Healthcare experiences of patients with Down syndrome who are Black, African American, of African descent, or of mixed race.

Scant research has explored the healthcare experiences of people with Down syndrome (DS) in the United States who are Black, African American, of African descent, or of mixed race. The purpose of this study was to identify and describe the barriers and facilitators that such patients and their caregivers face when accessing healthcare. We gathered data in three ways: focus groups with caregivers, a national survey completed by caregivers, and in-depth interviews with primary care providers. Many caregivers and primary care physicians felt that patients with DS who are Black, African American, of African descent, or of mixed race receive a lower quality of medical care than their white counterparts with DS. Caregivers mentioned feeling tired of being reminded by the medical community about their race and wanting acknowledgment that raising a child with DS can be hard at times. Many felt that the medical community's conscious and unconscious racial biases do negatively impact the care of their loved ones with DS. Caregivers desired more race concordant medical providers or, when not possible, medical providers who are willing to learn more about DS and build trusted, longitudinal relationships. Primary care providers discussed the need for funded resources and support services to effectively care for their patients with DS.

Healthcare experiences of patients with Down syndrome from primarily Spanish-speaking households.

We report on the health care experiences of individuals with Down syndrome (DS) from families who are primarily Spanish-speaking. Data were collected through three methods: (1) a nationally distributed, 20-item survey, (2) two focus groups with seven family caregivers of individuals with DS who self-identified as living in primarily Spanish speaking households, and (3) 20 interviews with primary care providers (PCPs) who care for patients who are underrepresented minorities. Standard summary statistics were used to analyze the quantitative survey results. Focus group and interview transcripts, as well as an open-ended response question in the survey, were analyzed using qualitative coding methods to identify key themes. Both caregivers and PCPs described how language barriers make giving and receiving quality care difficult. Caregivers additionally described condescending, discriminatory treatment within the medical system and shared feelings of caregiver stress and social isolation. Challenges to care experienced by families of individuals with DS are compounded for Spanish-speaking families, where the ability to build trust with providers and in the health care system may be compromised by cultural and language differences, systemic issues (lack of time or inability to craft more nuanced schedules so that patients with higher needs are offered more time), mistrust, and sometimes, overt racism. Building this trust is critical to improve access to information, care options, and research opportunities, especially for this community that depends on their clinicians and nonprofit groups as trusted messengers. More study is needed to understand how to better reach out to these communities through primary care clinician networks and nonprofit organizations.

Views on the impact of the COVID-19 pandemic on health in people with Down syndrome from diverse backgrounds.

Down syndrome (DS) has a unique medical and psychological profile. To date, few studies have asked individuals with DS about their views of health, and fewer have explored the impact of COVID-19 on the health of individuals with DS and their families. We used a mixed methods approach including two studies on the health of individuals with DS and their parents conducted during the COVID-19 pandemic: (1) eight virtual focus groups, comprised of 20 parents and 8 individuals with DS to obtain participants' views of health, and (2) a 20-item questionnaire on health care experience of patients with DS who are African American or come from primarily Spanish-speaking homes. Focus group transcripts were coded using a hybrid inductive/deductive framework and thematically analyzed using the Framework Method. This questionnaire included questions regarding the impact of COVID-19 on caregivers and their loved ones with DS; responses to these questions were summarized using descriptive statistics. Individuals with DS discussed the impact of the COVID-19 pandemic on their physical and social health including masking, online learning, and online communication with friends and family. Parents of individuals with DS discussed how the COVID-19 pandemic negatively impacted their child's physical, social, and mental health, as a result of virtual schooling and decreased socialization. There were unexpected positives of the pandemic such as improved hygiene and eased scheduling with telehealth visits. Caregivers noted COVID-19 impacted their own anxiety, employment, and other domains that have potential ripple effects on the health of their children. The COVID-19 pandemic had a pervasive impact on the mental health and wellness of caregivers as well as the physical, social, and mental health of individuals with DS.

The Relationship Between Obesity and Amputation-free Survival in Patients Undergoing Lower-limb Revascularisation for Chronic Limb-threatening Ischaemia: A Retrospective Cohort Study.

