Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Prevalence, diagnostic features, and medical outcomes of females with Turner syndrome with a trisomy X cell line (45,X/47,XXX): Results from the InsighTS Registry.

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly more likely to have structural renal anomalies (18% vs. 3%; p = 0.03). They were twice as likely to have congenital heart disease (32% vs. 15%, p = 0.08) and less likely to experience spontaneous menarche (46% vs. 75% of those over age 10, p = 0.06), although not statistically significant. Congenital anomalies, hypertension, and hearing loss were primarily attributable to a higher proportion of 45,X cells, while preserved ovarian function was most associated with a higher proportion of 46,XX cells. In this large TS cohort, 45,X/47,XXX was more common than previously reported, individuals were phenotypically less affected than those with 45,X, but did have trends for several more TS-related diagnoses than individuals with 45,X/46,XX.

Safety and feasibility of establishing an adjuvant hepatic artery infusion program.

BACKGROUND: Hepatic artery infusion (HAI) is less frequently used in the adjuvant setting for resectable colorectal liver metastasis (CRLM) due to concerns regarding toxicity. Our objective was to evaluate the safety and feasibility of establishing an adjuvant HAI program. METHODS: Patients who underwent HAI pump placement between January 2019 and February 2023 for CRLM were identified. Complications and HAI delivery were compared between patients who received HAI in the unresectable and adjuvant settings. RESULTS: Of 51 patients, 23 received HAI for unresectable CRLM and 28 in the adjuvant setting. Patients with unresectable CRLM more commonly had bilobar disease (n = 23/23 vs n = 18/28, p < 0.01) and more preoperative liver metastases (median 10 [IQR 6-15] vs 4 [IQR 3-7], p < 0.01). Biliary sclerosis was the most common complication (n = 2/23 vs n = 4/28); however, there were no differences in postoperative or HAI-specific complications. In the most recent two years, 0 patients in the unresectable group vs 2 patients in the adjuvant group developed biliary sclerosis. All patients were initiated on HAI with no difference in treatment times or dose reductions. CONCLUSION: Adjuvant HAI is safe and feasible for patients with resectable CRLM. HAI programs can carefully consider including patients with resectable CRLM if managed by an experienced multidisciplinary team with quality assurance controls in place.

Postoperative Packing of Perianal Abscess Cavities (PPAC2): randomized clinical trial.

BACKGROUND: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is less painful and if it is associated with adverse outcomes. METHODS: The Postoperative Packing of Perianal Abscess Cavities (PPAC2) trial was a multicentre, RCT (two-group parallel design) of adult participants admitted to an NHS hospital for incision and drainage of a primary perianal abscess. Participants were randomized 1:1 (via an online system) to receive continued postoperative wound packing or non-packing. Blinded data were collected via symptom diaries, telephone, and clinics over 6 months. The objective was to determine whether non-packing of perianal abscess cavities is less painful than packing, without an increase in perianal fistula or abscess recurrence. The primary outcome was pain (mean maximum pain score on a 100-point visual analogue scale). RESULTS: Between February 2018 and March 2020, 433 participants (mean age 42 years) were randomized across 50 sites. Two hundred and thirteen participants allocated to packing reported higher pain scores than 220 allocated to non-packing (38.2 versus 28.2, mean difference 9.9; P < 0.0001). The occurrence of fistula-in-ano was low in both groups: 32/213 (15 per cent) in the packing group and 24/220 (11 per cent) in the non-packing group (OR 0.69, 95 per cent c.i. 0.39 to 1.22; P = 0.20). The proportion of patients with abscess recurrence was also low: 13/223 (6 per cent) in the non-packing group and 7/213 (3 per cent) in the packing group (OR 1.85, 95 per cent c.i. 0.72 to 4.73; P = 0.20). CONCLUSION: Avoiding abscess cavity packing is less painful without a negative morbidity risk. REGISTRATION NUMBER: ISRCTN93273484 (https://www.isrctn.com/ISRCTN93273484). REGISTRATION NUMBER: NCT03315169 (http://clinicaltrials.gov).

Perianal abscess is a common, painful condition due to infection and swelling around the anus caused by blockage of the anal glands. The treatment of perianal abscess has stayed the same for over 50 years. An operation is performed under general anaesthetic to cut the skin and drain the infection. This is followed by continued internal dressing (packing) of the remaining cavity (hole) until the skin has healed over. Packing changes are needed multiple times a week for several weeks. Packing is the accepted treatment as it is believed to reduce the chance of the abscess coming back, and also reduces the chance of perianal fistula forming. There are no medical studies to support this idea. Perianal fistula (an abnormal passage between the skin around the anus, and the inside of the anal canal or rectum) is a long-term condition, which causes pain, and pus (and sometimes faeces) discharge, and often needs another operation (or multiple operations) to fix it. This trial was performed to demonstrate if no packing of a perianal abscess would result in a reduction of pain, with no increase in unwanted abscess recurrences and fistulas, in comparison to the standard treatment of packing. The trial recruited 433 people, who were randomly chosen to enter one of two groups; one to have their wound packed and the other to have no packing of the wound. After being discharged from hospital following surgery, the patients attended or were visited by a community nurse for the dressing to be changed or wound packed. Each patient provided information on pain from their wound, including worst pain each day and pain before, during, and after the changing of their dressing or packing. This and other information was gathered for the first 10 days after surgery and periodically until 6 months after surgery. The no-packing group experienced much less pain than the packing group. There was no difference in abscess recurrence and fistula formation between the non-packing and packing groups. The findings demonstrate that no packing of perianal abscess wounds after drainage operation is the best treatment.

Impact on blood loss and transfusion rates following administration of tranexamic acid in major oncological abdominal and pelvic surgery: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Major bleeding and receiving blood products in cancer surgery are associated with increased postoperative complications and worse outcomes. Tranexamic acid (TXA) reduces blood loss and improves outcomes in various surgical specialities. We performed a systematic review and meta-analysis to investigate TXA use on blood loss in elective abdominal and pelvic cancer surgery. METHODS: A literature search was performed for studies comparing intravenous TXA versus placebo/no TXA in patients undergoing major elective abdominal or pelvic cancer surgery. RESULTS: Twelve articles met the inclusion criteria, consisting of 723 patients who received TXA and 659 controls. Patients receiving TXA were less likely to receive a red blood cell (RBC) transfusion (p < 0.001, OR 0.4 95% CI [0.25, 0.63]) and experienced less blood loss (p < 0.001, MD -197.8 ml, 95% CI [-275.69, -119.84]). The TXA group experienced a smaller reduction in haemoglobin (p = 0.001, MD -0.45 mmol/L, 95% CI [-0.73, -0.18]). There was no difference in venous thromboembolism (VTE) rates (p = 0.95, OR 0.98, 95% CI [0.46, 2.08]). CONCLUSIONS: TXA use reduced blood loss and RBC transfusion requirements perioperatively, with no significant increased risk of VTE. However, further studies are required to assess its benefit for cancer surgery in some sub-specialities.

Frailty in Older Patients Undergoing Emergency Laparotomy: Results From the UK Observational Emergency Laparotomy and Frailty (ELF) Study.

OBJECTIVE: This study aimed to document the prevalence of frailty in older adults undergoing emergency laparotomy and to explore relationships between frailty and postoperative morbidity and mortality. SUMMARY BACKGROUND DATA: The majority of adults undergoing emergency laparotomy are older adults (≥65 y) that carry the highest mortality. Improved understanding is urgently needed to allow development of targeted interventions. METHODS: An observational multicenter (n=49) UK study was performed (March-June 2017). All older adults undergoing emergency laparotomy were included. Preoperative frailty score was calculated using the progressive Clinical Frailty Score (CFS): 1 (very fit) to 7 (severely frail). Primary outcome measures were the prevalence of frailty (CFS 5-7) and its association to mortality at 90 days postoperative. Secondary outcomes included 30-day mortality and morbidity, length of critical care, and overall hospital stay. RESULTS: A total of 937 older adults underwent emergency laparotomy: frailty was present in 20%. Ninety-day mortality was 19.5%. After age and sex adjustment, the risk of 90-day mortality was directly associated with frailty: CFS 5 adjusted odds ratio (aOR) 3.18 [95% confidence interval (CI), 1.24-8.14] and CFS 6/7 aOR 6·10 (95% CI, 2.26-16.45) compared with CFS 1. Similar associations were found for 30-day mortality. Increasing frailty was also associated with increased risk of complications, length of Intensive Care Unit, and overall hospital stay. CONCLUSIONS: A fifth of older adults undergoing emergency laparotomy are frail. The presence of frailty is associated with greater risks of postoperative mortality and morbidity and is independent of age. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.

