Citations

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT‐NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles—relating to classification categories, approaches to classification, nomenclature, and grading—that the group hopes will also inform the future classification of CNS neoplasms.

Habitual reward‐seeking behavior is a hallmark of addictive behaviors. Although habitual behavior could be reversed to goal‐directed behavior, this shifting is not well studied. Here, we identify a role of astrocyte activation in the dorsomedial striatum (DMS) on transition from habitual to goal‐directed reward‐seeking behavior. Utilizing the Inscopix endomicroscopy/fiber photometry in vivo calcium imaging and the cell‐type specific activation of designer receptors exclusively activated by designer drugs (DREADDs), we confirmed that GFAP‐driven activation of hM3Dq DREADDs increases intensity and frequency of calcium signaling in the DMS astrocytes of ALDH1L1‐GCaMP6s expressing mice. We found that this chemogenetic activation of the DMS astrocytes increase and decrease neuronal excitability of direct pathway Medium Spiny Neurons (dMSNs) and indirect pathway Medium Spiny Neurons (iMSNs), respectively. Specifically, it reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in the dMSNs, whereas it increased the amplitude of the sEPSCs and decreased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the iMSNs. The changes in synaptic events induced by astrocytic activation were significantly inhibited by either of the pretreatments of DPCPX (Adenosine A1R antagonist, 1 μM), PSB12379 (Inhibitor of ectonucleotidase, CD73, 10 μM), NBTI [Inhibitor of the astrocytic adenosine transporter, equilibrative nucleoside transporter 1 (ENT1, slc29a1), 10 μM], and genetic deletion of ENT1. These data suggest that astrocytic activation‐induced synaptic activities are, in part, adenosine‐dependent. In the evaluation tests of goal‐directed and habitual reward‐seeking, the chemogenetic activation of the DMS astrocytes shifted the habitual behavior to goal‐directed action in sucrose reward‐seeking for WT, but not ENT1 KO mice. The astrocytic activation‐induced shifting was rescued when ENT1 expression was normalized in the DMS astrocytes of the ENT1 KO mice. On the other hand, when mice were trained to have goal‐directed behavior, the astrocytic activation in the DMS did not change the reward‐seeking behavioral pattern. Together, our results indicate that astrocyte‐regulated adenosine signaling in the DMS determines goal‐directed and habitual behaviors by selectively regulating synapses in the MSNs. The interaction between astrocytes and neurons via adenosine signaling could be a potential therapeutic target for maladaptive reward‐seeking behaviors. Support or Funding Information This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, and National Institute on Alcohol Abuse and Alcoholism (K01 AA027773 to SK, R01 AA018779 to DSC).

Abstract Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours.

Abstract Background: Current therapy in adult systemic mastocytosis (SM) includes observation alone, topical therapy for cutaneous disease, symptomatic non-cytoreductive therapy and cytoreductive therapy. The latter involves several drugs whose individual merit in the treatment of SM has not been well characterized. Patients and Methods: Diagnosis of SM was according to the 2001 WHO criteria (World Health Organization Classification of Tumours of Hematopoietic and Lymphoid Tissues, p 1–351. Lyon, France: IARC Press; 2001). Response to cytoreductive therapy was assessed by consensus criteria (Eur J Clin Invest.2007;37:435). The study population was selected from a series of 342 adult SM patients referred to our institution and seen between 1964 and 2008. KITD816V mutation analysis was performed by DNA sequencing. Results: A total of 134 study patients received treatment that included at least one cytoreductive drug as either first-line (n=105) or second-line (n=29) therapy. Interferon-alpha with or without prednisone (n=58), hydroxyurea (n=43), imatinib mesylate (n=42) and 2-chlorodeoxyadenosine (n=26) were the most frequently used cytoreductive agents accounting for 120 of the 134 study cases; the remaining 14 patients received other cytoreductive drugs, none of which were effective. i. Interferon-alfa (IFN-a) with or without prednisone IFN-a with or without prednisone (24 and 34 patients, respectively) was given to 12 patients with indolent SM (ISM), 14 aggressive SM (ASM), and 32 SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). For all 58 patients receiving therapy, complete (CR), major (MR), and partial (PR) response/regression were achieved in 3, 7, and 14 patients, respectively, for an overall response rate (ORR) of 41%. ORR in ISM, ASM, and SM-AHNMD was 50%, 43%, and 38%, respectively. Median duration of response was 12 months (range, 1–117 months). Anemia and elevated ESR were significantly associated with inferior ORR; 29% vs. 56% (p=0.04) and 14% vs. 57% (p=0.01), respectively. BM detection of KITD816V did not appear to affect response rates (p=0.4). ii. Hydroxyurea (HU) HU was given to 2 ASM, 40 SM-AHNMD and 1 mast cell leukemia (MCL) patients. The drug was used as first-line therapy in 30 patients. MR and PR were achieved in 1 and 8 SM-AHNMD patients, respectively (ORR=21%). Median duration of response was 37 months (range, 5–84 months). iii. Imatinib mesylate (IM) in patients with SM and associated eosinophilia IM was given to 22 SM patients who had associated eosinophilia (SM-eos): 2 had ISM, 2 ASM, and 18 SM-AHNMD. The drug was used as first-line therapy in 9 patients. Ten of the 22 patients with SM-eos were known to harbor the FIP1L1-PDGFRA fusion mutation and all responded to IM (ORR=100%). None of 5 FIP1L1-PDGFRA-negative SM-eos patients had a response to IM. In the remaining 7 patients with unknown mutation status, 4 patients had a response to IM (1 CR, 1 MR, and 2 PR). iv. IM in patients with SM not associated with eosinophilia IM was administered to 20 SM patients without associated eosinophilia (7 ISM, 2 ASM, 10 SM-AHNMD, and 1 MCL). Response was documented in 4 (20%) patients (1 CR, 1 MR, and 2 PR) including 1 with ISM, 2 with ASM and 1 with SM-AHNMD. Median duration of response was 19.5 months (range, 9–69 months). Two patients developed interstitial pneumonitis. v. 2-Chlorodeoxyadenosine (2-CdA) 2-CdA was given to 10 ISM, 3 ASM, and 13 SM-AHNMD patients; the drug was used as first-line therapy in 8 patients. CR, MR and PR were achieved in 1, 7, and 4 patients, respectively (ORR=46%). ORR in ISM, ASM, and SM-AHNMD was 50%, 33%, and 46%, respectively. Median duration of response was 11 months (range, 3–74 months). Presence of leukocytosis (WBC > 10 x 109/L), monocytosis (absolute monocyte count > 0.9 x 109/L) or circulating immature myeloid cells was significantly associated with inferior response; 13% vs. 61% (p=0.02); 11% vs. 69% (p=0.006) and 0% vs. 71%, (p=0.001), respectively. Response was not affected by BM detection of KITD816V (p=1.0). Conclusions: Both IFN-a and 2-CdA are reasonable treatment options, with comparable efficacy, for symptomatic SM including the subcategories of ISM, ASM and SM-AHNMD. IFN-a response was significantly better in the absence of anemia or elevated ESR. 2-CdA response was similarly better in the absence of leukocytosis, monocytosis or circulating immature myeloid cells. The therapeutic value of IM was limited to FIP1L1-PDGFRA-positive disease.