BACKGROUND: The obesity paradox is a well-documented phenomenon in cardiovascular disease, however it remains poorly understood. We aimed to investigate the relationship between body mass (as measured by body mass index [BMI]) and 1-year amputation-free survival (AFS) for patients undergoing lower limb revascularisation for chronic limb-threatening ischaemia (CLTI). METHODS: A retrospective analysis was undertaken of all consecutive patients undergoing lower limb revascularisation for CLTI at the Leicester Vascular Institute between February 2018-19. Baseline demographics and outcomes were collected using electronic records. BMI was stratified using the World Health Organization criteria. One-year AFS (composite of major amputation/death) was the primary outcome. Kaplan-Meier survival analysis and adjusted Cox's proportional hazard models were used to compare groups to patients of normal mass. RESULTS: One-hundred and ninety patients were included. Overall, no difference was identified in 1-year AFS across all groups (pooled P = 0.335). Compared to patients with normal BMI (n = 66), obese patients (n = 43) had a significantly lower adjusted combined risk of amputation/death (aHR 0.39, 95% CI 0.16-0.92, P = 0.032), however no significant differences were observed for overweight (aHR 0.89, 95% CI 0.47-1.70, P = 0.741), morbidly obese (aHR 1.15, 95% CI 0.41-3.20, P = 0.797) and underweight individuals (aHR 1.86, 95% CI 0.56-6.20, P = 0.314). CONCLUSIONS: In the context of CLTI, obesity is potentially associated with favourable amputation-free survival at 1 year, compared to normal body mass. The results of this study support the notion of an obesity paradox existing within CLTI and question whether current guidance on weight management requires a more patient-specific approach.

The Impact of Anemia on One-Year Amputation-Free Survival in Patients Undergoing Revascularization for Chronic Limb-Threatening Ischemia: A Retrospective Cohort Study.

BACKGROUND: Anemia is potentially associated with increased morbidity and mortality following vascular surgery procedures. This study investigated whether peri-procedural anemia is associated with reduced 1-year amputation-free survival (AFS) in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI). METHODOLOGY: A retrospective analysis of patients diagnosed with CLTI between February 2018-February 2019, who subsequently underwent revascularization, was conducted. Hemoglobin concentration measured at index assessment was recorded and stratified by WHO criteria. Subsequent peri-procedural red blood cell transfusions (RBC) were also recorded. The primary outcome was 1-year AFS. Kaplan Meier survival analysis and Cox's proportional hazard modelling were conducted to assess the effect of anemia and peri-procedure transfusion on outcomes. RESULTS: 283 patients were analyzed, of which 148 (52.3%) were anemic. 53 patients (18.7%) underwent RBC transfusion. Patients with anemia had a significantly lower 1-year AFS (64.2% vs. 78.5%, P = 0.009). A significant difference in 1-year AFS was also observed based upon anemia severity (P = 0.008) and for patients who received RBC transfusion (45.3% vs 77.0%, P < 0.001). On multivariable analysis, moderately severe anemia was independently associated with increased risk of major amputation/death (aHR 1.90, 95% CI 1.06-3.38, P = 0.030). After adjusting for severity of baseline anemia, peri-procedural RBC transfusion was associated with a significant increase in the combined risk of major amputation/death (aHR 3.15, 95% CI 1.91-5.20, P < 0.001). CONCLUSION: Moderately severe peri-procedural anemia and subsequent RBC transfusion are independently associated with reduced 1-year AFS in patients undergoing revascularization for CLTI. Future work should focus on investigating alternative measures to managing anemia in this cohort.

A randomized controlled trial of an online health tool about Down syndrome.

PURPOSE: We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. METHODS: In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP. RESULTS: A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. CONCLUSIONS: DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

Pregnancy outcomes following recurrent miscarriage.

