Exploring novel immunotherapy biomarker candidates induced by cancer deformation.

Triple-negative breast cancer (TNBC) demands urgent attention for the development of effective treatment strategies due to its aggressiveness and limited therapeutic options [1]. This research is primarily focused on identifying new biomarkers vital for immunotherapy, with the aim of developing tailored treatments specifically for TNBC, such as those targeting the PD-1/PD-L1 pathway. To achieve this, the study places a strong emphasis on investigating Ig genes, a characteristic of immune checkpoint inhibitors, particularly genes expressing Ig-like domains with altered expression levels induced by "cancer deformation," a condition associated with cancer malignancy. Human cells can express approximately 800 Ig family genes, yet only a few Ig genes, including PD-1 and PD-L1, have been developed into immunotherapy drugs thus far. Therefore, we investigated the Ig genes that were either upregulated or downregulated by the artificial metastatic environment in TNBC cell line. As a result, we confirmed the upregulation of approximately 13 Ig genes and validated them using qPCR. In summary, our study proposes an approach for identifying new biomarkers applicable to future immunotherapies aimed at addressing challenging cases of TNBC where conventional treatments fall short.

Diagnostic value of 18F-FDG PET/CT versus diffusion-weighted MRI in detection of residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma: A prospective study.

BACKGROUND: Despite advances in treatment, residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma (SCC) remain a challenge in clinical management and require accurate and timely detection for optimal salvage therapy. This study aimed to compare the diagnostic value of Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. METHODS: A prospective study was conducted on 30 patients who presented with new symptoms after definitive (chemo) radiotherapy for laryngeal (n = 21) and hypopharyngeal (n = 9) carcinoma. Both 18F-FDG PET/CT and DW-MRI were performed and histopathologic analysis served as the standard of reference. RESULTS: Histopathology showed 20 patients as positive and 10 as negative for tumors. 18F-FDG PET/CT detected all tumors correctly but was falsely positive in one case. DW-MRI detected tumors in 18 out of 20 positive patients and correctly excluded tumors in all negative patients. The sensitivity and specificity of 18F-FDG PET/CT were 100% and 90%, respectively, while the values for DW-MRI were 90% and 100%, respectively. CONCLUSIONS: The study concludes that 18F-FDG PET/CT is slightly superior to DW-MRI in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. The combined use of 18F-FDG PET/CT and DW-MRI can potentially improve specificity in therapy response evaluation.

Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.

Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma.

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death various across various MCC cell lines, thus advancing cancer immunotherapy.

Exploring the Molecular and Developmental Dynamics of Endothelial Cell Differentiation.

The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor-specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.

Association between physical activity and health-related quality of life in middle-aged and elderly individuals with musculoskeletal disorders: Findings from a national cross-sectional study in Korea.

PURPOSE: This study aimed to identify the association between physical activity and health-related quality of life (HRQoL) in middle-aged and elderly individuals with musculoskeletal disorders. METHODS: This study used data from the 2016-2020 Korea National Health and Nutrition Examination Survey (KNHANES). We included only those over 40 years of age diagnosed with one or more of the following: osteoarthritis, rheumatism, and osteoporosis. In total, 4,731 participants (783 men and 3,948 women) were included as the study population. Multiple logistic regression analysis was performed to examine the association between physical activity and HRQoL. RESULTS: In the case of middle-aged and elderly individuals with musculoskeletal disorders, the likelihood of HRQoL worsening was significantly lower for those who regularly engaged in physical activity compared with that of those who did not engage in physical activity at all (men: OR 0.58, 95% CI 0.37-0.90; women: OR 0.64, 95% CI 0.53-0.79). Stratified analysis by the type and intensity of physical activity revealed that the possibility of poor HRQoL was lowest when leisure-related moderate-intensity physical activities were performed (men: OR 0.44, 95% CI 0.22-0.89; Women: OR 0.50, 95% CI 0.36-0.69). CONCLUSIONS: Our findings suggest that engaging in regular physical activity contributes to preventing exacerbation of HRQoL, even if the individual suffers from musculoskeletal disorders. It is necessary to provide an appropriate type and intensity of physical activity in consideration of the patients' pain and severity.

Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System.

Objective: : As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. Methods: : The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. Results: : After the quinpirole administration, the 24-hour total locomotor activity did not change (p = 0.169), but activities were significantly increased in the 12-hour dark phase sum (p = 0.013) and decreased in the 12-hour light phase sum (p = 0.009). Significant increases in the activities were observed in the dark-light difference (p = 0.005) and dark-light ratio (p = 0.005) as well. Conclusion: : This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.

The deformation of cancer cells through narrow micropores holds the potential to regulate genes that impact cancer malignancy.

Surgery, radiation, hormonal therapy, chemotherapy, and immunotherapy are standard treatment strategies for metastatic breast cancer. However, the heterogeneous nature of the disease poses challenges and continues to make it life-threatening. It is crucial to elucidate further the underlying signaling pathways to improve treatment efficacy. Our study established two triple-negative breast cancer cell lines (TW-1 and TW-2) that were physically deformed using 3 µm pores to investigate the relationship between cancer cell deformation and metastasis within a heterogeneous population. The physical transformation of TW-1 and TW-2 cells significantly affected their growth and migration speed, as evidenced by wound healing assays for collective cell migration and microchannel assays for single-cell migration. We conducted bulk RNA sequencing to gain insights into the genes influenced by physical deformation. Additionally, we evaluated the effects of trametinib resistance on breast cancer cell metastasis by assessing cell viability and migration rates. Interestingly, TW-1 and TW-2 cells exhibited resistance to trametinib treatment. We observed a significant upregulation of GABRA-3, a protein commonly expressed in malignant breast cancer, and the critical transcription factor Myc in TW-1 and TW-2 cells compared to the control group (Ori). However, we did not observe a significant difference in Myc expression between TW-1 and TW-2 cells. In contrast, in the trametinib-resistant cell lines (TW-1-Tra and TW-2-Tra), we found increased expression of OCT4 and SOX2 rather than GABRA-3 or Myc. These findings highlight the differential expression patterns of these genes in our study, suggesting their potential role in cancer cell deformation and drug resistance. Our study presents a potential in vitro model for metastatic and drug-resistant breast cancer cells. By investigating the correlation between cancer cell deformation and metastasis, we contribute to understanding breast cancer heterogeneity and lay the groundwork for developing improved treatment strategies.

Therapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapy.

BACKGROUND: Long-term complications are becoming more important as the survival rate of breast cancer improves. Treatment-related myeloid neoplasm is an important long-term complication in breast cancer survivors as it has a poor prognosis. OBJECTIVE: We evaluated the incidence and risk factors for the development of treatment-related acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) in patients treated with early breast cancer. METHODS: We accessed the national Korean database to identify 153,565 patients diagnosed with breast cancer between January 2007 and October 2016 who underwent surgery for breast cancer. We estimated the cumulative incidence of AML/MDS and analysed the risk factors for developing AML/MDS. RESULTS: Of 153,575 patients, 79,321 received anthracycline-based adjuvant therapy, 14,317 received adjuvant therapy without anthracyclines and 46,657 did not receive adjuvant chemotherapy. Overall, 120 developed AML (105 in the anthracycline group, 9 in the non-anthracycline group and 6 in the control group), and 128 developed MDS (96, 9 and 23 in each group). The 10-year cumulative incidence of AML/MDS was the highest in the anthracycline group (0.221% and 0.199%), followed by the non-anthracycline group (0.122% and 0.163%) and the control group (0.024% and 0.089%). The risk of developing AML/MDS was significantly higher in patients treated with anthracyclines (hazard ratio [HR] 9.531; p < 0.0001 for AML and HR 2.559; p < 0.0001 for MDS) compared to patients in the control group. CONCLUSION: This study found that anthracycline-based adjuvant therapy significantly increased the risk of AML/MDS in Korean breast cancer patients, with the risk persisting for at least 10 years. While the cumulative incidence was low, the long-term risks of AML/MDS should be taken into account considering the poor outcomes associated with these neoplasms.

Role of birthweight discordance in preterm twins' outcomes in the Korean neonatal network.

