PCAF promotes R-loop resolution via histone acetylation.

R-loops cause genome instability, disrupting normal cellular functions. Histone acetylation, particularly by p300/CBP-associated factor (PCAF), is essential for maintaining genome stability and regulating cellular processes. Understanding how R-loop formation and resolution are regulated is important because dysregulation of these processes can lead to multiple diseases, including cancer. This study explores the role of PCAF in maintaining genome stability, specifically for R-loop resolution. We found that PCAF depletion promotes the generation of R-loop structures, especially during ongoing transcription, thereby compromising genome stability. Mechanistically, we found that PCAF facilitates histone H4K8 acetylation, leading to recruitment of the a double-strand break repair protein (MRE11) and exonuclease 1 (EXO1) to R-loop sites. These in turn recruit Fanconi anemia (FA) proteins, including FANCM and BLM, to resolve the R-loop structure. Our findings suggest that PCAF, histone acetylation, and FA proteins collaborate to resolve R-loops and ensure genome stability. This study therefore provides novel mechanistic insights into the dynamics of R-loops as well as the role of PCAF in preserving genome stability. These results may help develop therapeutic strategies to target diseases associated with genome instability.

R-loops are harmful DNA-RNA hybrid structures that cause genome instability, disrupting normal cell functions. This study explored the role of the protein PCAF in resolving R-loops to maintain genome stability. The researchers found that depleting PCAF leads to increased R-loop formation, especially during transcription, compromising the genome. Mechanistically, PCAF facilitates histone acetylation, recruiting proteins like MRE11, EXO1, FANCM and BLM to R-loop sites. These proteins collaborate to resolve R-loop structures. The findings suggest that PCAF, histone acetylation, and these repair proteins work together to untangle R-loops and preserve genome integrity. Understanding this process provides insights into R-loop dynamics and PCAF's role in genome maintenance, potentially leading to therapeutic strategies for diseases associated with genome instability, such as cancer.

Tctp, a unique Ing5-binding partner, inhibits the chromatin binding of Enok in Drosophila.

The MOZ/MORF histone acetyltransferase complex is highly conserved in eukaryotes and controls transcription, development, and tumorigenesis. However, little is known about how its chromatin localization is regulated. Inhibitor of growth 5 (ING5) tumor suppressor is a subunit of the MOZ/MORF complex. Nevertheless, the in vivo function of ING5 remains unclear. Here, we report an antagonistic interaction between Drosophila Translationally controlled tumor protein (TCTP) (Tctp) and ING5 (Ing5) required for chromatin localization of the MOZ/MORF (Enok) complex and H3K23 acetylation. Yeast two-hybrid screening using Tctp identified Ing5 as a unique binding partner. In vivo, Ing5 controlled differentiation and down-regulated epidermal growth factor receptor signaling, whereas it is required in the Yorkie (Yki) pathway to determine organ size. Ing5 and Enok mutants promoted tumor-like tissue overgrowth when combined with uncontrolled Yki activity. Tctp depletion rescued the abnormal phenotypes of the Ing5 mutation and increased the nuclear translocation of Ing5 and chromatin binding of Enok. Nonfunctional Enok promoted the nuclear translocation of Ing5 by reducing Tctp, indicating a feedback mechanism between Tctp, Ing5, and Enok to regulate histone acetylation. Therefore, Tctp is essential for H3K23 acetylation by controlling the nuclear translocation of Ing5 and chromatin localization of Enok, providing insights into the roles of human TCTP and ING5-MOZ/MORF in tumorigenesis.

Perspectives of opioid prescribers in overdose hotspots and coldspots, Massachusetts, 2019.

BACKGROUND: Prescription opioids (POs) have had a devastating effect on people and public health systems in the U.S. Due to the urgency and complexity of the opioid crisis, there is a need to expand qualitative research on the medical community's perspectives on opioid prescribing practices and the role that prescription drug monitoring programs (PDMPs) have played in mitigating this crisis. METHODS: We conducted qualitative interviews with clinicians (n = 23) across specialties and a range of overdose hotspot and coldspot locations in Massachusetts during 2019. We aimed to capture their perspectives on the opioid crisis, changes in clinical practice, and experiences with opioid prescribing and PDMPs. RESULTS: Respondents consistently recognized the role clinicians played in the opioid crisis and reported reductions in their opioid prescribing, which were motivated by the crisis itself. The limitations of opioids in pain management were frequently discussed. While clinicians appreciated having greater awareness of their opioid prescribing and increased access to patient prescription histories, they also expressed concerns about surveillance of their prescribing and other unintended consequences. We observed that clinicians in opioid prescribing hotspots had more detailed and specific reflections on their experiences with the Massachusetts PDMP, MassPAT. CONCLUSION: Clinician perceptions of the severity of the opioid crisis in Massachusetts and thoughts on their role as prescribers were consistent across specialty, prescribing level, and practice location. Many clinicians in our sample cited use of the PDMP as an influence on their prescribing. Those practicing in opioid overdose hotspots had the most nuanced reflections about the system.

Effects of Multimodal Inpatient Rehabilitation vs Conventional Pulmonary Rehabilitation on Physical Recovery After Esophageal Cancer Surgery.

OBJECTIVE: To determine the effects of multimodal rehabilitation initiated immediately after esophageal cancer surgery on physical recovery compared with conventional pulmonary rehabilitation. DESIGN: Retrospective study. SETTING: Private quaternary care hospital. PARTICIPANTS: Fifty-nine inpatients (N=59) who participated in either conventional pulmonary rehabilitation (n=30) or in multimodal rehabilitation (n=29) after esophageal cancer surgery were included. INTERVENTIONS: Both groups performed pulmonary exercises, including deep breathing, chest expansion, inspiratory muscle training, coughing, and manual vibration. In the conventional pulmonary rehabilitation group, light-intensity mat exercise, stretching, and walking were performed. The multimodal rehabilitation group performed resistance exercises and moderate- to high-intensity aerobic interval exercises using a bicycle. MAIN OUTCOME MEASURES: The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30), pain, 6-minute walk test (6MWT), 30-second chair stand test, and grip strengths were assessed before and after the rehabilitation programs. RESULTS: Symptom scales of pain, dyspnea, and insomnia in the EORTC QLQ-C30 as well as 6MWT improved significantly after each program (P<.05). 6MWT (73.1±52.6 vs 28.4±14.3, P<.001, d=1.15), 30-second chair stand test (3.5±3.9 vs 0.35±2.0, P<.001, d=1.06), and left grip strength (1.2±1.3 vs 0.0±1.5, P=.002, d=0.42) improved significantly in the multimodal rehabilitation group compared with the pulmonary rehabilitation group. While right grip strength also showed more improvement for those undergoing the multimodal program, the mean strength difference was not clinically meaningful. CONCLUSIONS: A multimodal inpatient rehabilitation program instituted early after esophageal cancer surgery improved endurance for walking more than conventional pulmonary rehabilitation as measured by the 6MWT and the 30-second chair stand test.

The HIV Care Continuum in Small Cities of Southern New England: Perspectives of People Living with HIV/AIDS, Public Health Experts, and HIV Service Providers.

The HIV care continuum (HCC), comprised of five steps (screening, linkage to care, treatment initiation, retention, and viral suppression), is used to monitor treatment delivery to people living with HIV (PLWH). The HCC has primarily focused on large urban or metropolitan areas where the situation may differ from that in smaller cities. Three themes (i.e., knowledge, stigma, stability) that shaped HCC outcomes were identified from analysis of two qualitative studies involving HIV service providers, public health experts, and PLWH in smaller cities of southern New England. The findings suggest that enhancing HCC outcomes require a multiprong approach that targets both the individual and organizational levels and includes interventions to increase health literacy, staff communication skills, universal screening to assess patients' religiosity/spirituality and supplemental service needs. Interventions that further ensure patient confidentiality and the co-location and coordination of HIV and other healthcare services are particularly important in smaller cities.

