Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB).

Background: Molecular biomarkers are reshaping patient stratification and treatment decisions, yet their precise use and best implementation remain uncertain. Intratumor heterogeneity (ITH), an area of increasing research interest with prognostic value across various conditions, lacks defined clinical relevance in certain non-small cell lung cancer (NSCLC) subtypes. Exploring the relationship between ITH and tumor mutational burden (TMB) is crucial, as their interplay might reveal distinct patient subgroups. This study evaluates how the ITH-TMB dynamic affects prognosis across the two main histological subtypes of NSCLC, squamous cell and adenocarcinoma, with a specific focus on early-stage cases to address their highly unmet clinical needs. Methods: We stratify a cohort of 741 early-stage NSCLC patients from The Cancer Genome Atlas (TCGA) based on ITH and TMB and evaluate differences in clinical outcomes. Additionally, we compare driver mutations and the tumor microenvironment (TME) between high and low ITH groups. Results: In lung squamous cell carcinoma (LUSC), high ITH predicts an extended progression-free survival (PFS) (median: 21 vs. 14 months, P=0.01), while in lung adenocarcinoma (LUAD), high ITH predicts a reduced PFS (median: 15 vs. 20 months, P=0.04). This relationship is driven by the low TMB subset of patients. Additionally, we found that CD8 T cells were enriched in better-performing subgroups, regardless of histologic subtype or ITH status. Conclusions: There are significant differences in clinical outcomes, driver mutations, and the TME between high and low ITH groups among early-stage NSCLC patients. These differences may have treatment implications, necessitating further validation in other NSCLC datasets.

Effect of rigorous fluid management using monitoring of ECW ratio by bioelectrical impedance analysis in critically ill postoperative patients: A prospective, single-blind, randomized controlled study.

BACKGROUND & AIMS: Precise assessment of postoperative volume status is important to administrate optimal fluid management. Bioelectrical impedance analysis (BIA) which measures the body composition using electric character. Extracellular water (ECW) ratio by BIA represented as the ratio of ECW to total body water (TBW) and is known to reflect the hydration status. Based on this, we aimed to determine whether aggressive fluid control using ECW ratio could improve clinical outcomes through a single blind, randomized controlled trial. METHODS: From November 2021 to December 2022, intensive care unit (ICU) patients admitted after surgery were randomly assigned to an intervention group or a control group whether postoperative fluid management was controlled via BIA. Among patients in the intervention group, dehydrated patients received a bolus infusion with crystalloid fluid whereas diuretics were administrated to overhydrated patients until the value of ECW ratio fell within its normal setting range (0.390-0.406). Contrarily, BIA was performed once a day for the control group. Patients in the control group received traditional fluid treatment regardless of BIA results. Primary outcome was in-hospital mortality in two groups. The secondary outcomes were postoperative morbidities, 28-day mortality. RESULTS: 77 patients of the intervention group and 90 patients of the control group were finally analyzed. The in-hospital mortality (0 in intervention, 4.4% in control, p = 0.125) and 28-day mortality (1.3% in intervention, 14.4% in control, p = 0.002) showed lower incidence in the intervention group than in the control group. In multivariate analysis, the overhydrated status whose ECW ratio exceeding 0.406 [odds ratio (OR): 2.731, 95% confidence interval (CI): 1.001-7.663, p = 0.049] and high capillary leak index (CLI) value at ICU admission (OR: 1.024, 95% CI: 1.008-1.039, p = 0.002) were risk factors of postoperative morbidities. Regarding the 28-day mortality, high CLI value (OR: 1.025, 95% CI: 1.002-1.050, p = 0.037) and traditional strategy without BIA monitoring (OR: 9.903, 95% CI: 1.095-89.566, p = 0.041) were the significant predisposing factors. CONCLUSION: Our results revealed the rigorous fluid treatment with volume control based on ECW ratio by BIA failed to achieve significant improvement in in-hospital mortality, but it could reduce 28-day mortality of ICU patients. Monitoring of ECW ratio may help establish optimal fluid treatment strategies for postoperative ICU patients who are susceptible to fluid imbalances with fluid overload. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06097923, retrospectively registered on October 16, 2023, https://clinicaltrials.gov/study/NCT06097923?term=NCT06097923&rank=1.

Highly accurate measurement of the relative abundance of oral pathogenic bacteria using colony-forming unit-based qPCR.

PURPOSE: Quantitative polymerase chain reaction (qPCR) has recently been employed to measure the number of bacterial cells by quantifying their DNA fragments. However, this method can yield inaccurate bacterial cell counts because the number of DNA fragments varies among different bacterial species. To resolve this issue, we developed a novel optimized qPCR method to quantify bacterial colony-forming units (CFUs), thereby ensuring a highly accurate count of bacterial cells. METHODS: To establish a new qPCR method for quantifying 6 oral bacteria namely, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, Fusobacterium nucleatum, and Streptococcus mutans, the most appropriate primer-probe sets were selected based on sensitivity and specificity. To optimize the qPCR for predicting bacterial CFUs, standard curves were produced by plotting bacterial CFU against Ct values. To validate the accuracy of the predicted CFU values, a spiking study was conducted to calculate the recovery rates of the predicted CFUs to the true CFUs. To evaluate the reliability of the predicted CFU values, the consistency between the optimized qPCR method and shotgun metagenome sequencing (SMS) was assessed by comparing the relative abundance of the bacterial composition. RESULTS: For each bacterium, the selected primer-probe set amplified serial-diluted standard templates indicative of bacterial CFUs. The resultant Ct values and the corresponding bacterial CFU values were used to construct a standard curve, the linearity of which was determined by a coefficient of determination (r²) >0.99. The accuracy of the predicted CFU values was validated by recovery rates ranging from 95.1% to 106.8%. The reliability of the predicted CFUs was reflected by the consistency between the optimized qPCR and SMS, as demonstrated by a Spearman rank correlation coefficient (ρ) value of 1 for all 6 bacteria. CONCLUSIONS: The CFU-based qPCR quantification method provides highly accurate and reliable quantitation of oral pathogenic bacteria.

Tissue Mechanics and Hedgehog Signaling Crosstalk as a Key Epithelial-Stromal Interplay in Cancer Development.

Epithelial-stromal interplay through chemomechanical cues from cells and matrix propels cancer progression. Elevated tissue stiffness in potentially malignant tissues suggests a link between matrix stiffness and enhanced tumor growth. In this study, employing chronic oral/esophageal injury and cancer models, it is demonstrated that epithelial-stromal interplay through matrix stiffness and Hedgehog (Hh) signaling is key in compounding cancer development. Epithelial cells actively interact with fibroblasts, exchanging mechanoresponsive signals during the precancerous stage. Specifically, epithelial cells release Sonic Hh, activating fibroblasts to produce matrix proteins and remodeling enzymes, resulting in tissue stiffening. Subsequently, basal epithelial cells adjacent to the stiffened tissue become proliferative and undergo epithelial-to-mesenchymal transition, acquiring migratory and invasive properties, thereby promoting invasive tumor growth. Notably, transcriptomic programs of oncogenic GLI2, mechano-activated by actin cytoskeletal tension, govern this process, elucidating the crucial role of non-canonical GLI2 activation in orchestrating the proliferation and mesenchymal transition of epithelial cells. Furthermore, pharmacological intervention targeting tissue stiffening proves highly effective in slowing cancer progression. These findings underscore the impact of epithelial-stromal interplay through chemo-mechanical (Hh-stiffness) signaling in cancer development, and suggest that targeting tissue stiffness holds promise as a strategy to disrupt chemo-mechanical feedback, enabling effective cancer treatment.

Ethanol extract from Astilbe chinensis inflorescence suppresses inflammation in macrophages and growth of oral pathogenic bacteria.

