c-Axis Aligned 3 nm Thick In2O3 Crystal Using New Liquid DBADMIn Precursor for Highly Scaled FET Beyond the Mobility-Stability Trade-off.

Oxide semiconductors (OS) are attractive materials for memory and logic device applications owing to their low off-current, high field effect mobility, and superior large-area uniformity. Recently, successful research has reported the high field-effect mobility (µFE) of crystalline OS channel transistors (above 50 cm2 V-1 s-1). However, the memory and logic device application presents challenges in mobility and stability trade-offs. Here, we propose a method for achieving high-mobility and high-stability by lowering the grain boundary effect. A DBADMIn precursor was synthesized to deposit highly c-axis-aligned C(222) crystalline 3 nm thick In2O3 films. In this study, the 250 °C deposited 3 nm thick In2O3 channel transistor exhibited high µFE of 41.12 cm2 V-1 s-1, Vth of -0.50 V, and SS of 150 mV decade-1 with superior stability of 0.16 V positive shift during PBTS at 100 °C, 3 MV cm-1 stress conditions for 3 h.

Identification and expression analyses of B3 genes reveal lineage-specific evolution and potential roles of REM genes in pepper.

BACKGROUND: The B3 gene family, one of the largest plant-specific transcription factors, plays important roles in plant growth, seed development, and hormones. However, the B3 gene family, especially the REM subfamily, has not been systematically and functionally studied. RESULTS: In this study, we performed genome-wide re-annotation of B3 genes in five Solanaceae plants, Arabidopsis thaliana, and Oryza sativa, and finally predicted 1,039 B3 genes, including 231 (22.2%) newly annotated genes. We found a striking abundance of REM genes in pepper species (Capsicum annuum, Capsicum baccatum, and Capsicum chinense). Comparative motif analysis revealed that REM and other subfamilies (ABI3/VP1, ARF, RAV, and HSI) consist of different amino acids. We verified that the large number of REM genes in pepper were included in the specific subgroup (G8) through the phylogenetic analysis. Chromosome location and evolutionary analyses suggested that the G8 subgroup genes evolved mainly via a pepper-specific recent tandem duplication on chromosomes 1 and 3 after speciation between pepper and other Solanaceae. RNA-seq analyses suggested the potential functions of REM genes under salt, heat, cold, and mannitol stress conditions in pepper (C. annuum). CONCLUSIONS: Our study provides evolutionary and functional insights into the REM gene family in pepper.

Pre-treatment systemic inflammation response index and systemic immune inflammation in patients with primary central nerve system lymphoma as a useful prognostic indicator.

PURPOSE: The systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are based on neutrophil, monocyte, platelet, and lymphocyte counts. The SIRI and SII are used to predict the survival of patients with malignant tumors. It is well known that the inflammatory immune response is closely related to cancer occurrence and progression. In the present study, we evaluated the potential prognostic significance of SIRI and SII in patients with primary central nervous system lymphoma (PCNSL). METHODS: Fifty-eight consecutive patients were enrolled in this study between November 2006 and May 2022. Among the 58 patients, 47 patients with sufficient blood test data and follow-up were analyzed. The patients with steroid intake at the time point of the blood test and higher C-reactive protein were excluded. RESULTS: The median follow-up and survival times were 31 and 36 months, respectively. The optimal cutoff SIRI value was based on the receiver operating characteristic curve (ROC) for overall survival (OS) and stratified patients into low (< 1.43 × 109/L, n = 22) and high (≥ 1.43 × 109/L, n = 25) SIRI groups. The optimal cutoff SII value based on the ROC for OS stratified patients into low (< 694.9, n = 28) and high (≥ 694.9, n = 19) SII groups. A low SIRI value was associated with longer OS (p = 0.006). Furthermore, a low SII value was associated with longer OS (p = 0.044). The prognostic factors associated with prolonged survival in univariate analysis using the Cox proportional hazard model were age < 65 years, low SIRI, and low SII. The multivariate analysis demonstrated that age < 65 years and low SIRI independently predicted longer OS. CONCLUSION: Simple, less expensive, and routinely ordered preoperative blood count assessments such as SIRI and SII predict the OS of patients with PCNSL. This study demonstrated that PCNSL is associated with pre-treatment systemic immune-inflammation states.

Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair.

