Citations

Abstract Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial–mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.

Moyamoya angiopathy is a rare cerebral vasculopathy characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of abnormal collateral vessels. Children with moyamoya angiopathy become symptomatic because of cerebral ischemic complications, and many patients eventually need revascularization. In most pediatric patients with this disease, the etiology is likely genetic. We aim to report clinical characteristics of a single-center cohort of pediatric patients with moyamoya. We performed a retrospective chart review of patients <18 years with angiographically confirmed moyamoya disease evaluated at our institution. An in-house text search tool, Advanced Cohort Explorer, was used to filter electronic medical records for patients with a diagnosis of moyamoya angiopathy from January 1999 to December 2018. The inclusion criteria were age <18 years at the time of onset of disease and a diagnosis confirmed at Mayo clinic. Fifty-one patients met the inclusion criteria. Fifty-five percent of our cohort were male, and the median age was 9 years. Three patients had a family history of moyamoya disease. Approximately half of our patients had bilateral disease. Sixteen patients had a genetic or chromosomal diagnosis (Down syndrome and NF1 being most common). Congenital anomalies like heart defects and renal dysplasia were also noted. This study is unique in that it was a large study on pediatric patients with moyamoya angiopathy. It also highlights the importance of considering genetic syndromes as an underlying cause when moyamoya angiopathy starts early in life.

Abstract Background: There is a significant variation in disease incidence and outcomes among Multiple Myeloma (MM) patients (pts) from different ethnic backgrounds. Currently, there is a paucity of data regarding the influence of demographics and ethnicity on behavioral patterns of pts, their attitudes, beliefs, and knowledge about MM and its treatment, which could in turn affect outcomes. We conducted a questionnaire-based study to examine behavioral patterns of MM pts, especially focusing on ethnic minorities and how this may impact patient awareness and symptom complex related to the disease and its treatment. Methods: Apaper-basedquestionnaire consisting of 61 questions encompassing four broad categories was provided to participating pts at the University of Southern California Medical Centers. These included demographics, disease/treatment related quality of life (QoL), satisfaction regarding treatment, and satisfaction regarding treating physician/healthcare staff. Information on clinical characteristics and MM-related treatment was collected through an IRB-approved protocol. Pts were stratified by age, gender, and ethnicity (Hispanics vs. Non-Hispanics). Any missing patient responses were withdrawn from the final analysis of that question. Categorical and continuous variables were compared among groups using Chi-square and Kruskal-Wallis tests, respectively. All statistical analysis utilized SAS software (v9.3) with a two-sided significance level of 0.05. Results: A total of 89 pts (males: 40, females: 49) from March 2012 to October 2013 responded to the questionnaire of the 100 pts that were consented (81%). Median age was 59 (range: 23-81) years and 43 (48%) pts were Hispanic while 46 (52%) were Non-Hispanic. Baseline clinical characteristics are shown in Table 1A. As compared to Non-Hispanics, Hispanic pts were less likely to have completed college (70% vs. 30%, p<0.001), attend myeloma support groups (90% vs. 10%, p=0.026), feel they had sufficient disease/treatment-related information (72% vs. 22.5%, p<0.001). Hispanic pts were more likely to report being unemployed/without any income (57.5% vs. 9%, p<0.001), have 3-4 people living in the house (57.5% vs. 26 %, p=0.009), feeling ill (43% vs. 21%, p=0.029), have concern about deterioration in clinical condition (66% vs. 41%, p=0.022), and inability to work due to symptoms from MM or its treatment (38.6% vs. 11.9%, p=0.005) when compared to Non-Hispanics. With respect to MM treatment, Hispanic pts were less likely to report that side effects were as expected (34% vs. 57%, p=0.036) and believe that treating staff worked towards the same goal (88% vs. 100%, p=0.020) as them. Hispanic pts also reported a lower level of satisfaction with their doctor /treatment staff, as compared to Non-Hispanic pts and this difference was statistically significant as shown in Table 1B. Using gender as the stratification factor, we noted that female pts were more likely to report lack of energy (p=0.037), pain (p=0.010), satisfaction with discussion on emotional health (p=0.012) as compared to males. With age as the stratification factor, patients < 60 years of age were less likely to report expected effectiveness from treatment (p=0.031), satisfaction regarding appropriateness of treatment (p=0.008) or explanation of test results by their doctor (p=0.036), and were more likely to worry about deterioration in their condition (p=0.014). We did not find a statistically significant association between age, gender, or ethnicity and response to initial myeloma treatment. Conclusions: We found a significant association between MM patient ethnicity and the pts responses to questions pertaining to their QoL, satisfaction with treatment and treating physician. This difference in disease/treatment related knowledge and attitudes may be related to socio-cultural and behavioral patterns and may contribute to factors such as treatment compliance, effectiveness and symptom complex burden amongst others, that can impact outcomes among ethnic subgroups of MM pts. Efforts to mitigate these differences should focus on improving methods of patient education, spread more awareness among ethnic minorities, integration of psychosocial care into cancer therapy and promoting health psychology research. Disclosures No relevant conflicts of interest to declare.

