Exploring novel immunotherapy biomarker candidates induced by cancer deformation

by Se Min Kim, Namu Park, Hye Bin Park, JuKyung Lee, Changho Chun, Kyung Hoon Kim, Jong Seob Choi, Hyung Jin Kim, Sekyu Choi, Jung Hyun Lee

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.

Neural processing of prototypicality and simplicity of product design in forming design preferences

by Erin Cho, Shin-Ae Yoon, Hae-Jeong Park

The current study investigates the neural correlates when processing prototypicality and simplicity—affecting the preference of product design. Despite its significance, not much is known about how our brain processes these visual qualities of design when forming design preferences. We posit that, although fluency is the perceptual judgment accounting for the positive effects of both prototypicality and simplicity on design preference, the neural substrates for the fluency judgment associated with prototypicality would differ from those associated with simplicity. To investigate these issues, we conducted an fMRI study of preference decisions for actual product designs with different levels of prototypicality and simplicity. The results show a significant functional gradient between the preference processing of simplicity and prototypicality–i.e., involvement of the early ventral stream of visual information processing for simplicity evaluation but recruitment of the late ventral stream and parietal-frontal brain regions for prototypicality evaluation. The interaction between the simplicity and prototypicality evaluations was found in the extrastriate cortex in the right hemisphere. The segregated brain involvements suggest that the fluency judgment for prototypicality and simplicity contribute to preference choice in different levels of cognitive hierarchy in the perceptual mechanism of the design preference.

Reallocating time between device-measured 24-hour activities and cardiovascular risk in Asian American immigrant women: An isotemporal substitution model

by Chorong Park, Britta Larsen, Simona C. Kwon, Yuhe Xia, Marianna LaNoue, Victoria V. Dickson, Harmony R. Reynolds, Tanya M. Spruill

The 24-hour day consists of physical activity (PA), sedentary behavior, and sleep, and changing the time spent on one activity affects the others. Little is known about the impact of such changes on cardiovascular risk, particularly in Asian American immigrant (AAI) women, who not only have a higher cardiovascular risk but also place greater cultural value on family and domestic responsibilities compared to other racial/ethnic groups. The purpose of this study was to evaluate the effects of reallocating 30 minutes of each 24-hour activity component for another on BMI, waist circumference, and blood pressure in AAI women. Seventy-five AAI women completed 7 days of hip and wrist actigraphy monitoring and were included in the analysis (age = 61.5±8.0 years, BMI = 25.5±3.6 kg/m², waist circumference = 85.9±10.2 cm). Sleep was identified from wrist actigraphy data, and moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior identified from hip actigraphy data. On average, the women spent 0.5 hours in MVPA, 6.2 hours in light PA, 10 hours in sedentary activities, and 5.3 hours sleeping within a 24-hour day. According to the isotemporal substitution models, replacing 30 minutes of sedentary behavior with MVPA reduced BMI by 1.4 kg/m² and waist circumference by 4.0 cm. Replacing that same sedentary time with sleep reduced BMI by 0.5 kg/m² and waist circumference by 1.4 cm. Replacing 30 minutes of light PA with MVPA decreased BMI by 1.6 kg/m² and waist circumference by 4.3 cm. Replacing 30 minutes of light PA with sleep also reduced BMI by 0.8 kg/m² and waist circumference by 1.7 cm. However, none of the behavioral substitutions affected blood pressure. Considering AAI women’s short sleep duration, replacing their sedentary time with sleep might be a feasible strategy to reduce their BMI and waist circumference.

Ketogenic diet preserves muscle mass and strength in a mouse model of type 2 diabetes

by Sol Been Park, Soo Jin Yang

Diabetes is often associated with reduced muscle mass and function. The ketogenic diet (KD) may improve muscle mass and function via the induction of nutritional ketosis. To test whether the KD is able to preserve muscle mass and strength in a mouse model of type 2 diabetes (T2DM), C57BL/6J mice were assigned to lean control, diabetes control, and KD groups. The mice were fed a standard diet (10% kcal from fat) or a high-fat diet (HFD) (60% kcal from fat). The diabetic condition was induced by a single injection of streptozotocin (STZ; 100 mg/kg) and nicotinamide (NAM; 120 mg/kg) into HFD-fed mice. After 8-week HFD feeding, the KD (90% kcal from fat) was fed to the KD group for the following 6 weeks. After the 14-week experimental period, an oral glucose tolerance test and grip strength test were conducted. Type 2 diabetic condition induced by HFD feeding and STZ/NAM injection resulted in reduced muscle mass and grip strength, and smaller muscle fiber areas. The KD nutritional intervention improved these effects. Additionally, the KD altered the gene expression of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome- and endoplasmic reticulum (ER) stress-related markers in the muscles of diabetic mice. Collectively, KD improved muscle mass and function with alterations in NLRP3 inflammasome and ER stress.

Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial

by Alex Buga, David G. Harper, Teryn N. Sapper, Parker N. Hyde, Brandon Fell, Ryan Dickerson, Justen T. Stoner, Madison L. Kackley, Christopher D. Crabtree, Drew D. Decker, Bradley T. Robinson, Gerald Krystal, Katherine Binzel, Maryam B. Lustberg, Jeff S. Volek

Purpose

Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (βHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy.

Methods

Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary βHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months.

Results

Capillary βHB indicated women achieved nutritional ketosis (Phase I mean: 0.8 mM (n = 15); Phase II mean: 0.7 mM (n = 9)). Body weight decreased 10% after three months, primarily from body fat. Fasting plasma glucose, plasma insulin, and insulin resistance also decreased significantly after three months (p Conclusions

Women diagnosed with MBC undergoing chemotherapy can safely achieve and maintain nutritional ketosis, while improving body composition and insulin resistance, out to six months.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial

by Jonas Sundén-Cullberg, Puran Chen, Henrike Häbel, Paul Skorup, Helena Janols, Johan Rasmuson, Katarina Niward, Åse Östholm Balkhed, Katerina Chatzidionysiou, Hilmir Asgeirsson, Ola Blennow, Åsa Parke, Anna-Karin Svensson, Jagadeeswara Rao Muvva, Hans-Gustav Ljunggren, Karolinska KI/K COVID-19 Treatment Working Group , Anna-Carin Horne, Ulrika Ådén, Jan-Inge Henter, Anders Sönnerborg, Jan Vesterbacka, Piotr Nowak, Jon Lampa

Background

Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration.

Methods

The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes 9/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery.

Results

Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly.

Conclusion

Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020–00174824).

Evaluation of immunogenicity-induced DNA vaccines against different SARS-CoV-2 variants

by Se Eun Kim, So Hee Park, Woo-Jung Park, Gayeong Kim, Seo Yeon Kim, Hyeran Won, Yun-Ho Hwang, Heeji Lim, Hyeon Guk Kim, You-Jin Kim, Dokeun Kim, Jung-Ah Lee

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic worldwide. As of September 2023, the number of confirmed coronavirus cases has reached over 770 million and caused nearly 7 million deaths. The World Health Organization assigned and informed the characterization of variants of concern (VOCs) to help control the COVID-19 pandemic through global monitoring of circulating viruses. Although many vaccines have been proposed, developing an effective vaccine against variants is still essential to reach the endemic stage of COVID-19. We designed five DNA vaccine candidates composed of the first isolated genotype and major SARS-CoV-2 strains from isolated Korean patients classified as VOCs, such as Alpha, Beta, Gamma, and Delta. To evaluate the immunogenicity of each genotype via homologous and heterologous vaccination, mice were immunized twice within a 3-week interval, and the blood and spleen were collected 1 week after the final vaccination to analyze the immune responses. The group vaccinated with DNA vaccine candidates based on the S genotype and the Alpha and Beta variants elicited both humoral and cellular immune responses, with higher total IgG levels and neutralizing antibody responses than the other groups. In particular, the vaccine candidate based on the Alpha variant induced a highly diverse cytokine response. Additionally, we found that the group subjected to homologous vaccination with the S genotype and heterologous vaccination with S/Alpha induced high total IgG levels and a neutralization antibody response. Homologous vaccination with the S genotype and heterologous vaccination with S/Alpha and S/Beta significantly induced IFN-γ immune responses. The immunogenicity after homologous vaccination with S and Alpha and heterologous vaccination with the S/Alpha candidate was better than that of the other groups, indicating the potential for developing novel DNA vaccines against different SARS-CoV-2 variants.

Menopausal hormone therapy increases the risk of gallstones: Health Insurance Database in South Korea (HISK)-based cohort study

by Jin-Sung Yuk, Ji Young Park

Objective

To determine whether menopausal hormone therapy (MHT) increases the risk of gallstones and gallbladder cancer.

Design

A retrospective cohort study.

Patients or other participants

Data from the Korea National Health Insurance Corporation was obtained between January 1, 2002, and December 31, 2019.

Interventions

Participants were divided into MHT and non-MHT groups; the MHT group was analyzed in detail by dividing participants into tibolone, combined estrogen plus progestin by the manufacturer (CEPM) or physician (CEPP), oral estrogen alone, and topical estrogen subgroups.

Main outcome measures

The incidence of gallstones and gallbladder cancer was compared between the two groups.