Changes to care delivery at nine international pediatric diabetes clinics in response to the COVID-19 global pandemic.

BACKGROUND: Pediatric diabetes clinics around the world rapidly adapted care in response to COVID-19. We explored provider perceptions of care delivery adaptations and challenges for providers and patients across nine international pediatric diabetes clinics. METHODS: Providers in a quality improvement collaborative completed a questionnaire about clinic adaptations, including roles, care delivery methods, and provider and patient concerns and challenges. We employed a rapid analysis to identify main themes. RESULTS: Providers described adaptations within multiple domains of care delivery, including provider roles and workload, clinical encounter and team meeting format, care delivery platforms, self-management technology education, and patient-provider data sharing. Providers reported concerns about potential negative impacts on patients from COVID-19 and the clinical adaptations it required, including fears related to telemedicine efficacy, blood glucose and insulin pump/pen data sharing, and delayed care-seeking. Particular concern was expressed about already vulnerable patients. Simultaneously, providers reported 'silver linings' of adaptations that they perceived as having potential to inform care and self-management recommendations going forward, including time-saving clinic processes, telemedicine, lifestyle changes compelled by COVID-19, and improvements to family and clinic staff literacy around data sharing. CONCLUSIONS: Providers across diverse clinical settings reported care delivery adaptations in response to COVID-19-particularly telemedicine processes-created challenges and opportunities to improve care quality and patient health. To develop quality care during COVID-19, providers emphasized the importance of generating evidence about which in-person or telemedicine processes were most beneficial for specific care scenarios, and incorporating the unique care needs of the most vulnerable patients.

The financial impact of cancer care on renal cancer patients.

INTRODUCTION Advances in novel treatment options may render renal cell cancer (RCC) patients susceptible to the financial toxicity (FT) of cancer treatment, and the factors associated with FT are unknown. MATERIALS AND METHODS: Eligible patients were ≥ 18 years old and had a diagnosis of stage IV RCC for at least 3 months. Patients were recruited from Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre (Toronto, Canada). FT was assessed using the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-question survey scored from 0-44, with lower scores reflecting worse FT. Patient and treatment characteristics, out-of-pocket costs (OOP) and private insurance coverage (PIC) were collected. Factors associated with worse FT (COST score < 21) were determined. RESULTS: Sixty-five patients were approached and 80% agreed to participate (n = 52). The median age was 62 (44-88); 20% were female (n = 10); 43% were age ≥ 65 (n = 22); 63% were Caucasian (n = 31). Median COST score was 20.5 (3-44). Factors associated with worse FT were age < 65 (OR 9.5, p = 0.007), high OOP (OR 4.4, p = 0.04) and receiving treatment off clinical trial (in comparison to being on surveillance or on clinical trial) (OR 5.9, p = 0.03), when adjusting for other factors in multivariable logistic regression. However, there was no correlation between annual income or PIC and FT. CONCLUSION: Financial toxicity in the RCC population is more significant in younger patients and those on treatment outside of a clinical trial. Financial aid should be offered to these at-risk patients to optimize adherence to life prolonging RCC treatments.

Value assessment of oncology drugs using a weighted criterion-based approach.

BACKGROUND: Globally, the rising cost of anticancer therapy has motivated efforts to quantify the overall value of new cancer treatments. Multicriteria decision analysis offers a novel approach to incorporate multiple criteria and perspectives into value assessment. METHODS: The authors recruited a diverse, multistakeholder group who identified and weighted key criteria to establish the drug assessment framework (DAF). Construct validity assessed the degree to which DAF scores were associated with past pan-Canadian Oncology Drug Review (pCODR) funding recommendations and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS; version 1.1) scores. RESULTS: The final DAF included 10 criteria: overall survival, progression-free survival, response rate, quality of life, toxicity, unmet need, equity, feasibility, disease severity, and caregiver well-being. The first 5 clinical benefit criteria represent approximately 64% of the total weight. DAF scores ranged from 0 to 300, reflecting both the expected impact of the drug and the quality of supporting evidence. When the DAF was applied to the last 60 drugs (with reviewers blinded) reviewed by pCODR (2015-2018), those drugs with positive pCODR funding recommendations were found to have higher DAF scores compared with drugs not recommended (103 vs 63; Student t test P = .0007). DAF clinical benefit criteria mildly correlated with ESMO-MCBS scores (correlation coefficient, 0.33; 95% CI, 0.009-0.59). Sensitivity analyses that varied the criteria scores did not change the results. CONCLUSIONS: Using a structured and explicit approach, a criterion-based valuation framework was designed to provide a transparent and consistent method with which to value and prioritize cancer drugs to facilitate the delivery of affordable cancer care.