Autophagy has been shown to be a key cellular event controlling tumor growth in different neoplasms including hepatocellular carcinoma (HCC). Although this biological role of autophagy has been clearly established, the mechanism underlying its regulation remains elusive. Here, we demonstrate a role of sulfatase 2 (SULF2), a 6‐O‐endosulfatase modulating various growth factors and cytokine‐related signaling pathways controlling tumor cell proliferation and survival, in the regulation of autophagy in HCC cells. SULF2 increased autophagosome formation, shown by increased LC3B‐II protein and green fluorescent protein–LC3 puncta. Increased fusion between autophagosomes and lysosomes/lysosomal enzymes, higher expression of lysosomal membrane protein, and an increase in autolysosomes were also shown by western blot, immunofluorescence, and electron microscopy of SULF2‐expressing cells, indicating enhanced autophagic flux. In contrast, RNA‐interference silencing of SULF2 in Huh7 cells induced lysosomal membrane permeabilization with diffuse cytosolic staining of cathepsin D and punctate staining of galectin‐3. Analysis of the mechanism showed that inhibition of lysosome‐associated protein transmembrane 4 beta (LAPTM4B), a gene induced by SULF2, resulted in decreased autophagosome formation, decreased fusion between autophagosomes and lysosomes, and increased lysosomal membrane permeabilization. Interestingly, down‐regulation of LAPTM4B also phenocopies the knockdown of SULF2, significantly reducing cell viability and colony formation. Conclusion: Our results demonstrate a role for SULF2 in the regulation of autophagic flux that is mediated through LAPTM4B induction in HCC cells, and provide a foundation for future translational efforts targeting autophagy in liver malignancies.

Innate immune sensing is essential for the proinflammatory program in cellular senescence.

PURPOSE Nivolumab, an anti–programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. METHODS Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. RESULTS A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD ( P = .041). CONCLUSION Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.

Background: The deep intramuscular approach during buttock augmentation with fat grafting has been associated with a significantly increased risk for pulmonary fat embolism. This study was designed to provide guidance for injection into the subcutaneous fat. Methods: The authors investigated 150 Caucasian individuals with an equal distribution of men and women (n = 75 each) and a balanced distribution of age (n = 30 per decade: 20 to 29, 30 to 39, 40 to 49, 50 to 59, and 60 to 69 years) and body mass index (n = 50 per group: ≤24.9 kg/m2, between 25.0 and 29.9kg/m2, and ≥30 kg/m2). Ultrasound-based measurements were conducted of the thickness of the total, superficial, and deep gluteal fatty layers. Results: An increase in body mass index of 1.0 kg/m2 corresponded to an increase of 3 mm of the total gluteal subcutaneous fat of men and a 4-mm increase of the total gluteal subcutaneous fat in women. With increasing age, the thickness of the deep fatty layer increased, whereas with increasing body mass index the thickness of the superficial layer primarily increased. Formulas were generated to estimate the total thickness of the gluteal subcutaneous fatty layer for men [total thickness (in millimeters) = −33.56 + (age × 0.078) + (body mass index × 3.042)] and women [total thickness (in millimeters) = −56.997 + (age × 0.1) + (body mass index × 3.86)]. Conclusions: Knowing the total thickness of the gluteal subcutaneous fat (i.e., the safe space) allows surgeons to estimate their operating range for cannula motion even if no ultrasound machine is available during buttock augmentation with fat grafting. This can increase safety, potentially reducing the number of adverse events.