Chronic oral inflammation and biofilm-mediated infections drive diseases such as dental caries and periodontitis. This study investigated the anti-inflammatory and antibacterial potential of an ethanol extract from Astilbe chinensis inflorescence (GA-13-6) as a prominent candidate for natural complex substances (NCS) with therapeutic potential. In LPS-stimulated RAW 264.7 macrophages, GA-13-6 significantly suppressed proinflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and nitric oxide (NO), surpassing purified astilbin, a known bioactive compound found in A. chinensis. Furthermore, GA-13-6 downregulated the expression of cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS), indicating an inhibitory effect on the inflammatory cascade. Remarkably, GA-13-6 exhibited selective antibacterial activity against Streptococcus mutans, Streptococcus sanguinis, and Porphyromonas gingivalis, key players in dental caries and periodontitis, respectively. These findings suggest that complex GA-13-6 holds the potential for the treatment or prevention of periodontal and dental diseases, as well as various other inflammation-related conditions, while averting the induction of antibiotic resistance.

Dentin Mechanobiology: Bridging the Gap between Architecture and Function.

It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in mechanically supporting tooth function. Its intermediate stiffness and viscoelastic properties, attributed to its mineralized, nanofibrous extracellular matrix, provide flexibility, strength, and rigidity, enabling it to withstand mechanical loading without fracturing. Moreover, dentin's unique architectural features, such as odontoblast processes within dentinal tubules and spatial compartmentalization between odontoblasts in dentin and sensory neurons in pulp, contribute to a distinctive sensory perception of external stimuli while acting as a defensive barrier for the dentin-pulp complex. Since dentin's architecture governs its functions in nociception and repair in response to mechanical stimuli, understanding dentin mechanobiology is crucial for developing treatments for pain management in dentin-associated diseases and dentin-pulp regeneration. This review discusses how dentin's physical features regulate mechano-sensing, focusing on mechano-sensitive ion channels. Additionally, we explore advanced in vitro platforms that mimic dentin's physical features, providing deeper insights into fundamental mechanobiological phenomena and laying the groundwork for effective mechano-therapeutic strategies for dentinal diseases.

Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosis.

BACKGROUND: Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe TB diseases. Tuberculin skin test (TST) is commonly used for TB diagnosis, but its accuracy in neonates is influenced by various factors, including bacilli Calmette-Guérin (BCG) vaccination. This study aimed to identify predictors of positive TSTs in neonates exposed to HCWs with pulmonary TB. METHODS: A retrospective observational study was conducted to compare the frequency of predictors between TST-positive and TST-negative neonates. Demographic, epidemiological, and clinical data of neonates exposed to TB, along with that of HCW and household contacts, were collected retrospectively through contact investigations with the Korean National TB Surveillance System (KNTSS) database. TSTs using 2 tuberculin units of purified protein derivative RT23 were performed on exposed neonates at the end of preventive TB treatment. Firth logistic regression was performed to identify predictors of TST positivity. RESULTS: Contact investigations revealed that 152 neonates and 54 HCWs were exposed to infectious TB index cases in 3 neonatal care facilities. Of 152 exposed neonates, 8 (5.3%) had positive TST results. Age of 6 days or more at the initial exposure is a statistically significant predictor of positive TST (Firth coefficient 2.1, 95% confidence interval 0.3-3.9, P = 0.024); BCG vaccination showed no statistical significance in both univariable and multivariable analysis. Sex, prematurity, exposure duration, duration from initial exposure to contact investigation, and isoniazid preventive treatment duration were not significant predictors. CONCLUSION: Age at the initial exposure is a significant predictor of positive TST in neonates exposed to active pulmonary TB. Given the complexities of TST interpretation, including false positives due to BCG vaccination, careful risk assessment is necessary for appropriate decision-making and resource allocation in the management of neonatal TB exposure.

Strontium/Silicon/Calcium-Releasing Hierarchically Structured 3D-Printed Scaffolds Accelerate Osteochondral Defect Repair.

Articular cartilage defects are a global challenge, causing substantial disability. Repairing large defects is problematic, often exceeding cartilage's self-healing capacity and damaging bone structures. To tackle this problem, a scaffold-mediated therapeutic ion delivery system is developed. These scaffolds are constructed from poly(ε-caprolactone) and strontium (Sr)-doped bioactive nanoglasses (SrBGn), creating a unique hierarchical structure featuring macropores from 3D printing, micropores, and nanotopologies due to SrBGn integration. The SrBGn-embedded scaffolds (SrBGn-µCh) release Sr, silicon (Si), and calcium (Ca) ions, which improve chondrocyte activation, adhesion, proliferation, and maturation-related gene expression. This multiple ion delivery significantly affects metabolic activity and maturation of chondrocytes. Importantly, Sr ions may play a role in chondrocyte regulation through the Notch signaling pathway. Notably, the scaffold's structure and topological cues expedite the recruitment, adhesion, spreading, and proliferation of chondrocytes and bone marrow-derived mesenchymal stem cells. Si and Ca ions accelerate osteogenic differentiation and blood vessel formation, while Sr ions enhance the polarization of M2 macrophages. The findings show that SrBGn-µCh scaffolds accelerate osteochondral defect repair by delivering multiple ions and providing structural/topological cues, ultimately supporting host cell functions and defect healing. This scaffold holds great promise for osteochondral repair applications.

Chronic Opioid Treatment Arrests Neurodevelopment and Alters Synaptic Activity in Human Midbrain Organoids.

Understanding the impact of long-term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency. However, this has been limited by human brain inaccessibility and cross-species differences in animal models. Here, a human midbrain model is established that uses hiPSC-derived midbrain organoids to assess cell-type-specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single-cell mRNA sequencing of 25,510 cells from organoids in different treatment groups reveals that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single-cell level.

Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

Pathological dermal scars such as keloids present significant clinical challenges lacking effective treatment options. Given the distinctive feature of highly stiffened scar tissues, deciphering how matrix mechanics regulate pathological progression can inform new therapeutic strategies. Here, it is shown that pathological dermal scar keloid fibroblasts display unique metamorphoses to stiffened matrix. Compared to normal fibroblasts, keloid fibroblasts show high sensitivity to stiffness rather than biochemical stimulation, activating cytoskeletal-to-nuclear mechanosensing molecules. Notably, keloid fibroblasts on stiff matrices exhibit nuclear softening, concomitant with reduced lamin A/C expression, and disrupted anchoring of lamina-associated chromatin. This nuclear softening, combined with weak adhesion and high contractility, facilitates the invasive migration of keloid fibroblasts through confining matrices. Inhibiting lamin A/C-driven nuclear softening, via lamin A/C overexpression or actin disruption, mitigates such invasiveness of keloid fibroblasts. These findings highlight the significance of the nuclear mechanics of keloid fibroblasts in scar pathogenesis and propose lamin A/C as a potential therapeutic target for managing pathological scars.

The clinical efficacy and suitable implementation of two extracorporeal blood purification therapies: AN69-oXiris versus PMX-HP.

Purpose: In septic shock patients, pathogens and excessive endotoxins continuously overstimulate the host's immune system with a cytokine storm that can lead to multi-organ failure and even mortality. Various types of extracorporeal blood purification treatments have recently been introduced to remove excessive endotoxins and cytokines. Herein, we compared the clinical efficacy of two blood purification methods, PMX-HP and AN69-oXiris, and discussed their detailed indications according to disease severity. Materials and methods: From December 2016 to April 2023, patients who underwent emergent surgery due to septic shock secondary to peritonitis and subsequently received blood purification treatment with AN69-oXiris or PMX-HP were enrolled. Propensity score (PS)-matching was conducted to adjust for baseline characteristics between the two groups, and the changes in clinical parameters and outcomes were compared. Clinical outcomes were assessed in subgroups of patients who underwent PMX-HP treatment divided according to SOFA scores into low (0-7), intermediate (8-13), and high (> 13) disease severity groups. Results: Forty patients received blood purification therapy with either PMX-HP or AN69-oXiris during the study period. After 1:2 PS matching, six patients in the AN69-oXiris group and 12 patients in the PMX-HP group were finally analyzed. Vasoactive-inotropic scores (VISs) decreased in both groups after 48 h of treatment compared to the baseline values, but the change in VISs was more pronounced in the PMX-HP group {-57.6 [interquartile range (IQR) = -166.4 - (-10)] vs. -22.9 [IQR = -64-0], respectively, p = 0.041}. Decreases in cardiovascular SOFA scores were significantly pronounced in the PMX-HP group [-1.5 (IQR = -4 - 0) vs. 0 (IQR = -1 - 1), respectively, p = 0.035]. The 7-day mortality rate was significantly lower than the predicted mortality rate in a subgroup analysis of patients treated with PMX-HP in both the low disease severity group and the intermediate disease severity group. Conclusion: PMX-HP and AN69-oXiris could be therapeutic options for refractory septic shock patients with intra-abdominal origins, especially after the surgical elimination of the infectious sources. A tailored modality choice that takes into account patient characteristics, such as disease severity and cost burden, could optimize the efficacy of this strategy.

