A comparative cohort study of surgical approaches for adult spinal deformity at a minimum 2-year follow-up.

STUDY DESIGN: This study was a retrospective multi-center comparative cohort study. MATERIALS AND METHODS: A retrospective institutional database of operative adult spinal deformity patients was utilized. All fusions > 5 vertebral levels and including the sacrum/pelvis were eligible for inclusion. Revisions, 3 column osteotomies, and patients with < 2-year clinical follow-up were excluded. Patients were separated into 3 groups based on surgical approach: 1) posterior spinal fusion without interbody (PSF), 2) PSF with interbody (PSF-IB), and 3) anteroposterior (AP) fusion (anterior lumbar interbody fusion or lateral lumbar interbody fusion with posterior screw fixation). Intraoperative, radiographic, and clinical outcomes, as well as complications, were compared between groups with ANOVA and χ2 tests. RESULTS: One-hundred and thirty-eight patients were included for study (PSF, n = 37; PSF-IB, n = 44; AP, n = 57). Intraoperatively, estimated blood loss was similar between groups (p = 0.171). However, the AP group had longer operative times (547.5 min) compared to PSF (385.1) and PSF-IB (370.7) (p < 0.001). Additionally, fusion length was shorter in PSF-IB (11.4) compared to AP (13.6) and PSF (12.9) (p = 0.004). There were no differences between the groups in terms of change in alignment from preoperative to 2 years postoperative. There were no differences in clinical outcomes. While postoperative complications were largely similar between groups, operative complications were higher in the AP group (31.6%) compared to the PSF (5.4%) and PSF-IB (9.1) groups (p < 0.001). CONCLUSION: While there were differences in intraoperative outcomes (operative time and fusion length), there were no differences in postoperative clinical or radiographic outcomes. AP fusion was associated with a higher rate of operative complications.

Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Osteoimmunological Principles Adapted to Achieve Mechanically Superior Posterolateral Fusion in a New Zealand White Rabbit Model Using Antigen-Coated, Electrospun Beta-Tricalcium Phosphate.

Introduction Triggering the immune system via antigenic stimulation at the time of spinal fusion surgery may enhance bone morphogenesis and result in successful bony arthrodesis. We sought to demonstrate that bone morphogenesis could be enhanced via antigenic immunologic stimulation of a surgical fusion site. Methods New Zealand white rabbits underwent non-instrumented posterolateral fusion of L5-6 with implantation of either an immunologically activated graft (inert beta-tricalcium phosphate) or harvested autograft. Fusion was evaluated using plain radiographs, micro-computed tomography (CT), mechanical palpation, and biomechanical testing. The final evaluation was carried out at 12 weeks postoperatively. Results Eight rabbits received immunologically activated grafts; 10 received autografts and served as historical controls. Fusion rates were identical between groups (both 50%). Radiographs and micro CT of the fusion mass showed no significant difference between groups, and both showed good incorporation of the transverse processes into the fusion masses with radiographic evidence confirming trabeculation and bone remodeling. However, mechanical testing of the fusion sites showed superior fusion strength in the rabbits that received immunologically activated grafts, approaching a factor of two on flexion/extension, lateral bending, and axial rotation. Little to no graft material was appreciable in the non-fused antigen-treated specimens. Conclusions There is a long-standing need for a graft material that can replace autograft bone, due to the negative clinical consequences and financial costs pertaining to autologous bone harvesting. No allograft bone substitute to date has been able to reliably replicate the success of harvested autograft bone. This study suggests that immunological enhancement of inert beta-tricalcium phosphate can potentially be a substitute for allograft bone that can meet and even exceed the success of harvested autograft bone.

A mixed meal tolerance test predicts onset of type 2 diabetes in Southwestern Indigenous adults.

BACKGROUND/OBJECTIVE: To identify predictors of incident type 2 diabetes using a mixed meal tolerance test (MMTT). METHODS: Adult Indigenous Americans without diabetes (n = 501) from a longitudinal cohort underwent at baseline a 4-h MMTT, measures of body composition, an oral glucose tolerance test, an intravenous glucose tolerance test for acute insulin response (AIR), and a hyperinsulinemic-euglycemic clamp for insulin action (M). Plasma glucose responses from the MMTT were quantified by the total and incremental area under the curve (AUC/iAUC). RESULTS: At follow-up (median time 9.6 [inter-quartile range: 5.6-13.5] years), 169 participants were diagnosed with diabetes. Unadjusted Cox proportional hazards models, glucose AUC180-min (HR: 1.98, 95% CI: 1.67, 2.34, p < 0.0001), AUC240-min (HR: 1.93, 95% CI: 1.62, 2.31, p < 0.0001), and iAUC180-min (HR: 1.43, 95% CI: 1.20, 1.71, p < 0.0001) were associated with an increased risk of diabetes. After adjustment for covariates (age, sex, body fat percentage, M, AIR, Indigenous American heritage) in three subsequent models, AUC180-min (HR: 1.44, 95% CI: 1.10, 1.88, p = 0.007) and AUC240-min (HR: 1.41, 95% CI: 1.09, 1.84, p < 0.01) remained associated with increased risk of diabetes. CONCLUSIONS: Glucose responses to a mixed meal predicted the development of type 2 diabetes. This indicates that a mixed nutritional challenge provides important information on disease risk. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov identifier : NCT00340132, NCT00339482.

Assessment, management, and rehabilitation of traumatic peripheral nerve injuries for non-surgeons.

Electrodiagnostic evaluation is often requested for persons with peripheral nerve injuries and plays an important role in their diagnosis, prognosis, and management. Peripheral nerve injuries are common and can have devastating effects on patients' physical, psychological, and socioeconomic well-being; alongside surgeons, electrodiagnostic medicine specialists serve a central function in ensuring patients receive optimal treatment for these injuries. Surgical intervention-nerve grafting, nerve transfers, and tendon transfers-often plays a critical role in the management of these injuries and the restoration of patients' function. Increasingly, nerve transfers are becoming the standard of care for some types of peripheral nerve injury due to two significant advantages: first, they shorten the time to reinnervation of denervated muscles; and second, they confer greater specificity in directing motor and sensory axons toward their respective targets. As the indications for, and use of, nerve transfers expand, so too does the role of the electrodiagnostic medicine specialist in establishing or confirming the diagnosis, determining the injury's prognosis, recommending treatment, aiding in surgical planning, and supporting rehabilitation. Having a working knowledge of nerve and/or tendon transfer options allows the electrodiagnostic medicine specialist to not only arrive at the diagnosis and prognosticate, but also to clarify which nerves and/or muscles might be suitable donors, such as confirming whether the branch to supinator could be a nerve transfer donor to restore distal posterior interosseous nerve function. Moreover, post-operative testing can determine if nerve transfer reinnervation is occurring and progress patients' rehabilitation and/or direct surgeons to consider tendon transfers.

Mitochondrial antioxidants abate SARS-COV-2 pathology in mice.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.

Expanding chemistry through in vitro and in vivo biocatalysis.

Living systems contain a vast network of metabolic reactions, providing a wealth of enzymes and cells as potential biocatalysts for chemical processes. The properties of protein and cell biocatalysts-high selectivity, the ability to control reaction sequence and operation in environmentally benign conditions-offer approaches to produce molecules at high efficiency while lowering the cost and environmental impact of industrial chemistry. Furthermore, biocatalysis offers the opportunity to generate chemical structures and functions that may be inaccessible to chemical synthesis. Here we consider developments in enzymes, biosynthetic pathways and cellular engineering that enable their use in catalysis for new chemistry and beyond.

Canadian Cost-Effectiveness of Coronary Artery Calcium Screening Based on the Multi-Ethnic Study of Atherosclerosis.

Background: Cost-effectiveness of testing for coronary artery calcium (CAC) relative to other treatment strategies is not established in Canada. Objectives: The purpose of this study was to evaluate the cost-effectiveness of using CAC score-guided statin treatment compared with universal statin therapy among intermediate-risk, primary prevention patients eligible for statins. Methods: A state transition, microsimulation model used data from Canadian sources and the Multi-Ethnic Study of Atherosclerosis to simulate clinical and economic consequences of cardiovascular disease from a Canadian publicly funded health care system perspective. In the CAC score-guided treatment arm, statins were started when CAC ≥1. Outcome of interest was the incremental cost-effectiveness ratio at 5 and 10 years; an incremental cost-effectiveness ratio <$50,000 per quality-adjusted life year (QALY) gained was considered cost-effective. Sensitivity analyses examined uncertainty in model parameters. Results: Compared with universal statin treatment at 5 and 10 years, CAC score-guided statin treatment was projected to increase mean costs by $326 (95% CI: $325-$326) and $172 (95% CI: $169-$175), increase mean QALYs by 0.01 (95% CI: 0.01-0.01) and 0.02 (95% CI: 0.02-0.02), and cost $54,492 (95% CI: $52,342-$56,816) and $8,118 (95% CI: $7,968-$8,279) per QALY gained, respectively. The model was most sensitive to statin cost, CAC testing cost, adherence to statin monitoring, and disutility associated with daily statin use. At 5 years, CAC score-guided statin treatment was cost-effective when CAC test costs ranged from $80 to $160 in different scenarios. Conclusions: CAC score-guided statin initiation in comparison to universal statin treatment was borderline cost-neutral at 5 years and cost-effective at 10 years in statin-eligible Canadian patients at intermediate cardiovascular disease risk.

Restoring L4-S1 Lordosis Shape in Severe Sagittal Deformity: Impact of Correction Techniques on Alignment and Complication Profile.

BACKGROUND: Severe sagittal plane deformity with loss of L4-S1 lordosis is disabling and can be improved through various surgical techniques. However, data are limited on the differing ability of anterior lumbar interbody fusion (ALIF), pedicle subtraction osteotomy (PSO), and transforaminal lumbar interbody fusion (TLIF) to achieve alignment goals in severely malaligned patients. METHODS: Severe adult spinal deformity patients with preoperative PI-LL >20°, L4-S1 lordosis <30°, and full body radiographs and PROMs at baseline and 6-week postoperative visit were included. Patients were grouped into ALIF (1-2 level ALIF at L4-S1), PSO (L4/L5 PSO), and TLIF (1-2 level TLIF at L4-S1). Comparative analyses were performed on demographics, radiographic spinopelvic parameters, complications, and PROMs. RESULTS: Among the 96 included patients, 40 underwent ALIF, 27 underwent PSO, and 29 underwent TLIF. At baseline, cohorts had comparable age, sex, race, Edmonton frailty scores, and radiographic spinopelvic parameters (P > 0.05). However, PSO was performed more often in revision cases (P < 0.001). Following surgery, L4-S1 lordosis correction (P = 0.001) was comparable among ALIF and PSO patients and caudal lordotic apex migration (P = 0.044) was highest among ALIF patients. PSO patients had higher intraoperative estimated blood loss (P < 0.001) and motor deficits (P = 0.049), and in-hospital ICU admission (P = 0.022) and blood products given (P = 0.004), but were otherwise comparable in terms of length of stay, blood transfusion given, and postoperative admission to rehab. Likewise, 90-day postoperative complication profiles and 6-week PROMs were comparable as well. CONCLUSIONS: ALIF can restore L4-S1 sagittal alignment as powerfully as PSO, with fewer intraoperative and in-hospital complications. When feasible, ALIF is a suitable alternative to PSO and likely superior to TLIF for correcting L4-S1 lordosis among patients with severe sagittal malalignment.

Assessing human carcinogenicity risk of agrochemicals without the rodent cancer bioassay.

The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.

Critical Dialogue and Capacity-Building Projects Reduced Alcohol and Substance Use in a Randomized Clinical Trial Among Formerly Incarcerated Men.

Background: Rates of alcohol and/or substance use (ASU) among residents of predominantly Black and marginalized communities are similar to ASU rates in White communities. Yet ASU has worse consequences in predominantly Black and marginalized communities (e.g., higher incarceration). Objective: We randomized participants to one of 16 intervention conditions using a 24 full factorial design to optimize a multilevel intervention reducing ASU among 602 formerly incarcerated men with substance-use-disorders (SUD). Candidate intervention components included (1) critical dialogue (CD; six weekly 2-hour-long group sessions vs. no CD sessions), (2) Quality of Life Wheel (QLW; six weekly 1-hour-long group sessions vs. no QLW sessions), (3) capacity building projects (CBP; six weekly 1-hour-long group sessions vs. no CBP sessions), and (4) delivery by a trained peer versus licensed facilitators. Outcome was percentage of days in which participants used alcohol, cocaine, opioid, and/or cannabis in previous 30 days. Results: Intent-to-treat analysis did not meet a priori component selection criteria due to low intervention attendance. After controlling for intervention group attendance (percentage of sessions attended), peer-delivered CD and CBP produced statistically and clinically significant main and interaction effects in ASU over 5 months. Per the multiphase optimization strategy framework, we selected peer-delivered CD and CBP for inclusion as the optimized version of the intervention with a cost of US$1,380 per 10 individuals. No adverse intervention effects occurred. Conclusion: CD and CBP were identified as the only potentially effective intervention components. Future research will examine strategies to improve attendance and test the optimized intervention against standard of care in a randomized-controlled-trial.

Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice.

Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

Contemporary utilization of three-column osteotomy techniques in a prospective complex spinal deformity multicenter database: implications on full-body alignment and perioperative course.

BACKGROUND: Research has focused on the increased correction from a three-column osteotomy (3CO) during adult spinal deformity (ASD) surgery. However, an in-depth analysis on the performance of a 3CO in a cohort of complex spinal deformity cases has not been described. STUDY DESIGN/SETTING: This is a retrospective study on a prospectively enrolled, complex ASD database. PURPOSE: This study aimed to determine if three-column osteotomies demonstrate superior benefit in correction of complex sagittal deformity at the cost of increased perioperative complications. METHODS: Surgical complex adult spinal deformity patients were included and grouped into thoracolumbar 3COs compared to those who did not have a 3CO (No 3CO) (remaining cohort). Rigid deformity was defined as ΔLL less than 33% from standing to supine. Severe deformity was defined as global (SVA > 70 mm) or C7-PL > 70 mm, or lumbopelvic (PI-LL > 30°). Means comparison tests assessed correction by 3CO grade/location. Multivariate analysis controlling for baseline deformity evaluated outcomes up to six weeks compared to No 3CO. RESULTS: 648 patients were included (Mean age 61 ± 14.6 years, BMI 27.55 ± 5.8 kg/m2, levels fused: 12.6 ± 3.8). 126 underwent 3CO, a 20% higher usage than historical cohorts. 3COs were older, frail, and more likely to undergo revision (OR 5.2, 95% CI [2.6-10.6]; p < .001). 3COs were more likely to present with both severe global/lumbopelvic deformity (OR 4), 62.4% being rigid. 3COs had greater use of secondary rods (OR 4st) and incurred 4 times greater risk for: massive blood loss (> 3500 mL), longer LOS, SICU admission, perioperative wound and spine-related complications, and neurologic complications when performed below L3. 3COs had similar HRQL benefit, but higher perioperative opioid use. Mean segmental correction increased by grade (G3-21; G4-24; G5-27) and was 4 × greater than low-grade osteotomies, especially below L3 (OR 12). 3COs achieved 2 × greater spinopelvic correction. Higher grades properly distributed lordosis 50% of the time except L5. Pelvic compensation and non-response were relieved more often with increasing grade, with greater correction in all lower extremity parameters (p < .01). Due to the increased rate of complications, 3COs trended toward higher perioperative cost ($42,806 vs. $40,046, p = .086). CONCLUSION: Three-column osteotomy usage in contemporary complex spinal deformities is generally limited to more disabled individuals undergoing the most severe sagittal and coronal realignment procedures. While there is an increased perioperative cost and prolongation of length of stay with usage, these techniques represent the most powerful realignment techniques available with a dramatic impact on normalization at operative levels and reciprocal changes.

Differences in intratumor innate lymphoid cell composition between orthotopic and spontaneous pancreatic mouse models.

Pancreatic cancer remains an unmet medical need. Late diagnosis and the lack of efficient treatment significantly impact the prognosis of patients suffering from pancreatic cancer. Improving patient outcomes requires a deeper comprehension of the tumor ecosystem. To achieve this, a thorough exploration of the tumor microenvironment using pre-clinical models that accurately replicate human disease is imperative, particularly in understanding the dynamics of immune cell subsets. Surprisingly, the impact of model variations on the composition of the tumor microenvironment has been largely neglected. In this study, we introduce an orthotopic model of pancreatic ductal adenocarcinoma and a spontaneous model of insulinoma. Our findings reveal striking differences in the innate lymphoid cell infiltrate, highlighting the importance of considering model-specific influences when investigating the tumor microenvironment.

Space radiation damage rescued by inhibition of key spaceflight associated miRNAs.

Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage.

Acid accumulation is associated with metabolic alterations; higher energy, fat, and protein intake; and energy expenditure.

OBJECTIVE: The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24-h energy expenditure (EE). METHODS: Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m2. Measurements included body composition by dual-energy x-ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24-h EE in a whole-room indirect calorimeter. RESULTS: Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high-density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24-h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24-h EE was a partial mediator (40%), but the association remained significant (ß = 0.15; p < 0.0001). CONCLUSIONS: In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24-h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain.

Corneal injury repair and the potential involvement of ZEB1.

The cornea, consisting of three cellular and two non-cellular layers, is the outermost part of the eyeball and frequently injured by external physical, chemical, and microbial insults. The epithelial-to-mesenchymal transition (EMT) plays a crucial role in the repair of corneal injuries. Zinc finger E-box binding homeobox 1 (ZEB1), an important transcription factor involved in EMT, is expressed in the corneal tissues. It regulates cell activities like migration, transformation, and proliferation, and thereby affects tissue inflammation, fibrosis, tumor metastasis, and necrosis by mediating various major signaling pathways, including transforming growth factor (TGF)-ß. Dysfunction of ZEB1 would impair corneal tissue repair leading to epithelial healing delay, interstitial fibrosis, neovascularization, and squamous cell metaplasia. Understanding the mechanism underlying ZEB1 regulation of corneal injury repair will help us to formulate a therapeutic approach to enhance corneal injury repair.

RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL.

Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while pathogenic mtDNA mutations are observed in some cancer types, they are almost absent in others. We report here that the proofreading mutant DNA polymerase gamma ( PolG D256A ) induced a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC), and promoted the accumulation of defective mitochondria, which is responsible for decreased tumor cell proliferation and viability and increased cancer survival. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose. The glucose dependency sustained mitochondrial energetics but at the cost of a decreased NAD+/NADH ratio that inhibited de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of GSH and nucleotides, leading to impaired tumor growth that increased cancer survival. Unlike tumors with intact mitochondrial function, NSCLC with pathogenic mtDNA mutations were sensitive to dietary serine and glycine deprivation. Thus, mitochondrial function in NSCLC is required specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth, explaining why these cancers preserve functional mtDNA. In brief: High mtDNA mutation burden in non-small-cell lung cancer (NSCLC) leads to the accumulation of respiration-defective mitochondria and dependency on glucose and glycolytic metabolism. Defective respiratory metabolism causes a massive accumulation of cytosolic nicotinamide adenine dinucleotide + hydrogen (NADH), which impedes serine synthesis and, thereby, glutathione (GSH) and nucleotide synthesis, leading to impaired tumor growth and increased survival. Highlights: Proofreading mutations in Polymerase gamma led to a high burden of mitochondrial DNA mutations, promoting the accumulation of mitochondria with respiratory defects in NSCLC.Defective respiration led to reduced proliferation and viability of NSCLC cells increasing survival to cancer.Defective respiration caused glucose dependency to fuel elevated glycolysis.Altered glucose metabolism is associated with high NADH that limits serine synthesis, leading to impaired GSH and nucleotide production.Mitochondrial respiration defects sensitize NSCLC to dietary serine/glycine starvation, further increasing survival.