RESUMEN: El cuidado continuo de VIH (HCC), constado de cinco etapas (pruebas, vinculación al cuidado, inico del tratamiento, retención, y supresión viral), se emplea para monitorizar la entrega de tratamientos a las personas que vivien con VIH (PLWH). El HCC ha enfocado principalmente en áreas grandes y urbanas o áreas metropolitanas, donde la situación podría ser diferente que la de las ciudades más pequeñas. Tres temas (i.e., conocimiento, estigma, estabilidad) que formaron los resultados de HCC fueron identificados con análisis de dos estudios cualitativos que involucraron los proveedores de servicios de VIH, expertos de la salud pública, y PLWH en ciudades más pequeñas en las partes sureñas de Nueva Inglaterra. Los hallazgos sugieren que la mejora de los resultados de HCC requiere un enfoque multidimensional que se dirigen a ambos niveles del individuo y organización, y que incluyen intervenciones para aumentar la alfabetización sanitaria, la habilidad de comunicación del personal, la prueba universal para evaluar la religiosidad/espiritualidad de los pacientes y la necesidad de servicios suplementarios. Intervenciones que aseguran aún más la confidencialidad de los pacientes y el co-ubicación y coordinación de los servicios de VIH y otras asistencias medicas son particularmente importantes en ciudades pequeñas.

Role of SES on the association between childhood parental death and adulthood suicidal ideation: a mediation analysis using longitudinal dataset in South Korea.

BACKGROUND: We sought to examine the association between childhood experience of parental death (CEPD) and adulthood suicidal ideation, and the mediating role of adulthood SES in the association. METHODS: We analyzed a nationally representative dataset of 8609 adults from the Korea Welfare Panel Study, which is a longitudinal cohort dataset in South Korea. CEPD was measured using a question: "During your childhood (0-17 years old), have you experienced the death of parents?" We classified responses of CEPD during 2006-2011 into 'yes,' and the others into 'no.' Suicidal ideation over the past year was assessed annually during 2012-2019. As a potential mediator, adulthood educational attainment and household income in 2011 were included in the analysis. Logistic regression was applied to examine the association of CEPD with adulthood suicidal ideation across age groups (early adulthood, 19-39 years old; middle adulthood, 40-59 years old; late adulthood, ≥60 years old), after excluding people who reported lifetime suicidal ideation in 2011. Causal mediation analysis using a parametric regression model was applied to examine the mediating role of adulthood SES in the association between CEPD and adulthood suicidal ideation. RESULTS: After adjusting for potential confounders including childhood SES, CEPD was significantly associated with adulthood suicidal ideation among the late adulthood group (OR: 1.43; 95% CI: 1.13-1.81), while the association was not statistically significant among the early; and middle adulthood groups. In mediation analysis of adulthood household income, both indirect association (ORNIE: 1.05; 95% CI: 1.02-1.09) and direct association (ORNDE: 1.37; 95% CI: 1.09-1.73) were statistically significant among the late adulthood group. In the mediation analysis of adulthood education attainment among the late adulthood, only a direct association was statistically significant (ORNDE: 1.43; 95% CI: 1.14-1.80). CONCLUSIONS: These results suggest that CEPD could be a risk factor for adulthood suicidal ideation. Furthermore, the findings imply that income security policy might be necessary to reduce suicide among the late adulthood group.

Rejection of workers' compensation claims may increase depressive symptoms among firefighters with occupational injury: a nationwide study in South Korea.

OBJECTIVES: This study sought to examine whether the experience of occupational injuries was associated with depressive symptoms and whether the rejection of workers' compensation claims was associated with depressive symptoms among Korean firefighters. METHODS: We conducted a nationwide survey of 6793 Korean firefighters in 2015. Based on the experience of occupational injuries and workers' compensation claims over the past year, respondents were classified into four groups: "Not injured", "Injured, not applied", "Injured, applied, but rejected" and "Injured, applied, and accepted." Depressive symptoms over the preceding week were assessed using the 11-item version of the Centers for Epidemiologic Studies Depression Scale. RESULTS: Compared to firefighters who did not get injured, injured firefighters had a higher prevalence of depressive symptoms (PR 2.01, 95% CI 1.83, 2.22) after controlling for confounders including job assignment. Also, when we restricted the analysis to injured firefighters, a higher prevalence of depressive symptoms was observed among "Injured, applied, but rejected" (PR 1.70, 95% CI 1.11, 2.59) group, compared to "Injured, applied, and accepted" group. CONCLUSIONS: This finding suggests that rejection of workers' compensation claims, as well as the experience of occupational injuries, may increase the risk of depressive symptoms among Korean firefighters.

