Differences in code status practice patterns among emergency clinicians working in Japan and the United States.

OBJECTIVE: This study aimed to examine self-reported code-status practice patterns among emergency clinicians from Japan and the U.S. METHODS: A cross-sectional questionnaire was distributed to emergency clinicians from one academic medical center and four general hospitals in Japan and two academic medical centers in the U.S. The questionnaire was based on a hypothetical case involving a critically ill patient with end-stage lung cancer. The questionnaire items assessed whether respondent clinicians would be likely to pose questions to patients about their preferences for medical procedures and their values and goals. RESULTS: A total of 176 emergency clinicians from Japan and the U.S participated. After adjusting for participants' backgrounds, emergency clinicians in Japan were less likely to pose procedure-based questions than those in the U.S. Conversely, emergency clinicians in Japan showed a statistically higher likelihood of asking 10 out of 12 value-based questions. CONCLUSION: Significant differences were found between emergency clinicians in Japan and the U.S. in their reported practices on posing procedure-based and patient value-based questions. PRACTICE IMPLICATIONS: Serious illness communication training based in the U.S. must be adapted to the Japanese context, considering the cultural characteristics and practical responsibilities of Japanese emergency clinicians.

Palliative care screening tools in Japan: cross-sectional utility study.

OBJECTIVES: In Japan's ageing society, the utility of US-based and UK-based palliative care screening tools in the inpatient setting is unknown. The purpose of this study is to identify the unmet palliative care needs of patients who are admitted to an acute care hospital using the US-based and UK-based screening tools. METHODS: This single-centre, cross-sectional study included patients who were admitted to an acute care hospital in Tokyo, Japan, from November 2019 to January 2020. We used the Supportive and Palliative Care Indicator Tool and Palliative Care Screening Tool in the Emergency Department among admitted patients. RESULTS: 126 patients (51.6%) were screened positive in total. Among these patients, the main comorbid conditions were dementia/frailty (85.7%) and neurological disease (50.8%). CONCLUSIONS: One out of every two internal medicine inpatients at acute care hospitals may have palliative care needs. Given the lack of adequate palliative care workforce in Japan, a modified screening tool to capture the most high-risk patients may be necessary.

Development and multicentre validation of the FLEX score: personalised preoperative surgical risk prediction using attention-based ICD-10 and Current Procedural Terminology set embeddings.

BACKGROUND: Preoperative knowledge of surgical risks can improve perioperative care and patient outcomes. However, assessments requiring clinician examination of patients or manual chart review can be too burdensome for routine use. METHODS: We conducted a multicentre retrospective study of 243 479 adult noncardiac surgical patients at four hospitals within the Mass General Brigham (MGB) system in the USA. We developed a machine learning method using routinely collected coding and patient characteristics data from the electronic health record which predicts 30-day mortality, 30-day readmission, discharge to long-term care, and hospital length of stay. RESULTS: Our method, the Flexible Surgical Set Embedding (FLEX) score, achieved state-of-the-art performance to identify comorbidities that significantly contribute to the risk of each adverse outcome. The contributions of comorbidities are weighted based on patient-specific context, yielding personalised risk predictions. Understanding the significant drivers of risk of adverse outcomes for each patient can inform clinicians of potential targets for intervention. CONCLUSIONS: FLEX utilises information from a wider range of medical diagnostic and procedural codes than previously possible and can adapt to different coding practices to accurately predict adverse postoperative outcomes.

The differences in code status conversation approaches reported by emergency medicine and palliative care clinicians: A mixed-method study.

