Status 2 upgrade indication impacts posttransplant mortality in patients bridged with intraaortic balloon pump in the new heart allocation system.

To evaluate outcomes of patients undergoing heart transplants (HTs) using an intra-aortic balloon pump (IABP) under exception status. Adult patients supported by an IABP who underwent HT between November 18, 2018, and December 31, 2020, as documented in the United Network for Organ Sharing, were included. Patients were stratified according to requests for exception status. Kaplan-Meier methodology was used to look for differences in survival between groups. A total of 1284 patients were included; 492 (38.3%) were transplanted with an IABP under exception status. Exception status patients had higher body mass index, were more likely to be Black, and had longer waitlist times. Exception status patients received organs from younger donors, had a shorter ischemic time, and had a higher frequency of sex mismatch. The 1-year posttransplant survival was 93% for the nonexception and 88% for the exception IABP patients (hazard ratio: 1.85 [95% confidence interval: 1.12-2.86, P = .006]). The most common reason for requesting an exception status was inability to meet blood pressure criteria for extension (37% of patients). The most common reason for an extension request for an exception status was right ventricular dysfunction (24%). IABP patients transplanted under exception status have an increased 1-year mortality rate posttransplant compared with those without exception status.

Direct and Indirect Chimeric Antigen Receptor T-Cell Imaging with PET/MRI in a Tumor Xenograft Model.

Background Chimeric antigen receptor (CAR) T cells are a promising cancer therapy; however, reliable and repeatable methods for tracking and monitoring CAR T cells in vivo remain underexplored. Purpose To investigate direct and indirect imaging strategies for tracking the biodistribution of CAR T cells and monitoring their therapeutic effect in target tumors. Materials and Methods CAR T cells co-expressing a tumor-targeting gene (anti-CD19 CAR) and a human somatostatin receptor subtype 2 (hSSTr2) reporter gene were generated from human peripheral blood mononuclear cells. After direct labeling with zirconium 89 (89Zr)-p-isothiocyanatobenzyl-desferrioxamine (DFO), CAR T cells were intravenously injected into immunodeficient mice with a CD19-positive and CD19-negative human tumor xenograft on the left and right flank, respectively. PET/MRI was used for direct in vivo imaging of 89Zr-DFO-labeled CAR T cells on days 0, 1, 3, and 7 and for indirect cell imaging with the radiolabeled somatostatin receptor-targeted ligand gallium 68 (68Ga)-DOTA-Tyr3-octreotide (DOTATOC) on days 6, 9, and 13. On day 13, mice were euthanized, and tissues and tumors were excised. Results The 89Zr-DFO-labeled CAR T cells were observed on PET/MRI scans in the liver and lungs of mice (n = 4) at all time points assessed. However, they were not visualized in CD19-positive or CD19-negative tumors, even on day 7. Serial 68Ga-DOTATOC PET/MRI showed CAR T cell accumulation in CD19-positive tumors but not in CD19-negative tumors from days 6 to 13. Notably, 68Ga-DOTATOC accumulation in CD19-positive tumors was highest on day 9 (mean percentage injected dose [%ID], 3.7% ± 1.0 [SD]) and decreased on day 13 (mean %ID, 2.6% ± 0.7) in parallel with a decrease in tumor volume (day 9: mean, 195 mm3 ± 27; day 13: mean, 127 mm3 ± 43) in the group with tumor growth inhibition. Enhanced immunohistochemistry staining of cluster of differentiation 3 (CD3) and hSSTr2 was also observed in excised CD19-positive tumor tissues. Conclusion Direct and indirect cell imaging with PET/MRI enabled in vivo tracking and monitoring of CAR T cells in an animal model. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bulte in this issue.

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/ß, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis.

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.

The impact of Renin-Angiotensin System Inhibitors on bone fracture risk: a nationwide nested case-control study.

BACKGROUND: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort. METHODS: We employed a nested case-control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence. RESULTS: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59-0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49-0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs. CONCLUSIONS: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures.

Geographic information system-based determination of priority monitoring areas for hazardous air pollutants in an industrial city.

