The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.

Collection of biospecimens from the inspiration4 mission establishes the standards for the space omics and medical atlas (SOMA).

The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from four crew members longitudinally before (Launch: L-92, L-44, L-3 days), during (Flight Day: FD1, FD2, FD3), and after (Return: R + 1, R + 45, R + 82, R + 194 days) spaceflight, spanning a total of 289 days across 2021-2022. The collection process included venous whole blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies. Venous whole blood was further processed to obtain aliquots of serum, plasma, extracellular vesicles and particles, and peripheral blood mononuclear cells. In total, 2,911 sample aliquots were shipped to our central lab at Weill Cornell Medicine for downstream assays and biobanking. This paper provides an overview of the extensive biospecimen collection and highlights their processing procedures and long-term biobanking techniques, facilitating future molecular tests and evaluations.As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can aid future human spaceflight and space biology experiments.

Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight.

Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a "spaceflight signature" of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Collection of Biospecimens from the Inspiration4 Mission Establishes the Standards for the Space Omics and Medical Atlas (SOMA).

The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from the crew at different stages of the mission, including before (L-92, L-44, L-3 days), during (FD1, FD2, FD3), and after (R+1, R+45, R+82, R+194 days) spaceflight, creating a longitudinal sample set. The collection process included samples such as venous blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies, which were processed to obtain aliquots of serum, plasma, extracellular vesicles, and peripheral blood mononuclear cells. All samples were then processed in clinical and research laboratories for optimal isolation and testing of DNA, RNA, proteins, metabolites, and other biomolecules. This paper describes the complete set of collected biospecimens, their processing steps, and long-term biobanking methods, which enable future molecular assays and testing. As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can also aid future experiments in human spaceflight and space biology.

Harmful by Design-a Qualitative Study of the Health Impacts of Immigration Detention.

BACKGROUND: The USA has the largest immigration detention system in the world with over 20,000 individuals imprisoned by Immigration and Customs Enforcement (ICE) daily. Numerous reports have documented human rights abuses in immigration detention, yet little is known about its health impacts. OBJECTIVE: To characterize how the US immigration detention system impacts health from the perspective of people who were recently detained by ICE. DESIGN: Qualitative study using anonymous, semi-structured phone interviews in English or Spanish conducted between July 2020 and February 2021. PARTICIPANTS: Adults who had been detained by ICE for at least 30 days in the New York City metropolitan area within the previous 2 years, and that were fluent in English and/or Spanish. APPROACH: We explored participants' health histories and experiences trying to meet physical and mental health needs while in detention and after release. We conducted a reflective thematic analysis using an inductive approach. KEY RESULTS: Of 16 participants, 13 identified as male; five as lesbian, gay, bisexual, or queer; and four as Black; they were from nine countries. Participants had spent a median of 20 years living in the USA and spent a median of 11 months in immigration detention. Four themes emerged from our analysis: (1) poor conditions and inhumane treatment, (2) a pervasive sense of injustice, (3) structural barriers limiting access to care, and (4) negative health impacts of immigration detention. CONCLUSIONS: The narratives illustrate how structural features of immigration detention erode health while creating barriers to accessing needed medical care. Clinicians caring for immigrant communities must be cognizant of these health impacts. Community-based alternatives to immigration detention should be prioritized to mitigate health harms.

Desarrollo de habilidades en salud ambiental en asentamientos humanos precarios de la zona de planificación territorial 2 de la parroquia rural Posorja, Guayaquil / Development of skills in environmental health in precarious human settlements in territorial planning zone 2 of the rural parish of Posorja, Guayaquil

Se estima que aproximadamente siete millones de personas mueren anualmente por la contaminación del aire ambiental y doméstico, debido a enfermedades no transmisibles, especialmente en zonas con servicios públicos precarios; además la infraestructura y condiciones de las viviendas o hacinamiento se han asociado a la aparición de enfermedades agudas y crónicas. En Ecuador, para el año 2010, se reportó más de 2,5 millones de personas en zonas de asentamientos irregulares con deficientes saneamiento ambiental. Se realizó un estudio experimental con la participación de 85 jefes de familia en las comunidades de La Unión, Nuestra señora de Lourdes, las Acacias y Brisa del mar, de la parroquia rural Posorja, del cantón Guayaquil, Ecuador, para evaluar el desarrollo de habilidades de saneamiento ambiental. Para ello, se identificaron los problemas y las prioridades en salud ambiental, posteriormente se implementó el plan de desarrollo de habilidades en salud ambiental. Se observó deficiencias en cuanto a la construcción de viviendas, acceso al agua potable, disposición de excretas y desechos sólidos. Además, posterior a las jornadas de capacitación hubo un incremento en las habilidades cognoscitivas y prácticas en salud ambiental, al comparar con las competencias previas, especialmente en aspectos relacionados con el abastecimiento de agua potable, disposición de residuos sólidos y control de fauna nociva. Se logró fortalecer el desarrollo de habilidades en saneamiento ambiental de los habitantes, lo que incide en el mejoramiento de la salud pública y calidad de vida de las comunidades en estudio(AU)