Abstract Background: Systemic mastocytosis (SM) has a varied presentation ranging from indolent forms with limited morbidity over many years to the rapidly fatal mast cell leukemia (MCL). This heterogeneity complicates clinical decision making regarding choice and timing of therapy. The aim of this study was to evaluate the prognostic value of the 2001 World Health Organization (WHO) classification of SM, and to refine risk stratification within SM sub-groups to facilitate clinical decision making. Information on KITD816V and JAK2V617F mutation analysis and clinical correlates is also provided. Methods: Patient records in the institutional electronic database from January 1976 to October 2007 were reviewed and SM patients 18 years of age or older identified; the date of diagnosis ranged from July 1964 to October 2007. Only those patients where diagnosis was confirmed by bone marrow (BM) histology were included in the analysis. KITD816V mutation analysis was performed by DNA sequencing. JAK2V617F was screened by allele-specific quantitative PCR analysis. Results: i. Clinical characteristics at presentation: A total of 342 SM patients were identified (154 female; median age at diagnosis=57 years; range 19 to 87 years). Per the 2001 WHO classification, 159 had indolent SM (ISM; median age=49 years), 41 aggressive SM (ASM; median age=65 years), 138 SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD; median age=65 years), and 4 MCL (median age=55 years) (p-value for age <0.0001). 140 (41%) patients had urticaria pigmentosa (UP) (63% with ISM; p<0.0001), 160 (47%) mast cell (MC) mediator release symptoms (69% with ISM; p<0.0001), 107 (31%) skeletal symptoms, and 142 (42%) constitutional symptoms (61% with ASM/SM-AHNMD versus 19% with ISM; p<0.0001). 123 patients (36%) had palpable splenomegaly (57% with SM-AHNMD; p<0.0001). 56 patients (16%) exhibited prominent eosinophilia (absolute eosinophil count >1500/mcl) – 31% and 22% with SM-AHNMD and ASM, respectively, versus 3% with ISM (p<0.0001); 12 of 23 patients (52%) with eosinophilia who were tested carried the FIP1L1-PDGFRA mutation. Serum tryptase (normal <11.5 ng/mL) was measured in 160 patients (47%) and almost all (96%) had an elevated level (median=64 ng/mL; range=4 to 2000 ng/mL; 33 patients had >200 ng/mL). ii. Disease course and prognostic factors After a median follow-up of 20.7 months (range=0–417), 153 deaths were recorded. 17 patients (5%) transformed to acute myeloid leukemia (AML; n=14) or MCL (n=3), most frequently with SM-AHNMD (11% versus 0% for ISM; p<0.0001). The median overall survival was 63 months (ISM=198 months, ASM=41 months; SM-AHNMD=24 months, and MCL=2 months; p<0.0001). Multivariate analysis of parameters at the time of diagnosis showed a significant and independent association between inferior survival and WHO sub-type (p<0.0001), age at diagnosis (p<0.0001), history of weight loss (p=0.01), anemia (p=0.007), thrombocytopenia (p=0.0008), hypoalbuminemia (p=0.0008), and excess BM blasts (>5%; p=0.004). A similar analysis in ISM identified anemia (p=0.04), hypoalbuminemia (P=0.002), and BM MC ≥ 30% (p=0.03) as independent predictors of inferior survival; the corresponding parameters in ASM were age at diagnosis (p=0.002) and history of weight loss (p=0.003). iii)KITD816V andJAK2V617F analysis Archived bone marrow was available in 165 patients for KITD816V and JAK2V617F analysis. By DNA sequencing, overall KITD816V detection rate was 28%: ISM 20%, ASM 29%, SM-AHNMD 33% (p=0.4). In patients with ASM (p=0.003) and SM-AHNMD (p=0.001), detection of KITD816V was associated with inferior survival. Greater than 1% (range 1–57) JAK2V617F allele burden was detected in 6 patients (4%); all belonged to SM-AHNMD including 4 with non-MC lineage myeloproliferative neoplasm. Conclusions: The current study confirms the prognostic value of the WHO subclassification of SM and identifies advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess BM blasts as additional adverse prognostic factors. In ISM, presence of anemia, hypoalbuminemia, or BM MC ≥ 30% is associated with inferior survival. In ASM and SM-AHNMD, BM KITD816V allele burden might influence survival. JAK2V617F is rare in SM and when found, it is almost always in the context of SM-AHNMD.