Industrial cities are hotspots for many hazardous air pollutants (HAPs), which are detrimental to human health. We devised an identification method to determine priority HAP monitoring areas using a comprehensive approach involving monitoring, modeling, and demographics. The methodology to identify the priority HAP monitoring area consists of two parts: (1) mapping the spatial distribution of selected categories relevant to the target pollutant and (2) integrating the distribution maps of various categories and subsequent scoring. The identification method was applied in Ulsan, the largest industrial city in South Korea, to identify priority HAP monitoring areas. Four categories related to HAPs were used in the method: (1) concentrations of HAPs, (2) amount of HAP emissions, (3) the contribution of industrial activities, and (4) population density in the city. This method can be used to select priority HAP monitoring areas for intensive monitoring campaigns, cohort studies, and epidemiological studies.

Lineage-Independent Tumors in Bilateral Neuroblastoma.

Childhood tumors that occur synchronously in different anatomical sites usually represent metastatic disease. However, such tumors can be independent neoplasms. We investigated whether cases of bilateral neuroblastoma represented independent tumors in two children with pathogenic germline mutations by genotyping somatic mutations shared between tumors and blood. Our results suggested that in both children, the lineages that had given rise to the tumors had segregated within the first cell divisions of the zygote, without being preceded by a common premalignant clone. In one patient, the tumors had parallel evolution, including distinct second hits in SMARCA4, a putative predisposition gene for neuroblastoma. These findings portray cases of bilateral neuroblastoma as having independent lesions mediated by a germline predisposition. (Funded by Children with Cancer UK and Wellcome.).

Physician Radiation Exposure During Endomyocardial Biopsy and Right Heart Catheterization.

BACKGROUND: Cardiologists performing coronary angiography (CA) and percutaneous coronary intervention (PCI) are at risk of health problems related to chronic occupational radiation exposure. Unlike during CA and PCI, physician radiation exposure during right heart catheterization (RHC) and endomyocardial biopsy (EMB) has not been adequately studied. The objective of this study was to assess physicians' radiation doses during RHC with and without EMB and compare them to those of CA and PCI. METHODS: Procedural head-level physician radiation doses were collected by real-time dosimeters. Radiation-dose metrics (fluoroscopy time, air kerma [AK] and dose area product [DAP]), and physician-level radiation doses were compared among RHC, RHC with EMB, CA, and PCI. RESULTS: Included in the study were 351 cardiac catheterization procedures. Of these, 36 (10.3%) were RHC, 42 (12%) RHC with EMB, 156 (44.4%) CA, and 117 (33.3%) PCI. RHC with EMB and CA had similar fluoroscopy time. AK and DAP were progressively higher for RHC, RHC with EMB, CA, and PCI. Head-level physician radiation doses were similar for RHC with EMB vs CA (P = 0.07). When physicians' radiation doses were normalized to DAP, RHC and RHC with EMB had the highest doses. CONCLUSION: Physicians' head-level radiation doses during RHC with EMB were similar to those of CA. After normalizing to DAP, RHC and RHC with EMB were associated with significantly higher physician radiation doses than CA or PCI. These observations suggest that additional protective measures should be undertaken to decrease physicians' radiation exposure during RHC and, in particular, RHC with EMB.

An in silico study of the effects of left ventricular assist device on right ventricular function and inter-ventricular interaction.

BACKGROUND: Left ventricular assist device (LVAD) is associated with a high incidence of right ventricular (RV) failure, which is hypothesized to be caused by the occurring inter-ventricular interactions when the LV is unloaded. Factors contributing to these interactions are unknown. METHODS: We used computer modeling to investigate the impact of the HeartMate 3 LVAD on RV functions. The model was first calibrated against pressure-volume (PV) loops associated with a heart failure (HF) patient and validated against measurements of inter-ventricular interactions in animal experiments. The model was then applied to investigate the effects of LVAD on (1) RV chamber contractility indexed by V 60 derived from its end-systolic PV relationship, and (2) RV diastolic function indexed by V 20 derived from its end-diastolic PV relationship. We also investigated how septal wall thickness and regional contractility affect the impact of LVAD on RV function. RESULTS: The impact of LVAD on RV chamber contractility is small at a pump speed lower than 4k rpm. At a higher pump speed between 4k and 9k rpm, however, RV chamber contractility is reduced (by ~3% at 6k rpm and ~10% at 9k rpm). The reduction of RV chamber contractility is greater with a thinner septal wall or with a lower myocardial contractility at the LV free wall, septum, or RV free wall. CONCLUSION: RV chamber contractility is reduced at a pump speed higher than 4k rpm, and this reduction is greater with a thinner septal wall or lower regional myocardial contractility. Findings here may have clinical implications in identifying LVAD patients who may suffer from RV failure.

Cross-Activation of Regulatory T Cells by Self Antigens Limits Self-Reactive and Activated CD8+ T Cell Responses.

The interaction between regulatory T (Treg) cells and self-reactive T cells is a crucial mechanism for maintaining immune tolerance. In this study, we investigated the cross-activation of Treg cells by self-antigens and its impact on self-reactive CD8+ T cell responses, with a focus on the P53 signaling pathway. We discovered that major histocompatibility complex (MHC) I-restricted self-peptides not only activated CD8+ T cells but also induced the delayed proliferation of Treg cells. Following HLA-A*0201-restricted Melan-A-specific (pMelan) CD8+ T cells, we observed the direct expansion of Treg cells and concurrent suppression of pMelan+CD8+ T cell proliferation upon stimulation with Melan-A peptide. Transcriptome analysis revealed no significant alterations in specific signaling pathways in pMelan+CD8+ T cells that were co-cultured with activated Treg cells. However, there was a noticeable upregulation of genes involved in P53 accumulation, a critical regulator of cell survival and apoptosis. Consistent with such observation, the blockade of P53 induced a continuous proliferation of pMelan+CD8+ T cells. The concurrent stimulation of Treg cells through self-reactive TCRs by self-antigens provides insights into the immune system's ability to control activated self-reactive CD8+ T cells as part of peripheral tolerance, highlighting the intricate interplay between Treg cells and CD8+ T cells and implicating therapeutic interventions in autoimmune diseases and cancer immunotherapy.

Decreased frequency of transplantation and lower post-transplant survival free of re-transplantation in LVAD patients with the new heart transplant allocation system.

PURPOSE: To evaluate the effect of the new heart transplant (HT) allocation system in left ventricular assist device (LVAD) supported patients listed as bridge to transplantation (BTT). METHODS: Adult patients who were listed for HT between October 18, 2016 and October 17, 2019, and were supported with an LVAD, enrolled in the UNOS database were included in this study. Patients were classified in the old or new system if they were listed or transplanted before or after October 18, 2018, respectively. RESULTS: A total of 3261 LVAD patients were listed for transplant. Of these, 2257 were classified in the old and 1004 in the new system. The cumulative incidence of death or removal from the transplant list due to worsening clinical status at 360-days after listing was lower in the new system (4% vs. 7%, P = .011). LVAD Patients listed in the new system had a lower frequency of transplantation within 360-days of listing (52% vs. 61%, P < .001). A total of 1843 LVAD patients were transplanted, 1004 patients in the old system and 839 patients in the new system. The post-transplant survival at 360 days was similar between old and new systems (92.3% vs. 90%, P = .08). However, LVAD patients transplanted in the new system had lower frequency of the combined endpoint, freedom of death or re-transplantation at 360 days (92.2% vs. 89.6%, P = .046). CONCLUSION: The new HT allocation system has affected the LVAD-BTT population significantly. On the waitlist, LVAD patients have a decreased cumulative frequency of transplantation and a concomitant decrease in death or delisting due to worsening status. In the new system, LVAD patients have a decreased survival free of re-transplantation at 360 days post-transplant.

De novo assembly and phasing of a Korean human genome.

Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.

Changes in heart transplant waitlist and posttransplant outcomes in patients with restrictive and hypertrophic cardiomyopathy with the new heart transplant allocation system.

Historically, patients with restrictive (RCM) and hypertrophic cardiomyopathy (HCM) experienced longer wait-times for heart transplant (HT) and increased waitlist mortality. Recently, a new HT allocation system was implemented in the United States. We sought to determine the impact of the new HT system on RCM/HCM patients. Adult patients with RCM/HCM listed for HT between November 2015 and September 2019 were identified from the UNOS database. Patients were stratified into two groups: old system and new system. We identified 872 patients who met inclusion criteria. Of these, 608 and 264 were classified in the old and new system groups, respectively. The time in the waitlist was shorter (25 vs. 54 days, P < .001), with an increased frequency of HT in the new system (74% vs. 68%, P = .024). Patients who were transplanted in the new system had a longer ischemic time, increased use of temporary mechanical circulatory support and mechanical ventilation. There was no difference in posttransplant survival at 9 months (91.1% vs. 88.9%) (p = .4). We conclude that patients with RCM/HCM have benefited from the new HT allocation system, with increased access to HT without affecting short-term posttransplant survival.

Early transplantation-related mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia.

