Rapalogs induce non-apoptotic,autophagy-dependent cell death in HPV-negative TP53 mutant head and neck squamous cell carcinoma

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.     

Anatomic vs. reverse shoulder arthroplasty for glenohumeral osteoarthritis with intact rotator cuff: a retrospective comparison of patient-reported outcomes using the systems outcomes database with up to 5-year follow-up

BackgroundThe growing enthusiasm for the use of reverse shoulder arthroplasty (RSA) in the treatment of primary glenohumeral osteoarthritis (GHOA) with an intact rotator cuff is based on data derived from single-center studies with limited generalizability and follow-up. This study compared patient-reported outcomes (PROs) between RSA and total shoulder arthroplasty (TSA) for the treatment of primary GHOA with up to 5-year follow-up and examined temporal trends in the treatment of GHOA between 2012 and 2021.MethodsA retrospective review was performed on patients with primary GHOA undergoing primary arthroplasty surgery from the Surgical Outcomes System global registry between 2012 and 2021. PROs including the American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE) score, and visual analog scale (VAS) for pain were compared between RSA and TSA at 1, 2, and 5 years postoperatively.ResultsA total of 4451 patients were included, with 2693 (60.5%) undergoing TSA and 1758 (39.5%) undergoing RSA. Both RSA and TSA provided clinically excellent outcomes at 1 year postoperatively (ASES: 80.8 ± 17.9 vs. 85.9 ± 15.2, respectively; SANE: 74.8 ± 24.7 vs. 79.5 ± 22.9; VAS pain: 1.3 ± 2.0 vs. 1.1 ± 1.7; all P < .05) that were maintained at 2 years (ASES: 81.3 ± 19.3 vs. 87.3 ± 14.9; SANE: 74.8 ± 26.2 vs. 79.7 ± 24.7; VAS pain: 1.3 ± 2.1 vs. 1.0 ± 1.6; all P < .05) and 5 years (ASES: 81.7 ± 16.5 vs. 86.9 ± 15.3; SANE: 71.6 ± 28.5 vs. 78.2 ± 25.9; VAS pain: 1.0 ± 1.7 vs. 1.0 ± 1.7; all P < .05), with statistical significance favoring TSA. After controlling for age and sex, there was an adjusted difference of 4.5 units in the ASES score favoring TSA (P = .005) at 5 years postoperatively but no differences in adjusted SANE (P = .745) and VAS pain (P = .332) scores. The use of RSA for GHOA grew considerably over time, from representing only 17% of all replacements performed for GHOA in 2012 to nearly half (47%) in 2021 (P < .001).ConclusionRSA as a treatment for GHOA with an intact rotator cuff seems to yield PROs that are largely clinically equivalent to TSA extending to 5 years postoperatively. The observed statistical significance favoring TSA appears to be of marginal clinical benefit based on established minimal clinically important differences and may be a result of the large sample size. Further research using more granular clinical data and examining differences in range of motion and complications is warranted as it may change the value analysis.     

PAMAM versus PEI complexation for siRNA delivery: interaction with model lipid membranes and cellular uptake

Pharmaceutical Research - Cationic polymers have many advantages as vectors for mediated cellular entry and delivery of siRNA. However, toxicity related to their cationic charge has compromised...     

Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors

IntroductionRecent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.Patients and MethodsPatients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.ResultsIn total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.ConclusionIn accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.     

Rosmarinus plants: Key farm concepts towards food applications

Rosmarinus species are aromatic plants that mainly grow in the Mediterranean region. They are widely used in folk medicine, food, and flavor industries and represent a valuable source of biologically active compounds (e.g., terpenoids, flavonoids, and phenolic acids). The extraction of rosemary essential oil is being done using three main methods: carbon dioxide supercritical extraction, steam distillation, and hydrodistillation. Furthermore, interesting antioxidant, antibacterial, antifungal, antileishmanial, anthelmintic, anticancer, anti‐inflammatory, antidepressant, and antiamnesic effects have also been broadly recognized for rosemary plant extracts. Thus the present review summarized data on economically important Rosmarinus officinalis species, including isolation, extraction techniques, chemical composition, pharmaceutical, and food applications.     

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Journal of Neuro-Oncology - Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor...