Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate.

The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.

Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells.

Heat shock transcription factor 1 (HSF1) has been identified as a therapeutic target for pharmacological treatment of multiple myeloma (MM). However, direct therapeutic targeting of HSF1 function seems to be difficult due to the shortage of clinically suitable pharmacological inhibitors. We utilized the Ugi multicomponent reaction to create a small but smart library of α-acyl aminocarboxamides and evaluated their ability to suppress heat shock response (HSR) in MM cells. Using the INA-6 cell line as the MM model and the strictly HSF1-dependent HSP72 induction as a HSR model, we identified potential HSF1 inhibitors. Mass spectrometry-based affinity capture experiments with biotin-linked derivatives revealed a number of target proteins and complexes, which exhibit an armadillo domain. Also, four members of the tumor-promoting and HSF1-associated phosphatidylinositol 3-kinase-related kinase (PIKK) family were identified. The antitumor activity was evaluated, showing that treatment with the anti-HSF1 compounds strongly induced apoptotic cell death in MM cells.

Efficacy and Safety of Intravenous Ferric Carboxymaltose in Geriatric Inpatients at a German Tertiary University Teaching Hospital: A Retrospective Observational Cohort Study of Clinical Practice.

Current iron supplementation practice in geriatric patients is erratic and lacks evidence-based recommendations. Despite potential benefits in this population, intravenous iron supplementation is often withheld due to concerns regarding pharmacy expense, perceived safety issues, and doubts regarding efficacy in elderly patients. This retrospective, observational cohort study aimed to evaluate the safety and efficacy of intravenous ferric carboxymaltose (FCM, Ferinject) in patients aged >75 years with iron deficiency anaemia (IDA). Within a twelve-month data extraction period, the charts of 405 hospitalised patients aged 65-101 years were retrospectively analysed for IDA, defined according to WHO criteria for anaemia (haemoglobin: <13.0 g/dL (m)/<12.0 g/dL (f)) in conjunction with transferrin saturation <20%. Of 128 IDA patients screened, 51 (39.8%) received intravenous iron. 38 patient charts were analysed. Mean cumulative dose of intravenous FCM was 784.4 ± 271.7 mg iron (1-3 infusions). 18 patients (47%) fulfilled treatment response criteria (≥1.0 g/dL increase in haemoglobin between baseline and hospital discharge). AEs were mild/moderate, most commonly transient increases of liver enzymes (n = 5/13.2%). AE incidence was comparable with that observed in patients <75 years. No serious AEs were observed. Ferric carboxymaltose was well tolerated and effective for correction of Hb levels and iron stores in this cohort of IDA patients aged over 75 years.

[Efficacy and tolerability of ferric carboxymaltose in geriatric patients with anemia. Data from three non-interventional studies]. / Wirksamkeit und Verträglichkeit einer intravenösen Eisentherapie bei geriatrischen Patienten mit Anämie. Gepoolte Daten aus drei nicht-interventionellen Studien.

BACKGROUND: Anemia in the elderly is a common clinical finding. Prevalence in hospitalized geriatric patients approximates up to 40% presenting as iron deficiency anemia associated with absolute iron deficiency, anemia of chronic disease associated with functional iron deficiency or unexplained anemia. In patients with functional iron deficiency oral iron substitution is ineffective due to elevated hepcidin levels, such as in renal anemia. In these patients intravenous iron substitution represents a cornerstone. However, data among geriatric patients are limited. We conducted three non-interventional studies collecting data with respect to efficacy and tolerance of ferric carboxymaltose (ferinject) in three patient groups (cancer, chronic kidney disease [CKD], chronic inflammatory bowel disease [CIBD]) with anemia and functional iron deficiency. The present sub-analysis describes the results among the geriatric patients (age > 70 years) observed in all three observational studies. PATIENTS, METHODS: 264 patients were analyzed (mean age of 76.9 years [70-90 years; SD +/- 5.2 years]). Patients received an average amount of 1200 mg ferric carboxymaltose (746-1575 mg). RESULTS: Hemoglobin levels (p < 0.001), serum ferritin (p < 0.001) and transferrin saturation (p < 0.05) rose significantly in CKD patients; in CIBD patients hemoglobin and transferrin saturation rose significantly (p < 0.05) while the rise of ferritin failed to be significant. In oncologic patients the rise of hemoglobin and ferritin levels was of high statistic significance (p < 0.001) and transferrin saturation also rose significantly (p = 0.02) Fatigue, mental capacities as well as dyspnea improved among CKD-and CIBD-groups. No severe adverse reactions occurred. CONCLUSION: Administration of ferric carboxymaltose in geriatric patients is well tolerated and offers an effective treatment option for the treatment of functional iron deficiency.

An etiologic profile of anemia in 405 geriatric patients.

Background. Anemia is a common condition in the elderly and a significant risk factor for increased morbidity and mortality, reducing not only functional capacity and mobility but also quality of life. Currently, few data are available regarding anemia in hospitalized geriatric patients. Our retrospective study investigated epidemiology and causes of anemia in 405 hospitalized geriatric patients. Methods. Data analysis was performed using laboratory parameters determined during routine hospital admission procedures (hemoglobin, ferritin, transferrin saturation, C-reactive protein, vitamin B12, folic acid, and creatinine) in addition to medical history and demographics. Results. Anemia affected approximately two-thirds of subjects. Of 386 patients with recorded hemoglobin values, 66.3% were anemic according to WHO criteria, mostly (85.1%) in a mild form. Anemia was primarily due to iron deficiency (65%), frequently due to underlying chronic infection (62.1%), or of mixed etiology involving a combination of chronic disease and iron deficiency, with absolute iron deficiency playing a comparatively minor role. Conclusion. Greater awareness of anemia in the elderly is warranted due to its high prevalence and negative effect on outcomes, hospitalization duration, and mortality. Geriatric patients should be routinely screened for anemia and etiological causes of anemia individually assessed to allow timely initiation of appropriate therapy.

Free sphingobases induce RBOHD-dependent reactive oxygen species production in Arabidopsis leaves.

Sphingolipids are implied in several regulatory processes, including cell death. Levels of the free sphingobase t18:0 (phytosphingosine) increase in Arabidopsis in response to the bacterial pathogen Pseudomonas syringae. To gain information on sphingobase-induced signaling, we determined kinetics of leaf reactive oxygen species (ROS) levels and cell death in response to specific sphingobases. t18:0, d18:0 and d17:1, but not d20:0, induced ROS and cell death within 1.5-2h. Early sphingobase-induced ROS production was independent of cell death induction and required the NADPH oxidase Respiratory Burst Oxidase Homolog D (RBOHD). Specific sphingobases can therefore induce cell death and require RBOHD for early ROS induction in plants.

Slip resistance of non-slip socks--an accelerometer-based approach.

The present study investigated the relative slip resistance of commercially available non-slip socks during gait. Twenty-four healthy subjects (29.3±10.4 years) participated in the study. Each subject completed 4 different test conditions (barefoot, non-slip socks, conventional socks, backless slippers) in a randomized, balanced order. The slip resistance was estimated by measuring the heel deceleration time using a heel-mounted accelerometer. Repeated measures ANOVA and post hoc paired-sample t-test with Bonferroni correction were used for statistical analysis. Compared to barefoot walking absolute deceleration times [ms] were significantly increased when wearing conventional socks or slippers. No significant differences were observed between the barefoot and non-slip socks conditions. The present study shows that non-slip socks improved slip-resistance during gait when compared to conventional socks and slippers. Future investigations should verify the present findings in hospital populations prone to slip-related falls.

Rollator use and functional outcome of geriatric rehabilitation.

In a quasi-experimental pre- and postdesign, we examined the effect of rollator use on functional rehabilitation outcome in geriatric patients.From a sample of 458 geriatric inpatients, we matched 30 subjects who were not using assistive devices in their everyday lives but received a wheeled walker at the time of hospital admission (first-time user group) according to their admission scores on three motor performance tests (Timed Up-and-Go, Five-Times-Sit-to-Stand, and Performance-Oriented Mobility Assessment -Balance) with 30 patients who were actively using rollators as their primary walking aid for at least 3 months (long-term user group) and 30 control subjects without walking-aid assistance. Measurements were repeated after the inpatient rehabilitation regimen.The Kruskal-Wallis test did not reveal significant group differences in rehabilitation progress. Controls and device users, regardless of walking-aid experience, demonstrated nearly comparable mobility, strength, and balance improvements. More than half of each cohort (controls, n = 22; first-time, n = 17; long-term, n = 18) achieved functional gains in all three motor tests.The study showed that rollator assistance does not interfere with rehabilitation outcome and, to some extent, legitimates the prescription of assistive devices to improve confidence and restore or maintain motor ability at the highest possible level.

Cognitive status and ambulatory rehabilitation outcome in geriatric patients.

OBJECTIVE: To determine the effect of admission cognitive status on gait and stair climbing rehabilitation outcome in geriatric patients. DESIGN: Before-after trial. SUBJECTS: A total of 179 geriatric patients (139 women and 40 men; age range 67-97 years) consecutively admitted to a geriatric inpatient rehabilitation regimen (mean length of stay 28.7 (standard deviation 13.9) days). METHODS: Assessment of admission cognitive status by the Mini-Mental State Examination (MMSE); determination of the ambulatory status before and after rehabilitation by the Performance-Oriented Mobility Assessment (POMA) and standardized judgements about stair climbing ability. RESULTS: Approximately two-thirds of the patients demonstrated functional ability improvements in at least 5 points at the individual level during rehabilitation (as measured by the total POMA scale (POMA-T)). However, at rehabilitation discharge cognitively impaired patients still demonstrated a 3.4 times (95% confidence interval=1.4-8.6) higher chance of increased fall risk and only 24% of the cohort was able to negotiate stairs with slight or no limitations. CONCLUSION: Although cognitively impaired patients demonstrated an functional overall intervention response comparable with cognitively intact patients the present study evidenced that the geriatric cohort with reduced mental status (MMSE >17) are at greater risk of falling and have a greater need for supervision, both in hospital and at discharge.

Preventing falls in community-dwelling frail older people using a home intervention team (HIT): results from the randomized Falls-HIT trial.

OBJECTIVES: To evaluate the effect of an intervention by a multidisciplinary team to reduce falls in older people's homes. DESIGN: Randomized, controlled trial with follow-up of subjects for 1 year. SETTING: University-affiliated geriatric hospital and older patients' homes. PARTICIPANTS: Three hundred sixty subjects (mean age +/- standard deviation = 81.5 +/- 6.4) admitted from home to a geriatric hospital and showing functional decline, especially in mobility. INTERVENTION: The participants were randomly assigned to receive a comprehensive geriatric assessment followed by a diagnostic home visit and home intervention or a comprehensive geriatric assessment with recommendations and usual care at home. The home intervention included a diagnostic home visit, assessing the home for environmental hazards, advice about possible changes, offer of facilities for any necessary home modifications, and training in the use of technical and mobility aids. An additional home visit was made after 3 months to reinforce the recommendations. After 12 months of follow-up, a home visit was made to all study participants. MEASUREMENTS: Number of falls, type of recommended home modifications, and compliance with recommendations. RESULTS: After 1 year, there were 163 falls in the intervention group and 204 falls in the control group. The intervention group had 31% fewer falls than the control group (incidence rate ratio (IRR) = 0.69, 95% confidence interval (CI) = 0.51-0.97). The intervention was most effective in a subgroup of participants who reported having had two or more falls during the year before recruitment into the study. In this subgroup, the proportion of frequent fallers and the rate of falls was significantly reduced for the intervention group compared with the control group (21 vs 36 subjects with recurrent falls, P =.009; IRR = 0.63, 95% CI = 0.43-0.94). The compliance rate varied with the type of change recommended from 83% to 33% after 12 months of follow-up. CONCLUSION: Home intervention based on home visits to assess the home for environmental hazards, providing information about possible changes, facilitating any necessary modifications, and training in the use of technical and mobility aids was effective in a selected group of frail older subjects with a history of recurrent falling.