BACKGROUND: Transplantation-related mortality (TRM) is a major obstacle in allogeneic hematopoietic cell transplantation (allo-HCT). Approximately 60-80% of TRM occurs early, within 100 days of transplantation. METHODS: This was a nationwide population cohort study involving 5395 patients with acute leukemia who underwent allo-HCT between 2003 and 2015. Patient data were collected from the Korean National Health Insurance Service database. We investigated the cumulative incidence rates (CIRs) of early TRM at 50 and 100 days. RESULTS: The CIRs of early TRM at 50 and 100 days were 2.9 and 8.3%, respectively. There was no decrease in the CIRs of early TRM over time. The early mortality was significantly higher in patients with more than 9 months between the diagnosis and transplantation (CIRs of TRM at 50, 100 days; 6.0, 13.2%), previous transplantations (CIRs of TRM at 50, 100 days; 9.4, 17.2%), and cord blood transplantation (CIRs of TRM at 50, 100 days; 6.1, 8.3%). The early TRM was significantly lower in patients who received iron chelation before transplantation (CIRs of TRM at 50, 100 days; 0.3, 1.8%). CONCLUSIONS: In conclusion, the overall CIR of early TRM was less than 10%. The predictable factors for early TRM included age, time from diagnosis to transplantation, the number of prior transplantations, the graft source, and previous iron chelation therapy.

Optical Filter-Embedded Fiber-Optic Radiation Sensor for Ultra-High Dose Rate Electron Beam Dosimetry.

FLASH radiotherapy is an emerging radiotherapy technique used to spare normal tissues. It employs ultra-high dose rate radiation beams over 40 Gy/s, which is significantly higher than those of conventional radiotherapy. In this study, a fiber-optic radiation sensor (FORS) was fabricated using a plastic scintillator, an optical filter, and a plastic optical fiber to measure the ultra-high dose rate electron beams over 40 Gy/s used in FLASH radiotherapy. The radiation-induced emissions, such as Cherenkov radiation and fluorescence generated in a transmitting optical fiber, were spectrally discriminated from the light outputs of the FORS. To evaluate the linearity and dose rate dependence of the FORS, the outputs of the fiber-optic radiation sensor were measured according to distances from an electron scattering device, and the results were compared with those of an ionization chamber and radiochromic films. Finally, the percentage depth doses were obtained using the FORS as a function of depth in a water phantom. This study found that ultra-high dose rate electron beams over 40 Gy/s could be measured in real time using a FORS.

Docetaxel-resistant prostate cancer cells become sensitive to gemcitabine due to the upregulation of ABCB1.

BACKGROUND: Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. OBJECTIVE: We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. METHODS: Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. RESULTS: The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. CONCLUSION: This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

Association between Postoperative Detection of Circulating Tumor Cells and Recurrence in Patients with Prostate Cancer.

PURPOSE: The clinical implications of postoperative detection of circulating tumor cells in prostate cancer are largely unknown. We investigated the association between postoperative circulating tumor cell detection after radical prostatectomy and disease recurrence in prospectively enrolled patients with prostate cancer. MATERIALS AND METHODS: A total of 203 patients with an undetectable prostate specific antigen who had undergone radical prostatectomy for prostate cancer were prospectively enrolled. Circulating tumor cell sampling was performed at a median of 4.5 months after surgery. The primary end point was biochemical recurrence-free survival. Detection of circulating tumor cells in the blood of patients was performed using a novel approach with a replication-competent adenovirus controlled by prostate specific antigen/prostate specific membrane antigen transcription regulatory elements (Ad5/35E1aPSESE4). RESULTS: Circulating tumor cells were detected in 73 (36.0%) patients with undetectable prostate specific antigen concentrations after surgery. The 3-year biochemical recurrence-free survival rate from the time of surgery was significantly higher in circulating tumor cell-negative than in circulating tumor cell-positive cases (81.6% vs 48.9%, log rank p <0.001). Multivariable analysis showed that postoperative circulating tumor cell detection was independently associated with an increased risk of biochemical recurrence (HR 5.42, 95% CI 3.24-9.06, p <0.001). C-index was increased in combinations of multivariable model and postoperative circulating tumor cell detection compared with the multivariable model alone. CONCLUSIONS: Circulating tumor cells in the blood were frequently detected in patients with undetectable prostate specific antigen levels after radical prostatectomy for localized prostate cancer. Furthermore, circulating tumor cell detection was associated with an increased risk of biochemical recurrence, suggesting that circulating tumor cell detection precedes prostate specific antigen rise after surgery in cases of prostate cancer recurrence. Large-scale validation is needed in the future.

