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Recent studies have shown that novel antibody-drug conjugates (ADCs) can improve clinical outcomes in patients with HER2-low breast cancers. This study aimed to investigate alteration of HER2 status during breast cancer progression with an emphasis on HER2-low status. Using 386 paired samples of primary and recurrent breast cancers, HER2 discordance rate between primary and matched recurrent samples, the relationships between HER2 discordance and clinicopathological characteristics and clinical outcomes of the patients were analyzed. HER2 discordance rate between primary breast cancer and first recurrence was 25.9% (κ = 0.586) with mostly zero-to-low (10.6%) or low-to-zero (9.3%) conversion. There was no significant difference in the discordant rates according to type or location of the recurrence. Of 70 cases with a second recurrence, HER2 discordance rate between the primary tumor and the second recurrence was 27.1% (κ = 0.554). HER2 discordance was associated with lower HER2 level, lymphovascular invasion, and progesterone receptor positivity of the primary tumor. In further analyses, HER2-zero-to-low conversion was associated with lymph node metastasis and hormone receptor (HR) positivity, whereas HER2-low-to-zero conversion was associated with HR negativity and triple-negative subtype. In survival analyses, HER2 discordance was associated with decreased overall survival of patients in the HR-positive group but not in the HR-negative group. Furthermore, patients with HER2-low-to-zero converted tumors showed worse overall survival compared with those with HER2-low concordant tumors. In conclusion, HER2 status changes during breast cancer progression in significant proportions, mostly between zero and low status. As HER2 instability increases during progression and affects clinical outcome, HER2 status needs to be reevaluated in recurrent settings., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Viral vectors are being used for the treatment of cancer. Yet, their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1-/- mice and MyD88-/- mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single-cell RNA sequencing analyses, antibody blockade experiments, and knockout models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.

Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by the accumulation of clonal mononuclear phagocyte system cells expressing CD1a and CD207. In the past decade, molecular profiling of LCH as well as other histiocytic neoplasms demonstrated that these diseases are driven by MAPK activating alterations, with somatic BRAFV600E mutations in >50% of patients with LCH, and clinical inhibition of MAPK signaling has demonstrated remarkable clinical efficacy. At the same time, activating alterations in kinase-encoding genes, such as PIK3CA, ALK, RET, and CSF1R, which can activate mitogenic pathways independent from the MAPK pathway, have been reported in a subset of histiocytic neoplasms with anecdotal evidence of successful targeted treatment of histiocytoses harboring driver alterations in RET, ALK, and CSF1R. However, evidence supporting the biological consequences of expression of PIK3CA mutations in hematopoietic cells has been lacking, and whether targeted inhibition of PI3K is clinically efficacious in histiocytic neoplasms is unknown. Here, we provide evidence that activating mutations in PIK3CA can drive histiocytic neoplasms in vivo using a conditional knockin mouse expressing mutant PIK3CAH1047R in monocyte/dendritic cell progenitors. In parallel, we demonstrate successful treatment of PIK3CA-mutated, multisystemic LCH using alpelisib, an inhibitor of the alpha catalytic subunit of PI3K. Alpelisib demonstrated a tolerable safety profile at a dose of 750 mg per week and clinical and metabolic complete remission in a patient with PIK3CA-mutated LCH. These data demonstrate PIK3CA as a targetable noncanonical driver of LCH and underscore the importance of mutational analysis-based personalized treatment in histiocytic neoplasms., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We investigated the efficacy of intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents in branch retinal vein occlusion (BRVO). Databases, including PubMed, EMBASE, and the Cochrane Library, were searched on November 11, 2022. Studies comparing the pro-re-nata (PRN) regimen after the first treatment (PRN group) to three consecutive monthly injection regimens followed by the PRN regimen (3 + PRN group) were investigated. The primary outcomes were the change in best-corrected visual acuity (BCVA) and the change in central retinal thickness (CRT), with the secondary outcome being the injection frequency. Among 195 reports on anti-VEGF treatment, six comparative studies were included in this meta-analysis. The two groups had no statistically significant differences in terms of BCVA or CRT. However, the total number of injections during follow-up was significantly lower in the PRN group than in the 3 + PRN group (95% CI - 2.09 to - 0.83). The as-needed injection regimen is as effective as 3-monthly loading in terms of anatomical and functional improvement for BRVO, along with a lower treatment burden for patients and physicians., (© 2023. The Author(s).)

Purpose: Abnormal hypercoagulability and increased thromboembolic risk are common in patients with coronavirus disease (COVID-19). COVID-19 has been suggested to cause retinal vascular damage, with several studies on COVID-19 patients with retinal vascular occlusions. We reviewed and investigated studies on retinal vascular occlusions in patients diagnosed with COVID-19 and in those vaccinated for COVID-19., Methods: Studies that reported retinal vascular occlusion in COVID-19 patients or in vaccinated people were identified using the terms "retinal occlusion," together with "severe acute respiratory syndrome coronavirus 2", "SARS-CoV-2," "COVID-19," "coronavirus," and "vaccine," through systematic searches of PubMed and Google Scholar databases until January 7, 2022., Results: Thirteen cases of retinal artery occlusion (RAO) and 14 cases of retinal vein occlusion (RVO) were identified among patients diagnosed with COVID-19. Half of the patients with RAO or RVO revealed no systemic disorders except current or past COVID-19, and ocular symptoms were the initial presentation in five cases. Among patients with RAO, most presented with central RAO at 1-14 days of COVID-19 diagnosis, with abnormal coagulation and inflammatory markers. Among those with RVO, two-thirds presented with central RVO and one-third with RVO. Eleven cases with acute macular neuroretinopathy (AMN) and/or paracentral acute middle maculopathy (PAMM) were reported among patients with COVID-19, presenting scotoma resolved spontaneously in most cases. Among the 26 cases vaccinated with either mRNA or adenoviral vector vaccines for COVID-19 and presenting retinal vascular occlusions, there were more RVO cases than RAO cases, and ocular symptoms mostly occurred within 3 weeks after vaccination. One case presented bilateral AMN and PAMM after COVID-19 vaccination., Conclusion: Retinal vascular occlusions might be a manifestation of COVID-19, although rare, especially in patients at risk of systemic hypercoagulability and thromboembolism. For COVID-19 vaccines, the causal relationship is controversial because there are few case reports of retinal vascular occlusions after COVID-19 vaccination., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate the clinical results of vitrectomy alone as the primary treatment for rhegmatogenous retinal detachment (RD) in patients with atopic dermatitis (AD)., Methods: The medical records of patients with AD treated for rhegmatogenous retinal detachment (RD) were retrospectively reviewed. We investigated the characteristics of retinal breaks and detachments, applied surgical methods, and results., Results: Twenty eyes of 14 patients with AD who presented with rhegmatogenous RD and treated by vitrectomy were included in this analysis. Sixteen eyes (80%) were treated with vitrectomy, either alone or in combination with cataract surgery, and the retina was successfully attached to 94% of the eyes. There were four cases in which vitrectomy was combined with encircling. Reoperation was needed in half of the eyes that received vitrectomy with encircling, which presented nearly total detachment, severe proliferative vitreoretinopathy, and pseudophakia., Conclusions: Vitrectomy alone, in combination with cataract surgery, may be sufficient to treat rhegmatogenous RD in patients with AD. Additional encircling or buckling should still be considered in complicated cases.

