Cost-Effectiveness of Anti-BCMA Chimeric Antigen Receptor T Cell Therapy in Relapsed/Refractory Multiple Myeloma.

Despite its promising outcomes, anti-BCMA chimeric antigen receptor T cell therapy (CAR-T) is the most expensive myeloma treatment developed to date, and its cost-effectiveness is an important issue. This study aimed to assess the cost-effectiveness of anti-BCMA CAR-T compared to standard antimyeloma therapy in patients with relapsed/refractory multiple myeloma. The model included myeloma patients in Japan and the United States who have received ≥3 prior lines of antimyeloma therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. A Markov model was constructed to compare the CAR-T strategy, in which patients receive either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) followed by 3 lines of multiagent chemotherapy after relapse, and the no CAR-T strategy, in which patients receive only chemotherapy. Data from the LocoMMotion, KarMMa, and CARTITUDE-1 trials were extracted. Several assumptions were made regarding long-term progression-free survival (PFS) with CAR-T. Extensive scenario analyses were made regarding regimens for no CAR-T strategies. The outcome was an incremental cost-effectiveness ratio (ICER) with willingness-to-pay thresholds of ¥7,500,000 in Japan and $150,000 in the United States. When a 5-year PFS of 40% with cilta-cel was assumed, the ICER of the CAR-T strategy versus the no CAR-T strategy was ¥7,603,823 per QALY in Japan and $112,191 per QALY in the United States over a 10-year time horizon. When a 5-year PFS of 15% with ide-cel was assumed, the ICER was ¥20,388,711 per QALY in Japan and $261,678 per QALY in the United States over a 10-year time horizon. The results were highly dependent on the PFS assumption with CAR-T and were robust to changes in most other parameters and scenarios. Although anti-BCMA CAR-T can be cost-effective even under current pricing, a high long-term PFS is necessary.

Accumulation of annexin A2 and S100A10 prevents apoptosis of apically delaminated, transformed epithelial cells.

In various epithelial tissues, the epithelial monolayer acts as a barrier. To fulfill its function, the structural integrity of the epithelium is tightly controlled. When normal epithelial cells detach from the basal substratum and delaminate into the apical lumen, the apically extruded cells undergo apoptosis, which is termed anoikis. In contrast, transformed cells often become resistant to anoikis and able to survive and grow in the apical luminal space, leading to the formation of multilayered structures, which can be observed at the early stage of carcinogenesis. However, the underlying molecular mechanisms still remain elusive. In this study, we first demonstrate that S100A10 and ANXA2 (Annexin A2) accumulate in apically extruded, transformed cells in both various cell culture systems and murine epithelial tissues in vivo. ANXA2 acts upstream of S100A10 accumulation. Knockdown of ANXA2 promotes apoptosis of apically extruded RasV12-transformed cells and suppresses the formation of multilayered epithelia. In addition, the intracellular reactive oxygen species (ROS) are elevated in apically extruded RasV12 cells. Treatment with ROS scavenger Trolox reduces the occurrence of apoptosis of apically extruded ANXA2-knockdown RasV12 cells and restores the formation of multilayered epithelia. Furthermore, ROS-mediated p38MAPK activation is observed in apically delaminated RasV12 cells, and ANXA2 knockdown further enhances the p38MAPK activity. Moreover, the p38MAPK inhibitor promotes the formation of multilayered epithelia of ANXA2-knockdown RasV12 cells. These results indicate that accumulated ANXA2 diminishes the ROS-mediated p38MAPK activation in apically extruded transformed cells, thereby blocking the induction of apoptosis. Hence, ANXA2 can be a potential therapeutic target to prevent multilayered, precancerous lesions.

Influential factors of long-term and seasonal 137Cs change in agricultural and forested rivers: Temperature, water quality and an intense Typhoon Event.

