Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.

HIGH PLOIDY2-mediated SUMOylation of transcription factor ARR1 controls two-component signaling in Arabidopsis.

Cytokinins regulate plant growth, development, and responses to environmental stresses such as cold via phosphorelay from cytokinin receptors to the ARABIDOPSIS RESPONSE REGULATORs (ARRs). However, the molecular mechanisms underlying the activation of type-B ARR transcriptional activity in Arabidopsis (Arabidopsis thaliana) remain unclear. Here, we show that the E3 SUMO ligase HIGH PLOIDY2 SUMOylates ARR1, a type-B ARR, at K236, triggering its activation. Cold- or cytokinin-induced phosphorylation of ARR1 at D89 is crucial for its interaction with HPY2. Lysine 236 is critical for ARR1's transactivation without compromising its DNA-binding ability, while D89 is crucial for ARR1's binding to target gene promoters. Cytokinin enhances ARR1's chromatin binding, but cold does not. ARR1 K236 plays a critical role in promoting histone H3 acetylation in response to both cytokinin and cold without affecting chromatin binding. The K236R mutation in ARR1 reduces target gene expression and alters cytokinin and cold response phenotypes. This study unveils a mechanism of ARR1 activation wherein phosphorylated ARR1 interacts with HPY2 and binds to chromatin in response to cytokinin. Cold triggers a phosphorelay targeting chromatin-bound ARR1. HPY2 then catalyzes ARR1 SUMOylation at K236, enhancing histone H3 acetylation and leading to transcriptional activation of ARR1 in response to both cold and cytokinin.

Single-cell RNA sequencing reveals myeloid and T cell co-stimulation mediated by IL-7 anti-cancer immunotherapy.

BACKGROUND: Immune checkpoint inhibitors unleash inhibitory signals on T cells conferred by tumors and surrounding stromal cells. Despite the clinical efficacy of checkpoint inhibitors, the lack of target expression and persistence of immunosuppressive cells limit the pervasive effectiveness of the therapy. These limitations may be overcome by alternative approaches that co-stimulate T cells and the immune microenvironment. METHODS: We analyzed single-cell RNA sequencing data from multiple human cancers and a mouse tumor transplant model to discover the pleiotropic expression of the Interleukin 7 (IL-7) receptor on T cells, macrophages, and dendritic cells. RESULTS: Our experiment on the mouse model demonstrated that recombinant IL-7 therapy induces tumor regression, expansion of effector CD8 T cells, and pro-inflammatory activation of macrophages. Moreover, spatial transcriptomic data support immunostimulatory interactions between macrophages and T cells. CONCLUSION: These results indicate that IL-7 therapy induces anti-tumor immunity by activating T cells and pro-inflammatory myeloid cells, which may have diverse therapeutic applicability.

High-resolution phylogeographical surveillance of Hantaan orthohantavirus using rapid amplicon-based Flongle sequencing, Republic of Korea.

Orthohantaviruses, etiological agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome, pose a critical public health threat worldwide. Hantaan orthohantavirus (HTNV) outbreaks are particularly endemic in Gyeonggi Province in northern area of the Republic of Korea (ROK). Small mammals were collected from three regions in the Gyeonggi Province during 2017 and 2018. Serological and molecular prevalence of HTNV was 25/201 (12.4%) and 10/25 (40%), respectively. A novel nanopore-based diagnostic assay using a cost-efficient Flongle chip was developed to rapidly and sensitively detect HTNV infection in rodent specimens within 3 h. A rapid phylogeographical surveillance of HTNV at high-resolution phylogeny was established using the amplicon-based Flongle sequencing. In total, seven whole-genome sequences of HTNV were newly obtained from wild rodents collected in Paju-si (Gaekhyeon-ri) and Yeoncheon-gun (Hyeonga-ri and Wangnim-ri), Gyeonggi Province. Phylogenetic analyses revealed well-supported evolutionary divergence and genetic diversity, enhancing the resolution of the phylogeographic map of orthohantaviruses in the ROK. Incongruences in phylogenetic patterns were identified among HTNV tripartite genomes, suggesting differential evolution for each segment. These findings provide crucial insights into on-site diagnostics, genome-based surveillance, and the evolutionary dynamics of orthohantaviruses to mitigate hantaviral outbreaks in HFRS-endemic areas in the ROK.

