Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.

The bitter end: T2R bitter receptor agonists elevate nuclear calcium and induce apoptosis in non-ciliated airway epithelial cells.

Bitter taste receptors (T2Rs) localize to airway motile cilia and initiate innate immune responses in retaliation to bacterial quorum sensing molecules. Activation of cilia T2Rs leads to calcium-driven NO production that increases cilia beating and directly kills bacteria. Several diseases, including chronic rhinosinusitis, COPD, and cystic fibrosis, are characterized by loss of motile cilia and/or squamous metaplasia. To understand T2R function within the altered landscape of airway disease, we studied T2Rs in non-ciliated airway cell lines and primary cells. Several T2Rs localize to the nucleus in de-differentiated cells that typically localize to cilia in differentiated cells. As cilia and nuclear import utilize shared proteins, some T2Rs may target to the nucleus in the absence of motile cilia. T2R agonists selectively elevated nuclear and mitochondrial calcium through a G-protein-coupled receptor phospholipase C mechanism. Additionally, T2R agonists decreased nuclear cAMP, increased nitric oxide, and increased cGMP, consistent with T2R signaling. Furthermore, exposure to T2R agonists led to nuclear calcium-induced mitochondrial depolarization and caspase activation. T2R agonists induced apoptosis in primary bronchial and nasal cells differentiated at air-liquid interface but then induced to a squamous phenotype by apical submersion. Air-exposed well-differentiated cells did not die. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.

Methods and Techniques to Facilitate the Development of Clostridium novyi NT as an Effective, Therapeutic Oncolytic Bacteria.

The tumor microenvironment is characterized by anomalous vascularization, hypoxia, and acidity at the core of solid tumors that culminates in concentrated necrosis and immune system dysregulation among other effects. While this environment presents several challenges for the development of oncotherapeutics that deliver their activity via the enhanced permeability and retention (EPR) effect of the leaky blood vessels around a tumor, oncolytic bacteria, or a class of bacteria with a noted capacity to lyse solid tumors, are attracted to the very environment found at the center of solid tumors that confounds other therapeutics. It is this capacity that allows for a potent, active penetration from the tumor margins into the core, and subsequent colonization to facilitate lysis and immune reactivation. Clostridium novyi in particular has recently shown great promise in preclinical and clinical trials when administered directly to the tumor. These studies indicate that C. novyi is uniquely poised to effectively accomplish the long sought after "holy grail" of oncotherapeutics: selective tumor localization via intravenous delivery. This study reports the development of efficient methods that facilitate experimental work and therapeutic translation of C. novyi including the ability to work with this obligate micro-anaerobe on the benchtop. Additionally, this study seeks to utilize this newfound experimental flexibility to address several gaps in the current knowledge regarding the efficacy of CRIPSR/Cas9-mediated gene insertion in this species to further develop this oncolytic bacteria and the genetic customization of bacteria in general.

The next frontier of oncotherapy: accomplishing clinical translation of oncolytic bacteria through genetic engineering.

The development of a 'smart' drug capable of distinguishing tumor from host cells has been sought for centuries, but the microenvironment of solid tumors continues to confound therapeutics. Solid tumors present several challenges for current oncotherapeutics, including aberrant vascularization, hypoxia, necrosis, abnormally high pH and local immune suppression. While traditional chemotherapeutics are limited by such an environment, oncolytic microbes are drawn to it - having an innate ability to selectively infect, colonize and eradicate solid tumors. Development of an oncolytic species would represent a shift in the cancer therapeutic paradigm, with ramifications reaching from the medical into the socio-economic. Modern genetic engineering techniques could be implemented to customize 'Frankenstein' bacteria with advantageous characteristics from several species.

Lay abstract Side effects of chemotherapeutics are thought to often be a reflection of our inability to target these toxic substances to only cancer cells; hence, scientists have spent centuries searching for alternative treatments that would confine their actions to tumor cells, sparing healthy tissue. Unfortunately, the dense nature of tumor tissue along with altered blood vessels, that lead to diminished tumor tissue oxygenation, altered tissue pH and cellular metabolic inactivity or even cell death have proven challenging. Importantly, these barriers have contributed to local and even sometimes systemic suppression of the patient's immune system that can allow the tumor to grow and progress unchecked. While most non-cancer cells are inhibited by the local tumor environment, certain microbes, including some bacteria and viruses, are drawn to it, possessing a natural ability to selectively infect, colonize and eradicate solid tumors. These microbes may also restore the patient's immune balance. However, use of these microbes is not without its own problems; nevertheless, modern genetic engineering techniques could be implemented to develop customized, safe, effective bacteria with advantageous characteristics. The development and clinical translation of cancer-fighting bacteria would represent a shift in cancer therapeutics and would have ramifications that reach beyond medical efficacy into the realm of socioeconomics. This review seeks to marry the current field of oncolytic bacteria with the expanding field of modern bacterial genetic engineering techniques in prospect of such a therapeutic.

Meta-analysis of Intraprocedural Comparative Effectiveness of Vascular Plugs Vs Coils in Proximal Splenic Artery Embolization and Associated Patient Radiation Exposure.

PURPOSE: To compare vascular plugs to coil embolization of the proximal splenic artery and evaluate differences in radiation exposure to the patients. METHODS: An electronic literature search was performed for relevant studies from January 2000 to July 2018 that compared the efficacy of vascular plugs vs coils in splenic artery embolization. Only studies that investigated coil or vascular plug use, without combination with other embolic agents, were included. Meta-analysis was performed using a fixed effects model approach with the inverse variance-weighted average method to determine pooled differences in time to vessel occlusion, procedure time, fluoroscopy time, total number of devices used, and radiation exposure. Heterogeneity was assessed using the I square statistic. Pooled outcomes were compared, and quality assessments were evaluated using the Newcastle Ottawa Scale. RESULTS: Eight studies met inclusion criteria. 81 patients were embolized with vascular plugs and 52 patients with coils only. The most common indication for splenic artery embolization was trauma. Time to vessel occlusion was shorter in the vascular plug group by 7.11 minutes (P = 0.003). Fluoroscopy time was shorter by 13.82 minutes in the vascular plug cohort, and these patients received less radiation (-439 mGy) compared to the coil group (P = 0.006 and P = 0.02, respectively). The number of devices was significantly fewer in the vascular plug group (-3.54; P < 0.001). Procedure time was not statistically significant. CONCLUSION: Our data supports the vascular plug is superior to coils for embolization of the proximal splenic artery with respect to occlusion time, fluoroscopy time, patient radiation exposure, and number occlusive devices used.

A Meta-analysis of Comparative Outcome and Cost-Effectiveness of Internal Iliac Artery Embolization with Vascular Plug Versus Coil.

PURPOSE: To evaluate the comparative outcome and cost of vascular plugs versus coils for internal iliac artery embolization prior to endovascular aortic aneurysm repair. METHOD: A search was performed for internal iliac artery embolization studies in adult patients from January 2005 to July 2018. Inclusion criteria included embolization of unilateral or bilateral IIAs with either coils or plug(s) prior to endovascular aortic repair. Meta-analysis was performed using a fixed effects model with the inverse variance-weighted average method to determine pooled differences in surgical time, fluoroscopy time, radiation exposure, number of devices used, cost of devices, and post-embolization buttock claudication. Heterogeneity was assessed using the Chi-square statistic. Pooled outcomes were compared, and quality assessments were evaluated using the Newcastle-Ottawa scale. RESULT: Six studies met inclusion criteria. One hundred and eighty-one patients were included in the study, of which 87 were in the plug group and 94 in the coil group. Vascular plug use led to 35.32 min shorter surgery time (p < 0.001), 15.64 min less fluoroscopy time (p < 0.001), 157,599 mGy/cm2 less radiation (p < 0.001), and 5.88 fewer occlusive devices (p < 0.001) than the use of coils alone. The estimated total cost of occlusion devices was $575.45 USD lower in the plug cohort (p < 0.001). The development of buttock claudication 12 months after EVAR was 11% less likely in the plug cohort but was not statistically significant (p = 0.71). CONCLUSION: The vascular plug appears to be superior to coils in embolization of the internal iliac artery due to shorter surgical time, fluoroscopy time, radiation exposure, and total cost of occlusive devices.

Prevalence of body dissatisfaction among a United States adult sample.

Body dissatisfaction (BD) is a primary determinant of eating disorders and has been linked to chronic disease via decreased likelihood of cancer screening self-exams and smoking cessation. Yet, there are few recent estimates of the prevalence of BD among United States adults. Using an internet-based, opt-in, cross-sectional survey, United States adults (N=1893) completed assessments of demographic variables, body areas satisfaction, appearance evaluation, fitness evaluation, health evaluation, and overweight preoccupation. Results revealed that the range of BD is 13.4%-31.8% among women and 9.0%-28.4% among men. Compared to previous assessments of prevalence (1973, 1986, 1995, 1997), the prevalence of BD among United States adults may have plateaued or declined over time.

The use of humor and its influences on spirituality and coping in breast cancer survivors.

PURPOSE/OBJECTIVES: To describe patients' perspectives concerning the use of humor in their care and recovery. DESIGN: Descriptive. SETTING: Community-based. SAMPLE: Nine women with a diagnosis of breast cancer. METHODS: Open-ended interviews were conducted with participants to identify their use of humor, its influence on spirituality, and their perceptions of how nurses use humor in caring for them during their treatment for breast cancer. MAIN RESEARCH VARIABLE: The use of humor as a coping skill. FINDINGS: The narrative data revealed three major categories, each with five to six themes illuminating humor as a coping factor, the relationship between humor and nursing, and the relationship between humor and spirituality. CONCLUSIONS: Participants identified humor as an important coping factor. They also believed it played a role in their spirituality and their perception of the meaning and purpose of life. Nurses' use of humor is important to foster deeper, more trusting relationships with patients. IMPLICATIONS FOR NURSING: Humor must be recognized as an element of spiritual coping in patients with breast cancer. A need exists for further education for nurses concerning the importance of humor in the care of patients to promote recovery and improve the nurse-patient relationship. Research is needed to explore the use of cultural influences on humor, family perspectives of humor, and the influences of the overall environment.