Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications.

Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well-recognized hosts of drug-resistant leukaemic cells, standard in vitro studies are routinely performed under supra-physiologic (21% O2 , ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy-induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high-potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher-potency statin (eg rosuvastatin)-based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.

Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney.

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.

The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model.

BACKGROUND: Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model. METHODS: Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. RESULTS: We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates. CONCLUSIONS: This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia.

COVID-19: Factors Predicting Depressive Symptoms in People Aging With Long-Term Physical Disabilities.

The mental health impact of the COVID-19 pandemic may be greater than that of the viral infection. This impact is likely greater for disadvantaged groups such as people with long-term physical disabilities (PwLTPD). This cross-sectional study used a multiple linear regression model to examine factors associated with depressive symptoms and to understand their relative importance during the onset of the COVID-19 pandemic. The model explained 58% of the variance in depressive symptoms. Anxiety was the most important predictor, accounting for 8% of variance. Higher levels of anxiety, loneliness, and financial stress; prior diagnosis of depression; and non-Black race predicted a higher level of depressive symptoms in PwLTPD during the onset of the COVID-19 pandemic. Occupational therapy practitioners should strategically acknowledge predictors of depression that cannot be modified and actively address those that can be modified through evidence-based interventions to improve depressive symptoms in PwLTPD.

Interventions to promote independent participation among community-dwelling middle-aged adults with long-term physical disabilities: a systematic review.

PURPOSE: People aging with long-term physical disabilities (PAwLTPD) are aging at an accelerated rate beginning in middle-age. They face age-related challenges in conjunction with their existing disabilities; thus, maintaining independence as they age is often difficult. The aim of this systematic review was to examine the effectiveness of rehabilitation interventions for middle-aged PAwLTPD to participate independently in the home and community. MATERIALS AND METHODS: We searched four databases - MEDLINE, CINAHL, Web of Science, and EMBASE - for studies published from January 2005 to December 2020. Information from included studies was extracted using a critical appraisal form. Studies were categorized based on common themes, assigned level of evidence, and assessed for risk of bias. RESULTS: Fourteen articles were included. Common themes derived were fall risk reduction, functional capacity, community mobility, and function within the home. The strongest evidence supports wheelchair skills training programs (WSTPs) among manual wheelchair users and targeted paretic limb exercise post-stroke. Moderate evidence supports exercise and multicomponent interventions for those with multiple sclerosis, adaptive strategy training and WSTPs to improve satisfaction with mobility for power wheelchair users, and home modifications/assistive technology for mobility-impaired individuals. CONCLUSION: Interventions with strong and moderate evidence should be routinely offered for middle-aged PAwLTPD. Future research should focus on developing evidence-based interventions for middle-aged PAwLTPD.IMPLICATIONS FOR REHABILITATIONMiddle-aged PAwLTPD face the same aging-related challenges as people without disabilities but will experience additional difficulties due to compounding effects of long-term health conditions and aging.Current effective interventions to promote participation for middle-aged PAwLTPD have been measured over a wide range of outcomes, and many interventions should be used by clinicians on a case-by-case basis.Wheelchair skills training was found to have the strongest evidence and is recommended for use with middle-aged PAwLTPD who use manual and power wheelchairs.

Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis.

Severe sepsis is one of the leading causes of death worldwide. High mortality rates in sepsis are frequently associated with neutropenia. Despite the central role of neutrophils in innate immunity, the mechanisms causing neutropenia during sepsis remain elusive. Here, we show that neutropenia is caused in part by apoptosis and is sustained by a block of hematopoietic stem cell (HSC) differentiation. Using a sepsis murine model, we found that the human opportunistic bacterial pathogen Pseudomonas aeruginosa caused neutrophil depletion and expansion of the HSC pool in the bone marrow. "Septic" HSCs were significantly impaired in competitive repopulation assays and defective in generating common myeloid progenitors and granulocyte-monocyte progenitors, resulting in lower rates of myeloid differentiation in vitro and in vivo. Delayed myeloid-neutrophil differentiation was further mapped using a lysozyme-green fluorescent protein (GFP) reporter mouse. Pseudomonas's lipopolysaccharide was necessary and sufficient to induce myelosuppresion and required intact TLR4 signaling. Our results establish a previously unrecognized link between HSC regulation and host response in severe sepsis and demonstrate a novel role for TLR4.

Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells.

Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of "metalloenediynes" can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that "tuning" of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating.

Safety of intravenous alteplase within 4.5 hours for patients awakening with stroke symptoms.

BACKGROUND: Up to 25% of acute stroke patients first note symptoms upon awakening. We hypothesized that patients awaking with stroke symptoms may be safely treated with intravenous alteplase (IV tPA) using non-contrast head CT (NCHCT), if they meet all other standard criteria. METHODS: The SAfety of Intravenous thromboLytics in stroke ON awakening (SAIL ON) was a prospective, open-label, single treatment arm, pilot safety trial of standard dose IV tPA in patients who presented with stroke symptoms within 0-4.5 hours of awakening. From January 30, 2013, to September 1, 2015, twenty consecutive wakeup stroke patients selected by NCHCT were enrolled. The primary outcome was symptomatic intracerebral hemorrhage (sICH) in the first 36 hours. Secondary outcomes included NIH stroke scale (NIHSS) at 24 hours; and modified Rankin Score (mRS), NIHSS, and Barthel index at 90 days. RESULTS: The average age was 65 years (range 47-83); 40% were women; 50% were African American. The average NIHSS was 6 (range 4-11). The average time from wake-up to IV tPA was 205 minutes (range 114-270). The average time from last known well to IV tPA was 580 minutes (range 353-876). The median mRS at 90 days was 1 (range 0-5). No patients had sICH; two of 20 (10%) had asymptomatic ICH on routine post IV tPA brain imaging. CONCLUSIONS: Administration of IV tPA was feasible and may be safe in wakeup stroke patients presenting within 4.5 hours from awakening, screened with NCHCT. An adequately powered randomized clinical trial is needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01643902.

Individualized Breast Cancer Characterization through Single-Cell Analysis of Tumor and Adjacent Normal Cells.

There is a need to individualize assays for tumor molecular phenotyping, given variations in the differentiation status of tumor and normal tissues in different patients. To address this, we performed single-cell genomics of breast tumors and adjacent normal cells propagated for a short duration under growth conditions that enable epithelial reprogramming. Cells analyzed were either unselected for a specific subpopulation or phenotypically defined as undifferentiated and highly clonogenic ALDH+/CD49f+/EpCAM+ luminal progenitors, which express both basal cell and luminal cell-enriched genes. We analyzed 420 tumor cells and 284 adjacent normal cells for expression of 93 genes that included a PAM50-intrinsic subtype classifier and stemness-related genes. ALDH+/CD49f+/EpCAM+ tumor and normal cells clustered differently compared with unselected tumor and normal cells. PAM50 gene-set analyses of ALDH+/CD49f+/EpCAM+ populations efficiently identified major and minor clones of tumor cells, with the major clone resembling clinical parameters of the tumor. Similarly, a stemness-associated gene set identified clones with divergent stemness pathway activation within the same tumor. This refined expression profiling technique distinguished genes truly deregulated in cancer from genes that identify cellular precursors of tumors. Collectively, the assays presented here enable more precise identification of cancer-deregulated genes, allow for early identification of therapeutically targetable tumor cell subpopulations, and ultimately provide a refinement of precision therapeutics for cancer treatment. Cancer Res; 77(10); 2759-69. ©2017 AACR.

Accuracy of Prospective Predictions of 30-Day Hospital Readmission.

OBJECTIVE: This study examined how accurately inpatient case managers predicted 30-day readmission and whether objective patient characteristics improved prediction accuracy. METHODS: In this prospective study, inpatient case managers at a psychiatric hospital rated their concern (1, not concerned; 5, very concerned) about readmission after discharge of 282 privately insured patients. Sensitivity and specificity of the ratings were calculated. Logistic regression identified whether patient characteristics that could affect 30-day readmission improved prediction accuracy. RESULTS: Concern levels ≥3 yielded 86% sensitivity, 37% specificity, and a positive predictive value (PPV) of 13%; levels ≥4 yielded 39% sensitivity, 78% specificity, and a PPV of 17%. Concern level independently predicted readmission; appointments within seven days postdischarge further improved model accuracy (p=.03) (area under the curve=.67, 95% confidence interval=.58-.78). CONCLUSIONS: Although not highly accurate, case manager concern identified some patients at higher risk of 30-day readmission. Appointments within seven days of discharge improved prediction accuracy.

Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase.

The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-kappaB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-kappaB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.

Multiple osteocartilaginous exostoses of the lower extremity: a case report.

An osteochrondoma is a benign osseous tumor capped by cartilage. Osteochondromas occurring at the distal tibia and fibula are uncommon and even more so when occurring at the first metatarsal head. Osteochondromas usually occur at the metaphysis of long bones; however, they can occur at other cortical bone metaphyses. This is a case report of a 54-year-old male with incidental radiographic findings of multiple osteochondromas around his ankles as well as a solitary osteochondromatous lesion growing proximally off the left first metatarsal head. The multiple osteochrondomas were evident on multiple views, and subsequent histological analysis of the solitary osteochondromatous lesion via total surgical excision confirmed a diagnosis of multiple hereditary osteochrondromatosis.

Breast-feeding and contraception in Peru.

This retrospective study examined duration of breast-feeding and concurrent contraceptive use among 5,648 Peruvian women. Data were gathered during 1986-1992 as part of the Demographic and Health Survey (DHS). The women gave birth to 7,951 infants, 95% of whom were breastfed; 44% of the mothers used contraception while breastfeeding. Consistent with the literature, mothers using oral contraception breastfed for significantly less time than those using other methods. Unexpectedly, mothers using periodic abstinence or withdrawal breastfed longer (15.5 and 15.3 months) than those using other methods or non-contraceptors. Among mothers changing contraceptive methods while breastfeeding the same child, those changing to abstinence and withdrawal breastfed longest (18 months). The relationship of duration of breast-feeding with contraceptive use remained after controlling for other predictors of duration of breast-feeding. Additional data are needed to explain this phenomenon in Peru and perhaps elsewhere.

New graduate nurses' perception of the workplace: have they experienced bullying?

This study investigated the bullying experience in the workplace of newly licensed registered nurses (RNs). Preventing newly licensed nurses from leaving the profession is important, especially because there is a nursing shortage. Education of staff and administrators provides recognition of negative behaviors in the workplace. Participants in this research study included 135 newly licensed RN's from 5 nursing schools in Northwestern Ohio licensed in years 2007-2010. Quantitative methods and a descriptive design process included chi-square tests and descriptive statistical methods. Bullying workplace behaviors were identified by participants utilizing the survey tool, the Negative Acts Questionnaire-Revised, and a questionnaire on work relationships and bullies recognized in the workplace. Nursing peers, physicians, or a patient's family were the main sources of bullying, and 29.5% had considered leaving the nursing profession. Education of staff is imperative for providing recognition of negative behaviors in the workplace. Bullying occurs in the workplace and is affecting the new graduates' work performance. Retaining newly graduated nurses is the ultimate goal for maintaining RN's in the workforce.

The relevance of standards of professional school nursing practice.

This descriptive correlational study assessed school nurses' knowledge of and perceived relevance of the Standards of Professional School Nursing Practice. Of the 1,162 Ohio school nurses sent questionnaires, 345 returned usable questionnaires (30%). The typical respondent was a 50-year-old Caucasian woman with 24 years of nursing experience, 12 years of school nursing experience, and a caseload of 3 public schools serving 1,500 students. Factors that positively related to the school nurses' knowledge and perceptions of the relevance of the standards were age, advanced degree preparation, school nursing experience, and practicing in a metropolitan area. Factors that negatively related to knowledge and perceived relevance were practicing in a rural area and caseload of special needs students. Standards of practice provide a mechanism for defining and supporting practice roles for nurses. Thus, it is important to increase awareness and use of the standards, especially among school nurses practicing in rural areas.

Modulation of in vitro proliferation kinetics and primitive hematopoietic potential of individual human CD34+CD38-/lo cells in G0.

Whether cytokines can modulate the fate of primitive hematopoietic progenitor cells (HPCs) through successive in vitro cell divisions has not been established. Single human marrow CD34+CD38-/lo cells in the G0 phase of cell cycle were cultured under 7 different cytokine combinations, monitored for proliferation on days 3, 5, and 7, then assayed for long-term culture-initiating cell (LTC-IC) function on day 7. LTC-IC function was then retrospectively correlated with prior number of in vitro cell divisions to determine whether maintenance of LTC-IC function after in vitro cell division is dependent on cytokine exposure. In the presence of proliferation progression signals, initial cell division was independent of cytokine stimulation, suggesting that entry of primitive HPCs into the cell cycle is a stochastic property. However, kinetics of proliferation beyond day 3 and maintenance of LTC-IC function were sensitive to cytokine stimulation, such that LTC-IC underwent an initial long cell cycle, followed by more synchronized shorter cycles varying in length depending on the cytokine combination. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) transplantation studies revealed analogous results to those obtained with LTC-ICs. These data suggest that although exit from quiescence and commitment to proliferation might be stochastic, kinetics of proliferation, and possibly fate of primitive HPCs, might be modulated by extrinsic factors.

Duplex Doppler ultrasound of the hepatic artery in patients with acute alcoholic hepatitis.

BACKGROUND: Acute alcoholic hepatitis (AAH) is a clinical diagnosis associated with increased hepatic artery diameter and flow. Duplex Doppler ultrasound (DDU) has been shown to accurately measure arterial flow in both liver and kidney transplant patients. The authors conducted a blinded, controlled study to evaluate the accuracy of measuring hepatic artery parameters with DDU in diagnosing AAH. STUDY: Duplex Doppler ultrasound was performed by an investigator, blinded to group makeup, on 22 consecutive hospital inpatients with the clinical diagnosis of AAH. The diagnosis of AAH was based on specific criteria, including the following: recent alcohol abuse, hyperbilirubinemia, prolonged prothrombin time, leukocytosis, hepatomegaly, hepatic bruit, and marked redistribution of isotope on 99mTc-sulfur colloid liver-spleen scan. Controls were 12 cirrhotic patients without AAH and 17 healthy volunteers. Duplex Doppler ultrasound measurements were obtained most consistently from the proximal right hepatic artery. Measured parameters included the following: peak systolic velocity (PSV); resistive index = (PSV - end diastolic velocity [EDV])/PSV; pulsatility index = (PSV - EDV)/mean velocity; and hepatic artery diameter. RESULTS: The mean hepatic artery diameter was significantly larger in patients with AAH (3.55 +/- 0.72 mm) than in patients with cirrhosis (2.75 +/- 0.69 mm; p = 0.003) and healthy controls (2.68 +/- 0.69 mm; p = 0.001). The mean PSV was significantly higher in patients with AAH (187 +/- 52 cm/s) compared with cirrhotic (67 +/- 51 cm/s) and healthy (66 +/- 51 cm/s) controls (p = 0.0001). The mean resistive index was lower in AAH patients (0.60 +/- 0.11) compared with cirrhotic (0.69 +/- 0.10; p value was not significant) and healthy controls (0.72 +/- 0.11; p = 0.004). The mean pulsatility index was lower in AAH patients (1.04 +/- 0.47) compared with cirrhotic (1.36 +/- 0.45; p value was not significant) and healthy controls (1.53 +/- 0.45; p = 0.01). CONCLUSIONS: In the appropriate clinical setting, an elevated hepatic artery diameter or PSV measurement is suggestive of AAH. Duplex Doppler ultrasound offers a noninvasive test to assist in the diagnosis of AAH.

Breast-feeding and contraception in Peru.

This retrospective study examined duration of breast-feeding and concurrent contraceptive use among 5,648 Peruvian women. Data were gathered during 1986-1992 as part of the Demographic and Health Survey (DHS). The women gave birth to 7,951 infants, 95% of whom were breastfed; 44% of the mothers used contraception while breastfeeding. Consistent with the literature, mothers using oral contraception breastfed for significantly less time than those using other methods. Unexpectedly, mothers using periodic abstinence or withdrawal breastfed longer (15.5 and 15.3 months) than those using other methods or non-contraceptors. Among mothers changing contraceptive methods while breastfeeding the same child, those changing to abstinence and withdrawal breastfed longest (18 months). The relationship of duration of breast-feeding with contraceptive use remained after controlling for other predictors of duration of breast-feeding. Additional data are needed to explain this phenomenon in Peru and perhaps elsewhere.