Risk Factor Analysis of Lymph Node Metastasis for Rectal Neuroendocrine Tumors: Who Needs a Radical Resection in Rectal Neuroendocrine Tumors Sized 1-2 cm?

BACKGROUND: Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial. OBJECTIVE: This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1‒2 cm in size. METHODS: Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods. RESULTS: LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013). CONCLUSIONS: Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.

Validity assessment of oral health promotion activities targeting the older population for community care in South Korea: A Delphi study.

OBJECTIVE: The purpose of this study was to establish an oral health activity assessment tool for older people and evaluate its validity. BACKGROUND: To provide reasonable and efficient oral health promotion services with limited medical resources, a tool including categories and items of oral health promotion activities for older people should be prepared. MATERIALS AND METHODS: The tool initially consisted of 76 items on oral health promotion activities for older people classified into assessment-performance-evaluation stages. Topics for each stage included general and oral health, daily health, oral health status, behaviour, and awareness. In addition, two Delphi surveys were conducted on 10 experts who met the selection criteria, and the final items were derived based on the review opinions. RESULTS: As a result of the first and second Delphi surveys, the content validity for all items was ≥0.60 and the content validity index was ≥0.80. In the first survey, the degree of convergence in some items was 0-0.88. After modifying the contents according to expert opinions, the degree of convergence was improved from 0 to 0.50 in the second survey. The degree of agreement ranged from 0.75 to 1.00, indicating that experts agreed. Finally, a total of 65 items were derived. CONCLUSION: A 65-item tool was derived through two Delphi surveys for the assessment of oral health activities for older people. The use of the tool developed in this study would likely contribute to better prevention of oral diseases and the promotion of oral health among older people.

Immunogenicity and efficacy of pembrolizumab and doxorubicin in a phase I trial for patients with metastatic triple-negative breast cancer.

Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0-2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3-4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477.

Lung transplantation in pulmonary sarcoidosis.

Sarcoidosis is a systemic inflammatory disease of unknown etiology and variable clinical course. Pulmonary sarcoidosis is the most common presentation and accounts for most morbidity and mortality related to sarcoidosis. While sarcoidosis generally has good outcomes, few patients experience chronic disease. A minority of patients progress to a specific phenotype of sarcoidosis referred to advanced pulmonary sarcoidosis (APS) which includes advanced fibrosis, pulmonary hypertension and respiratory failure, leading to high morbidity and mortality. In patients with advanced disease despite medical therapy, lung transplantation may be the last viable option for improvement in quality of life. Though post-transplant survival is similar to that of other end-stage lung diseases, it is imperative that patients are evaluated and referred early to transplant centers with experience in APS. A multidisciplinary approach and clinical experience are crucial in detecting the optimal timing of referral, initiating comprehensive transplantation evaluation and listing, discussing surgical approach, and managing perioperative and post-transplant care. This review article seeks to address these aspects of lung transplantation in APS.

ROOT MERISTEM GROWTH FACTOR1 (RGF1)-RGF1 INSENSITIVE 1 peptide-receptor pair inhibits lateral root development via the MPK6-PUCHI module in Arabidopsis.