BACKGROUND: Recurrent miscarriage affects 1-2% of the population, and the literature has focussed on causes, treatment, and live birth rate. AIM: This study aimed to assess the reproductive outcomes for patients who attended a specialist recurrent miscarriage clinic for investigation and treatment. METHODS: Prospective analysis of all patients who attended a recurrent miscarriage clinic from January 2014 to January 2021. RESULTS: Of the 488 patients who attended a specialist clinic, 318 had a further pregnancy with 299 included in this study. The median age was 37 years, with 55.6% having a previous live birth. The subsequent live birth rate was 75.3%, 22.0% had a further pregnancy loss, 1.7% had an ongoing pregnancy, and 1% attended another institution after the second trimester. The rate of preeclampsia was 2.2%, pregnancy-induced hypertension was 2.2%, fetal growth restriction was 5.3%, preterm birth ≤ 34 weeks was 1.8%, and preterm birth > 34 weeks < 37 weeks was 6.6%. CONCLUSION: Patients who attend a dedicated recurrent miscarriage clinic for investigation and treatment have a high live birth rate in a subsequent pregnancy. A subsequent pregnancy following recurrent pregnancy loss does not appear to be associated with an increased risk of adverse pregnancy outcomes.

Evaluation of the type and frequency of extemporaneous formulations dispensed in hospital and community pharmacies.

Background: Extemporaneous compounding is practiced globally by pharmacists to allow for dispensing of personalised doses of medicinal products not commercially available. Extemporaneous compounding must result in a product which is safe and effective. However, data on formulation and expiry of extemporaneous products may not be readily available. Pharmacists access various resources including compounding databases to obtain information on composition, preparation, and expiry of extemporaneous preparations. Objectives: The aim of this study was to evaluate the type and frequency of extemporaneous compounding in hospital and community pharmacies in the Republic of Ireland (ROI) and to obtain contemporary information on compounding practices and resources used. Methods: All community and hospital pharmacists registered with the Pharmaceutical Society of Ireland, were invited to participate in an on-line survey. The study was approved by the Royal College of Surgeons in Ireland (RCSI) research ethics committee. Results: A total of 202 pharmacists responded to the survey, of which 145 were community-based, 52 hospital-based, and 5 practicing in both. On average, hospital and community pharmacists (n = 138) dispensed <2-10 prescriptions for extemporaneous products per month. Pharmacists reported compounding 13 different types of extemporaneous preparations. Of these, dermatological preparations and oral liquid formulations (OLFs) were most commonly compounded. Extemp.ie, an Irish compounding database, was the most frequently used resource for compounding guidance and product expiry. Conclusions: The results of this study show that extemporaneous compounding is still practiced in hospital and community pharmacies in the ROI. The limited response of 4.6% obtained may reflect that extemporaneous compounding is concentrated in a relatively small number of pharmacies. There remains a clinical need for extemporaneous products in the ROI and extemporaneous compounding continues to be an invaluable skillset for pharmacists.

Second-trimester miscarriage: a review of postnatal investigations and subsequent pregnancy outcomes.

BACKGROUND: Second-trimester loss is pregnancy loss after the 12th and before the 24th completed weeks of pregnancy. This study aims to review cases of second-trimester miscarriage who attended a large maternity hospital and to examine pregnancy outcomes in this group of women. METHODS: This study is a review of cases of second-trimester miscarriage using descriptive, exploratory design, involving a retrospective chart review. RESULTS: In this study, 106 cases of second-trimester miscarriage were reviewed. The cause of the miscarriage was found in 42.5% (n = 45) of cases. The majority of women, 84.5% (n = 82) had a normal pelvic ultrasound scan and 18.3% (n = 17) of cases were diagnosed with antiphospholipid syndrome. In women who became pregnant again, 60.9% (n = 39) had a live birth. CONCLUSIONS: Establishing the cause of second-trimester miscarriage can be challenging, despite completing all recommended investigations. Outcomes in subsequent pregnancies are reassuring. This review highlights the need to undertake all recommended investigations to elicit the cause of second-trimester miscarriage and underpins the need for further research in this area.

Implementing Schwartz Rounds in an Irish maternity hospital.

