Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.

LKB1 signaling and patient survival outcomes in hepatocellular carcinoma.

The liver is a major organ that is involved in essential biological functions such as digestion, nutrient storage, and detoxification. Furthermore, it is one of the most metabolically active organs with active roles in regulating carbohydrate, protein, and lipid metabolism. Hepatocellular carcinoma is a cancer of the liver that is associated in settings of chronic inflammation such as viral hepatitis, repeated toxin exposure, and fatty liver disease. Furthermore, liver cancer is the most common cause of death associated with cirrhosis and is the 3rd leading cause of global cancer deaths. LKB1 signaling has been demonstrated to play a role in regulating cellular metabolism under normal and nutrient deficient conditions. Furthermore, LKB1 signaling has been found to be involved in many cancers with most reports identifying LKB1 to have a tumor suppressive role. In this review, we use the KMPlotter database to correlate RNA levels of LKB1 signaling genes and hepatocellular carcinoma patient survival outcomes with the hopes of identifying potential biomarkers clinical usage. Based on our results STRADß, CAB39L, AMPKα, MARK2, SIK1, SIK2, BRSK1, BRSK2, and SNRK expression has a statistically significant impact on patient survival.

Robust Arm Impedocardiography Signal Quality Enhancement Using Recursive Signal Averaging and Multi-Stage Wavelet Denoising Methods for Long-Term Cardiac Contractility Monitoring Armbands.

Impedance cardiography (ICG) is a low-cost, non-invasive technique that enables the clinical assessment of haemodynamic parameters, such as cardiac output and stroke volume (SV). Conventional ICG recordings are taken from the patient's thorax. However, access to ICG vital signs from the upper-arm brachial artery (as an associated surrogate) can enable user-convenient wearable armband sensor devices to provide an attractive option for gathering ICG trend-based indicators of general health, which offers particular advantages in ambulatory long-term monitoring settings. This study considered the upper arm ICG and control Thorax-ICG recordings data from 15 healthy subject cases. A prefiltering stage included a third-order Savitzky-Golay finite impulse response (FIR) filter, which was applied to the raw ICG signals. Then, a multi-stage wavelet-based denoising strategy on a beat-by-beat (BbyB) basis, which was supported by a recursive signal-averaging optimal thresholding adaptation algorithm for Arm-ICG signals, was investigated for robust signal quality enhancement. The performance of the BbyB ICG denoising was evaluated for each case using a 700 ms frame centred on the heartbeat ICG pulse. This frame was extracted from a 600-beat ensemble signal-averaged ICG and was used as the noiseless signal reference vector (gold standard frame). Furthermore, in each subject case, enhanced Arm-ICG and Thorax-ICG above a threshold of correlation of 0.95 with the noiseless vector enabled the analysis of beat inclusion rate (BIR%), yielding an average of 80.9% for Arm-ICG and 100% for Thorax-ICG, and BbyB values of the ICG waveform feature metrics A, B, C and VET accuracy and precision, yielding respective error rates (ER%) of 0.83%, 11.1%, 3.99% and 5.2% for Arm-IG, and 0.41%, 3.82%, 1.66% and 1.25% for Thorax-ICG, respectively. Hence, the functional relationship between ICG metrics within and between the arm and thorax recording modes could be characterised and the linear regression (Arm-ICG vs. Thorax-ICG) trends could be analysed. Overall, it was found in this study that recursive averaging, set with a 36 ICG beats buffer size, was the best Arm-ICG BbyB denoising process, with an average of less than 3.3% in the Arm-ICG time metrics error rate. It was also found that the arm SV versus thorax SV had a linear regression coefficient of determination (R2) of 0.84.

Variation in genome content and predatory phenotypes between Bdellovibrio sp. NC01 isolated from soil and B. bacteriovorus type strain HD100.

Defining phenotypic and associated genotypic variation among Bdellovibrio may further our understanding of how this genus attacks and kills different Gram-negative bacteria. We isolated Bdellovibrio sp. NC01 from soil. Analysis of 16S rRNA gene sequences and average amino acid identity showed that NC01 belongs to a different species than the type species bacteriovorus. By clustering amino acid sequences from completely sequenced Bdellovibrio and comparing the resulting orthologue groups to a previously published analysis, we defined a 'core genome' of 778 protein-coding genes and identified four protein-coding genes that appeared to be missing only in NC01. To determine how horizontal gene transfer (HGT) may have impacted NC01 genome evolution, we performed genome-wide comparisons of Bdellovibrio nucleotide sequences, which indicated that eight NC01 genomic regions were likely acquired by HGT. To investigate how genome variation may impact predation, we compared protein-coding gene content between NC01 and the B. bacteriovorus type strain HD100, focusing on genes implicated as important in successful killing of prey. Of these, NC01 is missing ten genes that may play roles in lytic activity during predation. Compared to HD100, NC01 kills fewer tested prey strains and kills Escherichia coli ML35 less efficiently. NC01 causes a smaller log reduction in ML35, after which the prey population recovers and the NC01 population decreases. In addition, NC01 forms turbid plaques on lawns of E. coli ML35, in contrast to clear plaques formed by HD100. Linking phenotypic variation in interactions between Bdellovibrio and Gram-negative bacteria with underlying Bdellovibrio genome variation is valuable for understanding the ecological significance of predatory bacteria and evaluating their effectiveness in clinical applications.

Obesity and leptin in breast cancer angiogenesis.

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.

Obesity-associated epigenetic alterations and the obesity-breast cancer axis.

Both breast cancer and obesity can regulate epigenetic changes or be regulated by epigenetic changes. Due to the well-established link between obesity and an increased risk of developing breast cancer, understanding how obesity-mediated epigenetic changes affect breast cancer pathogenesis is critical. Researchers have described how obesity and breast cancer modulate the epigenome individually and synergistically. In this review, the epigenetic alterations that occur in obesity, including DNA methylation, histone, and chromatin modification, accelerated epigenetic age, carcinogenesis, metastasis, and tumor microenvironment modulation, are discussed. Delineating the relationship between obesity and epigenetic regulation is vital to furthering our understanding of breast cancer pathogenesis.

A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity.

Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated a comprehensive cell atlas of 55 neuroblastoma patient tumors, collected from two pediatric cancer institutions, spanning a range of clinical, genetic, and histologic features. Our atlas combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, and two spatial proteomic methods. Sc/snRNA-seq revealed three malignant cell states with features of sympathoadrenal lineage development. All of the neuroblastomas had malignant cells that resembled sympathoblasts and the more differentiated adrenergic cells. A subset of tumors had malignant cells in a mesenchymal cell state with molecular features of Schwann cell precursors. DNA methylation profiles defined four groupings of patients, which differ in the degree of malignant cell heterogeneity and clinical outcomes. Using spatial proteomics, we found that neuroblastomas are spatially compartmentalized, with malignant tumor cells sequestered away from immune cells. Finally, we identify spatially restricted signaling patterns in immune cells from spatial transcriptomics. To facilitate the visualization and analysis of our atlas as a resource for further research in neuroblastoma, single cell, and spatial-omics, all data are shared through the Human Tumor Atlas Network Data Commons at www.humantumoratlas.org.

Safe endovascular retrieval of a vena cava filter after duodenal perforation.

The use of vena cava filters (VCF) is a common procedure utilized in the prevention of pulmonary embolism (PE), yet VCFs have some significant and known complications, such as strut penetration and migration. Deep vein thrombosis (DVT) and PE remain a major cause of morbidity and mortality in the United States. It is estimated that as many as 900,000 individuals are affected by these each year with estimates suggesting that nearly 60,000-100,000 Americans die of DVT/PE each year. Currently, the preferred treatment for DVT/PE is anticoagulation. However, if there are contraindications to anticoagulation, an inferior vena cava (IVC) filter can be placed. These filters have both therapeutic and prophylactic indications. Therapeutic indications (documented thromboembolic disease) include absolute or relative contraindications to anticoagulation, complication of anticoagulation, failure of anticoagulation, propagation/progression of DVT during therapeutic anticoagulation, PE with residual DVT in patients with further risk of PE, free-floating iliofemoral IVC thrombus, and severe cardiopulmonary disease and DVT. There are also prophylactic indications (no current thromboembolic disease) for these filters. These include severe trauma without documented PE or DVT, closed head injury, spinal cord injury, multiple long bone fractures, and patients deemed at high risk of thromboembolic disease (immobilized or intensive care unit). Interruption of the IVC with filters has long been practiced and is a procedure that can be performed on an outpatient basis. There are known complications of filter placement, which include filter migration within the vena cava and into various organs, as well as filter strut fracture. This case describes a 66-year-old woman who was found to have a filter migration and techniques that were utilized to remove this filter.

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse.

BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems.

Methods for highly multiplexed RNA imaging are limited in spatial resolution and thus in their ability to localize transcripts to nanoscale and subcellular compartments. We adapt expansion microscopy, which physically expands biological specimens, for long-read untargeted and targeted in situ RNA sequencing. We applied untargeted expansion sequencing (ExSeq) to the mouse brain, which yielded the readout of thousands of genes, including splice variants. Targeted ExSeq yielded nanoscale-resolution maps of RNAs throughout dendrites and spines in the neurons of the mouse hippocampus, revealing patterns across multiple cell types, layer-specific cell types across the mouse visual cortex, and the organization and position-dependent states of tumor and immune cells in a human metastatic breast cancer biopsy. Thus, ExSeq enables highly multiplexed mapping of RNAs from nanoscale to system scale.

Outcomes of a combined antegrade and retrograde approach for dilatation of radiation-induced esophageal strictures (with video).

BACKGROUND: Treatment of head, neck, and esophageal cancers with radiation therapy can lead to esophageal strictures. In some cases, these can progress to complete esophageal obstruction, precluding typical antegrade endoscopic dilation. OBJECTIVE: The aim of this study was to review our experience with a combined antegrade/retrograde technique for dilation of complete esophageal strictures. DESIGN: Case series. SETTING: Tertiary-care referral center. PATIENTS: Twelve patients with complete esophageal radiation-induced strictures. INTERVENTIONS: In collaboration with otolaryngologists who performed direct antegrade esophagoscopy, retrograde endoscopy via gastrostomy was simultaneously performed. While visualizing the stricture from both sides and transilluminating, it was recannulated with use of a biliary or spring-tipped guidewire, and then dilated. MAIN OUTCOME MEASUREMENTS: Dilation method, complications, and postdilation oral intake. RESULTS: Combined antegrade and retrograde dilation was technically possible in 10 of the 12 patients (83%). Two cases were unsuccessful due to an inability to achieve transillumination. The only significant complication was a contained esophageal perforation that was managed nonoperatively. The mean number of repeat dilations was 7 (range, 1-22); none were complicated by perforation. Esophageal patency allowing at least some oral intake and tolerance of secretions was ultimately successful in 8 patients (67%). LIMITATIONS: Retrospective, single center. CONCLUSIONS: A combined antegrade/retrograde approach for dilation of complete esophageal radiation-induced strictures in collaboration with colleagues from otolaryngology is a viable treatment option. The procedure is technically feasible, effective, and well tolerated, although there may be an increased risk of esophageal perforation. This strategy may obviate a more invasive surgical approach.

Would Parents Consent to a Comparative Effectiveness Trial of Oral Doxycycline Versus Intravenous Ceftriaxone for the Treatment of Children with Lyme Meningitis?

Children with Lyme meningitis are often treated with intravenous ceftriaxone, although oral doxycycline may be effective. Parents were surveyed after observing a video describing a hypothetical Lyme meningitis treatment trial. Eighty-four of 102 (82%) would consent to their child participating. Parents would accept 2 additional days of symptoms (noninferiority margin) with doxycycline even if ceftriaxone hastened symptom resolution.

Sex differences in language dysfunction in schizophrenia.

OBJECTIVE: Normal sex differences in language functions are disrupted in schizophrenia. However, identification of specific language components most vulnerable in schizophrenia and how they may differ by sex remain unexamined. The current study investigated this issue in the domains of phonology, semantics, and grammar, which have been closely linked with neuroanatomic regions for which sex differences have been identified. METHOD: Thirty-one outpatients with DSM-III-R schizophrenia and 27 healthy subjects comparable within sex on age, handedness, parental socioeconomic status, and ethnicity were systematically ascertained from a Boston catchment area. The subjects were administered an extensive language battery in the context of a comprehensive neuropsychological battery that included measures of phonology, semantics, and grammar. RESULTS: Male patients performed significantly worse than their healthy counterparts on all three domains, with phonology least affected. In contrast, language function was relatively preserved in the female patients, compared to their healthy counterparts, with phonology most affected. Across domains, the effect sizes in comparisons of male patients and healthy male subjects had a twofold difference, whereas the difference in effect sizes in comparisons of female patients and healthy female subjects was less in all areas. CONCLUSIONS: Findings were consistent with prior evidence of overall language dysfunction in schizophrenia and may have implications for understanding sex differences in neuroanatomic abnormalities in regions associated with phonological processing.

Colonoscopy Findings in HIV-Infected Men and Women from an Urban U.S. Cohort Compared with Non-HIV-Infected Men and Women.

INTRODUCTION: As HIV-infected patients live longer, non-AIDS-defining cancers are now a major cause of morbidity and mortality. The purpose of this study was to compare the prevalence, type, and location of colorectal neoplastic lesions found on colonoscopy in HIV-infected patients from an urban U.S. cohort with non-HIV-infected patients. METHODS: We collected clinical data and colonoscopy findings on 263 HIV-infected patients matched with 657 non-HIV-infected patients on age, race, and sex. Frequency distributions and descriptive statistics were used to characterize the study population. The primary exposure was HIV infection, and the primary outcome was any adenoma or adenocarcinoma. Logistic regression models were used to estimate odds ratios with 95% confidence intervals (CIs). RESULTS: Participants were primarily African American and 40% were women. HIV-infected patients were less likely to have any neoplastic lesions (21.3% vs. 27.7%, p < .05), adenoma (20.5% vs. 27.1%, p = .04), tubular adenomas >10 mm (0.4% vs. 2.9%, p = .02), and serrated adenomas (0.0% vs.2.6%, p = <.01). There was a nonsignificant increased prevalence of adenocarcinoma in HIV-infected individuals compared with non-HIV-infected individuals (1.5% vs. 0.8%, p = .29). The lower prevalence of any adenoma remained after controlling for age, sex, smoking status, body-mass index, and diabetes mellitus [adjusted odds ratio (aOR), 0.61; 95% CI, 0.43-0.88]. HIV-infected patients had a lower prevalence of colorectal neoplastic lesions, including high-risk adenomas, than non-HIV-infected patients. CONCLUSIONS: Our findings suggest that HIV infection in a primarily African American population is associated with a lower prevalence of colorectal adenomas, but not adenocarcinoma, found by colonoscopy.

Social class in family therapy education: experiences of low SES students.

In this article, we report the results of a national survey of students in COAMFTE-accredited family therapy programs who self-identify as coming from lower- or working-class backgrounds. Results of the study reveal opportunity and tension relative to family, friends, and community because of social mobility associated with graduate education. Participants describe family therapy education as middle-class centered, pointing to lack of attention to social class, marginalization, classism, and unacknowledged class barriers as salient experiences in their graduate programs. Finally, participants share a number of suggestions for program improvement.