Results

This study enrolled 1,004,034 and 381,711 patients in the non-MHT and the MHT groups, respectively. The incidence of gallstones was 2.6% in the non-MHT group and 3.4%, 2.6%, 3.4%, 3.2%, and 4.4% in the tibolone, CEPM, oral estrogen alone, CEPP, and topical estrogen groups, respectively. Cox proportional hazard analysis revealed that all hormones increased the risk of gallstones ([tibolone] hazard ratio [HR]: 1.347, 95% confidence interval [CI]: 1.309–1.387, [CEPM] HR: 1.146, 95% CI: 1.1–1.19, [oral estrogen alone] HR: 1.241, 95% CI: 1.18–1.305, [CEPP] HR: 1.164, 95% CI: 1.01–1.341, [topical estrogen] HR: 1.602, 95% CI: 1.295–1.983). However, the risk of gallbladder cancer did not change with any hormone therapy.

Conclusions

All types of MHT including tibolone, increased the risk of gallstones. This risk was the highest with topical estrogen, which may be a result of selection bias due to concerns regarding the adverse effects of CEE and MPA.

A genome-wide and candidate gene association study of preterm birth in Korean pregnant women

by Young Min Hur, Jae Young Yoo, Young Ah You, Sunwha Park, Soo Min Kim, Gain Lee, Young Ju Kim

Preterm birth (PTB) refers to delivery before 37 weeks of gestation. Premature neonates exhibit higher neonatal morbidity and mortality rates than term neonates; therefore, it is crucial to predict and prevent PTB. Advancements enable the prediction and prevention of PTB using genetic approaches, especially by investigating its correlation with single nucleotide polymorphisms (SNPs). We aimed to identify impactive and relevant SNPs for the prediction of PTB via whole–genome sequencing analyses of the blood of 31 pregnant women with PTB (n = 13) and term birth (n = 18) who visited the Ewha Womans University Mokdong Hospital from November 1, 2018 to February 29, 2020. A genome-wide association study was performed using PLINK 1.9 software and 256 SNPs were selected and traced through protein-protein interactions. Moreover, a validation study by genotyping was performed on 60 other participants (preterm birth, n = 30; term birth, n = 30) for 25 SNPs related to ion channel binding and receptor complex pathways. Odds ratios were calculated using additive, dominant, and recessive genetic models. The risk of PTB in women with the AG allele of rs2485579 (gene name: RYR2) was significantly 4.82-fold increase, and the risk of PTB in women with the AG allele of rs7903957 (gene name: TBX5) was significantly 0.25-fold reduce. Our results suggest that rs2485579 (in RYR2) can be a genetic marker of PTB, which is considered through the association with abnormal cytoplasmic Ca²⁺ concentration and dysfunctional uterine contraction due to differences of RYR2 in the sarcoplasmic reticulum.

Association between hypoglycemic agent use and the risk of occurrence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus

by Choungwon Jung, Soyoung Park, Hyunah Kim

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern with increasing prevalence and associated health impacts. Although no approved drugs are available for the NAFLD treatment, several hypoglycemic agents have been investigated as promising therapeutic agents. We aimed to compare the risk of occurrence of NAFLD with respect to the use of different hypoglycemic agents in patients with type 2 diabetes. This retrospective cohort study used data from the National Health Insurance Service–National Sample Cohort of South Korea. Participants newly diagnosed with type 2 diabetes (2003–2019) were included in this study. Two new user-active comparator cohorts were assembled: Cohort 1, new users of thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and Cohort 2, new users of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and DPP-4i. The occurrence of NAFLD was defined based claims that include diagnostic codes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models in 1:3 propensity score (PS)-matched cohorts. For 65,224 patients newly diagnosed with type 2 diabetes, the overall prevalence of NAFLD was 42.6%. The PS-matched Cohort 1 included 6,351 and 2,117 new users of DPP-4i and TZD, respectively. Compared to DPP-4i, TZD use was associated with the decreased risk of NAFLD (HR, 0.66; 95% CI: 0.55–0.78). Cohort 2 consisted of 6,783 and 2,261 new users of DPP-4i and SGLT-2i, respectively; SGLT-2i use was associated with a decreased risk of NAFLD (HR, 0.93; 95% CI: 0.80–1.08). This population-based cohort study supports the clinical implications of prioritizing TZD and SGLT-2i over DPP-4i in reducing the risk of occurrence of NAFLD in patients with type 2 diabetes. However, the findings lacked statistical significance, highlighting the need for further verification studies.

