Case Western Reserve University
  • Cleveland, Ohio, United States
Recent publications
Parabacteroides distasonis (Pdis) is the type species for the new Parabacteroides genus, and a gut commensal of the Bacteroidetes phylum. Emerging reports (primarily based on reference strain/ATCC-8503) concerningly propose that long-known opportunistic pathogen Pdis is a probiotic. We posit there is an urgent need to characterize the pathogenicity of Pdis strain-strain variability. Unfortunately, no methods/insights exist to classify Bacteroidetes for this purpose. Herein, we developed a virulence gene-based classification system for Pdis and Bacteroidetes to facilitate pathogenic-vs-probiotic characterization. We used DNA in silico methods to develop a system based on the virulence (lipopolysaccharide/bacterial wall) 'rfbA O-antigen-synthesis gene'. We then performed phylogenetic analysis of rfbA from fourteen Pdis complete genomes (21 genes), other Parabacteroides, Bacteroidetes, and Enterobacteriaceae; and proposed a PCR-based Restriction-Fragment Length Polymorphism method. Cluster analysis revealed that Pdis can be classified into four lineages (based on gene gaps/insertions) which we designated rfbA-Types I, II, III, and IV. In context, we found 14 additional rfbA-types (I-XVIII) interspersed with numerous Bacteroidetes and pathogenic Enterobacteriaceae forming three major "rfbA-superclusters." For laboratory rfbA-Typing implementation, we developed a PCR-primer strategy to amplify Pdis rfbA genes (100%-specificity) to conduct MboII-RFLP and sub-classify Pdis. In-silico primers for other Bacteroidetes are proposed/discussed. Comparative analysis of lipopolysaccharide/lipid-A gene lpxK confirmed rfbA as highly discriminant. In conclusion, rfbA-Typing classifies Bacteroidetes/Pdis into unique clusters/superclusters given rfbA copy/sequence variability. Analysis revealed that most pathogenic Pdis strains are single-copy rfbA-Type I . The relevance of the rfbA strain variability in disease might depend on their hypothetical modulatory interactions with other O-antigens/lipopolysaccharides and TLR4 lipopolysaccharide-receptors in human/animal cells.
Spirometry is necessary to diagnose chronic obstructive pulmonary disease (COPD), yet a large proportion of patients are diagnosed and treated without having received testing. This study explored whether the effects of interventions using the electronic health record (EHR) to target patients diagnosed with COPD without confirmatory spirometry impacted the incidence rates of spirometry referrals and completions. This retrospective before and after study assessed the impact of provider-facing clinical decision support that identified patients who had a diagnosis of COPD but had not received spirometry. Spirometry referrals, completions, and results were ascertained 1.5 years prior to and 1.5 years after the interventions were initiated. Inhaler prescriptions by class were also tallied. There were 10,949 unique patients with a diagnosis of COPD who were eligible for inclusion. 4,895 patients (44.7%) were excluded because they had completed spirometry prior to the cohort start dates. The pre-intervention cohort consisted of 2,622 patients, while the post-intervention cohort had 3,392. Spirometry referral rates pre-intervention were 20.2% compared to 31.6% post-intervention (p < 0.001). Spirometry completion rates rose from 13.2% pre-intervention to 19.3% afterwards (p < 0.001). 61.7% (585 of 948) had no evidence of airflow obstruction. After excluding patients with a diagnosis of asthma, 25.8% (126 of 488) patients who had no evidence of airflow obstruction had prescriptions for long-acting bronchodilators or inhaled steroids. A concerted EHR intervention modestly increased spirometry referral and completion rates in patients with a diagnosis of COPD without prior spirometry and decreased misclassification of disease.
Modulation of commensal gut microbiota is increasingly recognized as a promising strategy to reduce mortality in patients with malignant diseases, but monitoring for dysbiosis is generally not routine clinical practice due to equipment, expertise and funding required for sequencing analysis. A low-threshold alternative is microbial diversity profiling by single-cell flow cytometry (FCM), which we compared to 16S rRNA sequencing in human fecal samples and employed to characterize longitudinal changes in the microbiome composition of patients with aggressive B-cell non-Hodgkin lymphoma undergoing chemoimmunotherapy. Diversity measures obtained from both methods were correlated and captured identical trends in microbial community structures, finding no difference in patients' pretreatment alpha or beta diversity compared to healthy controls and a significant and progressive loss of alpha diversity during chemoimmunotherapy. Our results highlight the potential of FCM-based microbiome profiling as a reliable and accessible diagnostic tool that can provide novel insights into cancer therapy-associated dysbiosis dynamics.
Background Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia. Results In this study, blood samples were obtained from well-suppressed ART-experienced HIV-1 patients monitored in Uganda (n = 62) or the U.S. (n = 50), with plasma HIV-1 loads < 50 copies/ml and CD4 ⁺ T-cell counts > 300 cells/ml. The peripheral HIV-1 reservoir, i.e., cell-associated HIV-1 RNA and proviral DNA, was characterized using our novel deep sequencing-based EDITS assay. Ugandan patients were slightly younger (median age 43 vs 49 years) and had slightly lower CD4 ⁺ counts (508 vs 772 cells/ml) than U.S. individuals. All Ugandan patients were infected with non-B HIV-1 subtypes (31% A1, 64% D, or 5% C), while all U.S. individuals were infected with subtype B viruses. Unexpectedly, we observed a significantly larger peripheral inducible HIV-1 reservoir in U.S. patients compared to Ugandan individuals (48 vs. 11 cell equivalents/million cells, p < 0.0001). This divergence in reservoir size was verified measuring proviral DNA (206 vs. 88 cell equivalents/million cells, p < 0.0001). However, the peripheral HIV-1 reservoir was more diverse in Ugandan than in U.S. individuals (8.6 vs. 4.7 p-distance, p < 0.0001). Conclusions The smaller, but more diverse, peripheral HIV-1 reservoir in Ugandan patients might be associated with viral (e.g., non-B subtype with higher cytopathicity) and/or host (e.g., higher incidence of co-infections or co-morbidities leading to less clonal expansion) factors. This highlights the need to understand reservoir dynamics in diverse populations as part of ongoing efforts to find a functional cure for HIV-1 infection in LMICs.
Background: Significant aortic regurgitation (AR) leads to left ventricular (LV) remodeling; however, little data exist regarding sex-based differences in LV remodeling in this setting. We sought to compare LV remodeling and AR severity, assessed by echocardiography and cardiovascular magnetic resonance (CMR), to discern sex-based differences. Methods: Patients with ≥ moderate chronic AR by echocardiography who underwent CMR within 90 days between December 2005 and October 2015 were included. Nonlinear regression models were built to assess the effect of AR regurgitant fraction (RF) on LV remodeling. A generalized linear model and Bland Altman analyses were constructed to evaluate differences between CMR and echocardiography. Referral for surgical intervention based on symptoms and LV remodeling was evaluated. Results: Of the 243 patients (48.3 ± 16.6 years, 58 (24%) female), 119 (49%) underwent surgical intervention with a primary indication of severe AR, 97 (82%) men, 22 (18%) women. Significant sex differences in LV remodeling emerged on CMR. Women demonstrated significantly smaller LV end-diastolic volume index (LVEDVI) (96.8 ml/m2 vs 125.6 ml/m2, p < 0.001), LV end-systolic volume index (LVESVI) (41.1 vs 54.5 ml/m2, p < 0.001), blunted LV dilation in the setting of increasing AR severity (LVEDVI p value < 0.001, LVESVI p value 0.011), and LV length indexed (8.32 vs 9.69 cm, p < 0.001). On Bland Altman analysis, a significant interaction with sex and LV diameters was evident, demonstrating a significant increase in the difference between CMR and echocardiography measurements as the LV enlarged in women: LVEDVI (p = 0.006), LVESVI (p < 0.001), such that echocardiographic measurements increasingly underestimated LV diameters in women as the LV enlarged. LV length was higher for males with a linear effect from RF (p < 0.001), with LV length increasing at a higher rate with increasing RF for males compared to females (two-way interaction with sex p = 0.005). Sphericity volume index was higher for men after adjusting for a relative wall thickness (p = 0.033). Conclusions: CMR assessment of chronic AR revealed significant sex differences in LV remodeling and significant echocardiographic underestimation of LV dilation, particularly in women. Defining optimal sex-based CMR thresholds for surgical referral should be further developed. Trial registration: NA.
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, has been associated with organ-specific cancers and autism spectrum disorder (ASD) and/or developmental delay (DD). Predicting precise clinical phenotypes in any one PHTS individual remains impossible. We conducted an untargeted metabolomics study on an age- and sex-matched series of PHTS individuals with ASD/DD, cancer, or both phenotypes. Using agnostic metabolomic-analyses from patient-derived lymphoblastoid cells and their spent media, we found 52 differentially abundant individual metabolites, 69 cell/media metabolite ratios, and 327 pair-wise metabotype (shared metabolic phenotype) ratios clearly distinguishing PHTS individuals based on phenotype. Network analysis based on significant metabolites pointed to hubs converging on PTEN-related insulin, MAPK, AMPK, and mTOR signaling cascades. Internal cross-validation of significant metabolites showed optimal overall accuracy in distinguishing PHTS individuals with ASD/DD versus those with cancer. Such metabolomic markers may enable more accurate risk predictions and prevention in individual PHTS patients at highest risk.
Background Resistance to standard therapy is a major reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Developing novel therapy to overcome PDAC drug-resistance is urgently needed. CRABP-II was highly expressed in all PDAC but not expressed in normal pancreatic tissues and chronic pancreatitis. CRABP-II was shown to promote PDAC migration and metastasis while its potential role in promoting PDAC drug-resistance was not known. Methods A paired cohort of human primary and relapsing PDAC tissues was assessed for CRABP-II expression by immunohistochemistry. CRISPR/cas9 gene editing was used to establish CRABP-II knockout cell lines and MTT assays were performed to assess gemcitabine sensitivity in vitro. Cleaved caspase-3/PARP blots and Annexin V staining were conducted to detect cell apoptosis. Gene expression microarray, Q-PCR, western blots, Co-IP and RNA-IP were used to study the molecular function of CRABP-II. Sucrose gradient ultracentrifugation was applied to isolate lipid rafts and LC–MS-MS was used to assess cholesterol content. Both subcutaneous CDX models and orthotopic PDX models were established to examine the efficacy of SNIPER-11 and the synergistic effect between SNIPER-11 and gemcitabine in vivo. Results A higher expression of CRABP-II was found in relapsing PDAC tissue and was associated with poor prognosis. Gemcitabine-resistant cell lines exhibited increased level of CRABP-II, while CRABP-II knockout resensitized PDAC cells to gemcitabine. Mechanistically, aberrant expression of CRABP-II increased the stability of SREBP-1c mRNA through cooperation with HuR and upregulated the downstream genes of SREBP-1c to favor cholesterol uptake and accumulation in lipid rafts. Increased lipid raft cholesterol accumulation facilitated ATK survival signaling and PDAC drug resistance. The small compound SNIPER-11 treatment effectively induced CRABP-II protein degradation, induced apoptosis, and suppressed tumor growth. Combination of SNIPER-11 and gemcitabine significantly reduced the lipid raft cholesterol content in CDX/PDX and profoundly inhibited tumor progression. Conclusions These findings identified CRABP-II as a novel regulator of cholesterol metabolism and suggested that CRABP-II is a selective target for overcoming PDAC drug resistance.
Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
Background The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. Results Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridial es . Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. Conclusions The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption.
Background The implementation of the Sustainable Development Goals (SDGs) requires much planning and the provision of resources, especially regarding the necessary investments, technologies and infrastructures needed. Yet, it is presently unclear how available these elements are, what gaps exist, what changes have taken place in terms of their availability since the adoption of the SDGs and what their requirements will be in the future. The knowledge gap has become even more concerning because of the impact of the COVID-19 pandemic. Using a bibliometric analysis, an assessment of the global progress of SDG implementation and requirements, identifying challenges through the development of a matrix, and a set of 11 case studies to triangulate the holistic analysis, an assessment of the global progress of the SDGs implementation and the impact of the COVID-19 pandemic on this process was carried out. Results The findings suggest that the scope and width of resources limitation are currently undermining the implementation of the SDGs. Apart from the fact that the pace of progress has been insufficient, the potential of the SDGs in pursuing sustainability and improving life quality is not fully realised. This trend suggests that a substantial acceleration of the efforts is needed, especially for the five SDGs whose progress since 2015 has not been optimal, namely SDG2, SDG11, SDG13, SDG15, and SDG16, while SDG3, SDG7, SDG9, SDG14, and SDG17 show signs of progress. The case studies showed that different industries have dissimilar effects on achieving the SDGs, with the food sector correlating with 15 SDGs, as opposed to the energy sector correlating with 6 SDGs. Accordingly, the priority level assessment in terms of achieving the SDGs, points to the need to further advance the above-mentioned five SDGs, i.e., 2, 11, 13, 15 and 16. Conclusions This study fills in a knowledge gap in respect of the current need for and availability of investments, new technologies, and infrastructures to allow countries to pursue the SDGs. It is suggested that this availability is rather limited in specific contexts. In respect of the needs to be addressed, these include resource-related constraints, limited technologies and infrastructures, affecting SDG2, SDG11, SDG13, SDG15, and SDG16, whose progress needs to be enhanced. Since the global progress in the process of implementation of the SDGs depends directly and indirectly on addressing the resource gaps, it is suggested that this topic be further investigated, so that the present imbalances in the three dimensions of sustainable development: the economic, social and environmental, be adequately addressed.
Introduction: Cauda equina syndrome (CES) is most caused by lumbar disc herniation, and the associated treatment involves prompt surgical decompression. Rarer causes of CES include perineural (Tarlov) cysts. Clinical presentation: A 62-year-old female with history of rheumatoid arthritis, hip and knee replacements, and chronic low back pain presented with worsening back pain, left leg weakness and pain for 6 weeks, and bowel/bladder incontinence with diminished sensation in the perianal region for 24 h prior to presentation. MRI demonstrated severe spinal stenosis at L4-S1, central disc herniation at L5-S1, and compression of the cauda equina, consistent with CES. A lumbar decompression was performed. Patient did well at 2-week follow up, but presented 5 weeks post-discharge with increased left leg pain/weakness and genitalia anesthesia. Imaging was unremarkable. Two months later, the patient presented with diminished sensation in the buttocks and bilateral lower extremities and bowel/bladder incontinence. Imaging demonstrated a large cystic presacral mass with involvement of the left sciatic foramen and S3 neural foramen. A team of plastic, orthopedic, and neurological surgeons performed an S3 sacral laminectomy, foraminotomy, partial sacrectomy, and S3 rhizotomy, and excision of the large left hemorrhagic pudendal mass. Final pathology demonstrated a perineural cyst with organizing hemorrhage. On follow-up, the patient's pain and weakness improved. Conclusion: CES-like symptoms were initially attributed to a herniated disk. However, lumbar decompression did not resolve symptoms, prompting further radiographic evaluation at two separate presentations. This represents the first reported case of a pudendal tumor causing symptoms initially attributed to a herniated disc.
Introduction The American Medical Association recently declared homicides of transgender individuals an epidemic. However, transgender homicide victims are often classified as nontransgender. Our objective was to describe existing data and coding of trans (i.e., transgender) victims and to examine the risk factors for homicides of trans people relative to nontrans people across the United States. Methods A retrospective review of the Centers for Disease Control and Prevention’s National Violent Death Reporting System for the years 2003-2018 identified victims defined as transgender either through the “transgender” variable or narrative reports. Fisher’s exact tests and logistic regression models were run to compare the demographics of trans victims to those not identified as trans. Results Of the 147 transgender victims identified, 14.4% were incorrectly coded as nontrans despite clear indication of trans status in the narrative description, and 6% were coded as hate crimes. Relative to nontrans victims, trans victims were more frequently Black (54.4% versus 40.7%, P = 0.001), had a mental health condition (26.5% versus 11.3%, P < 0.001), or reported being a sex worker (9.5% versus 0.2%, P < 0.001). There were disproportionately few homicides of transgender people in the South (13.6% of trans victims versus 29.1% of nontrans victims, P < 0.001). Conversely, the West and Midwest accounted for a higher-than-expected proportion of trans victims relative to nontrans victims (23.1% of trans victims versus 16.2% of nontrans victims, P = 0.03; 24.5% of trans victims versus 16.8% of nontrans victims, P = 0.02, respectively). Conclusions Though the murder of transgender individuals is a known public health crisis, inconsistencies still exist in the assessment and reporting of transgender status. Further, these individuals were more likely to have multiple distinct vulnerabilities. These findings provide important information for injury and violence prevention researchers to improve reporting of transgender status in the medical record and local trauma registries.
Background Inadequate housing contributes to the risk of family separation in nearly one-quarter of child maltreatment investigations. Child welfare struggles to identify and address the demand for housing assistance. A range of housing interventions shows promise for stabilizing families. Still, aid remains difficult to access, and little evidence exists for prioritizing households to interventions. Inefficient decisions about who to serve with scarce housing resources threaten to diminish resources and unintentionally place children at greater risk. Objective The present study leverages computational modeling to simulate the complex dynamics of coordinated child welfare response to inadequate housing. Simulations address the lack of microdata on current service delivery to inform policy-making that protects children from family insecurity. Participants and settings A series of simulated policy experiments test strategies for maximizing access to appropriate housing assistance and minimizing system-wide family separations using US estimates of housing insecurity and child welfare involvement. Models incorporate the feedback loops involved in seeking and waiting for needed services, using information on national rates of housing insecurity among child welfare-involved families. Results Results demonstrate population-level improvements in family stability from enhanced targeting of housing assistance to families most likely to benefit, plus expanded access to housing interventions. Neither improved screening procedures nor more housing supports alone improve child welfare outcomes. Conclusions Findings emphasize the importance of data-driven upstream policies for protecting inadequately housed children at risk of maltreatment.
Whiskers of some animals, such as rats and cats, can actively sense stimuli from their surrounding environment. Such a capability is attractive for intelligent mobile robots. However, an artificial whisker with similar abilities has not been fully developed so that the robots acquire their surrounding environment information in an active approach such as rats. In this paper, we propose a new bioinspired active whisking tactile sensor (MAWS) capable of sensing the distance, shape, size, and orientation ofcaves and environmental conditions. Two orthogonally distributed linear Hall sensors are mounted beneath a circular permanent magnet for spatial localization of the whisker. The whisker is then actuated and controlled by an array of nine electromagnetic coils by tuning the excitation current and phase sequence. Conical pendulum and bidirectional sweeping strategies were designed tomimic the simultaneous perception behavior of rats. A reactive obstacle avoidance experiment was also conducted to evaluate the performance of the proposed MAWS installed on a mobile robot.
Hemangiopericytomas account for less than 1% of all intracranial tumors. In 2016, World Health Organization (WHO) unified the two terms into a single medical condition known as solitary fibrous tumor/hemangiopericytoma (SFT/HPC). Our patient is an 80-year-old woman with a past medical history of sick sinus syndrome status post pacemaker placement. She presented to the emergency department with progressive headaches for one month duration. Her headaches worsened at night, waking her up from sleep. They also increased in intensity by bending forward. Review of systems was significant for bilateral lower extremity weakness accompanied by difficulty walking. The motor exam was remarkable for right upper and right lower extremity 3/5 weakness. The gait was ataxic. A Computed tomography scan of the head without contrast revealed a large dural-based right parietal hyperdense mass with surrounding edema, mass effect, and compression of the right lateral ventricle atrium. A right-to-left midline shift was also noted. Given the fact that our patient had a pacemaker, she was not a candidate for a brain MRI. Neurosurgery successfully resected the mass. Histopathological studies confirmed WHO grade III anaplastic solitary fibrous tumor/hemangiopericytoma. The patient was discharged on adjuvant radiation with imaging surveillance given the grade and the extent of resection. This case highlights a rare type of intracranial mass that resembles meningioma on imaging studies. It also illustrates that solitary fibrous tumor/hemangiopericytoma should be kept as a differential diagnosis for brain masses, given its aggressive nature, and its potential of metastasis and recurrence.
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Muhammad Noman Hasan
  • Department of Mechanical and Aerospace Engineering
Rehan Khan
  • Department of Pathology (University Hospitals Case Medical Center)
Anant Madabhushi
  • Department of Biomedical Engineering
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10900 Euclid Avenue, 44106, Cleveland, Ohio, United States
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Barbara R. Snyder
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http://www.case.edu
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216-368-2000