In this study, the effect of temperature, water quality, and the impact of an intense typhoon event on change in 137Cs concentration in the water of agricultural and forested rivers near the Fukushima Daiichi nuclear power plant (Japan) was evaluated using monthly stationary observations obtained under baseflow conditions 2.8-10.6 years after the nuclear accident in 2011. The dissolved 137Cs concentration fluctuated seasonally with water temperature in all rivers, and the increase in dissolved 137Cs concentration for unit increase in temperature was higher in forested rivers than in agricultural rivers. The relationship between water temperature and the apparent distribution coefficient of 137Cs well followed the van 't Hoff equation in the two agricultural rivers, where the enthalpy of reaction was estimated as -15.6 and -19.6 kJ mol-1. The van 't Hoff equation was not well followed for a forested river, where the suspended solids mainly comprised organic matter, suggesting that the dominant process determining dissolved 137Cs concentrations in forested rivers is not only water temperature effect on ion exchange, but rather the input of 137Cs and K+ (competing with 137Cs for exchange sites on mineral particles) into the water phase via litter leaching. Suspended solids concentrations in agricultural rivers correlated negatively with 137Cs concentrations in suspended solids, suggesting an increased proportion of coarse particles or the input of soils with low 137Cs concentration from decontaminated agricultural land. At some sites, 137Cs concentrations in dissolved form and in suspended solids were reduced sharply in association with the passage of Typhoon Hagibis in October 2019, suggesting that Typhoon Hagibis caused large-scale surface erosion that removed the source of 137Cs.

Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect.

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.

Engineered macrophages acting as a trigger to induce inflammation only in tumor tissues based on arginase 1-responsive TNF-α accelerated release.

Herein, we report engineered macrophages, termed "MacTrigger," acting as a trigger to induce an inflammatory environment only in tumor tissues. This led to intensive anti-tumor effects based on the removal potential of foreign substances. The strength of this study is the utilization of two unique functions of macrophages: (1) their ability to migrate to tumor tissues and (2) polarization into the anti-inflammatory M2 phenotype in the presence of tumor tissues. The MacTrigger accelerated the release of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), when it was polarized to the M2 phenotype. When the MacTrigger was administered to tumor-bearing mice, tumor growth was significantly inhibited compared with the non-treatment group, the un-transfected macrophages group, and the group with engineered macrophages capable of randomly releasing TNF-α. Additionally, the ratio of the M1 phenotype to the M2 phenotype in tumor tissues was >1 only in the MacTrigger group. Moreover, the ratios of natural killer cells and CD8+T cells in tumor tissues were increased compared with other groups. These results indicate that MacTrigger can induce inflammation in tumor tissues, leading to effective anti-tumor effects. In normal tissues, especially the liver, notable side effects were not observed. This is because, in the liver, the MacTrigger was not polarized to the M2 phenotype and could not induce inflammation. These results suggest that the MacTrigger is a "trigger" that can induce inflammation only in tumor tissues, then allowing the body to attack tumor tissues through the innate immunity system.

Engineered macrophages acting as a trigger to induce inflammation only in tumor tissues.

Herein, we report engineered macrophages, termed "MacTrigger," acting as a trigger to induce an inflammatory environment only in tumor tissues. This led to intensive anti-tumor effects based on the removal potential of foreign substances. The strength of this study is the utilization of two unique functions of macrophages: (1) their ability to migrate to tumor tissues and (2) polarization into the anti-inflammatory M2 phenotype in the presence of tumor tissues. The MacTrigger accelerated the release of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), when it was polarized to the M2 phenotype. When the MacTrigger was administered to tumor-bearing mice, tumor growth was significantly inhibited compared with the non-treatment group, the un-transfected macrophages group, and the group with engineered macrophages capable of randomly releasing TNF-α. Additionally, the ratio of the M1 phenotype to the M2 phenotype in tumor tissues was >1 only in the MacTrigger group. Moreover, the ratios of natural killer cells and CD8+T cells in tumor tissues were increased compared with other groups. These results indicate that MacTrigger can induce inflammation in tumor tissues, leading to effective anti-tumor effects. In normal tissues, especially the liver, notable side effects were not observed. This is because, in the liver, the MacTrigger was not polarized to the M2 phenotype and could not induce inflammation. These results suggest that the MacTrigger is a "trigger" that can induce inflammation only in tumor tissues, then allowing the body to attack tumor tissues through the innate immunity system.

Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Effect of cumulative daunorubicin dose on cardiotoxicity after allogeneic stem cell transplantation.

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m2/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m2 (range, 0-950 mg/m2), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m2). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m2 was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.

Radiation Myelopathy Caused by Palliative Radiotherapy and Intrathecal Methotrexate.

Radiation myelopathy is a rare, late-stage adverse event that develops following irradiation at or above 50 Gy. Here, we report a case of irreversible paraplegia caused by palliative radiation (20 Gy in 5 fractions) to the spinal cord combined with intrathecal methotrexate (IT-MTX). A 69-year-old man presented with back pain, prompting a diagnosis of acute myeloid leukemia. At the first visit, he complained of muscle weakness and hypoesthesia in both legs; spinal magnetic resonance imaging (MRI) revealed an epidural mass compressing the spinal cord at the fifth to seventh level of the thoracic vertebrae. This was considered to be an extramedullary lesion of leukemia, and he received remission induction therapy including IT-MTX; palliative radiation (20 Gy in 5 fractions) of the epidural mass was initiated the following day. Then, during the course of consolidation therapy, a second IT-MTX was performed after 1 month and a third after 3 months. While the consolidation therapy was complete, yielding remission, he developed sudden paraplegia, as well as bladder and bowel dysfunction (BBD), 10 months later. Spinal MRI showed extensive intramedullary high signal intensity on T2-weighted image, including the irradiation field. It was thought myelopathy was due to irradiation of the spinal cord combined with IT-MTX. He immediately received steroid pulse therapy; however, the paraplegia and BBD did not improve. It is extremely rare for irreversible radiation myelopathy to occur with IT-MTX and palliative radiation to the spinal cord. We believe that even with low-dose palliative radiation, caution is required for combined use with IT-MTX.

Basal extrusion of single-oncogenic mutant cells induces dome-like structures with altered microenvironments.

At the initial stage of carcinogenesis, oncogenic transformation occurs in single cells within epithelial layers. However, the behavior and fate of the newly emerging transformed cells remain enigmatic. Here, using originally established mouse models, we investigate the fate of RasV12-transformed cells that appear in a mosaic manner within epithelial tissues. In the lung bronchial epithelium, most majority of RasV12-transformed cells are apically extruded, whereas noneliminated RasV12 cells are often basally delaminated leading to various noncell-autonomous changes in surrounding environments; macrophages and activated fibroblasts are accumulated, and normal epithelial cells overlying RasV12 cells overproliferate and form a convex multilayer, which is termed a 'dome-like structure'. In addition, basally extruded RasV12 cells acquire certain features of epithelial-mesenchymal transition (EMT). Furthermore, the expression of COX-2 is profoundly elevated in RasV12 cells in dome-like structures, and treatment with the COX inhibitor ibuprofen suppresses the recruitment of activated fibroblasts and moderately diminishes the formation of dome-like structures. Therefore, basal extrusion of single-oncogenic mutant cells can induce a tumor microenvironment and EMT and generate characteristic precancerous lesions, providing molecular insights into the earlier steps of cancer development.

Aerobic exercise and cognitive functioning in schizophrenia: An updated systematic review and meta-analysis.

This study serves as an update to a recent systematic review and meta-analysis to summarize the effect of aerobic exercise on cognition in schizophrenia and determine the most effective method of aerobic exercise. We searched for controlled studies investigating the effect of aerobic exercise on cognition in schizophrenia published until January 2021. Fifteen studies were included. A random-effects model was used to estimate the standardized mean differences (SMDs) between cognitive outcomes of aerobic exercises and controls. Compared with controls, aerobic exercises resulted in significant improvements in global cognition (SMD = 0.21), attention/vigilance (SMD = 0.32), working memory (SMD = 0.27), and verbal learning (SMD = 0.30). Significant improvements in global cognition were observed with group exercise (SMD = 0.28), exercise supervised by exercise professionals (SMD = 0.27), as well as with ≥ 90 min/week (SMD = 0.26) and ≥ 12 weeks duration (SMD = 0.22). Our findings provide information beneficial for determining the most effective aerobic exercise method to improve cognition in schizophrenia.

