Ursolic acid induces apoptosis and autophagy in oral cancer cells

Oral squamous cell carcinoma (OSCC) is the fifth common cause of cancer mortality in Taiwan with high incidence and recurrence and needs new therapeutic strategies. In this study, ursolic acid (UA), a triterpenoid, was examined the antitumor potency in OSCC cells. Our results showed that UA inhibited the proliferation of OSCC cells in a dose‐ and time‐dependent manner in both Ca922 and SCC2095 oral cancer cells. UA induced caspase‐dependent apoptosis accompanied with the modulation of various biological biomarkers including downregulating Akt/mTOR/NF‐κB signaling, ERK, and p38. In addition, UA inhibited angiogenesis as evidenced by abrogation of migration/invasion and blocking MMP‐2 secretion in Ca922 cells. Interestingly, UA induced autophagy in OSCC cells, as manifested by LC3B‐II conversion and increased p62 expression and accumulation of autophagosomes. Inhibition by autophagy inhibitor enhanced UA‐mediated apoptosis in Ca922 cells. The experiment provides a rationale for using triterpenoid in the treatment of OSCC.     

Absolute lymphocyte count and risk of short-term infection in patients with immune thrombocytopenia

Patients with immune thrombocytopenia (ITP) may be at increased risk of infection because of the steroids and other immunosuppressive agents used in its treatment. This study aimed to identify events that are associated with infection within 6 months of diagnosis and the impact that infection has on survival. We retrospectively evaluated 239 patients (107 men, 132 women; median age 61 years) diagnosed between January 1997 and August 2011. Every patient received steroid treatment according to the platelet count and the extent of bleeding. Logistic regression analysis was used to identify risk factors associated with the development of infection within 6 months of ITP being diagnosed. Sixty-two patients (25.9 %) developed an infection within 6 months of diagnosis. Multivariate analysis revealed that a lower absolute lymphocyte count (ALC) at diagnosis (<1?×?10⁹/l) was an independent risk factor for infection (P?=?0.039; 95 % confidence interval, 1.033–3.599; odds ratio, 1.928). The time to infection event is significant shorter in those of low ALC, compared with those of higher ALC (P?=?0.032). Furthermore, the 1-year mortality rate after ITP diagnosis was significantly higher in those patients who developed an infection (P?=?0.001). ITP patients with a low absolute lymphocyte count at diagnosis have an increased risk of infection, and those who develop infections have lower 1-year survival.     

A “Bone Marrow Score” for Predicting Hematological Disease in Immunocompetent Patients With Fevers of Unknown Origin

Delayed diagnosis of hematological malignancies in immunocompetent patients with fever of unknown origin (FUO) remains an exhausting challenge for non-hematologist physicians. This retrospective cohort study aimed to establish a scoring system, “bone marrow (BM) score”, to identify FUO patients who require early bone marrow biopsy (BMB) to diagnose hematological disease.Two cohorts, comprising 85 (training) and 20 (validation) eligible immunocompetent patients, with FUOs diagnosed between January 1, 2006 and July 31, 2013, underwent BMBs and were enrolled in the study. Demographic, laboratory, imaging, diagnostic, and outcome data were collected and retrospectively analyzed. Factors associated with hematological etiologies diagnosed using BMBs in the training cohort were identified and scored according to the relative hazards. These were further validated using the validation cohort.For the training cohort, 29 of 85 (34.1%) patients had hematological etiologies diagnosed using BMB. Seven factors significantly predicted the diagnostic yield of hematological diseases in the BM and were scored, with the 6 points for leucoerythroblastic changes in peripheral blood smears, 5.5 for elevated ferritin level (>1000 ng/mL), 4 for splenomegaly, 2 for thrombocytopenia, 1.5 for each of elevated lactate dehydrogenase levels and anemia, and 1 for neutropenia. When the cut-off value of the scoring system was set to 6, its sensitivity and specificity to diagnose hematological diseases in the BM of immunocompetent FUO patients were 93% and 58%, respectively. For the validation cohort, 7 of 20 (35%) patients had hematological disease, and all had BM scores higher than the cut-off, with the sensitivity and specificity at 100% and 77%, respectively.As immunocompetent FUO patients with hematological disease have poor prognoses, the “BM score” is valuable for non-hematologist physicians to identify immunocompetent FUO patients requiring early BMB.     