Background and Objectives : We investigated and compared the efficacy of three and five monthly loading regimens of an intravitreal aflibercept injection (IVA) in patients with diabetic macular edema (DME). Materials and Methods : This was a retrospective study that included patients diagnosed with DME and treated with an either three or five monthly aflibercept loading regimen from July 2018 to March 2022. Information on clinical characteristics and changes in the central retinal thickness (CRT) were obtained from medical records. Results : In total, 44 eyes of 44 patients with DME treated with IVA were included in this study, with 30 eyes treated with 3-monthly loadings (three-loading group) and 14 eyes with 5-monthly loadings (five-loading group). The mean CRT significantly decreased from the baseline one month after loading in both the three-loading and five-loading groups ( p < 0.001). Four cases were refractory to treatment in the three-loading group, while there were no cases of refractory DME in the five-loading group. The stability rate was significantly higher in the five-loading group at three months after loading ( p = 0.033). Conclusions : Five-monthly loading regimens of IVA might be favorable for DME considering the rate of refractory cases, stable duration, and the importance of early responsiveness to IVA in DME.

Objective: This study aimed to evaluate the preference for antivascular endothelial growth factor (anti-VEGF) versus laser ablation therapy as primary and additional treatment in aggressive retinopathy of prematurity (ROP) and type 1 ROP., Methods: This multicentre retrospective study was conducted at nine medical centres across South Korea. A total of 94 preterm infants with ROP who underwent primary treatment between January 2020 and December 2021 were enrolled. All eyes were classified as having type 1 ROP or aggressive ROP. Data on the zone, primary treatment chosen, injection dose, presence of reactivation and additional treatment were collected and analysed., Results: Seventy infants (131 eyes) with type 1 ROP and 24 infants (45 eyes) with aggressive ROP were included. Anti-VEGF injection was selected as the primary treatment in 74.05% of the infants with type 1 ROP and 88.89% with aggressive ROP. Anti-VEGF injection was selected as the ROP was located in zone I or posterior zone II, and laser ablation was selected when it was located in zone II. The anti-VEGF injection doses varied and tended to be higher in the aggressive ROP group. Infants with aggressive ROP were 2.08 times more likely to require additional treatment than those with type 1 ROP. When ROP reactivation occurred, laser therapy was preferred as an additional treatment., Conclusion: In Korea, the preference for anti-VEGF therapy or laser therapy differed according to ROP subtype, zone and primary or secondary treatment. These findings suggest that ROP treatment are considered according to ROP subtype, location and reactivation., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19.

Downregulation of human leukocyte antigen (HLA) class I is one mechanism of escaping anti-tumor immunity by tumor cells. This study was conducted to compare HLA class I expression in ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC) and to evaluate its association with immune cell infiltration of the tumors and clinical outcome of the patients. A total of 830 cases comprising 288 DCIS and 542 IBC were included in this study. Immunohistochemistry for HLA class I expression was performed using HLA-ABC in tissue microarrays and was analyzed in relation to clinicopathologic characteristics of tumors and infiltration of CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells. As a whole, there was no difference in HLA class I expression between DCIS and IBC when dichotomized into high or low expression. However, in the HR-negative group, a high level of HLA class I expression was more frequent in IBC than DCIS. On the contrary, in the HR-positive group, a complete loss of HLA class I expression was more frequently observed in IBC than DCIS. High HLA class I expression level was generally associated with aggressive clinicopathologic features of IBC and was associated with high CD4+, CD8+, and FOXP3+ TIL and PD-L1+ immune cell infiltration in both DCIS and IBC. In survival analyses, HLA class I expression was not associated with clinical outcome in DCIS and IBC as a whole; however, low HLA class I expression was associated with poor clinical outcome in HR-negative IBC, especially in triple-negative subtype. In conclusion, this study showed that HLA class I expression increased in association with increased immune cell infiltration during in situ to invasive transition of HR-negative breast cancer, and HLA class I down-regulation had a prognostic value in HR-negative breast cancer., (© 2022. The Author(s).)

Background: MicroRNAs (miRNAs) control diverse biologic processes during tumor progression. This study was conducted to identify miRNAs that are implicated in progression of in situ to invasive breast cancer (IBC) and to evaluate their association with clinicopathological features of ductal carcinoma in situ (DCIS)., Methods: We performed miRNA microarray analyses to find differentially expressed miRNAs between DCIS and IBC in a test set, and validated expression levels of selected miRNAs using a different set of tumors. Finally, we evaluated the relationship between clinicopathological features and the expression of selected miRNAs in DCIS samples., Results: We found that miR-145-5p, miR-205-5p and miR-451a are significantly down-regulated in IBC compared to DCIS in the whole group, and in the estrogen receptor (ER)-positive and ER-negative subgroups. In a validation set, miR-145, miR-205, and miR-451 also showed lower expression levels in IBC than in DCIS, irrespective of ER status. Moreover, their expression levels were significantly lower in the invasive component compared to the in situ component within same tumors. MiR-145, miR-205 and miR-451 commonly showed lower expression levels in DCIS with positive HER2 status and high Ki-67 proliferation index. Especially, miR-145 and miR-205 showed lower expression levels in DCIS with microinvasion, compared to pure DCIS. In addition, lower miR-205 expression level was associated with high nuclear grade, comedo type necrosis, and hormone receptor negativity., Conclusions: Our study showed that miR-145, miR-205 and miR-451 expression decreased in IBC compared to DCIS, and their expression levels were low in DCIS with high-risk features for progression, implying their contributions in the progression of DCIS to invasive carcinoma as tumor suppressors., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

