Cisplatin chemotherapy causes permanent hearing loss in 40–80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity.

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work has demonstrated that increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms. Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan – elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms.

Aging is the greatest risk factor for the development of Parkinson’s disease (PD). However, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when inherited mutations that cause the disease can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages. If so, then interventions that increase lifespan should be beneficial in the treatment of PD. To test this hypothesis, we used the powerful genetics of C. elegans, as this worm has been used extensively in aging research. We crossed transgenic worm models of PD expressing either human mutant α-synuclein (A53T) or LRRK2 (G2019S) with the long-lived insulin-IGF1 receptor mutant, daf-2. The daf-2 mutation increased the lifespan of both PD mutants. The increase in lifespan resulting from the daf-2 mutation rescued the degeneration of dopamine neurons in both worm models of PD and importantly rescued deficits in dopamine-dependent behaviors including basal slowing, ethanol avoidance, and area-restricted searching. Increasing lifespan through daf-2 mutation also delayed the formation of small aggregates in a worm model of PD expressing α-synuclein in the body wall muscle and rescued deficits in resistance to different stresses that were present in the PD mutant worms. Overall, this work suggests that slowing down the aging process may provide an effective treatment for PD.

Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti–PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti–PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti–PD-L1/PD-1 therapy.

While the pathogenesis of Parkinson’s disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.

No abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the formation of α-synuclein-containing protein aggregates called Lewy bodies within the brain. A crucial role for α-synuclein in the pathogenesis of PD is also suggested by the fact that point mutations, increased copy number, or polymorphisms in the α-synuclein gene SNCA all cause or contribute to the development of PD. In addition to SNCA, an increasing number of other genes have been implicated in PD. While mutations in at least some of these genes have been shown to cause the formation of Lewy bodies, the role of α-synuclein in these genetic forms of PD remains poorly defined. Since C. elegans do not have a homolog of α-synuclein, this organism provides the opportunity to identify synergism between α-synuclein and other genes implicated in PD. To do this, we generated a novel C. elegans model in which wild-type α-synuclein is ubiquitously expressed from a single copy transgene, and examined the resulting effect on phenotypic deficits in PD deletion mutants affecting PARK2/pdr-1, PINK1/pink-1, DJ-1/djr-1.1 and ATP13A2/catp-6. While the PD deletion mutants exhibit only mild phenotypic deficits in absence of α-synuclein, expression of wild-type α-synuclein caused increased sensitivity to multiple stresses, induced deficits in dopamine-dependent behavior, and accelerated loss of dopamine neurons. Overall, these results suggest that the recessive loss of function mutations act together with α-synuclein to cause PD, and that α-synuclein lowering strategies may be effective in genetic forms of PD.

Objective: To create a longitudinal near-peer mentorship program for medical students applying to otolaryngology. Methods: A program for longitudinal near-peer mentorship was designed based on a needs analysis of senior medical students. Program objectives were to (1) provide didactic education on common otolaryngology consults, (2) facilitate resident-student networking, and (3) enable applicants to meet other students. Senior otolaryngology residents were matched with medical students from across the United States applying to otolaryngology for a series of online small group meetings. Sessions included resident-designed didactics covering high-yield clinical scenarios and a mentorship component focused on transition to residency topics. Program evaluation included anonymized pre- and post-tests for each didactic session and an anonymous post-program participant survey. Results: There were 40 student participants from across the United States, with an average attendance of 73% of sessions per participant. Performance on didactic testing improved for 2 of the 3 sessions. Participants stated they would be very likely to recommend each session to another student in the future (4.96/5.00, obs = 155). Participants stated the most valuable part of the program was interacting with residents (82% of responses), transition to residency advice (28%), and learning about otolaryngology consults (28%). Suggestions for improvement included expanding content, increasing the number of sessions, and involving additional faculty and residents. Conclusion: A longitudinal virtual experience can be valuable for near-peer mentorship for medical students applying to otolaryngology.