Venous-to-arterial carbon-dioxide tension difference as a useful predictor of patient prognosis after major surgery.

PURPOSE: Change in venous-to-arterial carbon dioxide partial pressure difference[P(v-a)CO2] could be a useful marker to assess tissue perfusion status. Herein, we assessed the predictive values of postoperative P(v-a)CO2 measurements for mortality in critically ill patients after major surgery. The correlation between P(v-a)CO2 values and other conventional parameters of patient prognosis was also evaluated. METHODS: Patients admitted to the intensive care unit(ICU) after abdominal surgery were enrolled. Arterial and venous blood gas analyses were performed within 1 h(T0) and after 24 h(T1) of admission to the ICU, respectively. The relationship between P(v-a)CO2 levels at T1 and other conventional parameters were assessed using a Bland-Altman plot. Logistic regression analysis was performed to examine the predisposing factors of mortality after surgery. RESULTS: A total of 231 patients were finally analyzed. We divided the participants into the high PvaCO2 group[P(v-a)CO2 ≥ 8.6] and the low PvaCO2 group[P(v-a)CO2 < 8.6]. Seven-day-, 28-day, and in-hospital mortality were significantly higher in the high PvaCO2 group than in the low PvaCO2 group. There was significant agreement between P(v-a)CO2 values at T1 and APACHE II scores, lactate levels at T1 and total SOFA scores at T1. In multivariate logistic analysis, an increased P(v-a)CO2 value at T1 was the only significant risk factor of 7-day mortality after surgery. [odds ratio:1.341, 95%confidence interval: 1.050-1.714, p=0.019]. CONCLUSION: P(v-a)CO2 measurements could be not only a significant predictor of postoperative prognosis, but also a useful surveillance parameter to maintain tissue perfusion after abdominal surgery in patients with a potential risk of fatal complication-related tissue hypoperfusion.

Rotational V-Y Fasciocutaneous Advancement Island Flap to Cover Deep Sacrococcygeal Defects due to Pilonidal Disease, Pressure Ulcers, and Other Inflammatory Conditions.

The sacrococcygeal area supports the lower body and endures mechanical forces during movement. However, current treatment methods for deep caudal sacrococcygeal defects have limitations, resulting in insufficient tissue for deep pocket obliteration and considering only the two-dimensional advancement plane in a three-dimensional defect topology. Our study proposes using a rotational V-Y fasciocutaneous advancement island flap to reconstruct deep caudal sacrococcygeal defects. By considering the three-dimensional nature of the defect, we distinguish a coccygeal plane of the V-Y flap from a sacral plane and set different directions and depths of movement for each plane. From March 2016 to July 2022, 12 patients underwent successful treatment with this surgery, and no complications or recurrences were observed in the study group. Our research found that patients in our study exhibited a smaller intercoccygeal angle than the average angle of the general Korean population, as previously reported. This implies a more pronounced curvature between the sacral and coccygeal planes. Therefore, our methods, which consider the three-dimensional structures of sacrococcygeal pathology, are significant. This technique provides a mechanically robust reconstruction after resecting deep sacrococcygeal pathology, with well-padded tissue to prevent dead space and wound disruption.

Advanced materials technologies to unravel mechanobiological phenomena.