We investigated the relationship between pachydrusen and choroidal thickness and age in eyes with polypoidal choroidal vasculopathy (PCV) and fellow eyes, compared to eyes with central serous chorioretinopathy (CSC). This retrospective study included 89 eyes with PCV and 146 eyes with CSC. The number, location, and shape of the pachydrusen and their association with choroidal thickness and age were analyzed. PCV eyes showed pachydrusen more frequently than eyes with CSC (52% vs. 20%, p < 0.001). Large solitary type and clustered type were more frequent in PCV eyes compared to CSC eyes (p = 0.003 and p = 0.001, respectively). Subfoveal choroidal thickness was associated with pachydrusen in eyes with PCV (odds ratio [OR] 1.006, 95% confidence interval [CI] 1.001−1.011, p = 0.027), while age was associated with pachydrusen in CSC eyes (OR 1.137, 95% CI, 1.073−1.205; p < 0.001). Pachydrusen were localized directly over the pachyvessel on optical coherence tomographic findings in approximately two thirds of PCV eyes and fellow eyes (62% and 67%, respectively). Risk factors for pachydrusen differ according to diseases. The presence of pachydrusen was associated with choroidal thickness in PCV, while the association with age was more prominent in CSC.

T cell-based therapies have been widely explored for the treatment of cancer and chronic infection, but B cell-based therapies have remained largely unexplored. To study the effect of B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer of virus-specific B cells resulted in increase in antibody titers and reduction of viral loads. Importantly, the efficacy of B cell therapy was partly dependent on antibody effector functions, and was improved by co-transferring virus-specific CD4 T cells. These findings provide a proof-of-concept that adoptive B cell therapy can be effective for the treatment of chronic infections, but provision of virus-specific CD4 T cells may be critical for optimal virus neutralization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chung, Dangi, Palacio, Sanchez and Penaloza-MacMaster.)

Deep learning-based approaches in histopathology can be largely divided into two categories: a high-level approach using an end-to-end model and a low-level approach using feature extractors. Although the advantages and disadvantages of both approaches are empirically well known, there exists no scientific basis for choosing a specific approach in research, and direct comparative analysis of the two approaches has rarely been performed. Using the Cancer Genomic Atlas (TCGA)-based dataset, we compared these two different approaches in microsatellite instability (MSI) prediction and analyzed morphological image features associated with MSI. Our high-level approach was based solely on EfficientNet, while our low-level approach relied on LightGBM and multiple deep learning models trained on publicly available multiclass tissue, nuclei, and gland datasets. We compared their performance and important image features. Our high-level approach showed superior performance compared to our low-level approach. In both approaches, debris, lymphocytes, and necrotic cells were revealed as important features of MSI, which is consistent with clinical knowledge. Then, during qualitative analysis, we discovered the weaknesses of our low-level approach and demonstrated that its performance can be improved by using different image features in a complementary way. We performed our study using open-access data, and we believe this study can serve as a useful basis for discovering imaging biomarkers for clinical application., (© 2022. The Author(s).)

Despite many studies, optimal treatment sequences or intervals are still questionable in retinal vein occlusion (RVO) macular edema. The aim of this study was to examine the real-world treatment patterns of RVO macular edema. A retrospective analysis of the Observational Medical Outcomes Partnership Common Data Model, a distributed research network, of four large tertiary referral centers (n = 9,202,032) identified 3286 eligible. We visualized treatment pathways (prescription volume and treatment sequence) with sunburst and Sankey diagrams. We calculated the average number of intravitreal injections per patient in the first and second years to evaluate the treatment intensities. Bevacizumab was the most popular first-line drug (80.9%), followed by triamcinolone (15.1%) and dexamethasone (2.28%). Triamcinolone was the most popular drug (8.88%), followed by dexamethasone (6.08%) in patients who began treatment with anti-vascular endothelial growth factor (VEGF) agents. The average number of all intravitreal injections per person decreased in the second year compared with the first year. The average number of injections per person in the first year increased throughout the study. Bevacizumab was the most popular first-line drug and steroids were considered the most common as second-line drugs in patients first treated with anti-VEGF agents. Intensive treatment patterns may cause an increase in intravitreal injections., (© 2022. The Author(s).)

We evaluated the effect of intravitreal bevacizumab injection (IVB) on choroidal thickness, and studied its association with the therapeutic response in chronic central serous chorioretinopathy (CSC). The clinical features of 78 eyes with chronic CSC treated with IVB from October 2014 to June 2020 were retrospectively evaluated. Visual acuity (VA), central retinal thickness (CRT), and sub-foveal choroidal thickness (SFCT) were analyzed at baseline, 1 month following initial IVB, and the last follow-up examination. Cases showing complete recovery (resolved eyes; n = 60) were compared with those with persistent subretinal fluid (refractory eyes; n = 18). The relationship between the potential risk factors and subretinal fluid resolution was examined using logistic regression. SFCT was significantly decreased along with the CRT following IVB at the resolved state. SFCT reduction following 1 month of IVB was notably greater in the resolved eyes. The association of refractory eyes with hypertension ( p = 0.003) and a thinner baseline SFCT ( p = 0.024) was significant. In most of the patients with chronic CSC, VA and CRT remarkably improved following treatment with IVB. Early changes in the SFCT following IVB were associated with the therapeutic response. Patients with hypertension and a thinner baseline SFCT could be unresponsive to IVB.

Background: To investigate the safety of vitrectomy with laser photocoagulation in eyes with small peripheral retinal breaks without air or gas tamponade., Methods: Among patients who underwent vitrectomy for various retinal disorders, those with small peripheral retinal breaks treated by laser photocoagulation without air or gas tamponade were included in this study. Their medical records were assessed retrospectively, and we investigated the characteristics of small peripheral retinal breaks and the incidence of postoperative retinal detachment (RD)., Results: Thirty-one eyes of 31 patients who presented with small peripheral retinal breaks requiring endolaser photocoagulation during vitrectomy were included in this analysis. There were two cases of iatrogenic retinal breaks that occurred during vitrectomy, while others were preexisting lesions, including retinal tears, atrophic retinal holes, and retinal holes with lattice degeneration. There were no cases of RD during the follow-up period of at least 6 months., Conclusions: Adequate laser treatment without gas or air tamponade may be sufficient during vitrectomy in cases with small peripheral retinal breaks without concurrent RD, along with complete removal of vitreoretinal traction., (© 2022. The Author(s).)

Purpose : To investigate the demographic and multimodal imaging features of macular telangiectasia (MacTel) type 2 in Korea and their relationship with visual acuity and the clinical stage. Methods : A retrospective multicentre cross-sectional study was conducted in six tertiary hospitals in Korea and the study included 84 patients. Demographic data and imaging data of fundus photography, fundus autofluorescence (FAF), confocal blue-light reflectance (CBR), fluorescein angiography (FAG), and optical coherence tomography (OCT) were collected. Results : The Korean patients with MacTel type 2 were predominantly female (75%), and the mean logMAR visual acuity was 0.282 ± 0.280 at initial presentation. Most commonly presented signs were the loss of retinal transparency in fundus photographs (68.3%); increased autofluorescence in FAF (83.6%); increased blue reflectance involving the centre in CBR (68.0%); telangiectatic vessels in FAG (88.2%); and hyporeflective cavities in OCT (77.7%). The eyes diagnosed in the first half of the study period (2009-2014) showed a tendency to be diagnosed at more advanced severe stages than those diagnosed in the second half of the study period (2015-2019), using new severity scales based on FAG, FAF and OCT findings. Conclusion : The clinical features of MacTel type 2 in Korean patients assessed by newer imaging modalities suggest that Korean patients and the Caucasian-dominant population show similar presentations. This study showed that MacTel type 2 can be diagnosed in the earlier phase of the disease by using new imaging modalities and through better understanding of the disease.

Tumor immune microenvironment plays a crucial role in tumor progression. We performed immune profiling to compare immune-related gene expression between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast using nCounter PanCancer immune Profiling Panel and found that CXCL10 was the most significant gene that had the highest difference in expression between them. Effect of CXCL10 on breast cancer cell proliferation and invasion was examined in vitro, and expression of CXCL10 and its relationship with immune cell infiltration was assessed in breast cancer samples. CXCL10 induced cell proliferation, migration and epithelial-mesenchymal transition in MCF-7 and MDA-MB-231 breast cancer cell lines. We confirmed that CXCL10 mRNA expression was significantly higher in invasive carcinoma than in DCIS, especially in hormone receptor (HR)-negative tumors using a validation set. CXCL10 mRNA expression showed a positive correlation with tumor infiltrating lymphocyte (TIL) density in both DCIS and invasive carcinoma; CXCL10-positive tumors generally showed higher infiltration of CD8+ and FOXP3+TILs as well as PD-L1+ immune cells compared to CXCL10-negative tumors, albeit with different patterns according to HR status. In conclusion, our study showed that CXCL10 promotes tumor cell proliferation, invasion, and immune cell infiltration, implying its contribution in the progression of DCIS to invasive carcinoma of the breast., (© 2021. The Author(s).)

We investigated the structural findings on spectral-domain optical coherence tomography (SD-OCT) related to the presence of right-angled vessels (RAV) in patients with macular telangiectasia (MacTel) type 2 with severity 3 in Korea. A retrospective multicenter cross-sectional study was conducted in six tertiary hospitals in Korea; the study included 116 MacTel type 2 eyes with severity 3. The SD-OCT findings were compared between eyes with RAV on fundus photography or fluorescein angiography and those without RAV. Logistic regression was performed to determine factors associated with the presence of RAV. Fifty eyes presented with RAV and 61 eyes without RAV. More eyes presented with only inner retinal (IR) cavities on SD-OCT among eyes without RAV than among those with RAV (P < 0.001). However, eyes with RAV presented with IR disorganization, outer retinal (OR) cavity, and ellipsoid zone (EZ) disruption more frequently than eyes without RAV did (all P < 0.001). These SD-OCT findings were significantly associated with the presence of RAV. The presence of RAV was closely related to IR disorganization, OR cavities, and EZ disruption on SD-OCT. These findings suggest an advanced phase of MacTel type 2., (© 2021. The Author(s).)

Prognostic implications of therapeutic response of metastatic lymph nodes (LNs) to neoadjuvant chemotherapy (NAC) remain unclear in patients with breast cancer. We aimed to evaluate the prognostic value of axillary LN regression after NAC in locally-advanced breast cancer patients. Therapeutic response of the LNs was evaluated in 563 breast cancer patients and classified into four grades according to the regression pattern. Initial pathologic N stage was estimated from the sum of the metastatic LNs and those with complete regression. In survival analyses, LN regression grade, pathologic N stage after NAC, and presumed initial pathologic N stage stratified clinical outcome of the patients in the whole group, in both ER-positive and ER-negative subgroups, and in those with residual breast disease. On multivariate analysis, LN regression grade and presumed initial pathologic N stage were revealed as independent prognostic factors. The number of completely-responsive LNs and the ratio of non-responsive LNs also revealed a prognostic value. In conclusion, regression grade of axillary LNs and presumed initial pathologic N stage have prognostic values in breast cancer patients who receive NAC. Thus, regression of axillary LNs should be evaluated and included in pathologic reporting of post-NAC resection specimens.

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression through both immunologic and non-immunologic mechanisms. This study was conducted to evaluate the expression of S100A8, a well-known MDSC marker, and the significance of its expression in pre-invasive and invasive breast cancers. S100A8 expression in tumor cells (TCs) and immune cells (ICs) was assessed by immunohistochemistry, and its association with clinicopathologic features and infiltration of other IC subsets including CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs) and PD-L1+ ICs was evaluated. S100A8 expression in TCs and ICs showed a positive correlation in pre-invasive carcinoma and invasive carcinoma. S100A8+ ICs, but not S100A8+ TCs, were significantly higher in number in invasive carcinoma than in pre-invasive carcinoma. Infiltration of S100A8+ ICs was revealed as a poor prognostic indicator in pre-invasive and invasive carcinomas, especially in hormone receptor-positive subgroup. Infiltration of CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ ICs was significantly higher in S100A8+ IC (+) group than in S100A8+ IC (-) group. Combined analyses of IC subset infiltration revealed that infiltration of S100A8+ ICs was associated with poor clinical outcome in the PD-L1+ IC (-), CD8+ TIL-low, and FOXP3+ TIL-low subgroups. In conclusion, S100A8+ ICs seem to undergo a dynamic change during breast cancer progression in association with other IC subset infiltration. The prognostic impact of S100A8+ IC infiltration was greater in less immunogenic tumors.

A Martelella endophytica (M. endophytica) strain YC6887 was previously isolated from the roots of a halophyte, Rosa rugosa, which was sequenced and characterized. The genomic and proteomic analysis showed a carbohydrate-degrading enzyme, endoglucanase Cel5A which was further characterized. The protein analysis revealed that this endoglucanase belongs to glycosidic hydrolase family 5 (GH5) with catalytic domain. This gene encodes 349-residue polypeptide and shows closest similarity with cellulases of other Martelella species. The protein was purified to homogeneity and shown that it was a 39 kDa protein. The purified recombinant Cel5A endoglucanase exhibited maximum activity at 50 °C and pH 4.5. The enzyme was salt tolerant and retained more than 50% residual activity up to 15% NaCl. The homology model structure of Cel5A displayed that it is stable and compact protein structure consisting of eleven α-helical structures and eight β-sheets. According to the predicted ligand binding site after superimposition with Pseudomonas stutzeri endoglucanase Cel5A (PDB ID: 4LX4), it consisted of five amino acid Asn157, Tyr116, Glu158, Glu270 and Trp303 that may be the expected active site of Cel5A from YC6887. This presented that our strain M. endophytica YC6887 that produces cellulase partially degrade the insoluble polysaccharides into reducing sugars.

Background: Photodynamic therapy (PDT) is known to occlude choroidal neovascularisation selectively, and there have been several reports on its adverse effects on the normal choroid and retinal pigment epithelium, resulting in decreased vision., Methods: This retrospective interventional case series aimed to investigate the changes in visual acuity and retinal thickness in the immediate post-treatment period after half-fluence PDT, administered alone or with anti-vascular endothelial growth factor and steroids, in 29 eyes (26 patients) with neovascular age-related macular degeneration. The patients' best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography images were measured 1 day, 1 week, and 1 month post-treatment., Results: Compared to the pre-treatment CFT (270.38 μm), the mean CFT was significantly increased 1 day post-treatment (387.07 μm, P = 0.001), which then started to decrease, with a mean CFT of 269.32 μm (P = 0.516) at 1 week, and of 240.66 μm (P = 0.066) at 1 month post-treatment. All CFT increases were due to the accumulation of subretinal fluid (SRF), rather than the intraretinal or subretinal pigment epithelium fluid. Relative to the pre-treatment BCVA (0.59 logMAR), the mean BCVA at 1 day (0.74 logMAR, P = 0.005) and 1 week (0.75 logMAR, P = 0.002) post-treatment was significantly deteriorated; however, it recovered to 0.62 logMAR at 1 month. The patterns of change in CFT and BCVA did not differ according to treatment modality., Conclusions: Half-fluence PDT resulted in accumulation of SRF in the immediate post-treatment period; this damage mostly recovered within a week, and the BCVA was restored within a month.

There have been substantial efforts in using deep learning (DL) to diagnose cancer from digital images of pathology slides. Existing algorithms typically operate by training deep neural networks either specialized in specific cohorts or an aggregate of all cohorts when there are only a few images available for the target cohort. A trade-off between decreasing the number of models and their cancer detection performance was evident in our experiments with The Cancer Genomic Atlas dataset, with the former approach achieving higher performance at the cost of having to acquire large datasets from the cohort of interest. Constructing annotated datasets for individual cohorts is extremely time-consuming, with the acquisition cost of such datasets growing linearly with the number of cohorts. Another issue associated with developing cohort-specific models is the difficulty of maintenance: all cohort-specific models may need to be adjusted when a new DL algorithm is to be used, where training even a single model may require a non-negligible amount of computation, or when more data is added to some cohorts. In resolving the sub-optimal behavior of a universal cancer detection model trained on an aggregate of cohorts, we investigated how cohorts can be grouped to augment a dataset without increasing the number of models linearly with the number of cohorts. This study introduces several metrics which measure the morphological similarities between cohort pairs and demonstrates how the metrics can be used to control the trade-off between performance and the number of models.

Purpose: Gastric cancer remains the leading cause of cancer-related deaths in Northeast Asia. Population-based endoscopic screenings in the region have yielded successful results in early detection of gastric tumors. Endoscopic screening rates are continuously increasing, and there is a need for an automatic computerized diagnostic system to reduce the diagnostic burden. In this study, we developed an algorithm to classify gastric epithelial tumors automatically and assessed its performance in a large series of gastric biopsies and its benefits as an assistance tool., Experimental Design: Using 2,434 whole-slide images, we developed an algorithm based on convolutional neural networks to classify a gastric biopsy image into one of three categories: negative for dysplasia (NFD), tubular adenoma, or carcinoma. The performance of the algorithm was evaluated by using 7,440 biopsy specimens collected prospectively. The impact of algorithm-assisted diagnosis was assessed by six pathologists using 150 gastric biopsy cases., Results: Diagnostic performance evaluated by the AUROC curve in the prospective study was 0.9790 for two-tier classification: negative (NFD) versus positive (all cases except NFD). When limited to epithelial tumors, the sensitivity and specificity were 1.000 and 0.9749. Algorithm-assisted digital image viewer (DV) resulted in 47% reduction in review time per image compared with DV only and 58% decrease to microscopy., Conclusions: Our algorithm has demonstrated high accuracy in classifying epithelial tumors and its benefits as an assistance tool, which can serve as a potential screening aid system in diagnosing gastric biopsy specimens., (©2020 American Association for Cancer Research.)