BACKGROUND: During acute health deterioration, emergency medicine and palliative care clinicians routinely discuss code status (e.g., shared decision making about mechanical ventilation) with seriously ill patients. Little is known about their approaches. We sought to elucidate how code status conversations are conducted by emergency medicine and palliative care clinicians and why their approaches are different. METHODS: We conducted a sequential-explanatory, mixed-method study in three large academic medical centers in the Northeastern United States. Attending physicians and advanced practice providers working in emergency medicine and palliative care were eligible. Among the survey respondents, we purposefully sampled the participants for follow-up interviews. We collected clinicians' self-reported approaches in code status conversations and their rationales. A survey with a 5-point Likert scale ("very unlikely" to "very likely") was used to assess the likelihood of asking about medical procedures (procedure based) and patients' values (value based) during code status conversations, followed by semistructured interviews. RESULTS: Among 272 clinicians approached, 206 completed the survey (a 76% response rate). The reported approaches differed greatly (e.g., 91% of palliative care clinicians reported asking about a patient's acceptable quality of life compared to 59% of emergency medicine clinicians). Of the 206 respondents, 118 (57%) agreed to subsequent interviews; our final number of semistructured interviews included seven emergency medicine clinicians and nine palliative care clinicians. The palliative care clinicians stated that the value-based questions offer insight into patients' goals, which is necessary for formulating a recommendation. In contrast, emergency medicine clinicians stated that while value-based questions are useful, they are vague and necessitate extended discussions, which are inappropriate during emergencies. CONCLUSIONS: Emergency medicine and palliative care clinicians reported conducting code status conversations differently. The rationales may be shaped by their clinical practices and experiences.

Generation of a recombinant Saffold Virus expressing UnaG as a marker for the visualization of viral infection.

BACKGROUND: Saffold virus (SAFV), which belongs to the genus Cardiovirus of the family Picornaviridae, is associated with acute respiratory or gastrointestinal illnesses in children; it is also suspected to cause severe diseases, such as acute flaccid paralysis and aseptic meningitis. However, the understanding of the mechanism of its pathogenicity is still limited due to the many unknowns about its lifecycle; for example, the cellular receptor for its infection remains to be determined. A system to monitor SAFV infection in vitro and in vivo is required in order to accelerate research on SAFV. RESULTS: We generated a recombinant SAFV expressing green fluorescent protein (GFP) or UnaG, a novel fluorescent protein derived from Japanese eel. HeLa cells infected by either GFP or UnaG-expressing SAFV showed a bright green fluorescent signal, enabling convenient monitoring of SAFV infection. However, the expression of GFP but not UnaG was quickly lost during virus passaging due to the difference in genetic stability in the SAFV virus genome; the UnaG gene was stably maintained in the virus genome after at least five passages. CONCLUSIONS: SAFV infection of cultured cells can easily be monitored using UnaG-expressing SAFV, which is superior to GFP in terms of genetic stability in the virus genome. This virus could be a useful tool for SAFV research, such as comparing the susceptibility of various cells to SAFV infection and evaluating the effects of antivirals on SAFV infection in high-throughput screening.

Challenges in Completing a Death Certificate after Voluntary Stopping of Eating and Drinking (VSED).

In recent years, health care providers and the general public in the United States have gained a greater awareness of Voluntary Stopping of Eating and Drinking (VSED) as a last resort option to escape from unbearable suffering, thanks to a growing number of publications, books, and documentaries. However, the challenges and issues that can arise in completing a death certificate after VSED are not well described in literature. In this article, we first present an example case of VSED in which the death certificate was issued listing suicide as the manner of death by the medical examiner. Then, we describe the challenges and issues related to death certificates in VSED cases. Because there is no consensus on whether VSED is natural death or suicide, the death certificate may need to be referred to a medical examiner in many jurisdictions, potentially resulting in suicide being designated as the manner of death. Such designations can cause reticence in providers and institutions that might otherwise support patients who choose VSED but are concerned about the legal or reputational implications of enabling a "suicide" at their facility. A suicide designation may also contribute to moral distress in health care staff and impose emotional and practical burdens on the patient's surviving loved ones. We suggest that there are 3 approaches to addressing challenges and issues associated with death certificates after VSED: (1) navigate the existing system with guidance developed by professional organizations, (2) make a legal exemption, and (3) change the death certification system. Debate involving a wide variety of experts is warranted.

Myeloid-associated differentiation marker is an essential host factor for human parechovirus PeV-A3 entry.

