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Background Sunitinib is a multi‐target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet‐derived growth factor receptor (PDGFR), colony‐stimulating factor receptor (CSFR), and the stem cell factor receptor c‐KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP‐12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non‐overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression‐free survival (PFS) in mRCC. Methods We undertook a phase II, multi‐center, single cohort, open‐label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy. Results Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8–25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non‐evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar‐plantar erythrodysesthesia syndrome. Conclusion Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.

Targeted therapies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib are better tolerated and have become standard of care for CLL. TABLE 1 Patient demographics and outcomes Patient demographic All cohorts n = 6 Cohort 1 (8 mg/m2) n = 3 Cohort 2 (12 mg/m2) n = 3 a Sex Male 5 2 3 Female 1 1 0 Age Median (range) 72 (52–75) 71 (52–75) 73 (60–75) <65 y 2 1 1 ≥65 y 4 2 2 BMI Median (range) 31.0 (21.2–38.2) 26.5 (21.2–32.9) 32.1 (29.9–38.2) Race White 6 (100%) 3 (100%) 3 (100%) Ethnicity Other (non-Hispanic/Latino) 6 (100%) 3 (100%) 3 (100%) ECOG score 0 1 (16.7%) 1 (33.3%) 0 (0%) 1 5 (83.3%) 2 (66.7%) 3 (100%) Years since diagnosis Median (range) 9.5 (8–12) 9 (8–12) 10 (9–10) Prior therapies Median (range) 2.5 (1–8) 2 (1–8) 3 (2–3) Prior ibrutinib 2 1 1 Patient outcomes # Cycles completed Median (range) 4.9 (1.7–6) 4.5 (2–5.3) 6 (1.7–6) # Days on study Median (range) 128 (49–178) 104 (100–154) 152 (49–178) Adverse events Median (range) 6 (2–12) 6 (6–12) 8 (2–12) Serious adverse events Total 2 1 b 1 a, c Dose limiting toxicity Total 1 0 1 Best response achieved d PR 1 a 0 1 SD 3 2 1 NE 2 1 1 a One patient initially received BNC105P 12 mg/m2 monotherapy in cycle 1 and ibrutinib 420 mg monotherapy in cycle 2 (days 1–7) but because of a 25%–50% drop in platelets from baseline (from Gr1 →Gr2) was dose reduced to 8 mg/m2 BNC105P and ibrutinib 280 mg daily (as proscribed in the protocol but not a defining DLT) and subsequently tolerated this dose for six cycles with a partial remission. b This SAE was a patient who developed cryptococcal pneumonia following heavy self-exposure to bat droppings (guano) while cleaning an attic. The SAE occurred on study cycle 3 day 7, which was outside the defined DLT time window for the study. c This SAE was sudden death (of unknown cause; no autopsy) of the patient described in footnote a who completed six cycles of 8 mg/m2 BNC105P + Ibrutinib 280 mg daily and was off combination study treatment and being treated only with ibrutinib monotherapy when the SAE occurred. d BMI, body mass index; ECOG, Eastern Cooperative Group; NE, not evaluable; PR, partial remission; SD, stable disease. Two SAEs occurred: one sudden death (unknown cause) occurred 10 days after completing study combination treatment while receiving ibrutinib monotherapy; one patient in cohort 1 developed cryptococcal pneumonia on C3D7 following heavy exposure to bat droppings (guano) at a timepoint beyond the defined DLT time window.

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer’s disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG2000/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26’s efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.

Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer’s Disease, CEs accumulate in vulnerable brain regions. Therefore, ACATs may be promising targets for treating AD. F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for antiatherosclerosis. Previously, we developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) in wild-type mice and performed an HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not overaccumulate in the brain or other tissues after repeated IVs. A histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that a 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and nonphosphorylated tau, and reduced neuroinflammation. This work lays the foundation for nanoparticle F to be used as a possible therapy for AD and other neurodegenerative diseases.

To determine if knee strength differences exist according to age group and sex among adolescents during late-stage anterior cruciate ligament reconstruction (ACLR) rehabilitation. Retrospective cohort study. Consecutive patients who had undergone ACLR with a hamstring autograft completed isokinetic knee strength assessment. Patients were categorized into early (ages 11–14 years) and middle (ages 15–17 years) adolescence. A two-way MANOVA was used to examine strength differences according to age group and sex. 144 patients were included in the analysis (56.9% females, age = 15.3 ± 1.5 years; days since surgery = 228.2 ± 41.2). Differences in quadriceps peak torque were identified between age groups on the involved (p = 0.001) and uninvolved limbs (p < 0.001), however, no differences in quadriceps peak torque were found between age groups when normalized to body mass (p = 0.16–0.49). Differences between groups according to sex were identified for each strength outcome (p < 0.01), with decreased normalized quadriceps (12–13%) and hamstring (13–16%) peak torque for females. No interactions between age group and sex were noted, F(8, 133) = 1.48, p = 0.17. Early adolescents produced less quadriceps and hamstring peak torque compared to middle adolescents after ACLR. No differences were found between age groups when normalized to body mass. •Knee strength outcomes were analyzed according to age and sex during late-stage ACLR rehabilitation in adolescents.•Females had decreased normalized quadriceps (12–13%) and hamstring (13–16%) peak torque compared to males.•Early adolescents produced less quadriceps and hamstring peak torque compared to middle adolescents.•No strength differences were found between age groups when peak torque was normalized to body mass.

Cholesterol is essential to cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is responsible by the enzymes acyl-CoA: cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 as the primary isoenzyme in most cells in humans. ACATs are targets for atherosclerosis therapies and may also be promising targets for treating Alzheimer’s Disease (AD). F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for anti-atherosclerosis. Previously, we had developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with egg phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) to wild-type (WT) mice and performed HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not over-accumulate in the brain or other tissues after repeated IVs. Histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and non-phosphorylated tau, and reduced neuroinflammation. This work lays the foundation with nanoparticle F as a possible therapy for AD and other neurodegenerative diseases.