BACKGROUND: Working in maternity hospital is usually a rewarding experience for staff. However, it can also be stressful and emotionally difficult work. Schwartz Rounds are a multidisciplinary forum which provides staff with an opportunity to reflect on the emotional impact of their work and support each other. AIMS: This paper will discuss the implementation of Schwartz Rounds in a maternity hospital and gives details of a pilot study to evaluate the initiative. METHODS: Schwartz Rounds were commenced in the hospital in September 2019, and an evaluation is in progress. A pilot study which evaluated 2 rounds has been completed. Staff who attended Schwartz Rounds were asked to complete an anonymous feedback form immediately following the Round. The data from feedback forms were analysed using descriptive statistics. RESULTS: Seventy-eight members of staff from almost all departments attended the rounds. Feedback forms were completed by 55 members of staff. Overall, the rounds were very positively evaluated by those who participated in the study. CONCLUSIONS: Schwartz Rounds are an effective way to support staff working in a maternity hospital.

A review of findings from placental histology in cases of stillbirth following the amendment to the Coroner's Act.

BACKGROUND: An amendment to the 1962 Coroner's Act in the Republic of Ireland mandated that all stillbirths and neonatal deaths were to be reported to the local coroner's office. In response to this, the bereavement team and department of anatomic pathology modified the pathway for placental examination following stillbirth and reporting deaths to the coroner. This paper is a review of the effect of this practice. METHODS: This study is a review of all cases of stillbirths for 9 months following the amendment of the Coroner's Act. A descriptive, exploratory design was used involving a retrospective chart review. RESULTS: Twenty-nine cases of stillbirth occurred during the study period. In cases where a placental examination was performed (n = 22), a cause of death was identified in the placenta or cord for seventeen (68%) of these cases. Seven cases had a consented autopsy with six cases confirming the initial diagnosis made at the time of gross placental examination. In one case, the cause of the stillbirth remained unexplained following placental examination and a full autopsy. No new information was gained from the autopsy in these seven cases. A further two cases had an autopsy directed by the coroner; the cause of death in these cases will be decided by the coroner. CONCLUSIONS: The introduction of the pathway has improved the care provided to bereaved parents by providing parents with timely information about the potential cause of stillbirth and thereby reduces the need for an autopsy examination.

Mental health difficulties among professional jockeys: a narrative review.

INTRODUCTION: Emerging academic literature and high-profile disclosures of mental health difficulties and mental illness from current and former professional jockeys suggest that further exploration of the mental health of jockeys is required. To date, a comprehensive review of jockeys' mental health has yet to be conducted. OBJECTIVES: To examine the existing literature related to jockeys' mental health, including the prevalence of symptoms associated with mental health difficulties and help-seeking. DESIGN: A narrative review of the literature was conducted with articles screened from inception until January 2021. RESULTS: Sixteen studies were included in the narrative review. Studies covered a range of mental health difficulties which included mood (depression), anxiety, distress, disordered eating and substance misuse. Rates of help-seeking among jockeys were also explored. Results indicated that jockeys reported higher levels of depressive and anxiety symptoms compared with other elite athletes. Substance misuse, in particular adverse alcohol use, also appears greater among jockeys than other elite athletes. Distress symptoms appear comparable with other elite athletes. Risk factors for mental health difficulties included injury, perceived stress, athlete burnout, career dissatisfaction and the contemplation of retirement. Weight-making negatively impacts jockeys' mood and attitudes towards eating, with lower competitive riding weights associated with more disordered eating attitudes. Moreover, help-seeking from mental health professionals appears low. CONCLUSION: The review identifies a high prevalence of symptoms of mental health difficulties among professional jockeys. Applied recommendations and future research considerations are proposed throughout the review article.

Racehorse Trainer Mental Health: Prevalence and Risk Factors.

