Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

Azacitidine and gemtuzumab ozogamicin as post-transplant maintenance therapy for high-risk hematologic malignancies.

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m2) was administered for 7 days, followed by GO (3 mg/m2) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies.

[FLT3-ITD mutation-positive acute myeloid leukemia undergoing clonal transition with PTPN11 mutation at relapse].

A 28-year-old man was diagnosed with acute myelomonocytic leukemia. He achieved complete remission (CR) after two cycles of induction therapy. However, after consolidation therapy, bone marrow aspiration performed to prepare for allogeneic hematopoietic stem cell transplantation revealed disease relapse. Companion diagnostics confirmed the presence of the FLT3-ITD mutation. The patient received gilteritinib monotherapy and achieved CR. Subsequently, he underwent unrelated allogeneic bone marrow transplantation. One year after transplantation, the patient relapsed, and gilteritinib was resumed. However, the leukemia progressed, and panel sequencing using a next-generation sequencer showed that the FLT3-ITD mutation disappeared. A mutation in PTPN11, which regulates the RAS/MAPK signaling pathway, was also detected. Gilteritinib was discontinued, and the patient achieved CR with salvage chemotherapy. He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.

[Ruptured mycotic cerebral aneurysm in an adult T-cell leukemia/lymphoma patient undergoing allogeneic stem cell transplantation].

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.

[Kidney transplantation for end-stage renal disease after third allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia].

An 18-year-old man underwent allogenic bone marrow transplantation (BMT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ph+ALL relapsed 3 months after the first BMT, and the patient underwent a second BMT. However, Ph+ALL relapsed 4 months after the second BMT, and he received a haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) from his father. Molecular complete remission was confirmed 29 days after haplo-PBSCT. However, the patient needed dialysis for end-stage renal disease due to thrombotic microangiopathy 3 years and 2 months after haplo-PBSCT. He received a kidney transplantation from his father 7 years and 10 months after haplo-PBSCT, and got off dialysis after the kidney transplantation. Immunosuppressive therapy with methylprednisolone, tacrolimus, and mycophenolate mofetil was started for kidney transplantation, but the dose of immunosuppressive agents was reduced successfully without rejection soon after kidney transplantation. The patient has maintained long-term remission since the haplo-PBSCT, and his kidney function was restored by the kidney transplantation from his father.

Phase angle as an indicator of physical activity in patients with stable chronic obstructive pulmonary disease.

OBJECTIVES: Phase angle (PhA) reflects cell membrane integrity and vitality and is an indicator of sarcopenia. PhA is associated with physical function in patients with stable chronic obstructive pulmonary disease (COPD). To our knowledge, the association between PhA and physical activity (PA) has not been investigated. Therefore, the aim of this study was to investigate whether PhA reflects PA in patients with COPD. METHODS: This single-center, cross-sectional, observational study included 103 patients with stable COPD (87 men; mean age, 74.7 ± 8.1 y; mean forced expiratory volume in 1s %predicted value, 58.9 ± 20.4%). PhA was measured by bioelectrical impedance analysis. Patients were stratified into low (n = 54) and high (n = 49) PhA groups based on median values (4.3° ± 0.6° and 5.4° ± 0.5°, respectively). PA was calculated as the average daily duration of high-intensity light PA (HLPA; 2.0-2.9 metabolic equivalents [METs] of PA) and moderate- to vigorous-intensity PA (MVPA; >3 METs). Correlation and multivariate analyses using multiple regression analysis were performed to confirm the association between PhA and PA. RESULTS: The high-PhA group demonstrated greater HLPA (104.4 [16.5-332.5] versus 131.3 [61.1-328.7] min, P = 0.005) and MVPA (19.5 [4.7-96.0] versus 46.6 [8.9-139.3] min, P < 0.001) than the low-PhA group. PhA was positively correlated with HLPA (r = 0.32, P < 0.001) and MVPA (r = 0.49, P < 0.001). MVPA (ß = 0.178, P = 0.029) and HLPA (ß = 0.158, P = 0.026) were associated with PhA independent of age, sex, body mass index, respiratory function, muscle strength, skeletal muscle mass index, and 6-min walking distance. CONCLUSION: In patients with COPD, PhA may reflect PA as well as muscle function.

Cytocidal Effect of Irradiation on Gastric Cancer Cells Infected with a Recombinant Mammalian Orthoreovirus Expressing a Membrane-Targeted KillerRed.

The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic virus and photodynamic therapy can be one of the promising modalities to overcome this. Mammalian orthoreovirus (MRV) is an oncolytic virus that has been used in clinical trials for several cancers. In this study, we developed and evaluated a recombinant MRV strain type 3 Dearing (T3D) that expresses membrane-targeting KillerRed (KRmem), a phototoxic fluorescent protein that produces cytotoxic reactive oxygen species upon light irradiation. KRmem was fused in-frame to the 3' end of the σ2 viral gene in the S2 segment using a 2A peptide linker, enabling the expression of multiple proteins from a single transcript. RNA electrophoresis, Western blotting, and immunofluorescence analyses confirmed functional insertion of KRmem into the recombinant virus. The growth activity of the recombinant virus was comparable to that of the wild-type MRV in a cultured cell line. The recombinant virus infected two GC cell lines (MKN45P and MKN7), and a significant cytocidal effect was observed in MKN45P cells infected with the recombinant virus after light irradiation. Thus, recombinant MRV-expressing KRmem has the potential to serve as a novel treatment tool for GC.

Elevation of Urinary Liver-Type Fatty Acid-Binding Protein Is a Harbinger of Poor Patient Prognosis after Allogeneic Stem Cell Transplantation.

Several recent studies have demonstrated that urinary levels of liver-type fatty acid-binding protein (L-FABP) can be used to stratify the prognosis of cardiac disease, cardiac intensive care unit admission, cirrhosis, and coronavirus disease 2019. Our initial prospective study revealed that urinary L-FABP (uL-FABP) was associated with a high probability of acute kidney injury after stem cell transplantation (SCT); however, the relevance of elevated uL-FABP to the prognosis of patients undergoing SCT remains to be determined. We aimed to investigate whether uL-FABP levels can be used to stratify patient prognosis after SCT. To achieve this aim, we conducted a new long-term follow-up study using data from patients enrolled in our preceding prospective cohort study. Patients were classified into high and low uL-FABP groups based on levels measured at baseline (ie, before initiating the conditioning regimen), using an uL-FABP cutoff of 8.4 µg/gCr, which was determined based on data from healthy adults. uL-FABP levels were also measured on days 0, 7, and 14 after SCT. Cox proportional hazard regression was used to examine the effects of each factor on survival outcomes, and Fine-Gray regression was used in the presence of competing risks. Multivariate analysis incorporating confounders was then performed for factors with P < .1 in univariate analysis. In total, 20 of 84 patients (23.8%), 57 of 84 patients (67.9%), 34 of 49 patients (69.4%), and 34 of 46 patients (73.9%) were classified into the high uL-FABP group at baseline and on days 0, 7, and 14, respectively. The 5-year overall survival (OS) rate was 23.9% in the high uL-FABP group and 68.9% in the low uL-FABP group. The multivariate analysis identified a high uL-FABP level at baseline as a significant prognostic factor for poor OS (hazard ratio [HR], 3.54; P = .002). The 5-year cumulative incidence rate for nonrelapse mortality (NRM) was 50.0% in the high uL-FABP group and 19.9% in the low uL-FABP group. In the multivariate analysis, high uL-FABP at baseline was a significant prognostic factor for NRM (HR, 3.37; P = .01). uL-FABP levels did not significantly stratify the cumulative incidence of relapse (HR, 2.13; P = .11). uL-FABP levels on days 0, 7, and 14 were not significant predictors of survival. High uL-FABP level before initiation of conditioning significantly influences OS and NRM following SCT, whereas a high uL-FABP level at any point after the conditioning regimen does not. Our results show that measuring uL-FABP level at baseline may be a simple way to predict survival in patients undergoing SCT.

Performance of artificial intelligence-based software for the automatic detection of lung lesions on chest radiographs of patients with suspected lung cancer.