Human parechovirus (PeV-A) is an RNA virus that belongs to the family Picornaviridae and it is currently classified into 19 genotypes. PeV-As usually cause mild illness in children and adults. Among the genotypes, PeV-A3 can cause severe diseases in neonates and young infants, resulting in neurological sequelae and death. In this study, we identify the human myeloid-associated differentiation marker (MYADM) as an essential host factor for the entry of six PeV-As (PeV-A1 to PeV-A6), including PeV-A3. The infection of six PeV-As (PeV-A1 to PeV-A6) to human cells is abolished by knocking out the expression of MYADM. Hamster BHK-21 cells are resistant to PeV-A infection, but the expression of human MYADM in BHK-21 confers PeV-A infection and viral production. Furthermore, VP0 capsid protein of PeV-A3 interacts with one extracellular domain of human MYADM on the cell membrane of BHK-21. The identification of MYADM as an essential entry factor for PeV-As infection is expected to advance our understanding of the pathogenesis of PeV-As.

Theilovirus 3C Protease Cleaves the C-Terminal Domain of the Innate Immune RNA Sensor, Melanoma Differentiation-Associated Gene 5, and Impairs Double-Stranded RNA-Mediated IFN Response.

Melanoma differentiation-associated gene 5 (MDA5), a member of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), has pivotal roles in innate immune responses against many positive-stranded RNA viruses, including picornavirus and coronavirus. Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler's murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.

Communication Training and Code Status Conversation Patterns Reported by Emergency Clinicians.

CONTEXT: During acute health decompensations for seriously ill patients, emergency clinicians often determine the intensity end-of-life care. Little is known about how emergency clinicians conduct these conversations, especially among those who have received serious illness communication training. OBJECTIVES: To determine the self-reported practice patterns of code status conversations by emergency clinicians with and without serious illness communication training. METHODS: A cross-sectional survey was conducted among emergency clinicians with and without a recent evidence-based, serious illness communication training tailored for emergency clinicians. Emergency clinicians were included from two academic medical centers. A five-point Likert scale ("very unlikely" to "very likely" to ask) was used to assess the self-reported likelihood of asking about patients' preferences for medical procedures and patients' values and goals. RESULTS: Among 161 respondents (71% response rate), 77 (48%) received the training. A total of 70% of emergency clinicians reported asking about procedure-based questions, and only 38% reported asking about patient's values regarding end-of-life care. For value-based questions, statistically significant differences were observed between emergency clinicians who underwent the training and those who did not in four of the seven questions asked (e.g., the higher odds of exploring the patient's life priorities [adjusted OR = 4.34, 95% CI = 1.95-9.65, P-value < 0.001]). No difference was observed in the self-reported rates of all procedure-based questions between the two groups. CONCLUSION: Most emergency clinicians reported asking about procedure-based questions, and some asked about patient's value-based questions. Clinicians with recent serious illness communication training may ask more about some values and priorities.

Five Key Papers About Emergency Department Fall Evaluation: A Curated Collection for Emergency Physicians.

The evaluation of patients who have experienced a fall has been an integral part of geriatric emergency care. All physicians who engage in the care of the geriatric population in acute settings need to familiarize themselves with the current literature on this topic. However, it can be challenging to navigate the large body of literature on this topic. The purpose of this article is to identify and summarize the key studies that can be helpful for faculty interested in an evidence-based fall evaluation. The authors compiled a list of key papers on emergency department (ED) based upon a structured literature search supplemented with suggestions by key informants and an open call on social media; 32 studies on ED evaluation were identified. Our authorship group then engaged in a modified Delphi technique to develop consensus on the most important studies about fall evaluation for emergency physicians. This process eventually resulted in the selection of the top five articles on fall evaluation. Additionally, we summarize these studies with regard to their relevance to emergency medicine (EM) trainees and junior faculty. Evaluation of older patients with a history of falls is a challenging but crucial component of EM training. We believe our review will be educational for junior and senior EM faculty to better understand these patients' care and to design an evidence-based practice.

