow velocities were measured on the common carotid arteries using duplex ultrasound. RESULTS: All participants' mean age was 54.73 ± 5.37 years, and 627 (68.3%) were postmenopausal. A total of 401 (43.7%) women reported VMS: 217 (23.6%), mild; 109 (11.9%), moderate; and 75 (8.2%), severe. The mean CIMT was 0.062 ± 0.017 mm and 0.064 ± 0.019 mm in premenopausal and menopausal women, respectively. In the multivariate linear regression analysis, the CIMT of women with moderate VMS was 0.102 mm (95% confidence interval [CI] = 0.002-0.009) more than that of women with no VMA, and the CIMT of women with severe VMS was 0.246 mm (95% CI = 0.012-0.021) more than that of women with no VMS, after adjusting for several confounders, including age, body mass index, and lifestyle factors. Severe VMS were associated with the risk of thickened CIMT (≥0.075 mm) and/or plaques (odds ratio = 2.90, 95% CI = 1.74-4.84) in the logistic regression analysis after adjusting for the same variables. CONCLUSIONS: Moderate and severe VMS are independently associated with increased CIMT in otherwise healthy Korean midlife women. Clinicians managing midlife women with bothersome VMS should consider screening for subclinical cardiovascular diseases.

Common bacterial metabolite indole directly activates nociceptive neuron through transient receptor potential ankyrin 1 channel.

ABSTRACT: Nociceptors are known to directly recognize bacterial cell wall components or secreted toxins, thereby leading to pain induced by bacterial infection. However, direct activation of nociceptors by bacterial metabolites remains unclear although bacteria produce numerous metabolites related to health and disease. In this study, we investigated whether and how a common bacterial metabolite, indole, which is produced by normal microflora of the gastrointestinal tract and oral cavity, can directly activate nociceptive sensory neurons. We found that indole elicits calcium response and evokes inward currents in subsets of dorsal root ganglia (DRG) neurons. Intraplantar (i.pl.) injection of indole produced nocifensive behaviors in adult mice, which were enhanced in complete Freund's adjuvant-induced chronic inflammatory condition. Indole increased calcitonin gene-related peptide release in DRG neurons, and i.pl. injection of indole increased hind paw thickness, suggesting its role in generation of neurogenic inflammation. These in vitro and in vivo indole-induced responses were pharmacologically blocked by transient receptor potential ankyrin 1 (TRPA1) antagonist, HC-030031, and significantly abolished in TRPA1 knockout (KO) mice, indicating that indole targets TRPA1 for its action in DRG neurons. Nocifensive licking behavior induced by the injection of live Escherichia coli was significantly decreased in tryptophanase mutant (TnaA KO) E. coli- injected mice that lack indole production, further supporting the idea that bacteria-derived indole can induce pain during infection. Identifying the mechanism of action of indole through TRPA1 provides insights into bacteria-neuron interactions and the role of bacterial metabolites in pain signaling, especially in inflammation-accompanied bacterial infection.

Inkjet-Printing-Based Density Profile Engineering of Single-Walled Carbon Nanotube Networks for Conformable High-On/Off-Performance Thin-Film Transistors.

Random networks of single-walled carbon nanotubes (SWCNTs) offer new-form-factor electronics such as transparent, flexible, and intrinsically stretchable devices. However, the long-standing trade-off between carrier mobility and on/off ratio due to the coexistence of metallic and semiconducting nanotubes has limited the performance of SWCNT-random-network-based thin-film transistors (SWCNT TFTs), hindering their practical circuit-level applications. Methods for high-purity separation between metallic and semiconducting nanotubes have been proposed, but they require high cost and energy and are vulnerable to contamination and nanotube shortening, leading to performance degradation. Alternatively, additional structures have been proposed to reduce the off-state current, but they still compromise carrier mobility and suffer from inevitable expansion in device dimensions. Here, we propose a density-modulated SWCNT network using an inkjet-printing method as a facile approach that can achieve superior carrier mobility and a high on/off ratio simultaneously. By exploiting picoliter-scale drops on demand, we form a low-density channel network near the source and drain junctions and a high-density network at the middle of the channel. The modulated density profile forms a large band gap near the source and drain junctions that efficiently blocks electron injection under the reverse bias and a narrow band gap at the high-density area that facilitates the hole transport under the on-state bias. As a result, the density-modulated SWCNT TFTs show both high carrier mobility (27.02 cm2 V-1 s-1) and a high on/off ratio (>106). We also demonstrate all-inkjet-printed flexible inverter circuits whose gain is doubled by the density-modulated SWCNT TFTs, highlighting the feasibility of our approach for realizing high-performance flexible and conformable electronics.

Vasomotor Symptoms: More Than Temporary Menopausal Symptoms.

Vasomotor symptoms (VMS), such as hot flashes and night sweating, are classic menopausal symptoms experienced by a majority of perimenopausal and postmenopausal women. VMS have received a great deal of attention due to their relationship with cardiometabolic risk. Further, accumulating evidence indicates that VMS are associated with an increased risk of several chronic diseases, including metabolic syndrome, type 2 diabetes mellitus, nonalcoholic fatty liver diseases, and osteoporosis in perimenopausal and postmenopausal women. These findings suggest VMS as biomarkers of impaired cardiometabolic conditions rather than just temporary symptoms in menopausal women, warranting further studies to confirm the casual relationship of VMS with these diseases and the exact underlying mechanism in this context.

Understanding the sensory characteristics and drivers of liking for gochujang (Korean fermented chili pepper paste).

The present study investigated the sensory characteristics of 31 types of gochujang, a Korean fermented chili paste, produced in various regions of Korea. Generic descriptive analysis was conducted to analyze the sensory properties of the samples. Among these, four samples were selected for consumer taste test based on their distinct sensory profiles. The drivers of liking for gochujang were identified when the samples were applied to four different food systems. Consumers (age range: 20's-60's) rated the acceptance of the samples. ANOVA and multivariate analyses were conducted on the data. The types of carbohydrate sources or usage of additional seasoning showed stronger influence on the sensory characteristics of gochujang than the production location. Samples with strong fermented soy and fish sauce characteristics were fairly unacceptable to the consumers. The positive drivers of gochujang were appropriate levels of spiciness and sweet odors/flavors, whereas the negative drivers were off-note and fermentation-related flavors.