Linking MATTERS: Barriers and Facilitators to Implementing Emergency Department-Initiated Buprenorphine-Naloxone in Patients with Opioid Use Disorder and Linkage to Long-Term Care.

BACKGROUND: In March 2019, our health system launched a project called Linking MATTERS (Medication for Addiction Treatment linkage Through Emergency depaRtmentS) to initiate evidence-based treatment for opioid use disorder (OUD) with buprenorphine-naloxone (B/N) in our emergency departments and connect patients to our primary care sites to continue their addiction care. Methods: Six months after project implementation, we conducted in-depth interviews with frontline providers (n = 14), including emergency physicians and hospitalists, recovery coaches, ED and outpatient nurses, and case managers. We used qualitative thematic analysis to identify barriers and facilitators to implementation and suggestions for improving the project. Results: We identified five salient themes: (1) provider trainings: mandated, rather than optional trainings, facilitated provider uptake; (2) provider attitudes: there was a growing recognition of addiction as a chronic, medical disease and the value of B/N in supporting patients' recovery, driven by a desire to make a difference in patients' lives; (3) patient engagement: frontline providers with lived experience of addiction who had designated time (such as recovery coaches) were optimally positioned to engage patients; (4) the linking mechanism: personal connections between ED and outpatient providers, rather than follow-up telephone calls, facilitated linkage; and (5) suggestions for improving the program, including: a physical space/bridge clinic to provide patient linkage, expansion of the recovery coach program, and standardized, evidence-based interdisciplinary trainings for all frontline providers. Conclusion: The insights provided will support further program modifications. Healthcare systems should explore whether the components we identified warrant attention locally based on their unique infrastructure and culture.

Candida auris colonization or infection of the ear: A single-center study in South Korea from 2016 to 2018.

Candida auris was first identified in Japan from specimens obtained from the ear, but most reports since have reported invasive infections or non-ear based cases. We reviewed all the microbiology records from a single center in South Korea from February 2016 to July 2018. One hundred eleven isolates were positive for C. auris from 79 patients. All 79 patients positive for C. auris had positive ear discharge samples. All but one of the patients with C. auris had been to the otorhinolaryngology clinic. Symptom-driven ear culture was done for all but one patient, whose culture was performed for surveillance. Ear discharges were mostly purulent (60%) or serous (34%). We performed the environmental cultures at the otorhinolaryngology outpatient clinic to evaluate the environmental contamination of C. auris, but C. auris was not isolated from medical equipment and environmental surfaces.

Recommendation for response to the COVID-19 pandemic: Korean context of "distancing in daily life," considering vulnerable population.

While the coronavirus disease 2019 (COVID-19) pandemic is an ongoing worldwide, including South Korea (hereinafter Korea), it is impossible to predict the duration of the pandemic. To stop the spread of COVID-19, "social distancing," which included mandatory lockdown, and attention to personal hygiene are being adopted globally as non-pharmaceutical preventive strategies. In Korea, after maintaining strong social distancing rules for a while, the government transitioned to implementing "distancing in daily life" since May 6, 2020. The distancing in daily life was combined with infection prevention activities to stop the COVID-19 pandemic, while guaranteeing one's daily life and economic activities.In this regard, the Ministry of Health and Welfare in Korea disclosed key rules for personal quarantine. The five key rules for individual infection control are as follows: to stay at home for 3-4 days if you feel unwell, keep a distance of two arms' length from others, to wash your hands for 30 s and cough or sneeze into your sleeves, ventilate at least twice a day and disinfect regularly, and stay connected while physically distancing. However, for vulnerable populations, it is very difficult to follow such rules.Thus, we attempted to recommend how the society could support such vulnerable populations who may face difficulties in following these individual infection control rules. Through our recommendations for the weakest part of our society, we expect to strengthen the overall social structure.

Chest wall recurrence in pT1-2N0-1 breast cancer patients after mastectomy without radiotherapy.

PURPOSE: In correlation with the nodal status in the era of modern radiotherapy, the chest wall recurrence (CWR) rate was investigated in pT1-2N0-1 breast cancer patients after a mastectomy without post-mastectomy radiotherapy (PMRT). METHODS: The data from the patients participating in two South Korean multi-institutional studies (KROG 14-22; N = 1842 and KROG 14-23; N = 1382) were analyzed. In total, 3224 pT1-2N0-1 breast cancer patients who underwent mastectomy without PMRT were analyzed. RESULTS: The median follow-up time was 72.2 months (range 0.8-125.2 months). The overall CWRs during the follow-up period were 1.68% in N0 patients and 2.82% in N1 patients. There was no statistically significant difference in 5-year and 10-year CWR-free survival (CWRFS) between the N0 and N1 patients. Of the 70 patients with CWR, 33 (1% of all the patients) had isolated CWR, and the 10-year overall survival rate in this group was 96.9%. After the propensity score matching of the N0 and N1 groups, there was still no difference in CWRFS by nodal status. CONCLUSIONS: The incidence of CWR in pT1-2N0-1 breast cancer patients is very low, especially with isolated recurrence. Also, the obtained data showed that the nodal status had no impact on CWRFS.

Does fluid collection impact radiotherapy outcomes after wide excision of lower extremity soft tissue sarcoma?

BACKGROUND: Fluid collection (FC) of lymph or blood may accumulate at the site of excision after surgery for soft tissue sarcoma, with reported incidence rates from 10% to 36%. The purpose of this study is to analyze the impact of FC on local recurrence (LR) and wound complication rates after adjuvant postoperative radiotherapy (PORT) in lower extremity soft tissue sarcoma (LE-STS). METHODS: Eighty-eight patients diagnosed with LE-STS were curatively treated with wide excision and PORT. FC developed in 51.1% of patients. Full FC volumes were included in the irradiation field throughout the full course of PORT for 36 patients (80.0%). A median of 61.2 and 63 Gy was prescribed for patients with and without FC, respectively. RESULTS: After a median follow-up of 4.3 years, patients with and without FC had 5-year local control rates of 77.7% and 90.8% (P = 0.105). Eight patients with FC had LR, of which six patients had recurrent tumors at or within 4 cm of the FC wall and three of these patients had out-of-field LR. Wound complication occurred after RT in 3 (6.7%) of 45 patients with FC and 1 (2.3%) of 43 patients without FC. CONCLUSIONS: FC presents a potential risk for increased LR, particularly near the FC wall. Based on reasonable wound complication rates, we suggest the need and feasibility of fully including FC volumes in the irradiation field.

Association between workplace discrimination and depressive symptoms among firefighters in South Korea.

BACKGROUND: Workplace discrimination is associated with poor mental health. However, there is a lack of studies examining the effects of discrimination on depressive symptoms among firefighters. METHODS: We analyzed a national cross-sectional survey of 6369 firefighters in South Korea. Workplace discrimination during the past year was measured and main reasons for the discriminatory experience (gender, birth region, age, education, field/office work, job division) were identified separately by gender and job division. Depressive symptoms during the previous week were measured by the CES-D11. RESULTS: Overall, 30.3% of firefighters experienced workplace discrimination and the main reasons for discrimination differed by gender and job division. Firefighters who experienced workplace discrimination had a higher likelihood of depressive symptoms than those who did not after adjusting for potential confounders (PR: 1.73; 95%CI: 1.55, 1.92). CONCLUSIONS: This finding suggests that experience of workplace discrimination could aggravate the mental health of firefighters who provide an important public service.

Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer.

OBJECTIVE: To investigate the disease course and identify prognostic factors for survival in patients with residual disease according to post-treatment magnetic resonance imaging (MRI) following definitive concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer. METHODS: We reviewed clinical data from the medical records of 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics stage IB2-IVA uterine cervical cancer treated with CCRT. Post-treatment MRI was checked in all patients 3months after CCRT completion. Out of the 545 patients, 53 with residual cervical cancer based on MRI following definitive CCRT were included in this analysis. RESULTS: Thirty-two patients were disease-free at the last follow-up. Of them, 31 had a residual tumor size of ≤2cm. Of these 32 women, 30 showed spontaneous regression of residual tumor during follow-up without salvage treatments, whereas the remaining two were alive with no evidence of disease after salvage surgery and chemotherapy. Disease progression was observed in 21 patients, including 7 local, 8 distant and 6 local and distant failures. Of these 21 women, 13 died of disease, 6 were alive with disease, and 2 remained disease-free after salvage treatments. Initial and residual tumor sizes were significant prognostic factors for overall survival; only residual tumor size was significant for local progression-free survival. CONCLUSIONS: About 60% of patients with residual disease detected on post-treatment MRI remained disease-free without further disease progression. Careful observation without immediate salvage treatments might be feasible in selected patients with a residual tumor size ≤2cm.

Association between interpersonal trust, reciprocity, and suicidal behaviors: A longitudinal cohort study in South Korea.

While a growing body of evidence suggest that social capital including interpersonal trust and reciprocity might be associated with mental health outcomes, few studies have explored the relationship with suicidal behaviors. This research examined the prospective association between interpersonal trust and reciprocity and suicidal behaviors using the Korea Welfare Panel Study, a nationally representative longitudinal cohort dataset in South Korea. Interpersonal trust and reciprocity were assessed at the 7th wave of the survey (2012), and each measure was classified into two categories (low vs. high). Experience of suicidal ideation, planning, and attempt was assessed between the 8th (2013) and 10th wave (2015) of the surveys. After adjusting for confounders including lifetime experience of suicidal behaviors at the 7th wave of the survey (2012) as well as socio-demographic information, the low interpersonal trust group was more likely to experience suicidal ideation (OR: 1.30, 95% CI: 1.11-1.53) compared to the high interpersonal trust group whereas no statistically significant association was observed in the reciprocity analysis.

Who is working while sick? Nonstandard employment and its association with absenteeism and presenteeism in South Korea.

OBJECTIVES: This study sought to examine whether nonstandard employment is associated with presenteeism as well as absenteeism among full-time employees in South Korea. METHODS: We analyzed a cross-sectional survey of 26,611 full-time employees from the third wave of the Korean Working Conditions Survey in 2011. Experience of absenteeism and presenteeism during the past 12 months was assessed through self-reports. Employment condition was classified into six categories based on two contract types (parent firm and subcontract) and three contract durations [permanent (≥1 year, no fixed term), long term (≥1 year, fixed term), and short term (<1 year, fixed term)]. RESULTS: We found opposite trends between the association of nonstandard employment with absenteeism and presenteeism after adjusting for covariates. Compared to parent firm-permanent employment, which has been often regarded as a standard employment, absenteeism was not associated or negatively associated with all nonstandard employment conditions except parent firm-long term employment (OR 1.88; 95 % CI 1.57, 2.26). However, presenteeism was positively associated with parent firm-long term (OR 1.64; 95 % CI 1.42, 1.91), subcontract-long term (OR 1.61; 95 % CI 1.12, 2.32), and subcontract-short term (OR 1.26; 95 % CI 1.02, 1.56) employment. CONCLUSIONS: Our results found that most nonstandard employment may increase risk of presenteeism, but not absenteeism. These results suggest that previous findings about the protective effects of nonstandard employment on absenteeism may be explained by nonstandard workers being forced to work when sick.

Targeted antitumor efficacy and imaging via multifunctional nano-carrier conjugated with anti-HER2 trastuzumab.

In this study, we prepared iron oxide nanoparticle and doxorubicin-loaded multifunctional nano-carrier (IONP/DOX-MFNC), capable of simultaneous cancer targeting via a herceptin monoclonal antibody, controlled anticancer drug delivery, as well as imaging modalities of magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging. IONP and DOX were efficiently loaded into the nano-carrier, and a desirable pH-responsive release of DOX was achieved by MFNC. The nano-carrier showed much higher cellular uptake and stronger cytotoxicity to HER2 overexpressed SK-BR-3 (human breast cancer cells) than MCF-7, a negative control cell, suggesting specific cancer targeting via HER2 receptor. In an in vivo tumor xenograft model, IONP/DOX-MFNC showed higher tumor uptake and significantly enhanced tumor regression than the nano-carrier without the antibody. Thus, DOX-loaded, multi-functional nano-carrier with HER2 antibody was effective for both imaging and therapy, showing the potential for early stage cancer diagnosis and simultaneous therapy. FROM THE CLINICAL EDITOR: In this study, efficacy -both for imaging and treatment - was demonstrated on a doxorubicin and iron oxide nanoparticle loaded multifunctional nano-carrier with HER2 antibody to show the potential for early stage cancer diagnosis and simultaneous therapy.

Ablation of calcineurin Aß reveals hyperlipidemia and signaling cross-talks with phosphodiesterases.

Insulin resistance, hyperlipidemia, and cardiovascular complications are common dysregulations of metabolic syndrome. Transplant patients treated with immunosuppressant drugs such as cyclosporine A (CsA), an inhibitor of calcineurin phosphatase, frequently develop similar metabolic complications. Although calcineurin is known to mediate insulin sensitivity by regulating ß-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Aß (CnAß(-/-)). We show that mice lacking calcineurin Aß are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAß(-/-) mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by ß-adrenergic G-protein-coupled receptor signaling pathways. CnAß(-/-) mice also exhibit additional pathophysiological phenotypes caused by the potentiated GPCR signaling pathways. A cell autonomous mechanism with sustained cAMP/PKA activation is found in CnAß(-/-) mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAß(-/-) mice, however, are sensitive to phosphodiesterase inhibitor. Indeed, we show that calcineurin regulates degradation of phosphodiesterase 3B, in addition to phosphodiesterase 4D. These results establish a role for calcineurin in lipid homeostasis. These data also indicate that potentiated cAMP signaling pathway may provide an alternative molecular pathogenesis for the metabolic complications elicited by CsA in transplant patients.

People-Oriented Culture and its association with burnout, depressive symptoms, and sleep problems during COVID-19 pandemic among EMS providers in Korea.

OBJECTIVE: This study examined how perceived people-oriented culture (POC) was associated with burnout, depressive symptoms, and sleep problems during the COVID-19 pandemic among emergency medical service (EMS) providers in Korea. METHODS: We conducted a cross-sectional survey among 693 EMS providers in 2021. RESULTS: Overall, 60% reported burnout and around 25% had depressive symptoms. Prevalence of poor sleep quality, unrestful sleep, and sleep disturbance were 46.5%, 58.2%, and 52.2%, respectively. Compared to high POC group, higher prevalence of depressive symptoms was observed among medium (PR: 1.57, 95% CI: 1.06, 2.32) and low (PR: 2.70, 95% CI: 1.92, 3.79) POC group. Similar trends were observed in the analysis of burnout and sleep problems. CONCLUSIONS: Our findings underscore that low POC could play a critical role in worsening burnout, depressive symptoms, and sleep problems among EMS providers.

Different perfusion pattern between acute and chronic pulmonary thromboembolism: evaluation with two-phase dual-energy perfusion CT.

OBJECTIVE: The purpose of this study was to evaluate whether two-phase dual-energy CT can differentiate between lung perfusion patterns of patients with chronic pulmonary thromboembolism (PTE) and those of patients with acute PTE. SUBJECTS AND METHODS: A total of 114 patients clinically suspected to have PTE were prospectively enrolled. All patients underwent dual-energy CT at pulmonary artery (PA) and delayed phases. Of 68 patients diagnosed with PTE on CT, 42 were finally included. Iodine-related attenuation values (IRAs) were measured in PA and delayed phases for each lung segment, and IRA change ratios were calculated using the formula 100% × [(IRA of delayed phase) - (IRA of PA phase)]/(IRA of PA phase). RESULTS: Among the 42 patients (19 men and 23 women; mean age, 60.3 ± 13.2 years; range, 28-82 years), 24 had a diagnosis of acute PTE and 18 of chronic PTE. Those segments with both perfusion and filling defects (n = 143) in patients with acute PTE showed no significant changes of mean IRA between PA and delayed phases, whereas the segments from patients with chronic PTE (n = 94) showed significantly increased IRA on delayed phase as compared with PA phase. The mean IRA change ratios in acute and chronic PTE were -3.14% and 191.9%, respectively (p < 0.0001). CONCLUSION: Chronic PTE segments were significantly more enhanced on the delayed phase of two-phase dual-energy CT images than were acute PTE segments, possibly resulting from more extensive systemic collateral formation in chronic PTE. Two-phase dual-energy CT can be used to differentiate distinct regional perfusion patterns between acute and chronic PTE.