Seasonality of mortality and in-hospital complications in hip fracture surgery: Retrospective cohort research using a nationwide inpatient database.

AIM: Among older patients undergoing hip fracture surgery, previous studies have shown a seasonal variation of in-hospital surgical complications. However, little is known about seasonal effects on mortality and systemic complications after hip fracture surgery. In the present study, we evaluated whether mortality and in-hospital systemic complications are influenced by seasonal differences. METHODS: We enrolled patients from a nationwide database who underwent hip fracture surgery between 2010 and 2018. The primary outcome was in-hospital mortality. The secondary outcomes were in-hospital systemic complications. The association between the seasonality and in-hospital outcomes was investigated using multivariable Cox, logistic regression and causal mediation analysis. RESULTS: With 425 856 patients (mean age 83.5 years; 79% women), overall in-hospital mortality was 5324 (1.2%). Fall and winter were associated with a higher mortality than spring (hazard ratio [HR] 1.16; P < 0.001; HR 1.14; P = 0.001, respectively). Across all the seasons, there were 36 834 overall systemic complications (8.6%), with respiratory infection being the most frequent (18 637 [4.4%]). Among these complications, only respiratory infection showed seasonal variation, with a higher prevalence in fall and winter. The mediated effect of respiratory infection on mortality was significantly higher in fall and winter compared with spring (fall, HR 1.06, proportion mediated 36.7%; winter, HR 1.14, proportion mediated 55.0%; all P < 0.001). CONCLUSIONS: We found a significantly higher mortality in fall and winter after hip fracture surgery. Specifically, in winter, the increased in-hospital death was largely attributed to the increased incidence of respiratory infection. Geriatr Gerontol Int 2021; 21: 398-403.

Influence of oxytetracycline susceptibility as a first-line antibiotic on the clinical outcome in dairy cattle with acute Escherichia coli mastitis.

The purpose of this study was to clarify the therapeutic effects of oxytetracycline (OTC) as a first-line antibiotic in cattle with acute Escherichia coli mastitis and systemic signs. Drug susceptibility was determined by the minimum inhibitory concentration (MIC) of E. coli isolated from cows with acute E. coli mastitis (n=38). Cattle were divided into OTC-susceptible (S, n=30) and OTC-resistant (R, n=8) groups. They were further subdivided according to susceptibility to the antibiotic used as a second treatment, into susceptible-susceptible (SS, n=30), resistant-susceptible (RS, n=5), and resistant-resistant (RR, n=3) groups. Clinical signs on the day after initial treatment were compared between S and R groups as short-term indicators of treatment effects. The 28-day survival rate of cattle was then compared among SS, RS, and RR groups as a long-term indicator of treatment effects. There were no differences in clinical signs between S and R groups on the day after the first dose, but the 28-day survival rate was significantly greater in the SS group than in the RR group (P=0.04). The results demonstrated that an effective drug is essential for first-line treatment of acute coliform mastitis. However, anticipating the effectiveness of a first-line antibiotic based on clinical symptoms at the second day of treatment is impossible. It is important to build a picture of drug resistance trends in cattle herds for empirical selection of antibiotics to be administered.

USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis.

Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing α-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with α-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits α-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

Randomized clinical trial to evaluate the effectiveness of enrofloxacin as a second-line antibiotic for treatment of acute Escherichia coli mastitis.

The objective of the present study was to evaluate the effectiveness of enrofloxacin (ERFX) as a second-line antibiotic for treatment of acute Escherichia coli (E. coli) mastitis. Forty-two cows with naturally occurring acute E. coli mastitis were enrolled. On the first day of treatment (day 0), empirically selected antibiotics (oxytetracycline: n = 32, kanamycin: n = 10) were administered. Although systemic signs improved in 10 cows (first-line group), the signs remained unchanged or worsened in 32 cows on day 1, including two cows that were found dead. The 30 surviving cows were randomly assigned to second-line groups constituting an ERFX group (n = 19) or a control group (n = 11) that was treated with other antibiotics. Response to each treatment was evaluated by measuring clinical signs from day 0 to day 3, subsequent quarter milk recovery, and the 60-day survival rate. Appetite on day 3 was significantly better in the ERFX group compared to the control group. No significant differences were observed in the 60-day survival rate or the subsequent milk recovery between the ERFX group and the control group. Thus, the use of ERFX as a second-line antibiotic for the treatment of acute E. coli mastitis could induce a rapid appetite recovery.

MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia.

Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer.

Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells.

Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs.

[Usefulness and Problems of Intraoperative Monitoring for Unruptured Aneurysm Surgery with the Motor Evoked Potential].

It has been pointed out that the motor evoked potential(MEP)with a subdural electrode is useful in the intraoperative monitoring for unruptured aneurysm surgery. However, in some cases, we experienced postoperative ischemic complications despite evaluating the motor function via MEP monitoring. Herein, we have reported the usefulness and problems of intraoperative monitoring with MEP to evaluate brain dysfunction caused by insufficiency of cerebral blood flow. Out of 279 aneurysm surgery procedures, we performed MEP monitoring in 142 cases and successfully recorded in 126 cases. We compared the ischemic complication rate of the group for which MEP was monitored with that of the group for which MEP was not monitored. The whole ischemic complication rate was decreased in the group that underwent MEP monitoring. Thus, it was suggested that MEP monitoring was useful for avoiding ischemic complications. In internal carotid artery aneurysms, the amplitude of MEP changed and recovered in 2 cases and disappeared in one case. In anterior cerebral artery aneurysms, the amplitude of MEP changed and recovered in 2 cases. In middle cerebral artery aneurysms, the amplitude of MEP changed and recovered in 5 cases. We could avoid ischemic complications by intraoperative MEP monitoring in many cases. However, in some cases, we found ischemic complications that were not detected by MEP monitoring with a subdural electrode. In these cases, transcranial stimulation in combination with subdural electrode might be effective in avoiding ischemic complications that might occur after dural closure.

Induction of Cell Death in Growing Human T-Cells and Cell Survival in Resting Cells in Response to the Human T-Cell Leukemia Virus Type 1 Tax.

Tax1 encoded by the human T-cell leukemia virus type 1 (HTLV-1) has been believed to dysregulate the expression of cellular genes involved in cell survival and mortality, leading to the development of adult T-cell leukemia (ATL). The function of Tax1 in ATL development however is still controversial, primarily because Tax1 induces cell cycle progression and apoptosis. To systemically understand cell growth phase-dependent induction of cell survival or cell death by Tax1, we established a single experimental system using an interleukin 2 (IL-2)-dependent human T-cell line Kit 225 that can be forced into resting phase by IL-2 deprivation. Introduction of Tax1 and HTLV-2 Tax (Tax2B) decreased mitochondrial activity alongside apoptosis in growing cells but not in resting cells. Cell cycle profile analysis indicated that Tax1 and Tax2B were likely to perturb the S phase in growing cells. Studies with Tax1 mutants and siRNA for NF-κB/RelA revealed that Tax1-mediated cell growth inhibition and apoptosis in growing Kit 225 cells depend on RelA. Interestingly, inactivation of the non-canonical NF-κB and p38 MAPK pathways relieved Tax1-mediated apoptosis, suggesting that the Tax1-NF-κB-p38 MAPK axis may be associated with apoptosis in growing cells. Inflammatory mediators such as CCL3 and CCL4, which are involved in oncogene-induced senescence (OIS), were induced by Tax1 and Tax2B in growing cells. In contrast, RelA silencing in resting cells reduced mitochondrial activity, indicating that NF-κB/RelA is also critical for Tax1-mediated cell survival. These findings suggest that Tax1-mediated cell survival and death depend on the cell growth phase. Both effects of Tax1 may be implicated in the long latency of HTLV-1 infection.

Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB.

Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-κB2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-κB2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-κB2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2.