Now showing items 21-40 of 25679

    • Monitoring Diversity in Faculty Using Applicant Flow Data: Lessons Learned

      Rosal, Milagros C; Duncan, Marlina; Hirabayashi, Natasja; Person, Sharina (2023-04-12)
      We applaud Dr Adaugo Amobi’s commentary in this issue of Medical Care regarding physician workforce diversity, the importance of systems to track physician hiring practices in aggregate and over time, and the use of these data to inform efforts to improve workforce diversity.
    • Atypical Fragility Fractures due to Bony or Soft Tissue Phosphaturic Mesenchymal Tumors: A Report of Two Cases

      Clegg, Stephanie M; Eiel, Emily S; Fine, Sara; Gafni, Rachel I; Most, Mathew J (2023-04-12)
      Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder where patients present with hypophosphatemia, chronic diffuse bone pain, and occasionally fractures. Benign phosphaturic mesenchymal tumors (PMT) are responsible for the TIO and are largely soft tissue tumors. Cases: Two male patients with TIO secondary to PMT were reported-one in the bony scapula and the other in the plantar foot soft tissue. The first case describes a 63-year-old Caucasian male, who sustained an intertrochanteric proximal femur stress fracture and approximately two years of diffuse bone pain and hypophosphatemia. Wide excision of a left scapula boney lesion resulted in immediate resolution of his electrolyte abnormalities and bone pain. Case 2 describes a 58-year-old male with four years of multifocal bone pain and atraumatic fractures. A 68Ga-DOTATATE-positron emission tomography/computed tomography (PET/CT) scan identified a soft tissue tumor in his plantar foot, which was ultimately excised. He also experienced near immediate resolution of his pain and no additional fractures. Conclusion: TIO is a rare condition presenting with chronic multifocal bone pain, stress fractures, and hypophosphatemia. These two cases highlight that the causative tumor may originate in soft tissue or bone. Furthermore, a high index of suspicion, along with fibroblast growth factor-23 testing and DOTATATE-PET/CT localization, can help with diagnosis and minimize treatment delays.
    • Impact of coronavirus disease 2019 (COVID-19) vaccination on menstrual bleeding quantity: An observational cohort study

      Darney, Blair G; Boniface, Emily R; Van Lamsweerde, Agathe; Han, Leo; Matteson, Kristen A; Cameron, Sharon; Male, Victoria; Acuna, Juan; Benhar, Eleonora; Pearson, Jack T; et al. (2023-04-10)
      Objective: To assess whether coronavirus disease 2019 (COVID-19) vaccination impacts menstrual bleeding quantity. Design: Retrospective cohort. Setting: Five global regions. Population: Vaccinated and unvaccinated individuals with regular menstrual cycles using the digital fertility-awareness application Natural Cycles°. Methods: We used prospectively collected menstrual cycle data, multivariable longitudinal Poisson generalised estimating equation (GEE) models and multivariable multinomial logistic regression models to calculate the adjusted difference between vaccination groups. All regression models were adjusted for confounding factors. Main outcome measures: The mean number of heavy bleeding days (fewer, no change or more) and changes in bleeding quantity (less, no change or more) at three time points (first dose, second dose and post-exposure menses). Results: We included 9555 individuals (7401 vaccinated and 2154 unvaccinated). About two-thirds of individuals reported no change in the number of heavy bleeding days, regardless of vaccination status. After adjusting for confounding factors, there were no significant differences in the number of heavy bleeding days by vaccination status. A larger proportion of vaccinated individuals experienced an increase in total bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; adjusted difference 4.0%, 99.2% CI 0.7%-7.2%). This translates to an estimated 40 additional people per 1000 individuals with normal menstrual cycles who experience a greater total bleeding quantity following the first vaccine dose' suffice. Differences resolved in the cycle post-exposure. Conclusions: A small increase in the probability of greater total bleeding quantity occurred following the first COVID-19 vaccine dose, which resolved in the cycle after the post-vaccination cycle. The total number of heavy bleeding days did not differ by vaccination status. Our findings can reassure the public that any changes are small and transient.
    • Advancing Maternal Health Equity Among Migrant Communities