Advancements in materials-driven mechanobiology have yielded significant progress. Mechanobiology explores how cellular and tissue mechanics impact development, physiology, and disease, where extracellular matrix (ECM) dynamically interacts with cells. Biomaterial-based platforms emulate synthetic ECMs, offering precise control over cellular behaviors by adjusting mechanical properties. Recent technological advances enable in vitro models replicating active mechanical stimuli in vivo. These models manipulate cellular mechanics even at a subcellular level. In this review we discuss recent material-based mechanomodulatory studies in mechanobiology. We highlight the endeavors to mimic the dynamic properties of native ECM during pathophysiological processes like cellular homeostasis, lineage specification, development, aging, and disease progression. These insights may inform the design of accurate in vitro mechanomodulatory platforms that replicate ECM mechanics.

Age-group-specific association of oral health and systemic health on cognitive function: a cross-sectional study of Korean elders.

BACKGROUND: Although the importance of oral and systemic healthcare for elderly people is increasing owing to the rapid ageing of the population in South Korea, studies on the relationship between oral health, systemic health, and cognitive function, as well as on the prediction of cognitive function by oral and systemic health depending upon age groups are lacking. METHODS: We included 5,975 out of 6,488 participants from the 8th wave of the Korean Longitudinal Study of Aging (KLoSA) panel data, divided the participants into three age groups, and performed a hierarchical multiple linear regression analysis to explain cognitive function with four types of predictors: oral health status, sociodemographic factors, objective health status, and subjective health status. RESULTS: Oral health status was positively correlated with systemic health status and cognitive function. Of all ages over 54, cognitive function was significantly predicted by oral health variables, such as the number of functional teeth, masticatory ability, and Geriatric Oral Health Assessment Index (GOHAI); sociodemographic variables, such as age, sex, education level, and residence; and systemic health variables, such as diagnosis of diabetes mellitus, cancer or malignant tumours, cerebrovascular disease and rheumatoid arthritis, depressive symptom, and self-rated health status. Oral health variables explained cognitive function differently by age group; GOHAI appeared important predictor in the group aged < 75 years, whereas the number of functional teeth did in the group aged ≥ 75 years. Educational level, masticatory ability, depressive symptoms, and self-rated health status were pivotal factors age-independently. CONCLUSIONS: The general and age-group-specific association between oral health, systemic health, and cognitive function were confirmed, suggesting that age-group-specific oral healthcare should be emphasized for the effective management of systemic and cognitive health in the elderly group.

A Comprehensive Landscape of De Novo Malignancy After Double Lung Transplantation.

Although the association between post-transplant malignancy (PTM) and immunosuppressive therapy after organ transplantation has been studied, an integrated review of PTM after lung transplantation is lacking. We investigated the incidence and types of de novo PTM and its impact on survival following double lung transplantation (DLT). The incidence and type of PTM as well as the annual and cumulative risks of each malignancy after DLT were analyzed. The overall survival (OS) of recipients with or without PTM was compared by the Kaplan-Meier survival method and landmark analysis. There were 5,629 cases (23.52%) with 27 types of PTMs and incidences and OS varied according to the types of PTMs. The recipients with PTM showed a significantly longer OS than those without PTM (p < 0.001). However, while the recipients with PTM showed significantly better OS at 3, and 5 years (p < 0.001, p = 0.007), it was worse at the 10-year landmark time (p = 0.013). And the single PTM group showed a worse OS rate than the multiple PTM group (p < 0.001). This comprehensive report on PTM following DLT can help understand the risks and timing of PTM to improve the implementation of screening and treatment.

Papillary thyroid cancer immune phenotypes via tumor-infiltrating lymphocyte spatial analysis.