Development and validation of an updated PICC length prediction formula based on anteroposterior chest radiographs for the ultrasound-guided bedside placement

by Hyoung Nam Lee, Sangjoon Lee, Sung-Joon Park, Youngjong Cho, Hwan Hoon Chung

Bedside peripherally inserted central catheter (PICC) placement is sometimes required when the patient’s intrahospital transport is restricted, and the ideal catheter length prediction is needed. This study aimed to develop an updated formula that predicts the optimal length of a PICC based on anteroposterior chest radiographs (AP-CXRs). This retrospective study collected PICC procedure data as the training and validation sets in three hospitals, including cubital crease-puncture point distance (CP), the actual PICC length (aCL), and the approach side. Horizontal and vertical measurement variables were set on the AP-CXRs. Two dependent variables were ipsilateral upper arm length (AL) and ideal truncal catheter length (iTCL). Simple and multiple regression analyses were used for formula development, and it was applied to the test set to evaluate the length prediction performance. The study included 309 patients in the training and validation sets and 91 intensive care patients in the test set. The final derived formula was: (AL + iTCL = CP + estimated PICC length, cm) = 19.831 − 0.062 × (contralateral clavicle length, cm) + 0.255 × (2nd ribs horizontal distance, cm) + 0.720 × (humero-vertebral distance, cm) + 0.761 × (thoraco-carinal distance, cm) + 1.024 × (the vertical distance of two vertebral body units, cm). (If approaching from the left, add 2.843cm, and if female, subtract 0.821cm.) In the test set, there was no case of length prediction failure. Moreover, the catheter tip position was evaluated as optimal in 82 cases (90.1%). This study’s results suggest an updated formula to predict the ideal PICC length using only AP-CXRs for bedside placement.

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

by Jung Hyun Lee, Il Yun, Chung-Mo Nam, Suk-Yong Jang, Eun-Cheol Park

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.

Effects of COVID-19 outbreak on Korean adolescents: Impact of altered economic perception on physical activity, sedentary behavior, and stress levels in an age-, gender-, and BMI-matched study

by Jisu Kim, In-Whi Hwang, Jeong-Hui Park, Youngdeok Kim, Jung-Min Lee

The current study is to examine the disparities in physical activity (PA), sedentary behavior (SB), and stress levels in Korean adolescents concerning changes in their perception of family economic status (ES) during COVID-19. Among a total of 6144 Korean adolescents aged 12 to 18, the participants were categorized into two groups based on their responses regarding changes in their family ES due to COVID-19: Declined ES (n = 3072) and Non-changed ES (n = 3072), with matching in terms of age, gender, and BMI. All variables were assessed using the 16^th year (2020) of the Korean Youth Risk Behavior Survey. Statistical analyses were conducted using the SPSS 26.0 version, employing independent t-tests to examine anthropometrics’ differences and multinominal logistic regression to predict the impact of perception of family ES on PA, SB, and stress while comparing the two groups. The significance level was set at α = 0.05. Adolescents in the Declined ES group were 1.2 times more likely to engage in MVPA for less than 420 mins/wk (OR = 1.16, p = 0.039), 1.7 times more likely to meet recommended muscular strength activities (i.e., ≥ 3 days/wk) (OR = 1.70, p p p

Randomized clinical trial to compare the efficacy of self-expanding bare metal nitinol stent and balloon angioplasty alone for below-the-knee lesions following successful balloon angioplasty: 1-year clinical outcomes

by Jihun Ahn, HyeYon Yu, Seung-Woon Rha, Byoung Geol Choi, Dong Oh Kang, Cheol Ung Choi, Sangho Park, Jon Seo, Kichang Kim, Minung Kim, Yong Hoon Kim, Yong Seong Seo

This prospective, multicenter, randomized study aimed to compare the 1-year clinical outcomes after primary stenting with self-expanding bare metal nitinol stent (SENS) and plain old balloon angioplasty (POBA) in patients with critical limb ischemia (CLI) and below-the-knee (BTK) lesions. Overall, 119 patients with CLI and BTK lesions were randomized to POBA alone (POBA group, 61 patients) or primary stenting with SENS (stenting group, 58 patients) after achieving acceptable POBA results in target BTK lesions. Clinical outcomes including amputation and revascularization rates were prospectively compared for 1 year. After 1 year, similar incidence rates of individual clinical endpoints, including cardiac death (6.5% vs. 5.1%, p > 0.999), myocardial infarction (1.6% vs. 0.0%, p > 0.999), repeat revascularization (19.6% vs. 18.9%, p = 0.922), target lesion revascularization (13.1% vs. 17.2%, p = 0.530), and amputation (4.9% vs. 0.0%, p = 0.244), were observed. POBA appeared to have acceptable treatment outcomes compared with primary stenting with SENS after 1 year in CLI patients with BTK lesions undergoing percutaneous transluminal angioplasty (PTA).