Racehorse trainers play an important role within the horseracing industry. Despite this, scarce empirical information exists regarding the mental health of this population. Thus, the purpose of the present study was to explore the prevalence of symptoms related to common mental disorders (CMDs) and their associations with specific risk factors for CMD. Participants completed an anonymous online questionnaire. CMDs were assessed including distress, depression, generalized anxiety and adverse alcohol use. The risk factors examined included career dissatisfaction, social support and financial difficulties. 124 participants (28% response rate) completed the questionnaire. In total, 45% met the threshold indicative of at least one CMD. Specifically, prevalence of symptoms associated with depression (41%), adverse alcohol use (38%), psychological distress (26%), and generalized anxiety (18%) was observed. Career dissatisfaction (28%) and financial difficulties (64%) were identified. Career dissatisfaction, lower levels of social support and financial difficulties all increased the likelihood of trainers meeting the criteria for at least one of distress, depression or generalized anxiety. The study was the first to highlight prevalence rates of symptoms associated with CMDs among racehorse trainers in Ireland and identify certain risk factors which may increase the likelihood of racehorse trainers meeting the criteria for a CMD. Assessment of risk factors can aid early identification of CMDs among racehorse trainers. Such benefits may include early diagnosis or signposting to professional support. Further research is required in examining other occupational stressors experienced by trainers and the impact these may have on symptoms of CMDs.

Development of lower limb stiffness and its contribution to maximum vertical jumping power during adolescence.

Maximum power production during multi-joint tasks increases as children grow older. Previous research suggests that in adults, maximum power production in jumping is related to lower limb stiffness. In a developmental context, the question arises as to whether the relationship between maximum power production and lower limb stiffness is age-dependent. The purpose of this study was to investigate the relationship between lower limb stiffness and peak power production in adolescents (AD) and pre-adolescents (PA). With institutional approval, two groups of pre-adults (pre-adolescents: 11-13 years of age, N=43; adolescents: 16-18 years of age, N=30) performed 30 two-legged hops at their preferred frequency and three maximum counter-movement jumps. AD produced significantly greater peak power during the counter-movement jump than PA (t(71)=-5.28, P<0.001) even when body mass was accounted for. Lower limb stiffness was significantly correlated with peak power production during the counter-movement jump in AD (R=0.62, P<0.001) but not in PA (R=0.26, P=0.10). When normalised to body mass, the relationship between lower limb stiffness and peak power also differed between the two age groups (R=0.30, P=0.11 for AD and R=0.02, P=0.88 for PA). In addition, we found that during hopping, both PA and AD behaved like a simple spring-mass system. Our findings highlight the importance of lower limb stiffness in the context of muscular power production during multi-joint tasks. They let us speculate that during adolescence, children acquire the ability to take greater advantage of elastic energy storage in the musculotendinous system when performing maximum counter-movement jumps.

An audit of healthcare professionals' knowledge regarding perinatal autopsy.

BACKGROUND: Perinatal autopsy is one the most valuable investigations to ascertain the cause of death (Nijkamp et al., Seminars in Fetal & Neonatal Medicine. 22:167-175, 2017; Korteweg et al., AJOG 53, e1-12, 2012; Late Interuterine Death and Stillbirth' RCOG Green-top Guideline No.55, 2015). Discussions about perinatal autopsy can be difficult for parents and healthcare professionals. Perinatal staff need a good level of knowledge and understanding regarding perinatal autopsy in order to discuss the procedure with parents. This study aims to investigate healthcare professionals' knowledge regarding perinatal autopsy. METHODS: An audit conducted in a large teaching hospital using a questionnaire was developed and distributed to healthcare professionals in the hospital. RESULTS: Seventy healthcare professionals participated in the audit. Of those surveyed, 64% (n = 45) have discussed perinatal autopsy with a mother and the majority of healthcare professionals (67%) found this difficult. Self-reported levels of understanding were found to be low with just 10% reporting 'excellent understanding'. CONCLUSIONS: The results of this audit highlight the need for further education among all healthcare professionals working with bereaved families.

Bereavement care education and training in clinical practice: Supporting the development of confidence in student midwives.