      Johnson-Agbakwu, Crista (2023-04-06)
      Crista Johnson-Agbakwu, MD, is the inaugural executive director of the new UMass Chan Medical School Collaborative in Health Equity. Dr. Johnson-Agbawku, professor of obstetrics & gynecology and population & quantitative health sciences, is an accomplished physician who has focused her career on reducing the disparities between social determinants of health and health care. This talk was planned in conjunction with the National Library of Medicine traveling exhibit, "Outside/Inside: Immigration, Migration, and Health Care in the United States," hosted at the UMass Chan Medical School Lamar Soutter Library March 13 - April 22, 2023.
    • Unmasked

      Chang, Chris (2023-04-06)
      Introduction: This week I share with you a post-pandemic reflection from Chris Chang, former Barre Family Health Center resident, who is now at the Austin Regional Clinic in Austin, Texas. He has written several times before for FMM. The reflection below explores how we return to "normal" after a tumultuous three years. Definitely, not easy. Chris wrote this to me: “After nearly exactly three years, our clinic today moved to optional masking for staff. It was a strange day filled with mixed emotions for me. I'm still working on wrapping my brain around it, and this is part of that process. It is a bookend to the poem "Heroics" that I wrote and sent in near the beginning of the pandemic. Many thanks for keeping the fire burning.”
    • The HHV-6B U20 Glycoprotein Inhibits NK Cell Responses By Binding ULBP1 And Blocking NKG2D Activation

      Weaver, Grant (2023-04-06)
      Many viruses impede host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Hosts will often counter this through NK cells that sense the absence of MHC-I and kill the infected cell. Human Herpesvirus 6B (HHV-6B) has also been shown to downregulate MHC-I but this does not result in NK-mediated elimination of the virus. Previous work has shown that HHV-6B downregulates three NK-activating stress ligands: MICB, ULBP1, and ULBP3. More recently, the U20 glycoprotein of HHV-6A was implicated in the downregulation of ULBP1 but the precise mechanism remains undetermined. We set out to better understand the role of HHV-6B U20 in modulating NK cell activity. We performed structural modeling studies that suggest that U20 is likely a viral nonclassical MHC (vMHC). These vMHCs are common tools used by herpesviruses to modulate host immune responses. Through in vitro studies with recombinant protein, we demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity (225nM). Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels (at the surface or in toto). Soluble U20 has the same effect and can also inhibit activation of ULBP1-stimulated primary NK cells. When taken together, these data suggest that U20 helps to downregulate NK cell activity by binding ULBP1, masking it from recognition by NKG2D at the surface of infected cells, resulting in a decrease in antiviral NK cell activation and killing.
    • Gliotransmission and adenosine signaling promote axon regeneration

      Wang, Fei; Ruppell, Kendra Takle; Zhou, Songlin; Qu, Yun; Gong, Jiaxin; Shang, Ye; Wu, Jinglin; Liu, Xin; Diao, Wenlin; Li, Yi; et al. (2023-04-06)
      How glia control axon regeneration remains incompletely understood. Here, we investigate glial regulation of regenerative ability differences of closely related Drosophila larval sensory neuron subtypes. Axotomy elicits Ca2+ signals in ensheathing glia, which activates regenerative neurons through the gliotransmitter adenosine and mounts axon regenerative programs. However, non-regenerative neurons do not respond to glial stimulation or adenosine. Such neuronal subtype-specific responses result from specific expressions of adenosine receptors in regenerative neurons. Disrupting gliotransmission impedes axon regeneration of regenerative neurons, and ectopic adenosine receptor expression in non-regenerative neurons suffices to activate regenerative programs and induce axon regeneration. Furthermore, stimulating gliotransmission or activating the mammalian ortholog of Drosophila adenosine receptors in retinal ganglion cells (RGCs) promotes axon regrowth after optic nerve crush in adult mice. Altogether, our findings demonstrate that gliotransmission orchestrates neuronal subtype-specific axon regeneration in Drosophila and suggest that targeting gliotransmission or adenosine signaling is a strategy for mammalian central nervous system repair.
    • Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study

      Men, Xiaoyu; Marshe, Victoria; Elsheikh, Samar S; Alexopoulos, George S; Marino, Patricia; Meyers, Barnett S; Mulsant, Benoit H; Rothschild, Anthony J; Voineskos, Aristotle N; Whyte, Ellen M; et al. (2023-04-04)
      Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18-85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer's disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.
    • Improved Performance of ChatGPT-4 on the OKAP Exam: A Comparative Study with ChatGPT-3.5 [preprint]

      Teebagy, Sean; Colwell, Lauren; Wood, Emma; Yaghy, Antonio; Faustina, Misha (2023-04-03)
      This study aims to evaluate the performance of ChatGPT-4, an advanced Artificial Intelligence (AI) language model, on the Ophthalmology Knowledge Assessment Program (OKAP) examination compared to its predecessor, ChatGPT-3.5. Both models were tested on 180 OKAP practice questions covering various ophthalmology subject categories. Results showed that ChatGPT-4 significantly outperformed ChatGPT-3.5 (81% vs. 57%; p<0.001), indicating improvements in medical knowledge assessment. The superior performance of ChatGPT-4 suggests potential applicability in ophthalmologic education and clinical decision support systems. Future research should focus on refining AI models, ensuring a balanced representation of fundamental and specialized knowledge, and determining the optimal method of integrating AI into medical education and practice.
    • UMCCTS Newsletter, April 2023

      UMass Center for Clinical and Translational Science (2023-04-03)
      This is the April 2023 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
    • Radiofrequency Ablation Provides Rapid and Durable Pain Relief for the Palliative Treatment of Lytic Bone Metastases Independent of Radiation Therapy: Final Results from the OsteoCool Tumor Ablation Post-Market Study

      Levy, Jason; David, Elizabeth; Hopkins, Thomas; Morris, Jonathan; Tran, Nam D; Farid, Hamed; Massari, Francesco; O'Connell, William G; Vogel, Alexander; Gangi, Afshin; et al. (2023-04-03)
      Purpose: The OsteoCool Tumor Ablation Post-Market Study (OPuS One) was a prospective, multi-national, single-arm study to investigate safety and effectiveness of radiofrequency ablation (RFA) for palliation of painful lytic bone metastases with 12 months of follow-up. RFA has demonstrated effective palliation of osseous metastases in small clinical studies with short-term follow-up; however, a long-term assessment with robust subject numbers is lacking. Materials and methods: Prospective assessments were conducted at Baseline, 3 days, 1 week, and 1, 3, 6, and 12-months. Pain and quality of life were measured prior to RFA and postoperatively using the Brief Pain Inventory, European Quality of Life-5 Dimension, and European Organization for Research and Treatment of Cancer Care Quality of Life Questionnaire for palliative care. Radiation, chemotherapy and opioid usage, and related adverse events were collected. Results: 206 subjects were treated with RFA at 15 institutions in OPuS One. Worst pain, average pain, pain interference and quality of life significantly improved at all visits starting 3 days post-RFA and sustained to 12 months (P < 0.0001). Post hoc analysis found neither systemic chemotherapy nor local radiation therapy at the index site of RFA influenced worst pain, average pain, or pain interference. Six subjects had device/procedure-related adverse events. Conclusion: RFA for lytic metastases provides rapid (within 3 days) and statistically significant pain and quality of life improvements with sustained long-term relief through 12 months and a high degree of safety, independent of radiation. Level of evidence: 2B, PROSPECTIVE, NON-RANDOMIZED, POST-MARKET STUDY: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors .
    • Challenges in Use of Practice-based Research Networks for a Medical Device Trial to Detect SARS-CoV-2

      Daly, Jeanette M; O'Connor, Laurel; Schmidt, Megan E; Ferrara, Laura K; Parang, Kim; Levy, Barcey T (2023-04-02)
      Introduction/objectives: Primary care practice-based research networks (PBRNs) participated in a point of care (POC) device study funded by by the National Institutes of Health and led by the University of Massachusetts Chan Medical School (UMass) to speed the development, validation, and commercialization of POC tests to detect SARS-CoV-2. The purposes of this study were to describe the characteristics of participating PBRNs and their respective collaborators in this device trial and describe complications challenging its execution. Methods: Semi-structured interviews were conducted with lead personnel from participating PBRNs and UMass. Results: Four PBRNs and UMass were invited to participate and 3 PBRNs and UMass participated. This device trial recruited 321 subjects in 6 months; 65 subjects from PBRNs. Each PBRN and the academic medical center site enrolled and recruited subjects differently. Main challenges identified were having adequate clinic personnel to enroll and aid in consent and questionnaire completion, frequently changing inclusion/exclusion criteria, use of the digital electronic data collection platform, and having access to a -80°C freezer to store supplies. Discussion: This trial involved numerous researchers, primary care clinic leaders and staff, and academic center sponsored program staff and attorneys resulting in a resource-intensive endeavor to enroll 65 subjects in the real-world clinical setting of primary care PBRNs with the academic medical center enrolling the rest. Multiple obstacles to standing up the study were encountered by the PBRNS. Conclusions: Primary care PBRNs rely largely on the goodwill established between academic health centers and participating practices. For future investigations involving device studies, collaborating PBRN leaders should assess whether recruitment criteria may change, obtain detailed lists of equipment needed, and/or know if the study is likely to be halted suddenly to appropriately prepare their member practices.
    • Experience with telemedicine in neuromuscular clinic during COVID-19 pandemic