BACKGROUND: Twin pregnancies can be complicated by birthweight (BW) discordance. We analyzed the impact of BW discordance on clinical outcomes of very-low-birthweight (VLBW) twins. METHODS: The study population was preterm infants in the Korean Neonatal Network registry. Multivariate logistic regression analyses were used to determine the contribution of BW discordance on respiratory morbidities and mortality of VLBW infants. Also, we assessed the effect of small for gestational age (SGA) on morbidity and mortality in discordant twins (DTs) and compared separately the clinical outcomes of smaller and larger DTs with different singletons matched for perinatal factors including BW percentile. RESULTS: A total of 935 twin pairs [1548 concordant twins (CTs) and 322 DTs] were included. BW discordance was associated with increased odds of moderate bronchopulmonary dysplasia, mortality, and composite outcomes. Compared with the CTs, the smaller, but not larger, DTs had greater odds of morbidities and mortality. DTs had higher odds of adverse neonatal outcome when combined with SGA. Meanwhile, DTs had morbidities and mortality similar to singletons matched for BW percentile. CONCLUSION: BW discordance in VLBW twins adversely affects neonatal mortality or respiratory morbidity which is predominant in smaller DTs. The impact of BW discordance could be increased through SGA.

Improving the Separation Properties of Polybenzimidazole Membranes by Adding Acetonitrile for Organic Solvent Nanofiltration.

In research on membranes, the addition of co-solvents to the polymer dope solution is a common method for tuning the morphology and separation performance. For organic solvent nanofiltration (OSN) applications, we synthesized polybenzimidazole (PBI) membranes with high separation properties and stability by adding acetonitrile (MeCN) to the dope solution, followed by crosslinking with dibromo-p-xylene. Accordingly, changes in the membrane structure and separation properties were investigated when MeCN was added. PBI/MeCN membranes with a dense and thick active layer and narrow finger-like macrovoids exhibited superior rejection properties in the ethanol solution compared with the pristine PBI membrane. After crosslinking, they displayed superior rejection properties (96.56% rejection of 366-g/mol polypropylene glycol). In addition, the membranes demonstrated stable permeances for various organic solvents, including acetone, methanol, ethanol, toluene, and isopropyl alcohol. Furthermore, to evaluate the feasibility of the modified PBI OSN membranes, ecamsule, a chemical product in the fine chemical industry, was recovered. Correspondingly, the efficient recovery of ecamsule from a toluene/methanol solution using the OSN process with PBI/MeCN membranes demonstrated their applicability in many fine chemical industries.

PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients.

PURPOSE: Mutations in the PIK3CA gene occur frequently in breast cancer patients. Activating PIK3CA mutations confer resistance to human epidermal growth factor receptor 2 (HER2)-targeted treatments. In this study, we investigated whether PIK3CA mutations were correlated with treatment response or duration in patients with HER2-positive (HER2+) breast cancer. Materials and Methods: We retrospectively reviewed the clinical information of patients with HER2+ breast cancer who received HER2-targeted therapy for early-stage or metastatic cancers. The pathologic complete response (pCR), progression-free survival (PFS), and overall survival were compared between patients with wild-type PIK3CA (PIK3CAw) and those with mutated PIK3CA (PIK3CAm). Next-generation sequencing was combined with examination of PFS associated with anti-HER2 monoclonal antibody (mAb) treatment. RESULTS: Data from 90 patients with HER2+ breast cancer were analyzed. Overall, 34 (37.8%) patients had pathogenic PIK3CA mutations. The pCR rate of the PIK3CAm group was lower than that of the PIK3CAw group among patients who received neoadjuvant chemotherapy for early-stage cancer. In the metastatic setting, the PIK3CAm group showed a significantly shorter mean PFS (mPFS) with first-line anti-HER2 mAb. The mPFS of second-line T-DM1 was lower in the PIK3CAm group than that in the PIK3CAw group. Sequencing revealed differences in the mutational landscape between PIK3CAm and PIK3CAw tumors. CONCLUSION: Patients with HER2+ breast cancer with activating PIK3CA mutations had lower pCR rates and shorter PFS with palliative HER2-targeted therapy than those with wild-type PIK3CA. Precise targeted-therapy is needed to improve survival of patients with HER2+/PIK3CAm breast cancer.

Magnetic resonance imaging of parotid gland tumors: a pictorial essay.

Imaging of parotid gland tumors is challenging due to the wide variety of differential diagnoses. Malignant parotid tumors can have very similar features to benign ones, such as slow growth and displacement instead of infiltration of neighboring structures. Malignant and benign tumors may therefore not be clinically distinguishable. Correct characterization of parotid tumors (i.e., benign or malignant) determines preoperative treatment planning and is important in optimizing the individualized surgical plan. Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluation of suspected parotid gland lesions and differentiation between benign and malignant lesions. Certain conventional MRI features can suggest whether a mass is more likely to be a benign or low-grade malignancy or a high-grade malignancy and adding diffusion-weighted imaging or advanced MRI techniques like perfusion can aid in this distinction. Morphological features seen on MRI, such as low signal on T2-w, infiltrative changes or ill-defined margins, change over time and diffusion restriction can point to the malignant nature of the lesion. MRI is useful for detection and localization of the lesion(s), and associated findings like perineural spread of tumor, lymph node involvement and infiltrative changes of the surrounding tissues. In this pictorial essay, we present selected images of a variety of benign and malignant parotid tumors and emphasize the MRI features that may be useful in their characterization.

Expression and purification of intracrine human FGF 11 and study of its FGFR-dependent biological activity.

Fibroblast growth factor 11 (FGF11) is one of intracrine FGFs (iFGFs), which function within cells. Unlike canonical FGFs, FGF11 remains intracellularly and plays biological roles in FGF receptor (FGFR)-independent manner. Here, we established an expression system of recombinant FGF11 proteins in E. coli and investigated whether the extracellular administration of FGF11 can activate cellular signaling. Human FGF11 has two isoforms, FGF11a and FGF11b, depending on the presence of nuclear localization sequences (NLSs) in the N-terminus. Because these two isoforms are unstable, we prepared an FGF11a-Mut by substituting three cysteine residues in the NLS with serine and FGF11b-ΔC with C-terminal truncation. The introduction of mutation in the NLS improved the solubility of FGF11 prepared from E. coli. Exogenous addition of FGF11b and FGF11b-ΔC to BALB3T3 increased cell proliferation, while FGF11a-Mut exerted no effect. FGF11b-ΔC showed higher cell proliferation activity and FGFR signaling than FGF11b. The cell-proliferating activities of FGF11b and FGF11b-ΔC were blocked by an FGFR1 inhibitor or a recombinant FGFR1, confirming the FGFR1-dependent extracellular activity of FGF11b. The analysis of circular dichroism suggested that the C-terminus of FGF11 has an α-helical structure, which may affect its interaction with FGFR1. These results suggest that the N-and C-terminus of recombinant FGF11 are involved in the activation of FGFR1. The above results provide novel insights into the function and mechanism of FGF11 that may aid the development of useful ligands for FGFR regulation.

Association between haemoglobin A1c and all-cause and cause-specific mortality in middle-aged and older Koreans: a prospective cohort study.

BACKGROUND: This study aimed to examine associations between haemoglobin A1c (HbA1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans. METHODS: Using 16 years of follow-up data from the Korean Genome and Epidemiology Study, we analysed 9294 individuals aged 40-69 years with no history of cardiovascular disease (CVD) or cancer. Participants were divided into a known diabetes group and five groups categorized by HbA1c levels (< 5.0%, 5.0-5.4%, 5.5-5.9%, 6.0-6.4%, and ≥ 6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA1c levels were calculated using a conventional and a time-dependent Cox proportional hazards model. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell counts. RESULTS: During a median follow-up period of 15.7 years, there were 944 deaths, including 185 deaths from CVD, 359 from cancer, and 125 from all external causes. Compared with participants with HbA1c levels of 5.5-5.9%, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels < 5.0%, 5.0-5.4%, 6.0-6.4%, and ≥ 6.5% and participants with known diabetes were 1.84 (1.35-2.51), 1.13 (0.95-1.34), 1.30 (1.04-1.62), 1.37 (0.97-1.93), and 2.03 (1.70-2.44), respectively. The risk of cancer mortality was significantly increased in HbA1c < 5.0% (HR, 2.21; 95% CI 1.42-3.44) and known diabetes (HR, 1.60; 95% CI 1.18-2.15). When we performed diverse subgroup analyses, low HbA1c levels at baseline were strongly associated with mortality in participants with liver diseases. CONCLUSIONS: We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions.

Molecular phylogenetic analyses based on the complete plastid genomes and nuclear sequences reveal Daphne (Thymelaeaceae) to be non-monophyletic as current circumscription.

The diverse members of the genus Daphne are prized for their fragrant flowers. Despite being promising ornamental plants in many countries, genetic information of Daphne is scarce. In this study, the plastomes of four species and one variety of Daphne were sequenced and analyzed. The plastomes were typical and contained a pair of inverted repeat (IR) regions that separated the large single-copy (LSC) region from the small single-copy (SSC) region. With a length ranging from 132,869 bp (D. genkwa) to 174,773 bp (D. championii), 106 to 141 genes were predicted. Comparative plastome analysis of the newly sequenced plastomes with four publicly available Daphne plastomes identified an expansion of the IRs, sequence variations, and mutational hotspots. Phylogenetic analyses indicated that the genus Daphne in its current circumscription is polyphyletic. Daphne genkwa was nested within the genus Wikstroemia, while D. championii was well resolved as sister to Edgeworthia. These findings concurred with results from our study that used nuclear ribosomal internal transcribed spacer sequence data. The conflicts on the molecular placement of D. championii and D. genkwa and the present taxonomic classification in Daphne suggest that a new intergeneric classification system of Daphneae warrants consideration.

Tailoring the Stabilization and Pyrolysis Processes of Carbon Molecular Sieve Membrane Derived from Polyacrylonitrile for Ethylene/Ethane Separation.

For ethylene/ethane separation, a CMS (carbon molecular sieve) membrane was developed with a PAN (polyacrylonitrile) polymer precursor on an alumina support. To provide an excellent thermal property to PAN precursor prior to the pyrolysis, the stabilization as a pre-treatment process was carried out. Tuning the stabilization condition was very important to successfully preparing the CMS membrane derived from the PAN precursor. The stabilization and pyrolysis processes for the PAN precursor were finely tuned, and optimized in terms of stabilization temperature and time, as well as pyrolysis temperature, heating rate, and soaking time. The PAN stabilized at >250 °C showed improved thermal stability and carbon yield. The CMS membrane derived from stabilized PAN showed reasonable separation performance for ethylene permeance (0.71 GPU) and ethylene/ethane selectivity (7.62), respectively. Increasing the pyrolysis temperature and soaking time gave rise to an increase in the gas permeance, and a reduction in the membrane selectivity. This trend was opposite to that for the CMS membranes derived from other polymer precursors. The optimized separation performance (ethylene permeance of 2.97 GPU and ethylene/ethane selectivity of 7.25) could be achieved at the pyrolysis temperature of 650 °C with a soaking time of 1 h. The separation performance of the CMS membrane derived from the PAN precursor was comparable to that of other polymer precursors, and surpassed them regarding the upper bound trade off.

Selective Laser Trabeculoplasty for Medically Uncontrolled Pseudoexfoliation Glaucoma in Korean Patients.

PURPOSE: This study investigated the efficacy and safety of selective laser trabeculoplasty (SLT) in Korean patients with medically uncontrolled pseudoexfoliation glaucoma (PEXG). METHODS: This retrospective observational study enrolled 43 medically uncontrolled PEXG patients who underwent a 360° SLT and were followed up for at least 12 months after SLT. The intraocular pressure (IOP) before and after SLT at 1 week, 1, 3, 6, and 12 months was evaluated. Treatment success was defined as an IOP reduction of ≥20% from the baseline and an IOP equal to lower than 22 mmHg without additional anti-glaucomatous intervention. Additionally, every follow-up medical record was reviewed to assess any possible side effects of SLT. RESULTS: Based on the Kaplan-Meier survival analysis, the treatment success rate at 12 months after SLT was 41.9% (18 eyes). For the success group at the 12 months follow-up, SLT showed a mean IOP reduction of 10.3 ± 5.0 mmHg (from 25.6 ± 4.4 to 15.2 ± 2.9 mmHg; 39.3%, p < 0.05). Among the 25 eyes that were considered as the treatment failure group, 14 eyes underwent glaucoma filtering surgeries, four eyes received additional SLT, and further intervention and follow-up was refused for seven eyes. During the overall follow-up period, there were no significant adverse events. CONCLUSIONS: SLT is a partially effective and safe procedure for lowering IOP in Korean patients with medically refractory PEXG. Therefore, it can be considered as one of the alternative treatment modalities in patients who are at high risk for conventional filtering surgery.

Contralateral Suppression at Adrenal Venous Sampling Is Associated with Renal Impairment Following Adrenalectomy for Unilateral Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling (AVS) is performed to distinguish the subtype of primary aldosteronism (PA). The clinical implication of contralateral suppression (CS; aldosterone/cortisolnondominant0.26 after adjusting for other factors. CONCLUSION: CS may not predict postoperative clinical and biochemical outcomes in subjects with unilateral aldosterone excess, but it is associated with postsurgical deterioration of renal function in subjects over 50 years with CSI ≤0.26.

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.