ROOT MERISTEM GROWTH FACTOR1 (RGF1) and its receptors RGF1 INSENSITIVEs (RGIs) regulate primary root meristem activity via a mitogen-activated protein kinase (MPK) signaling cascade in Arabidopsis. However, it is unknown how RGF1 regulates lateral root (LR) development. Here, we show that the RGF1-RGI1 peptide-receptor pair negatively regulates LR development via activation of PUCHI encoding AP2/EREBP. Exogenous RGF1 peptides inhibited LR development of the wild type. However, the rgi1 mutants were partially or fully insensitive to RGF1 during LR development, whereas four other rgi single mutants, namely rgi2, rgi3, rgi4, and rgi5, were sensitive to RGF1 in inhibiting LR formation. Consistent with this, the red fluorescent protein (RFP) signals driven by the RGF1 promoter were detected at stage I and the following stages, overlapping with RGI1 expression. PUCHI expression was significantly up-regulated by RGF1 but completely inhibited in rgi1. LR development of puchi1-1 was insensitive to RGF1. PUCHI expression driven by the RGI1 promoter reduced LR density in both the wild type and rgi1,2,3. Further, mpk6, but not mpk3, displayed significantly down-regulated PUCHI expression and insensitive LR development in response to RGF1. Collectively, these results suggest that the RGF1-RGI1 module negatively regulates LR development by activating PUCHI expression via MPK6.

Prognostic significance of peripheral neutrophils and lymphocytes in early untreated Parkinson's disease: an 8-year follow-up study.

BACKGROUND: To explore whether peripheral blood neutrophils and lymphocytes are associated with longitudinal motor and cognitive decline in patients with early Parkinson's disease (PD) and, to uncover the disease-specific mechanisms underlying these associations. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative cohort. We included 376 patients with recently diagnosed, drug-naïve PD and 178 matched healthy controls. The patients underwent annual assessments, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 test to measure motor function and the Montreal Cognitive Assessment (MoCA) to measure cognitive function, for up to 8 years of follow-up. Dopamine transporter (DAT) imaging was performed at baseline and the 1-year, 2-year and 4-year follow-up visits. RESULTS: At baseline, patients with PD showed higher neutrophil and lower lymphocyte counts, resulting in a higher neutrophil-to-lymphocyte ratio (NLR) than that in healthy controls. Higher neutrophil counts were associated with a greater increase in MDS-UPDRS part 3 scores in patients with PD (estimate: 0.25, 95% CI: 0.12 to 0.37, p<0.001). Correspondingly, higher neutrophil levels were related to a greater reduction in DAT activity in the caudate (estimate: -0.007, 95% CI: -0.014 to -0.001, p=0.046) and putamen (estimate: -0.0039, 95% CI: -0.0077 to -0.0002, p=0.042). However, there were no significant effects of lymphocyte count and NLR on changes in the MDS-UPDRS part 3 and MoCA scores and striatal DAT uptake over time. CONCLUSION: Among the blood biomarkers, only a higher neutrophil count was associated with faster motor progression along with accelerated nigrostriatal dopaminergic degeneration in patients with PD. The impact of neutrophils and lymphocytes on longitudinal cognitive changes remains unclear. TRIAL REGISTRATION NUMBER: NCT01141023.

Heart Failure-Smart Life: a randomized controlled trial of a mobile app for self-management in patients with heart failure.

BACKGROUND: It is an important strategy for healthcare providers to support heart failure patients with comprehensive aspects of self-management. A practical alternative to a comprehensive and user-friendly self-management program for heart failure patients is needed. This study aimed to develop a mobile self-management app program for patients with heart failure and to identify the impact of the program. METHODS: We developed a mobile app, called Heart Failure-Smart Life. The app was to provide educational materials using a daily health check-up diary, Q & A, and 1:1 chat, considering individual users' convenience. An experimental study was employed using a randomized controlled trial to evaluate the effects of the program in patients with heart failure from July 2018 to June 2019. The experimental group (n = 36) participated in using the mobile app that provided feedback on their self-management and allowed monitoring of their daily health status by cardiac nurses for 3 months, and the control group (n = 38) continued to undergo their usual care. The differences in the physical, psychosocial, and behavioral factors between the two groups over time were analyzed using the analysis of covariance. RESULTS: After 3 months of intervention, significant differences between experimental and control groups were shown in the New York Heart Association functional class (p = 0.003) and cardiac diastolic function (p = 0.024). The improvements over time in the experimental group tended to be higher than those in the control group in considered variables. However, no changes in psychosocial and behavioral variables were observed between the groups over time. CONCLUSIONS: This study provides evidence that the mobile app program may provide benefits to its users, specifically improvements of symptom and cardiac diastolic function in patients with heart failure. Healthcare providers can effectively and practically guide and support patients with heart failure using comprehensive and convenient self-management tools such as smartphone apps.