Abstract p53 deletion by fluorescence in situ hybridization (FISH) has been reported in about 10% of newly diagnosed patients (pts) with multiple myeloma (MM) and has been associated with a poor prognosis. Previous data from our centre has demonstrated that the progression-free survival (PFS) and overall survival (OS) of these pts after a single autologous stem cell transplant (ASCT) is only 16.9 and 48.2 months, respectively, compared to 24.4 and 76.6 mos, respectively, in all pts transplanted during the same time period (Mikhael et al, Blood2007; 110: abstract 953). Minimal information is available on the treatment (Tx) and course of these pts following disease progression. Therefore, we performed a retrospective review of all MM pts treated at our institution who were found to have p53 deletion. We identified 31 pts with relapsed/refractory (rel/ref) MM with this cytogenetic abnormality. At diagnosis, median age was 54 years (range, 31–70), hemoglobin 97 g/L (range, 67–149), creatinine 96 μmol/L (range, 28–1751), beta 2-microglobulin 314 nmol/L (range, 225–437), CRP 3 mg/L (range, 2–7) and LDH 205 U/L (range, 82–478); 58% were male. Immunoglobulin subtypes included: IgG (14 pts), IgA (8 pts), IgD (2 pts) and light chain only (7 pts). Concomitant cytogenetic abnormalities included 13q deletion in 68% and t(4;14) in 67% of pts evaluable. Thirty-nine percent developed plasma cell leukemia (PCL) at some point in the disease course, which was associated with a poor OS (p=0.005). All but 5 had undergone prior ASCT with a median time from diagnosis to ASCT of 8 (95% CI, 4–145) mos. Txs given for rel/ref MM consisted of the following regimens: thalidomide-based in 15, bortezomib-based in 12, lenalidomide-based in 11, alkylating agents in 9 and steroids only in 5 pts, and other regimens (D-PACE or investigational drugs) in 7 pts. The median follow-up from diagnosis in these pts is 45 (95% CI, 4–145) mos. The overall response rate (≥PR) (ORR), median PFS and median OS from the start of each regimen is shown below. Agent Median duration of Tx (mos) ORR(%) Median PFS (mos) Median OS (mos) Thalidomide 6.2 20% 5.0 11.9 Bortezomib 5.2 50% 5.6 36.1 Lenalidomide 10.6 60% 4.8 36.1 Alkylating agents 6.0 11% 5.1 30.0 Steroids 1.9 20% 1.9 33.4 Other 2.2 43% 6.3 33.4 We conclude: 1) Median PFS in pts with the p53 deletion is less than 6 months, with an OS of 2.5–3 yrs; 2) novel agents other than thalidomide produce the highest ORR in rel/ref MM with p53 deletion; 3) the short OS in the thalidomide group is likely related to the unavailability of other novel agents for subsequent relapses, as the majority of the pts were treated before 2004; 4) better strategies/drugs are required for these pts.