Incidence, prevalence, mortality, and causes of death in Waldenström macroglobulinemia: a nationwide, population-based cohort study.

BACKGROUND: The epidemiological features of Waldenström macroglobulinemia (WM) have seldom been investigated at a national level, particularly in East Asia. The goal of our study is to present the incidence, prevalence, mortality, survival with competing risks, and causes of death of patients with WM. METHODS: We used a national population-based database, operated by the Health Insurance Review and Assessment Service of the Korean government. This data includes information on all WM patients diagnosed according to uniform criteria, between 2003 and 2016. RESULTS: The total number of patients newly diagnosed with WM during the study period was 427, with a male-to-female ratio of 3.2:1. The incidence increased from 0.03 to 0.10 per 105 between 2003 and 2016, and the prevalence was 0.42 per 105 in 2016. A total of 217 patients with WM died during the study period (standardized mortality ratio = 7.57), and the overall survival (OS) of WM patients was 47.5%. On multivariate analysis, older age was associated with worse OS (P <  0.0001). WM was the most common cause of death (n = 102, 48.6%), followed by other malignant neoplasms (n = 82, 39.0%). CONCLUSIONS: The national incidence of WM in Korea, a racially homogeneous country in Asia, was lower than that in previous reports from other countries, reflecting ethnic disparities. However, the incidence increased, and mortality was the highest ever reported. The main cause of death was WM in itself. This study reflects the need for greater awareness of WM, particularly in Asian countries.

CMOS Depth Image Sensor with Offset Pixel Aperture Using a Back-Side Illumination Structure for Improving Disparity.

This paper presents a CMOS depth image sensor with offset pixel aperture (OPA) using a back-side illumination structure to improve disparity. The OPA method is an efficient way to obtain depth information with a single image sensor without additional external factors. Two types of apertures (i.e., left-OPA (LOPA) and right-OPA (ROPA)) are applied to pixels. The depth information is obtained from the disparity caused by the phase difference between the LOPA and ROPA images. In a CMOS depth image sensor with OPA, disparity is important information. Improving disparity is an easy way of improving the performance of the CMOS depth image sensor with OPA. Disparity is affected by pixel height. Therefore, this paper compared two CMOS depth image sensors with OPA using front-side illumination (FSI) and back-side illumination (BSI) structures. As FSI and BSI chips are fabricated via different processes, two similar chips were used for measurement by calculating the ratio of the OPA offset to pixel size. Both chips were evaluated for chief ray angle (CRA) and disparity in the same measurement environment. Experimental results were then compared and analyzed for the two CMOS depth image sensors with OPA.

The immunotherapeutic effects of recombinant Bacillus Calmette-Guérin resistant to antimicrobial peptides on bladder cancer cells.

PURPOSE: Although Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the most widely used bladder cancer immunotherapy, innate immune responses involving antimicrobial peptides (AMPs) cause BCG failure and unwanted side effects. Here, we generated genetically modified BCG strains with improved immunotherapeutic effects by adding genes that confer evasion of AMPs. MATERIALS AND METHODS: We constructed recombinant BCG (rBCG) strains expressing Streptococcal inhibitor of complement (Sic), which confers resistance to human α-defensin-1 and cathelicidin, and d-alanyl carrier protein ligase (dltA), which confers resistance to cationic AMPs. Sic and dltA were separately cloned into the pMV306 plasmid and introduced into BCG via electroporation. Then, the efficacy of the rBCGs was tested in a growth inhibition assay using two bladder cancer cell lines (5637, T24). RESULTS: We confirmed the presence of cDNA segments corresponding to the Sic and dltA genes in total mRNA of the rBCG strains containing Sic (rBCG-Sic) and dltA (rBCG-dltA), and these rBCGs showed higher survival against AMPs. The growth inhibitory effects of rBCGs on bladder cancer cells were significantly enhanced compared to those of the parent BCG, and THP-1 migration also increased. After 8 h of infection, the levels of internalization were higher in rBCG-infected bladder cancer cells than in BCG-infected cells, and cells infected with rBCGs showed increased release of antitumor cytokines, such as IL-6/12, TNF-α, and INF-γ, resulting in inhibition of bacterial killing and immune modulation via antimicrobial peptides. CONCLUSIONS: rBCG-Sic and rBCG-dltA can effectively evade BCG-stimulated AMPs, and may be significantly improved immunotherapeutic tools to treat bladder cancer.