Characteristics of deactivation and thermal regeneration of Nb-doped V2O5-WO3/TiO2 catalyst for NH3-SCR reaction.

This study investigated the effect of Nb doping into V2O5-WO3/TiO2 (VWT) catalyst for removing NOxvia the SCR (selective catalytic reduction) by NH3. The experimental results exhibited that Nb can improve the reactivity of the VWT catalyst at low temperatures. The addition of Nb also enhanced the tolerance to SO2 and H2O. The de-NOx efficiency of the V2O5-WO3-Nb2O5/TiO2 (VWNbT) catalyst was increased up to 12% over that of the VWT catalyst at 240 °C when the catalyst was poisoned for 24 h. The prepared catalysts were characterized by FT-IR, XRD, XPS, and N2 physisorption, elemental analysis. The results showed that the ammonium bisulfate (ABS) was less formed in the VWNbT than in the VWT. Moreover, evolved gas analysis was performed to examine the thermal decomposition behavior of the poisoned catalyst, and confirmed that the ABS deposited on the catalyst was sufficiently decomposed between about 300 and 400 °C. In particular, to most effectively recover the characteristics and activity of the catalysts, thermal treatment at a temperature of 400 °C is suitable.

Catalytic ozonation of methylethylketone over porous Mn-Cu/HZSM-5.

The catalytic ozonation of methylethylketone (MEK) was performed at the room temperature (25 °C) using the synthesized Mn and Cu-loaded zeolite (ZSM-5, SiO2/Al2O3 = 80) catalysts. The ZSM-5 zeolite was used as a porous support material due to the large surface area and high capacity for adsorption of volatile organic compounds. Since Mn and Cu-loaded zeolite catalysts were effective for the catalytic ozonation of VOCs such as MEK, according to the loaded concentration of Mn and Cu, there are four types of metal loaded ZSM5 catalysts synthesized [5 wt% Mn/ZSM-5, 5 wt% Cu/ZSM-5, 5 wt% Mn-1 wt% Cu/ZSM-5 (5Mn1CuZSM), and 5 wt% Cu-1 wt% Mn/ZSM-5]. The catalytic efficiency for the removal of MEK and ozonation using the different catalysts was also studied. Based on various experimental analysis processes, the characteristics of the synthesized catalysts were explored and the removal efficiencies of MEK and O3 together with the COx concentration generated from the destruction of MEK and O3 were explored. The results for the decomposition of MEK and O3 at the room temperature indicated that the Mn dominant ZSM-5 catalysts showed better efficiency for the conversion of MEK and O3. The 5 wt% Mn/ZSM-5 outweighed the rest of them for the removal of MEK while the 5Mn1CuZSM showed the best catalytic reactivity for the conversion of O3 and the CO2 selectivity. It was ascertained that during the reaction time of catalyst and reactants of 120 min the Mn dominantly deposited bimetallic catalyst, 5Mn1CuZSM, was determined as the most effective for the removal of MEK and O3 due to the high capability of production of Mn3+ species and more available adsorbed oxygen sites compared to the other catalysts. Finally, the durability measurement for the 5Mn1CuZSM catalyst was performed together with the produced CO and CO2 concentration for 420 min.