Objectives: The aim of this study was to evaluate the real-world incidence of endophthalmitis after intravitreal anti-vascular endothelial growth factor (VEGF) injections using data from the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM)., Methods: Patients with endophthalmitis that developed within 6 weeks after intravitreal anti-VEGF injections were identified in 3 large OMOP CDM databases., Results: We identified 23,490 patients who received 128,123 intravitreal anti-VEGF injections. The incidence rates of endophthalmitis were 15.75 per 10,000 patients and 2.97 per 10,000 injections. The incidence rates of endophthalmitis for bevacizumab, ranibizumab, and aflibercept (per 10,000 injections) were 3.64, 1.39, and 0.76, respectively. The annual incidence has remained below 5.00 per 10,000 injections since 2011 despite the increasing number of intravitreal anti-VEGF injections. Bevacizumab presented a higher incidence rate for endophthalmitis than ranibizumab and aflibercept (incidence rate ratio, 3.17; p=0.021)., Conclusions: The incidence of endophthalmitis after intravitreal anti-VEGF injections has stabilized since 2011 despite the explosive increase in anti-VEGF injections. The off-label use of bevacizumab accounted for its disproportionately high incidence of endophthalmitis. The OMOP CDM, which includes off-label uses, laboratory data, and a scalable standardized database, could provide a novel strategy to reveal real-world evidence, especially in ophthalmology.

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design., Competing Interests: Disclosures: N. Palacio and P. Penaloza-MacMaster reported that a provisional patent application was submitted (transient interferon blockade to enhance immune responses to antigens and improve vaccines). No other disclosures were reported., (© 2020 Palacio et al.)

We performed a retrospective cohort study including people diagnosed with diabetes from 2006 to 2015 according to the Korean National Health Insurance Service-National Sample Cohort database, to analyze the changes in the prevalence, screening rate, and treatment patterns for diabetic retinopathy (DR) over 10 years. The proportion of people who underwent fundus screening for DR steadily increased over the past decade. The prevalence of DR increased from 13.4% in 2006 to 15.9% in 2015, while that of proliferative DR steadily decreased from 1.29% in 2006 to 1.16% in 2015. The proportion of patients undergoing retinal photocoagulation constantly decreased. The prevalence of DR increased over the past decade, while its severity seemed to have improved, with a decreased rate of proliferative DR and retinal photocoagulation. A higher proportion of patients underwent ophthalmic screening using fundus examination, but still less than 30% of patients with diabetes underwent comprehensive examination in 2015.

We analysed the imaging findings of macular telangiectasia (MacTel) type 2 in Korea using spectral domain optical coherence tomography (SD-OCT) and investigated their relationship with visual acuity and clinical stages. A retrospective multicentre cross-sectional study was conducted in six tertiary hospitals in Korea and included 129 patients. We analysed all the SD-OCT images encompassing the macular area. Hyporeflective cavities (77.7%) were the most frequently detected abnormalities in SD-OCT. Disruption of the external limiting membrane, ellipsoid zone, and interdigitation zone were found in 67 (40.4%), 87 (52.4%), and 94 eyes (56.6%), respectively. Four eyes (2.4%) had lamellar macular hole, and five eyes (3.0%) full-thickness macular hole. Neovascularisation, either subretinal or intraretinal, was found in 14 eyes (8.4%). Eyes with outer retinal hyperreflective band disruption had lower visual acuity than those without them. The presented characteristic clinical features of OCT in MacTel type 2 can not only aid in differentiating this disease from others but are also helpful for better judgement of the disease stage in daily clinical practice. Inner retinal hyporeflective cavities without outer retinal abnormalities on SD-OCT, although classified as severity scale 3, could be considered a relatively early stage in the disease process in terms of vision.

In this invited article, we explain technical aspects of the lymphocytic choriomeningitis virus (LCMV) system, providing an update of a prior contribution by Matthias von Herrath and J. Lindsay Whitton. We provide an explanation of the LCMV infection models, highlighting the importance of selecting an appropriate route and viral strain. We also describe how to quantify virus-specific immune responses, followed by an explanation of useful transgenic systems. Specifically, our article will focus on the following protocols. © 2020 Wiley Periodicals LLC. Basic Protocol 1: LCMV infection routes in mice Support Protocol 1: Preparation of LCMV stocks ASSAYS TO MEASURE LCMV TITERS Support Protocol 2: Plaque assay Support Protocol 3: Immunofluorescence focus assay (IFA) to measure LCMV titer MEASUREMENT OF T CELL AND B CELL RESPONSES TO LCMV INFECTION Basic Protocol 2: Triple tetramer staining for detection of LCMV-specific CD8 T cells Basic Protocol 3: Intracellular cytokine staining (ICS) for detection of LCMV-specific T cells Basic Protocol 4: Enumeration of direct ex vivo LCMV-specific antibody-secreting cells (ASC) Basic Protocol 5: Limiting dilution assay (LDA) for detection of LCMV-specific memory B cells Basic Protocol 6: ELISA for quantification of LCMV-specific IgG antibody Support Protocol 4: Preparation of splenic lymphocytes Support Protocol 5: Making BHK21-LCMV lysate Basic Protocol 7: Challenge models TRANSGENIC MODELS Basic Protocol 8: Transfer of P14 cells to interrogate the role of IFN-I on CD8 T cell responses Basic Protocol 9: Comparing the expansion of naïve versus memory CD4 T cells following chronic viral challenge., (© 2020 Wiley Periodicals LLC.)

Aims: Hyperreflective foci (HF), detected in the retina of diabetic patients, suggest the presence of microglial activation and migration, while controversies still remain for the origin of HF to be precursors of hard exudates. We investigated the presence of HF and their association with dyslipidemia in serous retinal detachment (SRD)-type diabetic macular edema (DME)., Methods: Forty-two eyes in 42 patients with diabetic retinopathy (DR) and 22 eyes in 22 patients with branch retinal vascular occlusion (BRVO) showing macular edema were included in this study. The medical records and OCT findings were retrospectively reviewed in patients with SRD-type DME and compared with those with BRVO. The mean number of HF, the mean choroidal thickness, and lipid profiles were analyzed and compared between groups., Results: The mean number of HF was significantly higher in DR group compared to BRVO group. Significant correlation of HF was noted with triglycerides (r = 0.523, P = 0.002). Triglycerides were significantly associated with HF by linear regression (β = 0.012, 95% CI 0.001-0.024, P = 0.034) and remained significantly associated by multiple linear regression (β = 0.014, 95% CI 0.003-0.025, P = 0.014)., Conclusions: HF on OCT of DME patients could be indicative of activated microglia. HF are associated with dyslipidemia, especially high triglycerides, suggesting inflammatory reaction from dyslipidemia in diabetic retina.

Tumor-infiltrating lymphocyte (TIL) levels have prognostic and predictive values in treatment-naïve breast cancers. However, there have been controversies regarding TIL subset changes and their clinical implications in post-treatment breast cancers. This study aimed to explore change and prognostic significance of TIL subset infiltration after primary systemic therapy (PST) in breast cancer. One-hundred-fifty-five patients who had residual disease after anthracycline- or anthracycline plus taxane-based PST were included. The quantities of intratumoral and stromal TIL subsets (CD8+, CD4+, and FOXP3+ TILs) in pre- and post-PST breast cancer samples, as well as changes between them, were analyzed along with their correlations with clinicopathologic features and outcome of patients. As a whole, intratumoral CD8+ and CD4+ TILs increased after PST while stromal TILs decreased. Both intratumoral and stromal FOXP3+ TILs decreased after PST. The chemo-sensitive group [residual cancer burden (RCB) class I and II] showed the same pattern of change in intratumoral CD8+ TILs as the whole group, whereas the chemo-resistant group (RCB class III) showed no significant change in intratumoral CD8+ TIL infiltration after PST. Survival analyses for each TIL subset as well as their ratios revealed that high levels of intratumoral, stromal, and total CD8+ TIL infiltration after PST were independent predictors of longer patient survival. In subgroup analyses, CD8+ TIL infiltration after PST revealed prognostic significance in the chemo-resistant group but not in the chemo-sensitive group. In conclusion, infiltration of CD8+, CD4+, and FOXP3+ TIL changed after PST in the intratumoral and stromal compartments. Especially, increase of intratumoral CD8+ TILs was associated with chemo-responsiveness. Moreover, CD8+ TIL status in residual tumors after PST may be used as a potential prognostic marker in breast cancer patients who receive PST and provide additional prognostic information to chemo-resistant group., Competing Interests: The authors have declared that no competing interests exist.

The aim of the study was to evaluate the impact of the updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline on human epidermal growth factor receptor 2 (HER2) interpretation in breast cancer compared with that of the previous guidelines and also the significance of in situ hybridization (ISH) groups proposed by the updated guideline. HER2 ISH reports and immunohistochemistry (IHC) data from 1,348 invasive breast cancers diagnosed at a single institution were included in this study. HER2 IHC was reassessed using the 2018 guideline, and HER2 ISH status was determined by the 2007, 2013, and 2018 guidelines. When applying the updated guideline, most of the HER2 ISH-equivocal cases as per the previous guidelines were reclassified as ISH negative, and 0.8% of HER2 ISH-positive tumors as per the 2007 guideline and 2.5% of those as per the 2013 guideline were changed to ISH negative. Accordingly, the negative HER2 ISH results significantly increased in the 2018 guideline compared with the 2013 guideline. HER2 ISH-positive tumors in ISH group 3 (HER2/chromosome enumeration probe 17 [CEP17] ratio <2.0 and average HER2 copy number ≥6.0 per cell) were characterized by equivocal HER2 protein expression, CEP17 copy number gain, and low HER2 copy numbers compared with classic HER2 ISH-positive tumors in ISH group 1 (HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 per cell). HER2 ISH-negative tumors in ISH group 4 (HER2/CEP17 ratio <2.0 with average HER2 copy number ≥4.0 and < 6.0 per cell) revealed more aggressive clinicopathologic features and poorer clinical outcomes than those in ISH group 5 (HER2/CEP17 ratio <2.0 and average HER2 copy number <4.0 per cell), especially in the hormone receptor-positive subgroup. In conclusion, implementation of the updated 2018 ASCO/CAP guideline leads to a significant increase in HER2 ISH-negative results compared with the 2013 guideline, mainly via reclassification of the ISH-equivocal cases to ISH-negative ones. ISH groups proposed by the updated guideline provide additional information on the clinicopathologic characteristics of the tumors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. This study was conducted to evaluate the immune microenvironment of DCIS including the composition of tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells and to compare it with that of invasive breast cancer., Materials and Methods: A total of 671 cases including three different disease groups of pure DCIS, DCIS with microinvasion (DCIS-M), and invasive carcinoma were included in this study. CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ immune cells were detected with immunohistochemistry using tissue microarrays and were analyzed in relation to clinicopathologic characteristics and different disease groups., Results: In pure DCIS, high infiltrations of CD4+, CD8+, and FOXP3+ T cells and the presence of PD-L1+ immune cells were associated with high nuclear grade, comedo-type necrosis, hormone receptor (HR) negativity, and high Ki-67 proliferation index. All immune cell infiltrations were higher in invasive carcinoma than in pure DCIS regardless of the HR status. While CD4+ T cells were more abundant than CD8+ T cells in pure DCIS, CD8+ T cells were dominant in invasive carcinoma, especially in HR-negative tumors. Within individual cases of invasive carcinoma with DCIS component, all immune cell subset infiltration was higher in the invasive component than in the DCIS component; however, CD4+ TIL infiltration did not differ between the two components in HR-negative tumors. Comparing pure DCIS, DCIS-M, and DCIS associated with invasive carcinoma (DCIS-INV), CD4+ TIL infiltration revealed a gradual increase from pure DCIS to DCIS-M and DCIS-INV in the HR-negative group, whereas FOXP3+ TIL infiltration was significantly increased in DCIS-INV than in pure DCIS in the HR-positive group. The high infiltration of FOXP3+ TIL and the presence of PD-L1+ immune cells were associated with tumor recurrence in patients with pure DCIS., Conclusions: Our study showed that the immune microenvironment differs significantly not only between DCIS and invasive carcinoma but also between pure DCIS, DCIS-M, and DCIS-INV depending on the HR status.