The influence of social media on recruitment to surgical trials.

BACKGROUND: Social media has changed the way surgeons communicate worldwide, particularly in dissemination of trial results. However, it is unclear if social media could be used in recruitment to surgical trials. This study aimed to investigate the influence of Twitter in promoting surgical recruitment in The Emergency Laparotomy and Frailty (ELF) Study. METHODS: The ELF Study was a UK-based, prospective, observational cohort that aimed to assess the influence of frailty on 90-day mortality in older adults undergoing emergency surgery. A power calculation required 500 patients to be recruited to detect a 10% change in mortality associated with frailty. A 12-week recruitment period was selected, calculated from information submitted by participating hospitals and the numbers of emergency surgeries performed in adults aged > 65 years. A Twitter handle was designed (@ELFStudy) with eye-catching logos to encourage enrolment and inform the public and clinicians involved in the study. Twitter Analytics and Twitonomy (Digonomy Pty Ltd) were used to analyse user engagement in relation to patient recruitment. RESULTS: After 90 days of data collection, 49 sites from Scotland, England and Wales recruited 952 consecutive patients undergoing emergency laparotomy, with data logged into a database created on REDCap. Target recruitment (n = 500) was achieved by week 11. A total of 591 tweets were published by @ELFStudy since its conception, making 218,136 impressions at time of writing. The number of impressions (number of times users see a particular tweet) prior to March 20th 2017 (study commencement date) was 23,335 (343.2 per tweet), compared to the recruitment period with 114,314 impressions (256.3 per tweet), ending June 20th 2017. Each additional tweet was associated with an increase in recruitment of 1.66 (95%CI 1.36 to 1.97; p < 0.001). CONCLUSION: The ELF Study over-recruited by nearly 100%, reaching over 200,000 people across the U.K. Branding enhanced tweet aesthetics and helped increase tweet engagement to stimulate discussion and healthy competition amongst clinicians to aid trial recruitment. Other studies may draw from the social media experiences of the ELF Study to optimise collaboration amongst researchers. TRIAL REGISTRATION: This study is registered online at www.clinicaltrials.gov (registration number NCT02952430 ) and has been approved by the National Health Service Research Ethics Committee.

RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1).

MOAP-1 is a pro-apoptotic tumor suppressor molecule with a growing set of known interacting partners. We have demonstrated that during death receptor-dependent apoptosis, MOAP-1 is recruited to TNF-R1 or TRAIL-R1, followed by RASSF1A and Bax association. MOAP-1/Bax association promotes Bax conformational change resulting in the translocation of Bax into the mitochondrial membrane, mitochondrial membrane insertion and dysregulation resulting in several hallmark events that execute apoptosis. Although a role in apoptosis is established, it is currently unknown how MOAP-1 is regulated and how it links to Bax to promote apoptosis. In this study, we demonstrate robust association with RACK1, a versatile scaffolding protein that responds to activation of protein kinase C. Furthermore, we can demonstrate that RACK1 functions to bring the E3 ligase, TRAF2, to MOAP-1 in order to undergo a K63-dependent ubiquitination. Furthermore, RACK1 associates with MOAP-1 via electrostatic associations similar to those observed between MOAP-1/RASSF1A and MOAP-1/TNF-R1. These events illustrate the complex nature of MOAP-1 regulation and characterizes the important role of the scaffolding protein, RACK1, in influencing MOAP-1 biology.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

Trauma informed public health nursing visits to parents and children.

Adverse Childhood Experiences (ACEs) research has demonstrated a strong correlation between a traumatic childhood and poor health and social status in adulthood. Maternal/child Public Health Nursing (PHN) home visiting teams frequently encounter families experiencing trauma, thus offering a unique opportunity to assist parents in recognizing the potential harm such stress may have for their child. The Sonoma County Field Nursing team developed a trauma-informed model utilizing ACEs education in a self-reflective approach with parents to increase family resilience and reduce the risk for future childhood trauma. This paper presents the supporting research used to develop the trauma-informed approach and describes the execution of the model by the Sonoma County Field Nursing team.

Comparison of Clostridium difficile minimum inhibitory concentrations obtained using agar dilution vs broth microdilution methods.

Due to increasing antibiotic resistance among anaerobic bacteria, routine antimicrobial susceptibility testing is recommended by the Clinical and Laboratory Standards Institute (CLSI). This study compared the minimum inhibitory concentrations (MICs) from 920 Clostridium difficile isolates tested against seven antimicrobial agents using the two current CLSI reference methodologies, agar dilution method, vs broth microdilution method. A subset of isolate testing was performed independently by two laboratories to evaluate reproducibility. A negative bias was noted for MICs generated from broth microdilution compared to agar dilution and the reproducibility was variable and drug dependent. Therefore, broth microdilution is not recommended as an alternative to agar dilution for C. difficile antimicrobial susceptibility testing.

A System Approach to Advanced Practice Clinician Standardization and High Reliability.

Advanced practice clinicians (APCs) are an integral part of the health care team. Opportunities exist within Advocate Health Care to standardize and optimize APC practice across the system. To enhance the role and talents of APCs, an approach to role definition and optimization of practice and a structured approach to orientation and evaluation are shared. Although in the early stages of development, definition and standardization of accountabilities in a framework to support system changes are transforming the practice of APCs.

Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-ß, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis.

Dissection of a novel autocrine signaling pathway via quantitative secretome and interactome mapping.

Epidermal homeostasis is a balancing act governed by a multitude of underlying regulatory events, and several growth factors and signaling pathways have been implicated in regulation of the balance between proliferation and differentiation in keratinocytes. We show here that the signal transducer/transcription factor FIZ1 (Flt3 interacting zinc finger protein-1) is a previously unknown player in this regulatory axis, promoting an increase in proliferation of HaCaT human immortalized keratinocytes that is driven by more rapid G1/S progression and mediated by activation of the MAP/ERK kinase pathway. Utilizing quantitative SILAC-based secretome analysis, we identified the insulin growth factor binding protein IGFBP3 as the key mediating factor, demonstrating that elevated FIZ1 levels promote increased IGFBP3 expression and secretion and a concurrent increased sensitivity to IGF1 signaling, while antibody-based neutralization of IGFBP3 abrogates the FIZ1-induced growth advantage. To identify underlying protein-protein interactions likely to govern these events, we mapped the interactome of FIZ1 and found eight novel binding partners that form complexes with the protein in the cytoplasm and nucleus. These include signal transduction and transcription factors and the cell cycle regulatory NDR (Nuclear Dbf2-related) kinases. Our results provide further insight into the complex balance of epidermal homeostasis and identify FIZ1 as a novel therapeutic target.

Physiological monitoring and analysis of a manned stratospheric balloon test program.

INTRODUCTION: The Red Bull Stratos Project consisted of incremental high altitude parachute jumps [maximum altitude 127,852 ft (38,969 m)] from a pressurized capsule suspended from a stratospheric helium-filled balloon. A physiological monitoring system was worn by the parachutist to provide operational medical and acceleration data and to record a unique set of data in a supersonic environment. METHODS: Various physiological parameters, including heart rate (HR), respiratory rate (RR), skin temperature, and triaxial acceleration, were collected during the ascent, high altitude float, free fall, and parachute opening and descent stages of multiple low- and high altitude jumps. Physiologic data were synchronized with global positioning system (GPS) and audiovisual data for a comprehensive understanding of the environmental stressors experienced. RESULTS: HR reached maximum during capsule egress and remained elevated throughout free fall and landing. RR reached its maximum during free fall. Temperature data were unreliable and did not provide useful results. The highest accelerations parameters were recorded during parachute opening and during landing. During each high altitude jump, immediately after capsule egress, the parachutist experienced a few seconds of microgravity during which some instability occurred. Control was regained as the parachutist entered denser atmosphere. DISCUSSION: The high altitude environment resulted in extremely high vertical speeds due to little air resistance in comparison to lower altitude jumps with similar equipment. The risk for tumbling was highest at initial step-off. Physiological responses included elevated HR and RR throughout critical phases of free fall. The monitoring unit performed well despite the austere environment and extreme human performance activities.

Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.