Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells

The role of the Ras/MEK/ERK pathway was examined in relation to DNA damage in human multiple myeloma (MM) cells exposed to Chk1 inhibitors in vitro and in vivo. Exposure of various MM cells to marginally toxic concentrations of the Chk1 inhibitors UCN-01 or Chk1i modestly induced DNA damage, accompanied by Ras and ERK1/2 activation. Interruption of these events by pharmacologic (eg, the farnesyltransferase inhibitor R115777 or the MEK1/2 inhibitor PD184352) or genetic (eg, transfection with dominant-negative Ras or MEK1 shRNA) means induced pronounced DNA damage, reflected by increased gammaH2A.X expression/foci formation and by comet assay. Increased DNA damage preceded extensive apoptosis. Notably, similar phenomena were observed in primary CD138(+) MM cells. Enforced MEK1/2 activation by B-Raf transfection prevented R115777 but not PD184352 from inactivating ERK1/2 and promoting Chk1 inhibitor-induced gammaH2A.X expression. Finally, coadministration of R115777 diminished UCN-01-mediated ERK1/2 activation and markedly potentiated gammaH2A.X expression in a MM xenograft model, associated with a striking increase in tumor cell apoptosis and growth suppression. Such findings suggest that Ras/MEK/ERK activation opposes whereas its inhibition dramatically promotes Chk1 antagonist-mediated DNA damage. Together, these findings identify a novel mechanism by which agents targeting the Ras/MEK/ERK pathway potentiate Chk1 inhibitor lethality in MM.     

A randomized trial of functional electrical stimulation for walking in incomplete spinal cord injury: Effects on walking competency

Background

Multi-channel surface functional electrical stimulation (FES) for walking has been used to improve voluntary walking and balance in individuals with spinal cord injury (SCI).

Objective

To investigate short- and long-term benefits of 16 weeks of thrice-weekly FES-assisted walking program, while ambulating on a body weight support treadmill and harness system, versus a non-FES exercise program, on improvements in gait and balance in individuals with chronic incomplete traumatic SCI, in a randomized controlled trial design.

Methods

Individuals with traumatic and chronic (≥18 months) motor incomplete SCI (level C2 to T12, American Spinal Cord Injury Association Impairment Scale C or D) were recruited from an outpatient SCI rehabilitation hospital, and randomized to FES-assisted walking therapy (intervention group) or aerobic and resistance training program (control group). Outcomes were assessed at baseline, and after 4, 6, and 12 months. Gait, balance, spasticity, and functional measures were collected.

Results

Spinal cord independence measure (SCIM) mobility sub-score improved over time in the intervention group compared with the control group (baseline/12 months: 17.27/21.33 vs. 19.09/17.36, respectively). On all other outcome measures the intervention and control groups had similar improvements. Irrespective of group allocation walking speed, endurance, and balance during ambulation all improved upon completion of therapy, and majority of participants retained these gains at long-term follow-ups.

Conclusions

Task-oriented training improves walking ability in individuals with incomplete SCI, even in the chronic stage. Further randomized controlled trials, involving a large number of participants are needed, to verify if FES-assisted treadmill training is superior to aerobic and strength training.     

Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors

PurposeSeveral immune checkpoint inhibitors (ICIs) are FDA approved for treatment of genitourinary (GU) malignancies. We aim to determine demographic and clinicopathologic characteristics that significantly affect clinical outcomes in patients with advanced stage GU malignancies treated with ICIs.Materials and methodsWe performed a single-center, consecutive, retrospective cohort analysis on patients with metastatic or unresectable GU malignancies who were treated with ICIs at the University of Michigan. Immune-related adverse events (irAEs), putative immune-mediated allergies, and overall response rates (ORR) were assessed. Comorbidity index scores were calculated. Survival analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS), stratifying and controlling for a variety of clinicopathologic baseline factors including site of metastases.ResultsA total of 160 patients were identified with advanced renal cell carcinoma (RCC) or urothelial carcinoma. Median PFS and OS were 5.0 and 23.6 months for RCC, and 2.8 and 9.6 months for urothelial carcinoma, respectively. Patients who experienced increased frequency and higher grade irAEs had better ICI treatment response (P < 0.0001). Presence of liver metastases was associated with poor response to ICI therapy (P = 0.001). Multivariable modeling demonstrates that patients with urothelial carcinoma and liver metastases had statistically worse PFS and OS compared to patients with RCC or other sites of metastases, respectively.ConclusionGreater frequency and higher grades of irAEs are associated with better treatment response in patients with RCC and urothelial malignancy receiving ICI therapy. The presence of liver metastases denotes a negative predictive marker for immunotherapy efficacy.SummaryImmune checkpoint inhibitors (ICI) are increasingly used to treat genitourinary (GU) malignancies. However, clinical data regarding patients with advanced-stage GU malignancies treated with ICI is lacking. Thus, we performed a single-center, retrospective cohort study on patients with metastatic and unresectable renal cell carcinoma (RCC) and urothelial carcinoma who were treated with ICIs at the University of Michigan to provide demographic and clinicopathologic data regarding this population. We specifically focused on immune-related adverse events (irAEs), immune-mediated allergies, and the associated overall response rates (ORR). To better assess performance status, we calculated comorbidity scores for all patients. Finally, survival analyses for progression-free survival (PFS) and overall survival (OS) were performed using Kaplan-Meier analysis and Cox proportional hazards modeling, stratifying and controlling for clinicopathologic baseline factors, including sites of metastases, in our multivariable analysis. A total of 160 patients were identified with advanced RCC or urothelial carcinoma. We found decreased PFS (2.8 vs. 5.0 months) and decreased OS (9.8 vs. 23.6 months) for urothelial carcinoma compared to RCC patients. We noted that patients who experienced increased frequency and higher grades of irAEs had better treatment ORR with ICI therapy (P ≤ 0.0001). The presence of liver metastases was associated with worse ORR (P = 0.001), PFS (P = 0.0014), and OS (P = 0.0028) compared to other sites of metastases including lymph node, lung, and CNS/bone. The poor PFS and OS associated with urothelial carcinoma and liver metastases were preserved in our multivariable modeling after controlling for pertinent clinical factors. We conclude that greater frequency and higher grades of irAEs are associated with better treatment response in GU malignancy patients receiving ICI, a finding that is consistent with published studies in other cancers. The presence of liver metastases represents a significantly poor predictive marker in GU malignancy treated with ICI. Our findings contribute to the growing body of literature that seeks to understand the clinicopathologic variables and outcomes associated with ICI therapy.     

Preventing Fractures in Long-Term Care: Translating Recommendations to Clinical Practice

The Ontario Osteoporosis Strategy for long-term care (LTC) aims to support fracture risk-reduction. LTC specific recommendations for fracture prevention were developed in 2015. This article describes the use of the Knowledge-to Action framework to guide the development and application of research evidence on fracture prevention in older adults. Knowledge translation activities highlighted fractures as a significant source of morbidity in LTC, significant gaps in fracture risk assessment and treatment, and barriers and facilitators to guideline implementation. Multifaceted knowledge translation strategies, targeting staff in LTC homes in Ontario, Canada to support fracture guideline implementation have included education, audit and feedback, team-based action planning, and engagement of LTC residents, their families, and health professionals. Provincial administrative databases were accessed to monitor fracture rates between 2005 and 2015. Our research has identified enablers and barriers to knowledge use such as limited knowledge of osteoporosis, fracture risk, and prevention. Province-wide over a 10-year period, hip fracture rates in LTC decreased from 2.3% to 1.9%, and any fracture rates decreased from 4% to 3.6%. This body of work suggests that multifaceted knowledge translation initiatives are feasible to implement in LTC and can improve the uptake of clinical recommendations for fracture prevention. A key aspect of our fracture prevention knowledge translation activities has been the full engagement of key stakeholders to assist in the co-development and design of knowledge translation products.     

Effect of a Telephone Intervention Upon Self-Reported Medication Adherence and Self-Efficacy in Outpatients With Schizophrenia Spectrum Disorders (SSDs)

We conducted a randomized controlled trial to determine the effect of weekly telephone intervention upon self-reported medication adherence, medication adherence self efficacy, and symptom levels in 140 stable outpatients with SSDs for three months. To our knowledge, this is the first study examining medication adherence self efficacy in persons with SSDs. Study measures were administered in a private office by trained study staff immediately following the granting of informed consent, and again after three months. Participants ranged in age from 19–71 years with an average age of 46.1 years (SD 12.9). A majority were males (n = 80, 57.1%) with schizoaffective disorder (n = 94, 67.1%). Symptoms were lower and self-reported medication adherence was higher in experimental participant after three months, but differences were not statistically significant. Medication adherence self efficacy was essentially unchanged over the three month follow up period. This study extends the literature on adherence in SSDs by describing a clinic-based sample of stable outpatients, and is the first investigation to measure medication adherence self efficacy in this group. Our next project will examine the effectiveness of TIPS upon objectively measured medication adherence in this group over 6 months of follow up.     

Interpersonal factors predict increased desire for hastened death in late-stage cancer patients

Background: Cancer patients at the end of life sometimes express a wish that death would come quickly, but this desire for hastened death (DHD) remains little understood. Relationships with spousal caregivers may play a role in patients’ DHD.Purpose: This study examined factors that could predict an increase in the DHD in late-stage cancer patients over the course of 4 months, including marital and caregiving variables that have not previously been examined.Method: itPatients completed the Schedule of Attitudes Toward Hastened Death and other measures, including the Dyadic Adjustment Scale. Caregivers were asked how many hours they spent weekly in caregiving activities and completed the Caregiver Demands Scale. Approximately 4 months later, DHD was reassessed in surviving patients.Results: Sixty caregiver/patient dyads completed all measures. Desire for hastened death was generally low at both assessments; however, more depression and greater dyadic adjustment reported by patients, and more hours spent in caregiving activities by spouses, each independently predicted increased DHD in patients at the Time 2 assessment.Conclusions: Findings suggest that issues related to spousal caregivers play an important role in the course of DHD in cancer patients at the end of life. This research was supported by a grant from the National Institute of Nursing Research to Michael A. Weitzner (R01-NR05228). We are grateful to Lori Dietz for assistance in the article’s preparation.     

Promoting excellence in end-of-life care in ALS.

The type and quality of end-of-life care varies greatly in ALS; the time to initiate end-of-life care is not defined, and decision making is hampered by logistical and financial barriers. There has been no systematic review of these issues in ALS. The goals of this initiative are to: 1) improve end-of-life care for patients with ALS and families based on what limited evidence is available; 2) increase awareness, interest, and debate on the end-of-life care in ALS; and 3) identify areas needed for new prospective clinical research. The ALS Peer Workgroup reviewed the literature and 1) identified the current state of knowledge, 2) analysed the gaps in care, and 3) provided recommendations for standard of care and future research. It was shown that areas of investigation are needed on the incorporation of an interdisciplinary approach to care in ALS that includes: psychosocial evaluation and spiritual care; the use of validated instruments to assess patient and caregiver quality of life; and the establishment of proactive caregiver programs. Several public policy changes that will improve coverage for medical care, hospice, and caregiver costs are also reviewed. More clinical evidence is needed on how to provide optimal end-of-life care specifically in ALS.     

Impacts of climate variability and future climate change on harmful algal blooms and human health

Anthropogenically-derived increases in atmospheric greenhouse gas concentrations have been implicated in recent climate change, and are projected to substantially impact the climate on a global scale in the future. For marine and freshwater systems, increasing concentrations of greenhouse gases are expected to increase surface temperatures, lower pH, and cause changes to vertical mixing, upwelling, precipitation, and evaporation patterns. The potential consequences of these changes for harmful algal blooms (HABs) have received relatively little attention and are not well understood. Given the apparent increase in HABs around the world and the potential for greater problems as a result of climate change and ocean acidification, substantial research is needed to evaluate the direct and indirect associations between HABs, climate change, ocean acidification, and human health. This research will require a multidisciplinary approach utilizing expertise in climatology, oceanography, biology, epidemiology, and other disciplines. We review the interactions between selected patterns of large-scale climate variability and climate change, oceanic conditions, and harmful algae.