We investigated the prevalence of retinal vascular occlusion and intraocular bleeding and compare their risks in patients undergoing anticoagulant therapy, either with non-vitamin K-antagonist oral anticoagulants (NOAC) or warfarin. We performed a cohort study (January 2015 to April 2018) in 281,970 patients with nonvalvular atrial fibrillation (AF) using health claims in the nationwide database of the Health Insurance Review and Assessment service of Korea. A Cox-proportional hazard regression was used to calculate the hazard ratio (HR) for retinal vascular occlusion or intraocular bleeding. The HR of retinal vascular occlusion was estimated to 1.59 (95% confidence interval [CI], 1.35-1.86) for NOAC users compared to that with warfarin users. Among the various types of NOACs, all NOACs showed higher risk of retinal vascular occlusion than did warfarin. For intraocular bleeding, the HR was estimated to be 0.86 (95% CI, 0.75-0.98) for NOAC users compared with that with warfarin users. The risk of retinal vascular occlusion was higher in NOAC users than in warfarin users, while the risk of intraocular bleeding was lower with NOAC therapy. NOACs were not found to be as effective as warfarin for retinal vascular occlusion, but safe in terms of intraocular bleeding.

Purpose: Proteinuria is the second most common complication after hypertension after systemic administration of bevacizumab. Therefore we aimed to analyze the effect of intravitreal bevacizumab (IVB) injection on proteinuria in patients with diabetes., Methods: Patients scheduled to receive IVB injection from May 1, 2018, to December 31, 2018, were prospectively enrolled. In total, 53 patients with diabetes (26 with nonproliferative diabetic retinopathy and 27 with proliferative diabetic retinopathy) and 37 patients without diabetes were included. Urine tests were performed within 1 month of and 7 ± 1 days after IVB injection. Urinary protein, creatinine, and albumin concentrations were quantitatively measured, and urinary protein-to-creatinine ratio and urinary albumin-to-creatinine ratio (UACR) were calculated from these data before and after IVB injection., Results: The mean urinary microalbumin concentrations and urinary protein-to-creatinine ratio were significantly higher in patients with diabetes, both before and after IVB injection. There were no differences between patients with nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. About 80% of patients with diabetes showed improved albuminuria or at least no harmful effect in terms of albuminuria. Patients with deteriorated baseline UACR showed more residual increase in UACR after IVB injection ( P < 0.05 in all groups)., Conclusions: Close monitoring of renal function after IVB might be needed in patients with diabetes according to the severity of nephropathy., Translational Relevance: Our results may provide information regarding the renal function of IVB-treated patients with diabetes., Competing Interests: Disclosure: Y.-R. Chung, None; Y.H. Kim, None; H.-E. Byeon, None; D.H. Jo, None; J.H. Kim, None; K. Lee, None, (Copyright 2020 The Authors.)

The purpose of this study is to evaluate the prevalence rates of externalizing symptom, ADHD, as well as internalizing symptoms, depression, anxiety, suicidal ideation, self-esteem, and alcohol problem in Korea juvenile delinquency for the first time in Korea. A case-control study design was used. It also examined the associations with ADHD, suicidal ideation, depression, anxiety, self-esteem, and alcohol problem between the Juvenile Delinquency group and the comparison group in Korea.A series of questionnaires were provided to a total of 251 participants (149 from the juvenile delinquency group and 102 from the comparison group) from October 2015 to December 2015 in Korea. All participants were evaluated using KARS, SSI, BDI, BAI, RSI, and CAGE. This study showed the relationship between ADHD, suicidal ideation, depression, anxiety, self-esteem, and alcohol problem in Korean juvenile delinquency. Also this study showed that ADHD and self-esteem were important factors in predicting juvenile delinquency. Therefore, in order to prevent juvenile delinquency, special attention, and consideration are needed for adolescents with high ADHD or low self-esteem.

High salt stress caused by ionic and osmotic stressors eventually results in the suppression of plant growth and a reduction in crop productivity. In our previous reports, we isolated the endophytic bacterium Bacillus oryzicola YC7007 from the rhizosphere of rice ( Oryza sativa L.), which promoted plant growth and development and suppressed bacterial disease in rice by inducing systemic resistance and antibiotic production. In this study, Arabidopsis thaliana seedlings under salt stress that were bacterized with YC7007 displayed an increase in the number of lateral roots and greater fresh weight relative to that of the control seedlings. The chlorophyll content of the bacterized seedlings was increased when compared with that of untreated seedlings. The accumulation of salt-induced malondialdehyde and Na + in seedlings was inhibited by their co-cultivation with YC7007. The expression of stress-related genes in the shoots and roots of seedlings was induced by YC7007 inoculation under salt stress conditions. Interestingly, YC7007-mediated salt tolerance requires SOS1, a plasma membrane-localized Na + /H + antiporter, given that plant growth in sos2-1 and sos3-1 mutants was promoted under salt-stress conditions, whereas that of sos1-1 mutants was not. In addition, inoculation with YC7007 in upland-crops, such as radish and cabbage, increased the number of lateral roots and the fresh weight of seedlings under salt-stress conditions. Our results suggest that B. oryzicola YC7007 enhanced plant tolerance to salt stress via the SOS1-dependent salt signaling pathway, resulting in the normal growth of salt-stressed plants., (Copyright © 2020 Baek, Rokibuzzaman, Khan, Kim, Park, Yun and Chung.)

Diabetic macular edema (DME) is the abnormal accumulation of fluid in the subretinal or intraretinal spaces in the macula in patients with diabetic retinopathy and leads to severely impaired central vision. Technical developments in retinal imaging systems have led to many advances in the study of DME. In particular, optical coherence tomography (OCT) can provide longitudinal and microstructural analysis of the macula. A comprehensive review was provided regarding the role of inflammation using OCT-based classification of DME and current and ongoing therapeutic approaches. In this review, we first describe the pathogenesis of DME, then discuss the classification of DME based on OCT findings and the association of different types of DME with inflammation, and finally describe current and ongoing therapeutic approaches using OCT-based classification of DME. Inflammation has an important role in the pathogenesis of DME, but its role appears to differ among the DME phenotypes, as determined by OCT. It is important to determine how the different DME subtypes respond to intravitreal injections of steroids, antivascular endothelial growth factor agents, and other drugs to improve prognosis and responsiveness to treatment., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2019 Yoo-Ri Chung et al.)