Depression induced cognitive impairment, also referred to as the dementia syndrome of depression or pseudodementia, has been well characterized, yet the extent to which the more common mild depressive symptoms influence cognition has not been well studied. We sought to identify the influence of mild depressive symptoms on verbal fluency performance in a large sample of healthy community dwelling older adults. Letter and semantic fluency testing was conducted on 188 participants (ages 60-92 years) with no known history of neurologic or psychiatric disease. Depressive symptoms were assessed with the Geriatric Depression Scale (GDS). A total of 39 subjects obtained GDS scores consistent with mild depressive symptoms (GDS=10-19), and 149 subjects were identified as not depressed (GDS<10). ANOVA indicated that subjects with mild depressive symptoms performed significantly worse than normal controls on letter fluency (p<.05), but there was no significant difference between the groups on semantic fluency. Analysis of the nondepressed group stratified into young-old, middle-old, and oldest-old revealed a significant decline in semantic (p<.001) but not letter fluency with age. The nondepressed young-old showed the expected advantage for word list generation to semantic as compared to letter categories, yet this pattern was reversed in the older age groups, where letter fluency scores exceeded semantic fluency scores. Our results suggest that the presence of even mild depressive symptoms may confound using letter versus category discrepancies in the differential diagnosis of dementia. Further, our findings suggest that the commonly used strategy of examining letter-semantic fluency discrepancies may not be relevant for individuals of advanced age. Age-stratified normative data for fluency testing in older adults is also provided.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, “clinical benefit” was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

The urea channel UT-A1 and the water channel aquaporin-2 (AQP2) mediate vasopressin-regulated transport in the renal inner medullary collecting duct (IMCD). To identify the proteins that interact with UT-A1 and AQP2 in native rat IMCD cells, we carried out chemical cross-linking followed by detergent solubilization, immunoprecipitation, and LC-MS/MS analysis of the immunoprecipitated material. The analyses revealed 133 UT-A1-interacting proteins and 139 AQP2-interacting proteins, each identified in multiple replicates. Fifty-three proteins that were present in both the UT-A1 and the AQP2 interactomes can be considered as mediators of housekeeping interactions, likely common to all plasma membrane proteins. Among proteins unique to the UT-A1 list were those involved in posttranslational modifications: phosphorylation (protein kinases Cdc42bpb, Phkb, Camk2d, and Mtor), ubiquitylation/deubiquitylation (Uba1, Usp9x), and neddylation (Nae1 and Uba3). Among the proteins unique to the AQP2 list were several Rab proteins (Rab1a, Rab2a, Rab5b, Rab5c, Rab7a, Rab11a, Rab11b, Rab14, Rab17) involved in membrane trafficking. UT-A1 was found to interact with UT-A3, although quantitative proteomics revealed that most UT-A1 molecules in the cell are not bound to UT-A3. In vitro incubation of UT-A1 peptides with the protein kinases identified in the UT-A1 interactome revealed that all except Mtor were capable of phosphorylating known sites in UT-A1. Overall, the UT-A1 and AQP2 interactomes provide a snapshot of a dynamic process in which UT-A1 and AQP2 are produced in the rough endoplasmic reticulum, processed through the Golgi apparatus, delivered to endosomes that move into and out of the plasma membrane, and are regulated in the plasma membrane.

There is a paucity of large‐scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly‐diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60–88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale‐Geriatrics (CIRS‐G) score was 6 (range, 0–27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high‐dose methotrexate (HD‐MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R‐MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58‐month median follow‐up, median progression‐free survival (PFS) and overall survival (OS) were 17 months (95% CI 13–22 months) and 43 months (95% CI 31–56 months), respectively. Three‐year PFS and OS were highest with MTR (55% and 74%, respectively). With single‐agent methotrexate ± rituximab, 3‐year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS‐G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3‐year PFS was 65% versus 45% without maintenance (p = 0.02), with 3‐year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD‐MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.