BACKGROUND: We aimed to investigate clinicopathologic factors leading to different clinical outcomes in patients with deficient mismatch repair protein (d-MMR) gastric cancer (GC) treated with nivolumab plus chemotherapy (nivolumab chemotherapy). METHODS: This retrospective study included 28 patients with d-MMR advanced GC treated with first-line nivolumab chemotherapy. As a control group, 68 treated with first-line chemotherapy alone were included. Clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and PD-L1 combined positive score (CPS), were analyzed with regards to the efficacy outcomes. RESULTS: Progression-free survival (PFS) was longer (median PFS; not reached [NR] vs. 5.2 months, hazard ratio [HR] 0.28, P < 0.001), and overall survival (OS) tended to be longer (median OS; NR vs. 17.9 months, HR 0.43, P = 0.057) in patients treated with nivolumab chemotherapy than those treated with chemotherapy. The PFS benefit of nivolumab chemotherapy over chemotherapy was pronounced in the subgroup with a lower NLR (< 3.80 [median NLR]) (HR 0.10), whereas it was less prominent in patients with a high NLR (≥ 3.80) (HR 0.58). Among patients treated with nivolumab chemotherapy, PFS was worse in patients with a higher NLR (≥ 3.80) than in those with a lower NLR (< 3.80), and survival outcomes were similar between those with PD-L1 CPS ≥ 5 and < 5. CONCLUSION: Nivolumab chemotherapy was associated with better efficacy outcomes than chemotherapy alone among patients with d-MMR GC, but survival outcomes were poor even with nivolumab chemotherapy for those with a high NLR. Survival outcomes were not different according to PD-L1 CPS among d-MMR patients treated with nivolumab chemotherapy.

SMARCA4-deficient undifferentiated gastric carcinoma: a case series and literature review.

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities.

Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

BACKGROUND: We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. METHODS: This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. RESULTS: The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). CONCLUSION: PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum for metastatic, recurrent, or unresectable gastric cancer.

BACKGROUND: We examined the impact of mismatch repair (MMR) status on efficacy of first-line fluoropyrimidine plus platinum (FP) chemotherapy in patients with HER2-negative metastatic, recurrent, or unresectable gastric cancer (mGC). METHODS: Patients with mGC receiving first-line FP between 2015 and 2018 at Asan Medical Center, Korea, were reviewed. We evaluated the clinical characteristics and the efficacy of chemotherapy according to MMR status in patients with available immunohistochemistry results. RESULTS: Of 895 patients, we analyzed 543 with available MMR protein expression results, and deficient MMR (dMMR) was detected in 4.4% (n = 24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p = 0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR. Objective response rate was 27.3% in dMMR and 34.3% in pMMR (p = 0.556). No difference in progression-free survival was noted between patients with dMMR and pMMR (median, 5.6 vs. 5.8 months, p = 0.266). Patients with dMMR tended to have better overall survival than those with pMMR although this difference was not statistically significant (median, 17.9 vs. 12.2 months, p = 0.183). CONCLUSIONS: Efficacy of first-line FP was not different by MMR status in mGC patients.

Gastric microbiome signature for predicting metachronous recurrence after endoscopic resection of gastric neoplasm.

BACKGROUND: Changes in gastric microbiome are associated with gastric carcinogenesis. Studies on the association between gastric mucosa-associated gastric microbiome (MAM) and metachronous gastric cancer are limited. This study aimed to identify gastric MAM as a predictive factor for metachronous recurrence following endoscopic resection of gastric neoplasms. METHOD: Microbiome analyses were conducted for 81 patients in a prospective cohort to investigate surrogate markers to predict metachronous recurrence. Gastric MAM in non-cancerous corporal biopsy specimens was evaluated using Illumina MiSeq platform targeting 16S ribosomal DNA. RESULTS: Over a median follow-up duration of 53.8 months, 16 metachronous gastric neoplasms developed. Baseline gastric MAM varied with Helicobacter pylori infection status, but was unaffected by initial pathologic diagnosis, presence of atrophic gastritis, intestinal metaplasia, or synchronous lesions. The group with metachronous recurrence did not exhibit distinct phylogenetic diversity compared with the group devoid of recurrence but showed significant difference in ß-diversity. The study population could be classified into two distinct gastrotypes based on baseline gastric MAM: gastrotype 1, Helicobacter-abundant; gastrotype 2: Akkermansia-abundant. Patients in gastrotype 2 showed higher risk of metachronous recurrence than gastrotype (Cox proportional hazard analysis, adjusted hazard ratio [95% confidence interval]: 5.10 [1.09-23.79]). CONCLUSIONS: Gastric cancer patients can be classified into two distinct gastrotype groups by their MAM profiles, which were associated with different risk of metachronous recurrence.

Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. METHODS: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. RESULTS: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. CONCLUSIONS: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.

Antitumor Effects of Intravenous Natural Killer Cell Infusion in an Orthotopic Glioblastoma Xenograft Murine Model and Gene Expression Profile Analysis.

Despite standard multimodality treatment, containing maximum safety resection, temozolomide, radiotherapy, and a tumor-treating field, patients with glioblastoma (GBM) present with a dismal prognosis. Natural killer cell (NKC)-based immunotherapy would play a critical role in GBM treatment. We have previously reported highly activated and ex vivo expanded NK cells derived from human peripheral blood, which exhibited anti-tumor effect against GBM cells. Here, we performed preclinical evaluation of the NK cells using an in vivo orthotopic xenograft model, the U87MG cell-derived brain tumor in NOD/Shi-scid, IL-2RɤKO (NOG) mouse. In the orthotopic xenograft model, the retro-orbital venous injection of NK cells prolonged overall survival of the NOG mouse, indirectly indicating the growth-inhibition effect of NK cells. In addition, we comprehensively summarized the differentially expressed genes, especially focusing on the expression of the NKC-activating receptors' ligands, inhibitory receptors' ligands, chemokines, and chemokine receptors, between murine brain tumor treated with NKCs and with no agents, by using microarray. Furthermore, we also performed differentially expressed gene analysis between an internal and external brain tumor in the orthotopic xenograft model. Our findings could provide pivotal information for the NK-cell-based immunotherapy for patients with GBM.

Characterization of HIF-1α Knockout Primary Human Natural Killer Cells Including Populations in Allogeneic Glioblastoma.

Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Natural killer cells (NK) are major innate effector cells with broad cytotoxicity against tumors. Accordingly, NK cells are ideal candidates for cancer immunotherapy, including glioblastoma (GBM). Hypoxia is a common feature of solid tumors, and tumor cells and normal cells adapt to the tumor microenvironment by upregulating the transcription factor hypoxia-inducible factor (HIF)-1α, which can be detrimental to anti-tumor effector immune cell function, including that of NK cells. We knocked out HIF-1α in human primary NK cells using clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9). Then, cellular characterizations were conducted in normoxic and hypoxic conditions. Electroporating two HIF-1α-targeting guide RNA-Cas9 protein complexes inhibited HIF-1α expression in expanded NK cells. HIF-1α knockout human NK cells, including populations in hypoxic conditions, enhanced the growth inhibition of allogeneic GBM cells and induced apoptosis in GBM-cell-derived spheroids. RNA-sequencing revealed that the cytotoxicity of HIF-1α knockout NK cells could be related to increased perforin and TNF expression. The results demonstrated that HIF-1α knockout human NK cells, including populations, enhanced cytotoxicity in an environment mimicking the hypoxic conditions of GBM. CRISPR-Cas9-mediated HIF-1α knockout NK cells, including populations, could be a promising immunotherapeutic alternative in patients with GBM.

Unusual or Uncommon Histology of Gastric Cancer.

This review comprehensively examines the diverse spectrum of gastric cancers, focusing on unusual or uncommon histology that presents significant diagnostic and therapeutic challenges. While the predominant form, tubular adenocarcinoma, is well-characterized, this review focuses on lesser-known variants, including papillary adenocarcinoma, micropapillary carcinoma, adenosquamous carcinoma, squamous cell carcinoma (SCC), hepatoid adenocarcinoma, gastric choriocarcinoma, gastric carcinoma with lymphoid stroma, carcinosarcoma, gastroblastoma, parietal cell carcinoma, oncocytic adenocarcinoma, Paneth cell carcinoma, gastric adenocarcinoma of the fundic gland type, undifferentiated carcinoma, and extremely well-differentiated adenocarcinoma. Although these diseases have different nomenclatures characterized by distinct histopathological features, these phenotypes often overlap, making it difficult to draw clear boundaries. Furthermore, the number of cases was limited, and the unique histopathological nature and potential pathogenic mechanisms were not well defined. This review highlights the importance of understanding these rare variants for accurate diagnosis, effective treatment planning, and improving patient outcomes. This review emphasizes the need for ongoing research and case studies to enhance our knowledge of these uncommon forms of gastric cancer, which will ultimately contribute to more effective treatments and better prognostic assessments. This review aimed to broaden the pathological narrative by acknowledging and addressing the intricacies of all cancer types, regardless of their rarity, to advance patient care and improve prognosis.