Standard-of-care treatment options provide an excellent prognosis for papillary thyroid cancers (PTCs); however, approximately 10% of cases are advanced PTCs, resulting in less than 50% 5-year survival rates. Understanding the tumor microenvironment is essential for understanding cancer progression and investigating potential biomarkers for treatment, such as immunotherapy. Our study focused on tumor-infiltrating lymphocytes (TILs), which are the main effectors of antitumor immunity and related to the mechanism of immunotherapy. Using an artificial intelligence model, we analyzed the density of intratumoral and peritumoral TILs in the pathologic slides of The Cancer Genome Atlas PTC cohort. Tumors were classified into three immune phenotypes (IPs) based on the spatial distribution of TILs: immune-desert (48%), immune-excluded (34%), and inflamed (18%). Immune-desert IP was mostly characterized by RAS mutations, high thyroid differentiation score, and low antitumor immune response. Immune-excluded IP predominantly consisted of BRAF V600E-mutated tumors and had a higher rate of lymph node metastasis. Inflamed IP was characterized by a high antitumor immune response, as demonstrated by a high cytolytic score, immune-related cell infiltrations, expression of immunomodulatory molecules (including immunotherapy target molecules), and enrichment of immune-related pathways. This study is the first to investigate IP classification using TILs in PTC through a tissue-based approach. Each IP had unique immune and genomic profiles. Further studies are warranted to assess the predictive value of IP classification in advanced PTC patients treated with immunotherapy.

Antimicrobial activity of Limosilactobacillus fermentum strains isolated from the human oral cavity against Streptococcus mutans.

Oral probiotics have been recently gaining much attention owing to their potential to inhibit the progression of dental caries by controlling the cariogenic effects of Streptococcus mutans. We isolated and genotypically identified 77 lactic acid bacteria including 12 Limosilactobacillus fermentum probiotic candidates from the oral cavity of healthy volunteers. Among the 12 L. fermentum isolates, nine isolates effectively inhibited the growth of S. mutans via hydrogen peroxide (H2O2) production. The others neither suppressed the growth of S. mutans nor produced H2O2. Eight out of the nine H2O2-producing L. fermentum isolates exhibited strong adherence to oral epithelial KB cells while inhibiting the adherence of S. mutans to KB cells. The eight H2O2-producing isolates were neither haemolytic based on a blood-agar test, cytotoxic according to lactate dehydrogenase assay, nor resistant to eight antibiotics represented by the European Food Safety Authority guideline, indicating that the isolates have potential to suppress the cariogenesis driven by S. mutans while providing general probiotic benefits.

Atomic-scale observation of premelting at 2D lattice defects inside oxide crystals.

Since two major criteria for melting were proposed by Lindemann and Born in the early 1900s, many simulations and observations have been carried out to elucidate the premelting phenomena largely at the crystal surfaces and grain boundaries below the bulk melting point. Although dislocations and clusters of vacancies and interstitials were predicted as possible origins to trigger the melting, experimental direct observations demonstrating the correlation of premelting with lattice defects inside a crystal remain elusive. Using atomic-column-resolved imaging with scanning transmission electron microscopy in polycrystalline BaCeO3, here we clarify the initiation of melting at two-dimensional faults inside the crystals below the melting temperature. In particular, melting in a layer-by-layer manner rather than random nucleation at the early stage was identified as a notable finding. Emphasizing the value of direct atomistic observation, our study suggests that lattice defects inside crystals should not be overlooked as preferential nucleation sites for phase transformation including melting.

A multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related oxide system.

Since the high configurational entropy-driven structural stability of multicomponent oxide system was proposed Rost et al. in 2015, many experiments and simulations have been done to develop new multicomponent oxides. Although many notable findings have shown unique physical and chemical properties, high configurational entropy oxide systems that have more than 3 distinct cation sites are yet to be developed. By utilizing atomic-scale direct imaging with scanning transmission electron microscopy and AC-impedance spectroscopy analysis, we demonstrated for the first time that a multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related Ba5RE2Al2ZrO13 (RE = rare earth elements) oxide system can be synthesized even when adding eight different rare earth elements. In particular, as the number of added elements was increased, i.e., as the configurational entropy was increased, we confirmed that the chemical stability toward CO2 was improved without a significant decrement of the proton conductivity. The findings in this work broaden the use of the crystal structure to which the multicomponent model can be applied, and a systematic study on the correlation between the configurational entropy and proton conductivity and/or chemical stability is noteworthy.