Effect of dexamethasone and ramosetron on the prevention of postoperative nausea and vomiting in low-risk patients: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Several studies have investigated the effect of antiemetics on postoperative nausea and vomiting (PONV) in high-risk groups. However, few studies have investigated the effect of antiemetics in patients at low risk of developing PONV. METHODS: In this prospective, randomized, double-blinded trial, 177 patients undergoing surgery under general anesthesia were randomly allocated to three groups. Patients allocated to group C (control group) received 2 mL of intravenous 0.9% saline, those allocated to group R (ramosetron group) received 0.3 mg of intravenous ramosetron, and those allocated to group DR (ramosetron plus dexamethasone group) received 5 mg of intravenous dexamethasone and 0.3 mg of intravenous ramosetron. RESULTS: Finally, 174 patients completed the study, and the types of surgeries were orthopedic (n = 80), rhinologic (n = 47), urologic (n = 29), and others (n = 18). The incidence of PONV up to 48 h postoperatively was significantly lower in group DR than in group C. The incidence of PONV up to 0-1 h postoperatively was significantly lower in groups R and DR than in group C. The usage pattern of rescue antiemetics was consistent with the incidence of PONV. The percentage of patients requiring rescue analgesics 0-1 h postoperatively was significantly lower in groups R and DR than in group C. CONCLUSIONS: The combination of dexamethasone and ramosetron demonstrated a superior effect in preventing PONV for 48 h after surgery under general anesthesia than saline in patients at low risk of developing PONV. Compared with saline injections, ramosetron injections yielded better outcomes for the incidence of PONV and the use of rescue antiemetics and rescue analgesics 0-1 h postoperatively. TRIAL REGISTRATION: Clinical trial registration number: criskorea@korea.kr, KCT0006749.

Algorithm for Automatic Rod Feeding and Positioning Error Compensation for Underground Drilling Robots in Coal Mines.

In the pursuit of automating the entire underground drilling process in coal mines, the automatic rod feeding technology of drilling robots plays a crucial role. However, the current lack of positional accuracy in automatic rod feeding leads to frequent accidents. To address this issue, this paper presents an algorithm for compensating positioning errors in automatic rod feeding. The algorithm is based on a theoretical mathematical model and manual teaching methods. To enhance the positioning accuracy, we first calibrate the pull rope sensor to correct its measurement precision. Subsequently, we establish a theoretical mathematical model for rod feeding positions by employing spatial coordinate system transformations. We determine the target rod feeding position using a manual teaching-based approach. Furthermore, we analyze the relationship between the theoretical rod delivery position and the target rod delivery position and propose an anisotropic spatial difference compensation technique that considers both distance and direction. Finally, we validate the feasibility of our proposed algorithm through automatic rod feeding tests conducted on a coal mine underground drilling robot. The results demonstrate that our algorithm significantly improves the accuracy of rod feeding positions for coal mine underground drilling robots.

Children's experiences of intravenous injection using the draw, write, and tell method: A mixed-methods study.

PURPOSES: This study aimed to explore children's perceptions and experiences of receiving intravenous (IV) injections and the self-reported pain scores and management strategies that can support children while receiving IV injections. DESIGN AND METHODS: This mixed-methods study included 17 children aged 4-11 years who presented to the outpatient clinic of a pediatric hospital and received IV injections. Data were collected using the draw, write, and tell method (DWT) and Facial Pain Rating Scale. Descriptive statistics and content analyses were performed. RESULTS: The children's self-reported mean pain score was 4.82, indicating moderate pain. Many expressions indicated that IV injections were painful or caused tingling or stinging sensations. A vague fear of needles in addition to pain was identified after listening to the children and analyzing their own interpretation of drawings. Three main themes were identified: (1) physical and emotional experiences, (2) parents as my secure base, and (3) comfort and relief strategies. CONCLUSIONS: Children expressed their experiences during IV injections, the alleviation of their pain and fear, and their suggestions for comfort and relief strategies visually, auditorily, and verbally. Parents played an important role in supporting their children and reducing pain, anxiety, and distress related to the IV procedure. PRACTICE IMPLICATIONS: The DWT, as an arts-based and child-centered approach, is a useful and valid method to understand children's experience related to the IV injection. Children experience comfort and relief within a family-centered care context during IV injection. Nurses should promote children's and parents' participation in the development of strategies to reduce the negative effects of IV injections in children.

Antibody-Drug Conjugates in Breast Cancer: Current Status and Future Directions.

Antibody drug conjugates (ADCs) are novel medications that combine monoclonal antibodies with cytotoxic payloads, enabling the selective delivery of potent drugs to cancer cells expressing specific surface antigens. This targeted strategy seeks to optimize treatment effectiveness while reducing the risk of systemic toxicity, distinguishing ADCs from conventional chemotherapy. The rapid growth in ADC research has led to numerous developments and approvals for cancer treatment, with significant impacts on the management of breast cancer. ADCs like T-DXd for HER2-low disease and sacituzumab govitecan for triple negative breast cancer (TNBC) have provided valuable options for challenging subtypes of breast cancer. However, essential questions still need to be addressed, including the optimal order of ADCs amidst the growing number of newly developed ones and strategies to overcome resistance mechanisms. Preclinical studies have shed light on potential resistance mechanisms, emphasizing the potential benefit of combinational approaches with other agents such as immune checkpoint inhibitors (ICIs) and targeted tyrosine kinase inhibitors (TKIs) to enhance treatment effectiveness. Additionally, personalized approaches based on molecular profiling hold promise in tailoring ADC treatments to individual tumors, identifying unique molecular markers for each patient to optimize treatment efficacy while minimizing side effects.

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer.

Comparative Computational Analysis of Spike Protein Structural Stability in SARS-CoV-2 Omicron Subvariants.

The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike (S) protein mutations pose serious threats to current coronavirus disease 2019 (COVID-19) therapies. A comprehensive understanding of the structural stability of SARS-CoV-2 variants is vital for the development of effective therapeutic strategies as it can offer valuable insights into their potential impact on viral infectivity. S protein mediates a virus' attachment to host cells by binding to angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD), and mutations in this protein can affect its stability and binding affinity. We analyzed S protein structural stability in various Omicron subvariants computationally. Notably, the S protein sequences analyzed in this work were obtained directly from our own sample collection. We evaluated the binding free energy between S protein and ACE2 in several complex forms. Additionally, we measured distances between the RBD of each chain in S protein to analyze conformational changes. Unlike most of the prior studies, we analyzed full-length S protein-ACE2 complexes instead of only RBD-ACE2 complexes. Omicron subvariants including BA.1, BA.2, BA.2.12.1, BA.4/BA.5, BA.2.75, BA.2.75_K147E, BA.4.6 and BA.4.6_N658S showed enhanced stability compared to wild type, potentially due to distinct S protein mutations. Among them, BA.2.75 and BA.4.6_N658S exhibited the highest and lowest level of stability, respectively.

Genomic evidence of SARS-CoV-2 reinfection in the Republic of Korea.

As the coronavirus disease 2019 (COVID-19) pandemic continues, reinfection is likely to become increasingly common. However, confirming COVID-19 reinfection is difficult because it requires whole-genome sequencing of both infections to identify the degrees of genetic differences. Since the first reported case of reinfection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the Republic of Korea in April 2020, four additional cases were classified as suspected reinfection cases. We performed whole-genome sequencing of viral RNA extracted from swabs obtained at the initial infection and reinfection stages of these four suspected cases. The interval between initial infection and reinfection of all four suspected cases was more than 3 months. All four patients were young (10-29 years), and they displayed mild symptoms or were asymptomatic during the initial infection and reinfection episodes. The analysis of genome sequences combined with the epidemiological results revealed that only two of the four cases were confirmed as reinfection, and both were reinfected with the Epsilon variant. Due to the prolonged COVID-19 pandemic, the possibility of reinfections with SARS-CoV-2 variants is increasing, as reported in our study. Therefore, continuous monitoring of cases is necessary.