AIMS: To improve the confidence in student Midwives to provide bereavement careto parents following pregnancy loss and perinatal death. BACKGROUND: The one-day interactive Educational Training Workshop in Bereavement Care (ETWBC) was developed for student midwives in their final year of their B.Sc. Midwifery Degree Programme and those completing a Higher Diploma in Midwifery to help improve their confidence to provide bereavement care in clinical practice. DESIGN: A longitudinal sequential mixed-methods design was used to evaluate the outcome and processes of participation in the Workshop. This paper reports on the outcome evaluation. METHODS: Participants completed the study questionnaires at all 3 time points: pre/post workshop and 3 month follow-up. Thirty nine of the 41 student midwives (Higher Diploma and 4th year B.Sc.) participated in the workshop. 97.44% (n = 38) of the participants completed all the questionnaires. RESULTS: Participation in the ETWBC increased student's midwives confidence (measured using knowledge and skills scales); Bereavement support skills [F(2,72) = 21.150, p < .000, partial eta squared = 0.370] and Bereavement support knowledge [F(1.6,60) = 48.460, p < .000, partial eta squared = 0.567]to provide bereavement care. Improvement in Student Midwives' level of self-awareness of the needs of bereaved parents [F(2,72 )= 20.311, p < .000, partial eta squared = 0.361] and of their own personal needs [F (1.7, 61) = 30.387, p < .000, partial eta squared = 0.458] in relation to providing bereavement support were also found. CONCLUSION: Participation in the Education Training Workshop on Bereavement Care helped increase student midwives confidence to provide bereavement care to grieving parents and to increase their self-awareness around their clinical practice in this area. The ETWBC is recommended as a brief effective educational intervention for inclusion in Midwifery curricula which could be modified for use with other relevant professional groups.

Constitutive degradation of IkappaBalpha in human T lymphocytes is mediated by calpain.

BACKGROUND: Activation-induced induction of transcription factor NFkappaB in T lymphocytes is regulated by its inhibitor IkappaBalpha. NFkappaB activation has been demonstrated to occur either by phosphorylation on serine residues 32 and 36 of the inhibitor, IkappaBalpha, followed by ubiquitination and degradation of the inhibitor by the 26S proteasome, or by a proteasome-independent mechanism involving tyrosine phosphorylation, but not degradation. However, the mechanism underlying constitutive regulation of the levels of the inhibitor, IkappaB, in primary human T lymphocytes, remains to be fully delineated. RESULTS: We demonstrate here, the involvement of a proteasome-independent pathway for constitutive regulation of IkappaBalpha levels in primary human T lymphocytes. Pretreatment with a cell permeable calpain inhibitor, E64D, but not with a proteasome specific inhibitor, lactacystin, blocks stimulus-independent IkappaBalpha degradation in primary human T cells. However, E64D pre-treatment fails to impact on IkappaBalpha levels following stimulation with either TNFalpha or pervanadate. Other isoforms of the inhibitor, IkappaBbeta, and IkappaBgamma, appear not to be subject to a similar ligand-independent regulation. Unlike the previously reported decline in ligand-induced degradation of IkappaBalpha in T cells from the elderly, constitutive degradation does not exhibit an age-associated decline, demonstrating proteasome-independent regulation of the activity. CONCLUSION: Our studies support a role for an E64D sensitive protease in regulating constitutive levels of IkappaBalpha in T cells, independent of the involvement of the 26S proteasome, and suggests a biological role for constitutive degradation of IkappaBalpha in T cells.

Redox-regulated pathway of tyrosine phosphorylation underlies NF-κB induction by an atypical pathway independent of the 26S proteasome.

Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of signaling events distinct from tyrosine phosphorylation of IκBα. To delineate roles for the ubiquitin-proteasome pathway in the phospho-tyrosine dependent mechanism of NF-κB induction, we employed the proteasome inhibitor, Aclacinomycin, and the phosphotyrosine phosphatase inhibitor, pervanadate (PV). Results from these studies demonstrate that phospho-IκBα (Tyr-42) is not subject to proteasomal degradation in a murine stromal epithelial cell line, confirming results previously reported. Correspondingly, proteasome inhibition had no discernable effect on the key signaling intermediaries, Src and ERK1/2, involved in the phospho-tyrosine mechanisms regulating PV-mediated activation of NF-κB. Consistent with previous reports, a significant redox imbalance leading to the activation of tyrosine kinases, as occurs with pervanadate, is required for the induction of NF-κB. Strikingly, our studies demonstrate that proteasome inhibition can potentiate oxidative stress associated with PV-stimulation without impacting kinase activation, however, other cellular implications for this increase in intracellular oxidation remain to be fully delineated.

Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.