Daratumumab in first-line therapy is cost-effective in transplant-eligible patients with newly diagnosed myeloma.

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.

Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

Urine Xanthine Crystals in Hematologic Malignancies with Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation.

The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (p = 0.005). Muscle mass loss did not affect non-relapse mortality (p = 0.238) but was significantly associated with relapse (p = 0.067). Pre-transplant muscle mass loss may therefore reflect a poor prognosis for the primary disease.

Relationship of tumor load parameters before and after autologous stem cell transplantation with clinical prognosis in transplant-eligible patients with multiple myeloma: A retrospective analysis.

We retrospectively examined 57 patients with multiple myeloma who underwent autologous stem cell transplantation (ASCT) at our institution. A receiver-operating characteristic curve (ROC) analysis showed that the reduction rate of quantitative serum monoclonal protein (M-protein) before ASCT and the difference in involved and uninvolved free light chains (dFLC) 30 days after ASCT, respectively, had the greatest predictive value for all patients (area under the curve [AUC] 0.791 and 0.660, respectively). Based on the ROC curve-based cutoff values of tumor burden parameters, progression-free survival (PFS) in the high serum M-protein reduction (≥90 %) group was significantly better than that in the low serum M-protein reduction group (<90 %) (2-year PFS 79.5 % vs. 17.0 %, p < 0.001), but there were no significant differences in PFS between the low (<5.2 mg/L) and high (≥5.2 mg/L) dFLC groups (2-year PFS, 72.0 % vs. 46.0 %; p = 0.149). A multivariate analysis identified the reduction in serum M-protein as an independent predictive factor before ASCT for PFS (hazard ratio [HR] 0.287, p = 0.022) and high dFLC on day 30 after ASCT for PFS (HR 3.902, p = 0.040). These results demonstrate that a good prognosis can be expected with a reduction of serum M-protein before and after ASCT.

Risk Factors for Complications Associated with Peripherally Inserted Central Catheters During Induction Chemotherapy for Acute Myeloid Leukemia.

Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.

The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia.

At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.

Bacteroidetes Species Are Correlated with Disease Activity in Ulcerative Colitis.

Fecal microbiota transplantation following triple-antibiotic therapy (amoxicillin/fosfomycin/metronidazole) improves dysbiosis caused by reduced Bacteroidetes diversity in patients with ulcerative colitis (UC). We investigated the correlation between Bacteroidetes species abundance and UC activity. Fecal samples from 34 healthy controls and 52 patients with active UC (Lichtiger's clinical activity index ≥5 or Mayo endoscopic subscore ≥1) were subjected to next-generation sequencing with HSP60 as a target in bacterial metagenome analysis. A multiplex gene expression assay using colonoscopy-harvested mucosal tissues determined the involvement of Bacteroidetes species in the mucosal immune response. In patients with UC, six Bacteroides species exhibited significantly lower relative abundance, and twelve Bacteroidetes species were found significantly correlated with at least one metric of disease activity. The abundance of five Bacteroidetes species (Alistipes putredinis, Bacteroides stercoris, Bacteroides uniformis, Bacteroides rodentium, and Parabacteroides merdae) was correlated with three metrics, and their cumulative relative abundance was strongly correlated with the sum of Mayo endoscopic subscore (R = -0.71, p = 2 × 10-9). Five genes (TARP, C10ORF54, ITGAE, TNFSF9, and LCN2) associated with UC pathogenesis were expressed by the 12 key species. The loss of key species may exacerbate UC activity, serving as potential biomarkers.