Tubular adenoma arising in tubular colonic duplication: a case report.

Colonic duplication constitutes a rare congenital anomaly, characterized by the presence of hollow cystic or tubular structures exhibiting an epithelial-lined intestinal wall. Diagnostic challenges persist due to its low incidence and manifestation of nonspecific symptoms such as abdominal pain or constipation, resulting in a reluctance to pursue surgical resection. As associated malignancies in colonic duplication are rare, the inherent malignant potential of these anomalies remains undetermined. Additionally, despite reported instances of associated malignancies in colonic duplication, there is an absence of reports in the literature detailing tubular adenoma within these cases. The histologic features of the presented case are particularly noteworthy, situated at the precancerous stage, intimating potential progression towards adenocarcinoma within colonic duplication.

Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 Plus Imatinib for Advanced Treatment-Refractory Gastrointestinal Stromal Tumors.

PURPOSE: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Patients with advanced GIST whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3 + 3 dose escalation scheme was applied. Intravenous administration of PDR001 at 400 mg for every 4 weeks plus imatinib (300 and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate at 12 weeks. Exploratory biomarker analysis was performed based on PDL1 IHC, next-generation sequencing, and multiplexed IHC. RESULTS: No dose-limiting toxicity was observed in the phase Ib part (n = 10), and dose level II was selected as the recommended phase II dose. In the phase II part (n = 29), there was no objective response, and the disease control rate at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n = 36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3 to 4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T-cell density was associated with a favorable PFS but to a limited degree. Tumor mutational burden and PDL1 were not associated with better PFS. CONCLUSIONS: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Heterogeneity of claudin 18.2 expression in metastatic gastric cancer.

Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer (GC), but little is known about the heterogeneity of its expression in GC. This study investigated the heterogeneity of claudin 18.2 expression in 166 patients with metastatic GC whose surgical or paired primary-metastatic specimens were available. The prevalence of claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was 47.0%. Claudin 18.2-positive tumors exhibited more frequent peritoneal metastasis and a lower incidence of hepatic and distant lymph node involvement. Survival outcomes were comparable between patients with claudin 18.2-positive and -negative tumors. Intratumoral heterogeneity was noted in 38.5% of surgical specimens. Paired primary-metastatic site analysis revealed that 25.2% of patients had discordant results for claudin 18.2 positivity. Across different metastatic organ categories, peritoneal lesions showed the highest positivity rate (44.3%) and positive concordance rate (31.4%), whereas liver lesions had the lowest positivity rate (17.9%) and concordance rate (12.8%). In conclusion, claudin 18.2 expression exhibits intratumoral and intrapatient spatial heterogeneity in metastatic GC. Claudin 18.2 positivity is associated with more frequent peritoneal metastasis, and peritoneal lesions are more likely to have positively concordant claudin 18.2 results with the primary site than other metastatic sites.

Specific bacterial co-abundance groups are associated with inflammatory status in patients with ulcerative colitis.

BACKGROUND AND AIMS: While there is increasing interest in microbiome-directed therapies for patients with ulcerative colitis (UC), the identification of microbial targets remains elusive, underlining the need for novel approaches. METHODS: Utilizing metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease, available via the IBD Plexus Program of the Crohn's & Colitis Foundation, we used a tree-based dichotomous approach to assemble distinct clusters of species-level bacterial co-abundance groups (CAGs). We evaluated the abundance of bacterial CAGs and fungal taxa during remission (n=166) and activity (n=46). We examined if the bacterial CAGs identified in our cohorts were conserved in 2 healthy cohorts and in a Korean UC cohort. RESULTS: CAG3 and CAG8, dominated by bacteria from family Lachnospiraceae, were associated with remission. Low CAG8 and elevated Candida genus were predictive of active UC. Constituents from CAG8 were influential hub species of the remission-associated microbial UC network, including Ruminococcus gnavus, Erysipelatoclostridium ramosum, Blautia and Dorea species. These hub species interactions were preserved in 2 healthy cohorts and were partially recapitulated in a Korean UC cohort. CAG8 abundance correlated with the secondary bile acid production pathway. Bacterial CAGs did not correlate with Candida, however Bifidobacterium adolescentis and Alistipes putredinis were negatively associated with Candida. CONCLUSIONS: Lachnospiriceae-dominated bacterial CAGs were associated with remission in UC, with key bacterial interactions within the CAG also observed in 2 healthy cohorts and a Korean UC cohort. Bacterial CAG-based analyses may help to inform the design of candidate consortia for microbiome-based therapeutics.

Bulk RNA sequencing reveals the comprehensive genetic characteristics of human cord blood-derived natural killer cells.

Introduction: Innate immune cells are important in tumor immunotherapy. Natural killer cells (NKCs) are also categorized as innate immune cells and can control tumor growth and metastatic spread. Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. NKC-based immunotherapy is a promising treatment strategy against GBM. We previously reported a feeder-free expansion system that yielded large-scale highly purified and cytotoxic NKCs derived from human cord blood (CB). In the present study, we performed comprehensive genomic analyses of NKCs generated from human CB (CBNKCs) as compared those from human peripheral blood (PB) (PBNKCs). Methods: Frozen T cell-free CB mononuclear cells were cultured with recombinant human interleukin (rhIL)-18 and rhIL-2 in anti-NKp46 and anti-CD16 antibody immobilization settings. After 14-day expansion, the total RNA of the CBNKCs or PBNKCs was extracted and transcriptomic analyses was performed to determine their similarities and differences. We also examined CBNKC and PBNKC activity against a GBM cell line. Results: Differential expression gene analysis revealed that some NK activating and inhibitory receptors were significantly downregulated in the CBNKCs compared to PBNKCs. Furthermore, genes related to anti-apoptosis and proliferation were upregulated in the CBNKCs. Enrichment analysis determined that the gene sets related to immune response and cytokines were enriched in the CBNKCs. Gene set enrichment analysis demonstrated that the immune response pathway was upregulated in the CBNKCs. Cytotoxic assays using impedance-based cell analyzer revealed that the CBNKCs enhanced NKC-mediated cytotoxicity on GBM cells as compared to the PBNKCs. Conclusions: We demonstrated the characteristics of human CBNKCs. Cell-based therapy using the CBNKCs is promising for treating GBM.

Management Approaches and Patient Outcomes for Giant Pituitary Neuroendocrine Tumors Classified as Knosp Grade 3 and 4.

Background Treatment of patients with a giant pituitary neuroendocrine tumor (GPitNET) is challenging. Here, we present the methods used for the clinical management of patients who underwent GPitNET resection mainly via endoscopic endonasal surgery along with multimodal support to avoid surgical complications, which can affect the outcomes. Methodology The medical records of 25 patients with a GPitNET who underwent endonasal endoscopic surgery were retrospectively reviewed. Complications were analyzed and factors affecting the extent of resection were evaluated. Results Gross total resection was achieved in six (24%), near-total resection (>90%) in nine (36%), and partial resection in 10 (40%) patients. Multivariate analyses revealed that tumors invading the middle fossa had negative effects on the extent of resection (odds ratio = 0.092, p = 0.047). Postoperative vision improved or normalized in 16 (64%), remained stable in eight (32%), and worsened in one (4%), while a new hormonal deficit was noted in seven (28%) patients. Complications included permanent oculomotor nerve palsy in one (4%) and transient oculomotor palsy in one (4%), apoplexy of the residual tumor resulting in ischemic stroke in one (4%), postoperative cerebrospinal fluid leakage in one (4%), and permanent diabetes insipidus in six (24%) patients. Conclusions For GPitNETs that extend into the middle fossa, our study underscored the difficulties in surgical extraction and the necessity for tailored treatment approaches. To ensure the safest and most complete removal possible, the surgical strategy must be specifically adapted to each case. Additionally, employing a comprehensive support approach is essential to reduce the chance of complications in patients impacted by this condition.

Differences in the risk of clinical failure between thiopurine and methotrexate in bio-naïve patients with Crohn's disease: a Korean nationwide population-based study.

Background: Although immunomodulators are widely prescribed in patients with Crohn's disease (CD), it is unclear whether there is a difference in treatment outcomes between thiopurines and methotrexate (MTX). Objective: To compare the risk of clinical failure between thiopurines and MTX in bio-naïve patients with CD. Design: Nationwide, population-based study. Methods: We used claims data from the Korean National Health Insurance Service. After inverse probability of treatment weighting, logistic regression and Cox proportional hazard analyses were used to evaluate the risk of clinical failure in bio-naïve patients with CD treated with thiopurine (thiopurine group) or MTX (MTX group). Results: Overall, 10,296 adult and pediatric patients with CD [9912 (96.3%) and 384 (3.7%) in the thiopurine and MTX groups, respectively] were included. The odds ratios (ORs) of failure to induce remission were significantly higher in the MTX group than in the thiopurine group [adjusted OR (aOR), 1.115; 95% confidence interval (CI), 1.045-1.190; p = 0.001]. However, the opposite result was observed only in patients without concomitant steroid use: the MTX group had a lower risk of induction failure than the thiopurine group (aOR, 0.740; 95% CI, 0.673-0.813; p < 0.001). The risk of overall maintenance failure was higher in the MTX group than in the thiopurine group [adjusted hazard ratio (aHR), 1.117; 95% CI, 1.047-1.191; p = 0.001]. The risk of overall maintenance failure was higher in the standard-dose MTX group than in the low-dose MTX group (aHR, 1.296; 95% CI, 1.134-1.480; p < 0.001). There was no significant difference in the risk of maintenance failure according to the administration route of MTX. Conclusion: Thiopurine is more effective than MTX in inducing and maintaining remission in bio-naïve patients with CD; however, the concomitant use of steroids influences inducing remission.

Differences in treatment efficacy between thiopurine and methotrexate in patients with Crohn's disease who were not treated with biologics Immunomodulators (IMMs) used in the treatment of Crohn's disease (CD) include medications such as thiopurine and methotrexate (MTX). Although IMMs are widely prescribed for patients with CD, it remains unclear whether treatment outcomes differ according to the specific types and dosages of IMMs and administration routes of MTX. In this study, we investigated the risk of treatment failure between thiopurines and MTX in CD patients not undergoing biologic treatment. Patients treated with MTX had a higher risk of maintenance failure than those treated with thiopurines. There was no difference in the risk of treatment failure according to the dosage of thiopurine. However, the risk of maintenance failure was higher in patients receiving standard-dose MTX than in those receiving low-dose MTX. There was no difference in the risk of maintenance failure according to the administration route of MTX. Our study enriches the knowledge regarding the treatment efficacy of thiopurines and MTX for patients with CD and may help clinicians develop appropriate treatment plans.

Gut microbiome signature of metabolically healthy obese individuals according to anthropometric, metabolic and inflammatory parameters.

In this study, we investigated the characteristics of gut microbiome in the metabolically healthy obese (MHO) patients, and how they correlate with metabolic and inflammatory profiles. A total of 120 obese people without metabolic comorbidities were recruited, and their clinical phenotypes, metabolic and inflammatory parameters were analysed. The faecal microbial markers originating from bacterial cell and extracellular vesicle (EV) were profiled using 16S rDNA sequencing. The total study population could be classified into two distinct enterotypes (enterotype I: Prevotellaceae-predominant, enterotype II: Akkermansia/Bacteroides-predominant), based on their stool EV-derived microbiome profile. When comparing the metabolic and inflammatory profiles, subjects in enterotype I had higher levels of serum IL-1ß [false discovery rate (FDR) q = 0.050] and had a lower level of microbial diversity than enterotype II (Wilcoxon rank-sum test p < 0.01). Subjects in enterotype I had relatively higher abundance of Bacteroidetes, Prevotellaceae and Prevotella-derived EVs, and lower abundance of Actinobacteria, Firmicutes, Proteobacteria, Akkermansia and Bacteroides-derived EVs (FDR q < 0.05). In conclusion, HMO patients can be categorised into two distinct enterotypes by the faecal EV-derived microbiome profile. The enterotyping may be associated with different metabolic and inflammatory profiles. Further studies are warranted to elucidate the long-term prognostic impact of EV-derived microbiome in the obese population.