      Ghasemi, Mehdi; Poulliot, Kristy; Daniello, Kate M; Silver, Brian (2023-03-31)
      Objectives: The aim of the present study was to evaluate the feasibility and acceptability of telehealth for the care of neuromuscular patients during the COVID-19 pandemic. Methods: Neuromuscular patients or their caregivers, as well as health care providers (HCPs), who completed a televisit during the pandemic received an online survey, assessing satisfaction with the visit, quality of care, and experience with the televisit interference. Results: Surveys from 46 neuromuscular patients (including 18 with motor neuron disease [MND])/caregivers and 7 HCPs were completed. Several aspects of televisits including good communication, adequate time to discuss concern, provision of equal care, and telemedicine interference were rated favorably among participants. Telehealth was strongly satisfactory in 30 (65.22%) and satisfactory in 15 (32.61%) neuromuscular patients/caregivers. In 18 MND patients, this was 10 (55.56%) and 7 (38.89%), respectively. Moreover, 24 (52.17%) neuromuscular patients/caregivers would strongly agree and 18 (39.13%) would agree to participate again in televisits. This was 10 (55.56%) and 4 (33.33%) for MND cases, respectively. Various medical issues were addressed during the televisits including medication management, ordering tests/referrals, discussion of goals of care, and research. The predictive stepwise logistic model found younger age as a predicting factor for higher satisfaction from, or participation again in, televisits in neuromuscular patients. Limb onset location was also a predicting factor for strong satisfaction from televisits in MND cases. Conclusions: Telemedicine is feasible and highly effective at achieving personalized care that was rated satisfactory by the majority of neuromuscular patients/caregivers and HCPs during the COVID-19 pandemic.
    • The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

      Rozowsky, Joel; Gao, Jiahao; Borsari, Beatrice; Yang, Yucheng T; Galeev, Timur; Gürsoy, Gamze; Epstein, Charles B; Xiong, Kun; Xu, Jinrui; Li, Tianxiao; et al. (2023-03-30)
      Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.
    • World Federation for Interventional Stroke Treatment (WIST) multispecialty training guidelines for endovascular stroke intervention

      Grunwald, Iris Q; Mathias, Klaus; Bertog, Stefan; Snyder, Kenneth V; Sievert, Horst; Siddiqui, Adnan; Musialek, Piotr; Hornung, Marius; Papanagiotou, Panagiotes; Comelli, Simone; et al. (2023-03-30)
      Introduction: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. Aim: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. Material and methods: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. Results: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. Conclusions: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. Summary: The World Federation for Interventional Stroke Treatment (WIST) establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in endovascular treatment (EVT). WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centers to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. Simultaneous publication: The WIST 2023 Guidelines are published simultaneously in Europe (Adv Interv Cardiol 2023, PMID 37090217).
    • I wish I could do more

      Daniel, Paul E (2023-03-30)
      Introduction: This week we hear from Paul Daniel, a hospitalist in our department, and someone who leads teams to provide care in Haiti. Through his reflection he shares with us a feeling that no doubt many readers will identify with. That feeling of questioning if you are doing enough. It becomes particularly true when you interact with patients that you may never see again. See what Dr. Daniel has to say about this.
    • Mechanism of Sliding Clamp Loading During DNA Replication and Repair in Atomic Detail

      Liu, Xingchen (2023-03-30)
      DNA replication is a fundamental process that is essential for all forms of life, and it is made efficient by ring-shaped sliding clamp proteins. One such protein is the eukaryotic sliding clamp, Proliferating Cellular Nuclear Antigen (PCNA), which not only facilitates replication but also coordinates multiple cellular pathways, such as DNA repair, cell cycle regulation, and apoptosis. The proper function of PCNA is critical for maintaining genome stability, making it a crucial factor in human health. The clamp loader complex is the primary regulator of sliding clamp activity. Replication Factor C (RFC), the eukaryotic clamp loader, is responsible for opening the closed PCNA and loading it onto DNA. However, the mechanism by which RFC accomplishes this task has been elusive for years. Our research has contributed to this field by revealing multiple cryo-electron microscopy (cryo-EM) structures of the RFC:PCNA complex that describe the steps involved in the clamp loading reaction. Specifically, we found that RFC opens PCNA with a 'crab-claw' motion, allowing it to preferentially bind to PCNA before DNA. Additionally, during replication, primer-template DNA, which is RFC's primary DNA substrate, directly binds to the central chamber of the complex. Our study also sheds light on the mechanism by which RFC performs its role in loading PCNA during DNA repair. When RFC binds to gapped or nicked DNA during DNA repair, it uses an additional DNA binding site, and both sites work together to melt the DNA strands with their 'separation pins.' This discovery provides the first structural insight into how RFC accomplishes its crucial functions in DNA replication and repair. Overall, our findings provide detailed atomic-level insights into how RFC efficiently loads PCNA onto different DNA substrates, advancing our understanding of this essential biological process.
    • The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action

      Fioredda, Francesca; Skokowa, Julia; Tamary, Hannah; Spanoudakis, Michail; Farruggia, Piero; Almeida, Antonio; Guardo, Daniela; Höglund, Petter; Newburger, Peter E; Palmblad, Jan; et al. (2023-03-30)
      Neutropenia, as an isolated blood cell deficiency, is a feature of a wide spectrum of acquired or congenital, benign or premalignant disorders with a predisposition to develop myelodysplastic neoplasms/acute myeloid leukemia that may arise at any age. In recent years, advances in diagnostic methodologies, particularly in the field of genomics, have revealed novel genes and mechanisms responsible for etiology and disease evolution and opened new perspectives for tailored treatment. Despite the research and diagnostic advances in the field, real world evidence, arising from international neutropenia patient registries and scientific networks, has shown that the diagnosis and management of neutropenic patients is mostly based on the physicians' experience and local practices. Therefore, experts participating in the European Network for the Innovative Diagnosis and Treatment of Chronic Neutropenias have collaborated under the auspices of the European Hematology Association to produce recommendations for the diagnosis and management of patients across the whole spectrum of chronic neutropenias. In the present article, we describe evidence- and consensus-based guidelines for the definition and classification, diagnosis, and follow-up of patients with chronic neutropenias including special entities such as pregnancy and the neonatal period. We particularly emphasize the importance of combining the clinical findings with classical and novel laboratory testing, and advanced germline and/or somatic mutational analyses, for the characterization, risk stratification, and monitoring of the entire spectrum of neutropenia patients. We believe that the wide clinical use of these practical recommendations will be particularly beneficial for patients, families, and treating physicians.
    • Sarcoid-Like Reaction Involving Bone Marrow in Patient on Immune Checkpoint Inhibitor Therapy

      Scotti, Marcello; McIntosh, Lacey J (2023-03-29)
      Clinically useful high-quality radiologic depiction relevant to radiologists' practice. Treatment-induced sarcoid-like reactions, due to T-cell mediated non-caseating granuloma formation, are increasingly encountered in the precision oncology era [1, 2]. Most commonly involved sites are the lungs and lymph nodes. Sarcoid-like reaction in bone marrow is rare, with fewer than 100 reported cases. On imaging, sarcoid-like reaction of bone marrow may mimic skeletal metastasis. Thus, it is important that radiologists be aware of this entity. Although imaging may suggest sarcoid-like reaction of bone marrow, definitive diagnosis requires biopsy.
    • Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT)

      Zhou, Jeffrey Y. (2023-03-29)
      The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines and pyroptotic cell death. Caspase-1 cleaves pro-IL-1b to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 (AIM2) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediate the dsDNA activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT) dependent RNA-intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKa that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT), and advances understanding of the immunostimulatory potential of this potent adjuvant.