Abstract Background: Systemic mastocytosis (SM) sometimes coexists with an associated clonal hematological non mast cell lineage disease and such an occurrence is recognized by the 2001 World Health organization (WHO) classification system as SM-AHNMD (Leuk Res. 2001 25:603). However, SM-AHNMD has not been further stratified into prognostically relevant subgroups. This was the major objective of the current study, which also provides information on prevalence and relevance of detecting KITD816V and JAK2V617F mutations. Methods: Patient records in the institutional electronic database from January 1976 to October 2007 were reviewed and SM patients 18 years of age or older identified; the date of diagnosis ranged from July 1964 to October 2007. Only those cases where diagnosis was confirmed by bone marrow (BM) histology were included in the analysis. SM- and AHNMD-components were classified according to WHO criteria. Results: AHNMD sub-classification: Of 342 consecutive cases of SM that were screened, 138 (40%) were identified as having SM-AHNMD (median age 65 years, range 20–87). The most frequent AHNMD was chronic myelomonocytic leukemia (SM-CMML) seen in 38 (28%) patients. 23 (17%) patients had SM associated with myelodysplastic syndrome (SM-MDS), 22 (16%) with hypereosinophilic syndrome/chronic eosinophilic leukemia (SM-HES/CEL) and 33 (24%) with another myeloproliferative neoplasm (SM-MPN). The number of cases with other SM-AHNMD was much lower and included lymphoma 8 (6%), acute leukemia 3 (2%), MDS/MPN 3 (2%), and 8 (6%) cases of multiple myeloma, primary amyloidosis or chronic lymphocytic leukemia. Of the 33 SM-MPN patients, 2 had polycythemia vera, 6 essential thrombocythemia, and 2 myelofibrosis; the remaining 23 patients had an unclassified MPN in association with SM. Clinical characteristics at presentation: The combined incidence of urticaria pigmentosa (UP) was 18%, mast cell mediator release symptoms 28% and constitutional symptoms 62%. 76 patients (57%) had palpable splenomegaly. 99 patients (72%) had anemia, 18 (13%) leukopenia (43% with SM-MDS; p<0.0001) and 76 (55%) thrombocytopenia. 70 (51%) patients had leukocytosis and 63 (55%) displayed circulating immature myeloid cells (78% with CMML; p=0.001). 59 (54%) patients had elevated serum alkaline phosphatase level: SM-CMML 70%, SM-MPN 60%, SM-HES/CEL 40%, and SM-MDS 30% (p=0.01). Where evaluated, serum tryptase was elevated in 92% of the patients (median=75 ng/mL; range=4–1360). BM blasts were ≥5% in 25 patients (22%), including 48% with SM-MDS (p=0.004). 12 of 35 patients tested carried the FIP1L1-PDGFRA mutation (all had SM-HES/CEL; p<0.0001). Disease course and prognostic factors At a median follow up of 15 months (range 0–182), 99 deaths were recorded and the combined median survival was 24 months: SM-CMML 15 months; SM-MDS 15 months, SM-MPN 30 months; and SM-HES/CEL 87 months (p=0.003). Fifteen patients (11%) transformed to acute leukemia or mast cell leukemia. Multivariate analysis of parameters at the time of diagnosis showed a significant and independent association between inferior survival and SM-AHNMD sub-type (p=0.007), presence of constitutional symptoms (p=0.04), thrombocytopenia (p=0.01), presence of circulating immature myeloid cells (p=0.006), and hypoalbuminemia (p<0.0001). In SM-CMML, hypoalbuminemia was associated with inferior survival (p=0.03). KIT D816V and JAK2 V617F analysis: Archived BM was available in 88 patients for KITD816V and JAK2V617F analysis. By DNA sequencing, overall KITD816V detection rate was 33%: SM-CMML 48%, SM-MDS 21%, SM-HES 8%, and SM-MPN 45% (p=0.03). In patients with SM-HES/CEL (p=0.0009) and SM-MPN (p=0.04), detection of KITD816V was associated with inferior survival. Greater than 1% (range 5–57) JAK2V617F allele burden was detected in 6 patients (9%): 4 in SM-MPN, 1 in SM-CMML and 1 in SM-MDS. Conclusions: The WHO-defined SM-AHNMD comprises prognostically diverse subcategories among which SM-CMML is the most frequent. Survival is favorable in SM-HES/CEL and significantly worse in SM-CMML and SM-MDS. Additional independent predictors of inferior survival include constitutional symptoms, thrombocytopenia, circulating immature myeloid cells, and hypoalbuminemia. In SM-HES/CEL and SM-MPN, BM KITD816V allele burden may influence survival. JAK2V617F occurs infrequently in SM-AHNMD and when it does, it clusters with SM-MPN.

ABSTRACT Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports the mechanistic target of rapamycin complex 1 (mTORC1) signaling under basal and amino acid-stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase, and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling. This article has an associated First Person interview with the first author of the paper.