Management of cancer in the older adult

Cancer incidence and mortality rise exponentially in the elderly. With the aging of the population there is an urgent need to address this issue with evidence-based guidelines. Delayed diagnosis and incomplete workup and treatment are well documented in this population. Incorporation of a geriatric evaluation in oncology practice should be routinely implemented to prevent adverse outcomes. Treatment decisions in the elderly should not be based solely on survival gains but should also take quality of life into consideration. Cancer treatment is safe and effective in the elderly population. Social issues and other comorbidities should be addressed to improve compliance and outcome. Many unanswered questions regarding the optimal management of elderly cancer patients can be addressed only with the new clinical trials. Eliminating age bias among health care providers by providing education will help achieve optimal care for the elderly with cancer.     

Synthesis and in vitro anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates as potential SERMs with computational validation

A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive, i.e. MCF-7 (ER+), and triple-negative, i.e. MDA-MB-231 (ER−), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.

Design, synthesis and anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates.     

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies.     

Massive transfusion in paediatric and adolescent trauma patients: Incidence,patient profile,and outcomes prior to a massive transfusion protocol

Objectives

The purpose of this study was to quantify the incidence, patient profile, and outcomes associated with massive transfusion in paediatric trauma patients prior to establishing a massive transfusion protocol.

Methods

We performed a retrospective review of paediatric trauma patients treated at London Heath Sciences Centre between January 1, 2006, and December 31, 2011. Inclusion criteria were Injury Severity Score (ISS) greater than 12 and age less than 18 years.

Results

435 patients met the inclusion criteria. Three hundred and fifty-six (82%) did not receive packed red blood cells in the first 24 h, 66 (15%) received a non-massive transfusion (<40 mL/kg), and 13 (3%) received a massive transfusion (>40 mL/kg). Coagulopathy of any kind was more common in massive transfusion (11/13; 85%) than non-massive (32/66; 49%) (p = 0.037). Hyperkalemia (18% versus 23%; p = 0.98) and hypocalcemia (41% versus 46%; p = 1.00) were similar in both groups. Of the 13 massively transfused patients, 9 had multisystem injuries due to a motor vehicle collision, 3 had non-accidental head injuries requiring surgical evacuation, and 1 had multiple stab wounds. In the absence of a massive transfusion protocol, only 8 of the 13 patients received both fresh frozen plasma and platelets in the first 24 h. Massive transfusion occurred in patients from across the age spectrum and was associated with severe injuries (mean ISS = 33), a higher incidence of severe head injuries (92%), longer hospital stay (mean = 36 days), and increased mortality (38%).

Conclusions

This study is the first to describe the incidence, complications, and outcomes associated with massive transfusion in paediatric trauma patients prior to a massive transfusion protocol. Massive transfusion occurred in 3% of patients and was associated with coagulopathy and poor outcomes. Protocols are needed to ensure that resuscitation occurs in a coordinated fashion and that patients are given appropriate amounts of fresh frozen plasma, platelets, and cryoprecipitate.     

Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin’s ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.     

Hydroxyapatite nanorods loaded with parathyroid hormone (PTH) synergistically enhance the net formative effect of PTH anabolic therapy

Parathyroid hormone (PTH) has been a major contributor to the anabolic therapy for osteoporosis, but its delivery to bone without losing activity and avoiding adverse local effects remain a challenge. Being the natural component of bone, use of hydroxyapatite for this purpose brings a major breakthrough in synergistic anabolism. This study focuses on synthesis, characterization and evaluation of in vitro and in vivo efficacy of PTH (1-34) adsorbed hydroxyapatite nanocarrier for synergistic enhancement in the anabolic activity of PTH for bone regeneration. The negative zeta potential of this nanocarrier facilitated its affinity to the Ca²⁺ rich bone tissue and solubilization at low pH enhanced specific delivery of PTH to the resorption pits in osteoporotic bone. In this process, PTH retained its anabolic effect and at the same time an increase in bone mineral content indicated enhancement of the net formative effect of the PTH anabolic therapy.     

Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel

For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca²⁺-activated K⁺ channels (K_Ca2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca²⁺-dependent. Further, the Ca²⁺ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.Small-conductance Ca²⁺-activated K⁺ (SK or K_Ca2) channels are highly unique in that they are gated solely by changes in intracellular Ca²⁺ (Ca²⁺_i) concentration. Hence, the channels function to integrate changes in Ca²⁺ concentration with changes in membrane potentials. SK channels have been shown to be expressed in a wide variety of cells (1–3) and mediate afterhyperpolarizations following action potentials in neurons (1, 4, 5). We have previously documented the expression of several isoforms of SK channels in human and mouse atrial myocytes that mediate the repolarization phase of the atrial action potentials (6, 7). We further demonstrated that SK2 (K_Ca2.2) channel knockout mice are prone to the development of atrial arrhythmias and atrial fibrillation (AF) (8). Conversely, a recent study by Diness et al. suggests that inhibition of SK channels may prevent AF (9). Together, these studies underpin the importance of the precise control for the expression of these ion channels in atria and their potential to serve as a future therapeutic target for AF.Current antiarrhythmic agents target the permeation and gating properties of ion channel proteins; however, increasing evidence suggests that membrane localization of ion channels may also be pharmacologically altered (10). Furthermore, a number of disorders have been associated with mistrafficking of ion channel proteins (11, 12). We have previously demonstrated the critical role of α-actinin2, a cytoskeletal protein, in the surface membrane localization of cardiac SK2 channels (13, 14). Specifically, we demonstrated that cardiac SK2 channel interacts with α-actinin2 cytoskeletal protein via the EF hand motifs in α-actinin2 protein and the helical core region of the calmodulin (CaM) binding domain (CaMBD) in the C terminus of SK2 channel. Moreover, direct interactions between SK2 channel and α-actinin2 are required for the increase in cell surface localization of SK2 channel.Here, to further define the functional interactome of SK2 channel in the heart, we demonstrate the role of filamin A (FLNA), another cytoskeletal protein, in SK2 channel surface membrane localization. In contrast to α-actinin2 protein, FLNA interacts not with the C terminus, but with the N terminus of the cardiac SK2 channel. FLNA is a scaffolding cytoskeletal protein with two calponin homology domains that has been shown to be critical for the trafficking of a number of membrane proteins (15–19). Our data demonstrate that FLNA functions to enhance membrane localization of SK2 channels. Moreover, using live-cell imaging, we demonstrate the critical roles of Ca²⁺_i on the membrane localization of SK2 channel when the channels are coexpressed with α-actinin2, but not FLNA. A decrease in Ca²⁺_i results in a significant decrease in SK2 channel membrane localization. Our findings may have important clinical implications. A rise in Ca²⁺_i—for example, during rapid pacing or atrial tachyarrhythmias—is predicted to increase the membrane localization of SK2 channel and result in the abbreviation of the atrial action potentials and maintenance of the arrhythmias.