PURPOSE: This study aimed to evaluate the performance of the commercially available artificial intelligence-based software CXR-AID for the automatic detection of pulmonary nodules on the chest radiographs of patients suspected of having lung cancer. MATERIALS AND METHODS: This retrospective study included 399 patients with clinically suspected lung cancer who underwent CT and chest radiography within 1 month between June 2020 and May 2022. The candidate areas on chest radiographs identified by CXR-AID were categorized into target (properly detected areas) and non-target (improperly detected areas) areas. The non-target areas were further divided into non-target normal areas (false positives for normal structures) and non-target abnormal areas. The visibility score, characteristics and location of the nodules, presence of overlapping structures, and background lung score and presence of pulmonary disease were manually evaluated and compared between the nodules detected or undetected by CXR-AID. The probability indices calculated by CXR-AID were compared between the target and non-target areas. RESULTS: Among the 450 nodules detected in 399 patients, 331 nodules detected in 313 patients were visible on chest radiographs during manual evaluation. CXR-AID detected 264 of these 331 nodules with a sensitivity of 0.80. The detection sensitivity increased significantly with the visibility score. No significant correlation was observed between the background lung score and sensitivity. The non-target area per image was 0.85, and the probability index of the non-target area was lower than that of the target area. The non-target normal area per image was 0.24. Larger and more solid nodules exhibited higher sensitivities, while nodules with overlapping structures demonstrated lower detection sensitivities. CONCLUSION: The nodule detection sensitivity of CXR-AID on chest radiographs was 0.80, and the non-target and non-target normal areas per image were 0.85 and 0.24, respectively. Larger, solid nodules without overlapping structures were detected more readily by CXR-AID.

Outcomes of allogeneic hematopoietic cell transplantation under letermovir prophylaxis for cytomegalovirus infection.

Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Herein, we evaluated the impact of LMV prophylaxis on posttransplant outcomes using the registry database of the Japanese Society for Transplantation and Cellular Therapy. Adult patients who underwent allo-HCT between 2017 and 2019 were analyzed (n = 6004). LMV prophylaxis was administered to 1640 patients (LMV group) and it significantly reduced the incidence of csCMV infection compared with those not administered LMV prophylaxis (15.4% vs 54.1%; p < 0.01). However, it did not improve the 1-year NRM (hazard ratio [HR], 0.93; p = 0.40) and OS (HR, 0.96; p = 0.49). In the LMV group, 74 patients had breakthrough csCMV infection and showed inferior NRM (HR, 3.44; p < 0.01) and OS (HR, 1.93; p = 0.02) compared with those without infection. After completing LMV prophylaxis, 252 patients had late csCMV infection and showed inferior NRM (HR, 1.83; p < 0.01) and OS (HR, 1.58; p < 0.01). Our findings suggest that managing breakthrough and late csCMV infections is important for improving long-term outcomes.

The International Association for the Study of Lung Cancer Early Lung Imaging Confederation Open-Source Deep Learning and Quantitative Measurement Initiative.

INTRODUCTION: With global adoption of computed tomography (CT) lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open-source, cloud-based, globally distributed, screening CT imaging data set and computational environment that are compliant with the most stringent international privacy regulations that also protect the intellectual properties of researchers, the International Association for the Study of Lung Cancer sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be used for clinically relevant AI research. METHODS: In this second phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans. RESULTS: A total of 1394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness more than or equal to 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high-quality CT scans. CONCLUSIONS: These initial experiments revealed that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based data sets.

Electrolyzed hypochlorous acid water exhibits potent disinfectant activity against various viruses through irreversible protein aggregation.

It is essential to employ efficient measures to prevent the transmission of pathogenic agents during a pandemic. One such method involves using hypochlorous acid (HClO) solution. The oxidative properties of HClO water (HAW) can contribute to its ability to eliminate viral particles. Here, we examined a highly purified slightly acidic hypochlorous acid water (Hp-SA-HAW) obtained from the reverse osmosis membrane treatment of an electrolytically-generated SA-HAW for its anti-viral activity and mode of action on viral proteins. Hp-SA-HAW exhibited broad-spectrum antiviral effects against various viruses, including adenovirus, hepatitis B virus, Japanese encephalitis virus (JEV), and rotavirus. Additionally, Hp-SA-HAW treatment dose-dependently resulted in irreversibly aggregated multimers of the JEV envelope and capsid proteins. However, Hp-SA-HAW treatment had no discernible effect on viral RNA, indicating that Hp-SA-HAW acts against amino acids rather than nucleic acids. Furthermore, Hp-SA-HAW substantially reduced the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the ancestral variant and other multiple variants. Hp-SA-HAW treatment induced the aggregation of the SARS-CoV-2 spike and nuclear proteins and disrupted the binding of the purified spike protein of SARS-CoV-2 to human ACE2. This study demonstrates that the broad-spectrum virucidal activity of highly purified HClO is attributed to viral protein aggregation of virion via protein oxidation.

Combination of Donor Lymphocyte Infusion and Blinatumomab for B-Cell Lymphoblastic Lymphoma Relapse after Allogeneic Stem-Cell Transplantation.

A woman in her forties with relapsed B-cell lymphoblastic lymphoma was treated with blinatumomab, but the drug proved ineffective. Salvage therapy with clofarabine induced a complete remission, and she received an allogeneic stem-cell transplantation (allo-SCT) from an HLA-matched sibling donor. However, her disease relapsed only 4 months after the allo-SCT. Three courses of combination therapy with donor lymphocyte infusion (DLI) and blinatumomab were administered, and the tumor progression was well controlled for 6 months, leading to a second allo-SCT from an HLA-haploidentical donor. The remission was persistent for approximately 1 year, but the disease relapsed in her central nervous system, and she eventually died. Our case demonstrated the efficacy and safety of concomitant use of DLI and blinatumomab. This combination presumably enhanced a graft-versus-lymphoma effect of allogeneic T-cells without provoking graft-versus-host disease.

The Emergence and Widespread Circulation of Enteric Viruses Throughout the COVID-19 Pandemic: A Wastewater-Based Evidence.

Growing evidence shed light on the importance of wastewater-based epidemiology (WBE) during the pandemic, when the patients rarely visited the clinics despite the fact that the infections were still prevalent in the community as before. The abundance of infections in the community poses a constant threat of the emergence of new epidemic strains. Herein, we investigated enteric viruses in raw sewage water (SW) from Japan's Tohoku region and compared them to those from the Kansai region to better understand the circulating strains and their distribution across communities during the COVID-19 pandemic. Raw SW was collected between 2019 and 2022, concentrated by polyethylene-glycol-precipitation method, and investigated for major AGE viruses by RT-PCR. Sequence-based analyses were used to assess genotypes and evolutionary relationships. The most commonly detected enteric virus was rotavirus A (RVA) at 63.8%, followed by astrovirus (AstV) at 61.1%, norovirus (NoV) GII and adenovirus (AdV) at 33.3%, sapovirus (SV) at 25.0%, enterovirus (EV) at 19.4%, and NoV GI at 13.9%. The highest prevalence (46.0%) was found in the spring. Importantly, enteric viruses did not decline during the pandemic. Rather, several strains like NoV GII.2, DS-1-like human G3 (equine) RVA, MLB1 AstV, and different F41 HAdV emerged throughout the pandemic and spread widely over the Tohoku and Kansai regions. Tohoku's detection rate remained lower than that of the Kansai area (36 vs 58%). This study provides evidence for the emergence and spread of enteric viruses during the pandemic.

Clinical outcomes in transplant-eligible patients with relapsed or refractory diffuse large B-cell lymphoma after second-line salvage chemotherapy: A retrospective study.

OBJECTIVE: The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Although patients who fail first-line salvage chemotherapy are candidates for second-line salvage chemotherapy, the optimal treatment strategy for these patients has not yet been established. METHODS: The present, single-center, retrospective study included transplant-eligible patients with R/R DLBCL who received second-line salvage chemotherapy with curative intent. RESULTS: Seventy-six patients with R/R DLBCL received second-line salvage chemotherapy. Eighteen (23.7%) patients were responders to the first-line salvage chemotherapy. The overall response rate was 39.5%, and overall survival (OS) was significantly longer in patients who responded to second-line salvage chemotherapy than those who did not. Forty-one patients who proceeded to potentially curative treatment (autologous hematopoietic stem cell transplantation [ASCT], chimeric antigen receptor [CAR] T-cell therapy, or allogeneic hematopoietic stem cell transplantation) had a better prognosis than those who did not. Among the 46 patients who failed to respond to the second-line salvage regimen, only 18 (39.1%) could proceed to the curative treatments. However, among the 30 patients who responded to the second-line salvage regimen, 23 (76.7%) received one of the potentially curative treatments. Among 34 patients who received CAR T-cell therapy, OS was significantly longer in those who responded to salvage chemotherapy immediately prior to CAR T-cell therapy than in those who did not respond. In contrast, the number of prior lines of chemotherapy was not identified as a statistically significant prognostic factor of survival. No significant difference was detected in OS between patients receiving ASCT and those receiving CAR T-cell therapy after the response to second-line salvage chemotherapy. DISCUSSION: In this study, we demonstrated that chemosensitivity remained a crucial factor in predicting survival outcomes following CAR T-cell therapy irrespective of the administration timing, and that both ASCT and CAR T-cell therapy were acceptable after the response to second-line salvage chemotherapy.

[Polatuzumab vedotin, bendamustine, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma, including the outcome as a bridging treatment to CAR-T cell therapy or allogeneic hematopoietic stem cell transplant].

Pola-BR (polatuzumab vedotin, bendamustine, and rituximab) therapy received approval for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in Japan in March 2021. There have been few reports on the efficacy and safety of Pola-BR therapy in Japanese clinical practice. A retrospective analysis was performed on twenty-nine patients with R/R DLBCL who received Pola-BR therapy at our institution (intent to cellular immunotherapy cohort: 20 patients, stand-alone treatment cohort: nine patients). The overall response rate was 69.0% (complete response 27.6%). The median progression-free survival was 5.1 months, with a 9.5-month median overall survival. In the intent to cellular immunotherapy cohort, 11 of 19 patients received chimeric antigen receptor T-cell (CAR-T) infusions, and one patient received allogeneic stem cell transplantation. Four patients received Pola-BR therapy, including bendamustine before leukapheresis, and all produced CAR-T products successfully. 3 of the 28 patients experienced grade3 or higher adverse events, and two required treatment discontinuation. Our single institution, a real-world cohort of R/R DLBCL patients showed high efficacy outcomes and a tolerable toxicity profile for Pola-BR therapy, which is comparable to previous studies. More cases are needed to determine its impact on CAR-T therapy and stem cell transplantation.

Effective SARS-CoV-2 replication of monolayers of intestinal epithelial cells differentiated from human induced pluripotent stem cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe acute respiratory symptoms in humans. Controlling the coronavirus disease pandemic is a worldwide priority. The number of SARS-CoV-2 studies has dramatically increased, and the requirement for analytical tools is higher than ever. Here, we propose monolayered-intestinal epithelial cells (IECs) derived from human induced pluripotent stem cells (iPSCs) instead of three-dimensional cultured intestinal organoids as a suitable tool to study SARS-CoV-2 infection. Differentiated IEC monolayers express high levels of angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), host factors essential for SARS-CoV-2 infection. SARS-CoV-2 efficiently grows in IEC monolayers. Using this propagation system, we confirm that TMPRSS2 inhibition blocked SARS-CoV-2 infection in IECs. Hence, our iPSC-derived IEC monolayers are suitable for SARS-CoV-2 research under physiologically relevant conditions.

Deep learning-based automatic detection for pulmonary nodules on chest radiographs: The relationship with background lung condition, nodule characteristics, and location.

PURPOSE: Computer-aided diagnosis (CAD), which assists in the interpretation of chest radiographs, is becoming common. However, few studies have evaluated the benefits and pitfalls of CAD in the real world. This study aimed to evaluate the independent performance of commercially available deep learning-based automatic detection (DLAD) software, EIRL Chest X-ray Lung Nodule, in a cohort that included patients with background pulmonary abnormalities often encountered in clinical situations. METHODS: Patients with clinically suspected lung cancer for whom chest radiography was performed within a month before or after CT scan between June 2020 and May 2022 in our institution were enrolled. The reference standard was created using a bounding box annotated by two radiologists with reference to the CT. The visibility score, characteristics, location of the pulmonary nodules, presence of overlapping structures or pulmonary disease, and background lung score were manually determined. RESULTS: We included 388 patients. The DLAD software detected 222 of the 322 nodules visible on manual evaluation, with a sensitivity of 0.689 and a false-positive rate of 0.168. The detectability of the DLAD software was significantly lower for small and subsolid and nodules with overlapping structures. The visibility score and sensitivity of detection by the DLAD software were positively correlated. The relationship between the background lung score and detection by the DLAD software was unclear. CONCLUSION: The standalone performance of DLAD in detecting pulmonary nodules exhibited a sensitivity of 0.689 and a false-positive rate of 0.168. Understanding the characteristics of DLAD is crucial when interpreting chest radiographs with the assistance of the DLAD.

Identification of compounds that preferentially suppress the growth of T-cell acute lymphoblastic leukemia-derived cells.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range. Among them, auxarconjugatin-B and rumbrin commonly contained a polyenyl 3-chloropyrrol in their chemical structure, therefore we chose auxarconjugatin-B for further analyses. Auxarconjugatin-B suppressed the in vitro growth of five human T-ALL cell lines and two T-ALL patient-derived cells, but not that of adult T-cell leukemia patient-derived cells. Cultured normal T cells were several-fold resistant to auxarconjugatin-B. Auxarconjugatin-B and its synthetic analogue Ra#37 depolarized the mitochondrial membrane potential of CCRF-CEM cells within 3 h of treatment. These compounds are promising seeds for developing novel anti-T-ALL drugs.