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32‐year‐old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow‐legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29‐111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF‐κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12‐base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes and genetic basis of the mendelian disorders of RANK signaling activation. © 2014 American Society for Bone and Mineral Research.     

Effects of stent design on new clinical issue of longitudinal stent compression in interventional cardiology

In recent years, interventional cardiologists have discussed over a new clinical issue called longitudinal stent compression (LSC), a failure mode not previously observed in coronary stents. This phenomenon occurs when the physician attempts to cross a deployed stent with a second device, causing the stent to dramatically shorten when two devices are accidentally entangled. While this phenomenon has been observed with a number of stent platforms, it seems more common with the Element stent. In this paper, a computational LSC model using finite element analysis was developed. A systematic investigation was conducted in attempts to quantify individual contribution of the stent design pattern, connector number, design parameter, and connector location on LSC. Computational simulations were performed on two representative coronary stents resembling Element and Endeavor for comparison. Simulation results show that the connector number plays the most significant role in LSC. The LSC could be easily tripled or quadrupled for the same stent design simply by increasing the connector number from two to three. The design pattern and design parameter play a secondary role in LSC, with the LSC improved by up to 30 and 65 %, respectively. It was also found that the LSC could be doubled for the Element stent simply by rearranging its connector location. This small design tweak could help improve the current Element LSC significantly, while still maintaining the majority of its excellent deliverability. These findings could provide great insights into this new clinical issue and help optimize future stent design to reduce the associated risk involved in LSC.     

Gland-preserving robotic surgery for benign submandibular gland tumours: a comparison between robotic and open techniques

Benign tumours of the submandibular gland are usually treated surgically. Gland-preserving techniques, which can be used to completely remove the tumour, preserve the function of the gland and reduce complications, but conventional open operations result in obvious scars on the neck. We aimed to investigate the feasibility and efficacy of gland-preserving robotic surgery using a hairline approach. We compared robotic with open techniques for gland-preserving operations to remove benign tumours of the submandibular gland. Patients were matched for age and sex (4 in each group). All patients in the robotic surgery group had their tumours removed successfully through hairline approaches. No patient had operative complications or postoperative functional nerve deficit, and an aesthetically pleasing outcome was achieved by concealing the scars within the hairline. Robotic operations took longer than open operations. No recurrence was noted during follow-up. Gland-preserving robotic surgery is a feasible alternative to conventional techniques and has potential advantages for safety and aesthetic outcome.     

Current intensity‐ and polarity‐specific online and aftereffects of transcranial direct current stimulation: An fMRI study

Transcranial direct current stimulation (tDCS) induces polarity‐ and dose‐dependent neuroplastic aftereffects on cortical excitability and cortical activity, as demonstrated by transcranial magnetic stimulation (TMS) and functional imaging (fMRI) studies. However, lacking systematic comparative studies between stimulation‐induced changes in cortical excitability obtained from TMS, and cortical neurovascular activity obtained from fMRI, prevent the extrapolation of respective physiological and mechanistic bases. We investigated polarity‐ and intensity‐dependent effects of tDCS on cerebral blood flow (CBF) using resting‐state arterial spin labeling (ASL‐MRI), and compared the respective changes to TMS‐induced cortical excitability (amplitudes of motor evoked potentials, MEP) in separate sessions within the same subjects (n = 29). Fifteen minutes of sham, 0.5, 1.0, 1.5, and 2.0‐mA anodal or cathodal tDCS was applied over the left primary motor cortex (M1) in a randomized repeated‐measure design. Time‐course changes were measured before, during and intermittently up to 120‐min after stimulation. ROI analyses indicated linear intensity‐ and polarity‐dependent tDCS after‐effects: all anodal‐M1 intensities increased CBF under the M1 electrode, with 2.0‐mA increasing CBF the greatest (15.3%) compared to sham, while all cathodal‐M1 intensities decreased left M1 CBF from baseline, with 2.0‐mA decreasing the greatest (?9.3%) from sham after 120‐min. The spatial distribution of perfusion changes correlated with the predicted electric field, as simulated with finite element modeling. Moreover, tDCS‐induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand‐knob region. Our findings reveal lasting tDCS‐induced alterations in cerebral perfusion, which are dose‐dependent with tDCS parameters, but only partially account for excitability changes.