It is estimated that approximately seven million people die annually from environmental and domestic air pollution, due to non-communicable diseases, especially in areas with precarious public services; In addition, the infrastructure and conditions of the houses or overcrowding have been associated with the appearance of acute and chronic diseases. In Ecuador, for the year 2010, more than 2.5 million people were reported in areas of irregular settlements with deficient environmental sanitation. An experimental study was carried out with the participation of 85 heads of families in the communities of La Unión, Nuestra Señora de Lourdes, Las Acacias and Brisa del Mar, from the Posorja rural parish, from the Guayaquil canton, Ecuador, to evaluate the development of skills of environmental sanitation. In order to, environmental health problems and priorities were identified, and the environmental health skills development plan was subsequently implemented. Deficiencies were observed in terms of housing construction, access to drinking water, disposal of excreta and solid waste. In addition, after the training sessions, there was an increase in cognitive skills and practices in environmental health, when compared to previous skills, especially in aspects related to drinking water supply, solid waste disposal, and control of harmful fauna. It was possible to strengthen the development of skills in environmental sanitation of the inhabitants, which affects the improvement of public health and quality of life of the communities under study(AU)

Mapping the spatial variability of rainfall from a physiographic-based multilinear regression: model development and application to the Southwestern Iberian Peninsula.

A physiographic-based multilinear regression model supported by GIS was developed to estimate spatial rainfall variability in the Southwest Iberian Peninsula. The area study includes a wide diversity of landscape features and comprises four Portuguese regions and one Spanish province (totalizing 28,860 km2). The region suffers a very strong Mediterranean influence, with a major cleavage between winter and summer seasons. Thus, the analysis was carried out separately for the wet (October to March) and dry (April to September) semesters. From an initial set of 10 explanatory physiographic variables, five were selected to be used in the multilinear regression, as they allowed generating models by map algebra that fitted well with the last 40 years of monthly rainfall data records. These records were obtained from 163 weather stations, filtered from an initial set of 230 (142 stations in Portugal and 88 in Spain). The correlation between the physiographic-based multilinear regression model and a model obtained by interpolation from rainfall historical data showed to be good or very good in approximately 75% of the area under study. Results show that physiographic-based models can be effectively used to estimate rainfall where there is a lack of rain gauges, or to densify spatial resolution of rainfall between rain gauges.

Escáneres intraorales vs impresiones convencionales para diagnóstico y tratamiento odontológico / Intraoral scans vs. conventional impressions for dental diagnosis and treatment

Objetivo: Comparar métodos e identificar las ventajas y desventajas del flujo digital. Método: De tipo bibliográfica documental, mediante una búsqueda de artículos en bases de datos como: PubMed. Resultados: Fueron seleccionados 27 ya que contenían la información necesaria para cumplir con el objetivo principal de esta revisión. Conclusión: la toma de impresión todavía se considera que es incómodo para el paciente provocando en muchos desde nauseas hasta dificultad para respirar y atragantamientos, creando malas experiencias que generan desconfianza en el paciente cuando se encuentra en el ambiente odontológico, mientras que el escáner generalmente no origina este tipo de problemas.

Objective: To compare methods and identify the advantages and disadvantages of digital flow. Method: Bibliographic documentary type, by means of a search of articles in databases such as: PubMed. Results: 27 were selected as they contained the necessary information to fulfill the main objective of this review. Conclusion: Impression taking is still considered to be uncomfortable for the patient causing in many from nausea to difficulty breathing and choking, creating bad experiences that generate mistrust in the patient when in the dental environment, while the scanner generally does not originate this type of problems.

Tratamiento ortopédico funcional y mecánico para la corrección de la clase II esqueletal / Functional and mechanical orthopedic treatment for the correction of skeletal class II

Objetivo: Analizar las distintas alternativas de tratamiento basadas en Ortopedia Funcional y Mecánica, su efecto a nivel esqueletal, sus beneficios. Método: Revisión bibliográfica. Resultados: Se seleccionaron 15 artículos de un universo de 45, por cuanto eran los que tenían relación directa con el tema de investigación. Conclusión: Se ha logrado identificar las distintas alternativas de tratamiento con ortopedia funcional o mecánica que se pueden utilizar para el tratamiento de la Clase II esqueletal, corroboradas con resultados que evidencian Su efectividad tanto en los cambios craneofaciales, de tejidos blandos y dentales obtenidos al final de la terapéutica, los autores recomiendan la correcta evaluación de los pacientes, antes de determinar la aparatología a utilizar así cómo aprovechar los estadios tempranos de maduración y crecimiento para que los cambios en el patrón esqueletal sean más representativos, efectivos y alcancen el objetivo de mejorar la relación maxilo-mandibular.

Objective: To analyze the different treatment alternatives based on Functional and Mechanical Orthopedics, their effect at skeletal level, their benefits. Method: Bibliographic review. Results: 15 articles were selected from a universe of 45, as they were those directly related to the research topic. Conclusions: We have been able to identify the different treatment alternatives with functional or mechanical orthopedics that can be used for the treatment of skeletal Class II, corroborated with results that show their effectiveness in craniofacial, soft tissue and dental changes obtained at the end of the therapy, the authors recommend the correct evaluation of the patients before determining the appliances to be used, as well as taking advantage of the early stages of maturation and growth so that the changes in the skeletal pattern are more representative, effective and achieve the objective of improving the maxillomandibular relationship.

El conocimiento del Kichwa, segunda lengua oficial del Ecuador ¿compromete la comunicación médico/odontólogo-paciente? / Knowledge of the Kichwa, second official language of Ecuador, compromises the dentist/medical-patient communication?

Con el propósito de analizar el comportamiento de las relaciones entre médico/odontólogo y paciente, mediadas por la comunicación intercultural, se realizó un estudio que contó con la participación de 200 indígenas de la etnia Kichwa Salasaka y 33 profesionales sanitarios. Mediante la aplicación de encuestas fueron explorados elementos esenciales como los idiomas que ambos grupos dominan; asistencia a consulta de los indígenas; calidad de la atención; formación bilingüe del odontólogo y percepción de la comprensión por parte de ambos grupos. Entre los resultados obtenidos se encuentra la no comprensión de los pacientes de las orientaciones que reciben en la consulta, insuficiente conocimiento la lengua Kichwa por parte del equipo de salud y en consecuencia insuficiente transferencia de la información. Identificada la problemática comunicacional médico/odontólogo - paciente, se recomienda la implementación de políticas de salud sustentadas en el enfoque intercultural(AU)

With the purpose of analyzing the behavior of the medical/dentist-patient relations, mediated by the intercultural communication, a study was carried out that counted on the participation of 70 indigenous people of the ethnic Kichwa Salasaca and 33 doctors and dentist. Through the application of surveys, essential elements were explored such as the languages that both groups dominate; assistance to indigenous consultation; Quality of care; Bilingual training of the dentist and perception of the understanding on the part of both groups. Among the results obtained is the non-comprehension of the patients of the orientations they receive in the consultation, insufficient knowledge the Kichwa language by the health team and consequently insufficient transfer of the information. Identified the communicational problems medical/entist-patient, we recommend the implementation of health policies based on the intercultural approach(AU)

The periplasmic component of the DctPQM TRAP-transporter is part of the DctS/DctR sensory pathway in Rhodobacter sphaeroides.

Rhodobacter sphaeroides can use C4-dicarboxylic acids to grow heterotrophically or photoheterotropically, and it was previously demonstrated in Rhodobacter capsulatus that the DctPQM transporter system is essential to support growth using these organic acids under heterotrophic but not under photoheterotrophic conditions. In this work we show that in R. sphaeroides this transporter system is essential for photoheterotrophic and heterotrophic growth, when C4-dicarboxylic acids are used as a carbon source. We also found that over-expression of dctPQM is detrimental for photoheterotrophic growth in the presence of succinic acid in the culture medium. In agreement with this, we observed a reduction of the dctPQM promoter activity in cells growing under these conditions, indicating that the amount of DctPQM needs to be reduced under photoheterotrophic growth. It has been reported that the two-component system DctS and DctR activates the expression of dctPQM. Our results demonstrate that in the absence of DctR, dctPQM is still expressed albeit at a low level. In this work, we have found that the periplasmic component of the transporter system, DctP, has a role in both transport and in signalling the DctS/DctR two-component system.

The effectiveness of a longitudinal ultrasound curriculum for general pediatricians working in a Puerto Rican emergency department: a pilot study.

BACKGROUND: The Hospital Pediatrico Universitario (HOPU) is the principal institution in Puerto Rico offering medical services to the children of the island and the Caribbean. There is limited use of point-of-care ultrasound (PoCUS) in their emergency department (ED) and obtaining an ultrasound through radiology is prohibitively time consuming. The objective of this study is to increase PoCUS knowledge and comfort by the ED physicians in the HOPU pediatric emergency department. RESULTS: Thirteen general pediatricians completed the entire PoCUS course, but only 10 completed both the pre- and post-tests and therefore included in the analysis (N = 10). Pretest scores ranged from 30 to 63.3% with a mean of 41.6% [standard deviation (SD) 9.95]. The posttest scores ranged from 55 to 96%, with a mean of 66.1% (SD 12.26). The mean difference in scores was 24.42% (95% confidence interval 17.9, 30.9) with a significance of p < 0.05 and range of 8.3-36.6%. Physician experience and confidence with each topic improved from baseline. After the course, the majority of the participants (> 70%) had at least some confidence in 5 of the 6 topics. CONCLUSIONS: In EDs with limited resources, a longitudinal PoCUS educational curriculum is effective in improving the knowledge and comfort of physicians with limited PoCUS experience. The effectiveness of scheduled, repeated courses to refresh and refocus participants was highlighted following the unexpected challenges encountered during the course, including multiple natural disasters.

Analyzing Circulating Tumor Cells One at a Time.

Whole-genome sequencing has made a significant impact on cancer research, but traditional bulk methods fail to detect information from rare cells. Recently developed single-cell sequencing methods have provided new insights and unprecedented details about cancer progression and diversity. These advancements also enable the investigation of rare cells, such as circulating tumor cells (CTCs) derived from cancer patients. In this review, we outline various single-cell sequencing techniques that can elucidate the molecular properties of CTCs. In addition, we explain the drawbacks that need to be overcome for each method.

Pilot study of population-based newborn screening for spinal muscular atrophy in New York state.

PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1.5%. We identified one newborn with a homozygous SMN1 deletion and two copies of SMN2, which strongly suggests the severe type 1 SMA phenotype. The infant was enrolled in the NURTURE clinical trial and was first treated with Spinraza at age 15 days. She is now age 12 months, meeting all developmental milestones, and free of any respiratory issues.ConclusionOur pilot study demonstrates the feasibility of population-based screening, the acceptance by families, and the benefit of newborn screening for SMA. We suggest that SMA be considered for addition to the national recommended uniform screening panel.

An examination of the factors influencing mercury and methylmercury particulate distributions, methylation and demethylation rates in laboratory-generated marine snow.

In the marine environment, settling particulates have been widely studied for their role as effective vertical transporters of nutrients and metals scavenged from the euphotic zone to the benthos. These particulates are composed of transparent exopolymers, plankton and bacterial cells, detritus and organic matter, and form various size fractions from colloids (<0.2µm) to aggregates, and finally marine snow (>300 µm). As marine snow forms in the water column, anoxic layers form around and within the aggregation potentially creating a prime environment for the methylation of mercury (Hg), which occurs primarily in low oxygen environments. To examine this process, marine aggregates were produced from sieved estuarine seawater (100 µm) in 1-L glass bottles spiked with stable isotope enriched methylmercury (CH3199Hg) and inorganic mercury (200Hg(II)) at 18° C using a roller-table. After the rolling period, different particle-size fractions were collected and analyzed, including: visible marine snow (>300µm), particulates 8 to 300 µm, and particulates 0.2 to 8µm. Particulate analysis indicated higher incorporation of both forms of Hg into marine snow compared to unrolled treatments, with greater incorporation of 200Hg(II) than CH3199Hg. In addition, inorganic Hg was methylated and CH3Hg was demethylated in the larger particulate fractions (>8µm). Methylation and demethylation rates were assessed based on changes in isotopic composition of Hg(II) and CH3Hg, and found to be comparable to methylation rates found in sediments. These results indicate that net Hg methylation can occur in marine snow and smaller aggregates in oxic coastal waters, and that this net formation of CH3Hg may be an important source of CH3Hg in both coastal and open ocean surface environments.

MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma.

The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL.