MicroRNA-708 emerges as a potential candidate to target undruggable NRAS.

RAS, the most frequently mutated oncogene that drives tumorigenesis by promoting cell proliferation, survival, and motility, has been perceived as undruggable for the past three decades. However, intense research in the past has mainly focused on KRAS mutations, and targeted therapy for NRAS mutations remains an unmet medical need. NRAS mutation is frequently observed in several cancer types, including melanoma (15-20%), leukemia (10%), and occasionally other cancer types. Here, we report using miRNA-708, which targets the distinct 3' untranslated region (3'UTR) of NRAS, to develop miRNA-based precision medicine to treat NRAS mutation-driven cancers. We first confirmed that NRAS is a direct target of miRNA-708. Overexpression of miRNA-708 successfully reduced NRAS protein levels in melanoma, leukemia, and lung cancer cell lines with NRAS mutations, resulting in suppressed cell proliferation, anchorage-independent growth, and promotion of reactive oxygen species-induced apoptosis. Consistent with the functional data, the activities of NRAS-downstream effectors, the PI3K-AKT-mTOR or RAF-MEK-ERK signaling pathway, were impaired in miR-708 overexpressing cells. On the other hand, cell proliferation was not disturbed by miRNA-708 in cell lines carrying wild-type NRAS. Collectively, our data unveil the therapeutic potential of using miRNA-708 in NRAS mutation-driven cancers through direct depletion of constitutively active NRAS and thus inhibition of its downstream effectors to decelerate cancer progression. Harnessing the beneficial effects of miR-708 may therefore offer a potential avenue for small RNA-mediated precision medicine in cancer treatment.

Effects of thoracic sympathetic stimulation on palmar perfusion: a preliminary study in pigs.

OBJECTIVE: Ablation of the upper thoracic sympathetic ganglia that innervates the hands is the most effective and permanent cure of palmar hyperhidrosis. However, this type of sympathectomy causes irreversible neural damage and may result in severe compensatory hyperhidrosis. This experiment is designed to confirm the hypothesis, in which the stimulation of T2 sympathetic chain leads to increased palmar microcirculation, and thus results in treating hyperhidrosis. METHODS: In this study, we used electric stimulation to induce reversible blockade of the sympathetic ganglion in pigs and investigated its effect on palmar perfusion. An electrode was inserted to the T2 sympathetic ganglion of the pig through three different approaches: open dorsal, thoracoscopic, and fluoroscopy-guided approaches. Electric stimulation was delivered through the electrode using clinically available pulse generators. Palmar microcirculation was evaluated by laser speckle contrast imaging. RESULTS: The T2 sympathetic ganglion of the pig was successfully accessed by all the three approaches, as confirmed by changes in palmar microcirculation during electric stimulation. Similar effects were not observed when the electrode was placed on the T4 sympathetic ganglion or off the sympathetic trunk. CONCLUSION: We established a large animal model to verify the effect of thoracic sympathetic stimulation. Electric stimulation can be used for sympathetic blockade, as confirmed by increased blood perfusion of the palm. Our work suggests that sympathetic stimulation is a potential solution for palmar hyperhidrosis.

Effects of synthetic glucocorticoids on breast cancer progression.

Glucocorticoids (GCs) are widely prescribed as adjuvant therapy for breast cancer patients. Unlike other steroid hormone receptors, the GC receptor is not considered an oncogene. Research in the past few years has revealed the complexity of GC-mediated signaling, but it remains puzzling whether GCs promote or inhibit tumor progression in different cancer types. Here we evaluated the potential of using a synthetic GC, dexamethasone (DEX), in the treatment of breast cancer. We found that the administration of low-dose DEX suppressed tumor growth and distant metastasis in the MCF-7 and MDA-MB-231 xenograft mouse model, whereas treatment with high-dose DEX enhanced tumor growth and metastasis, respectively. Treatment of breast cancer cells with DEX inhibited cell adhesion, migration, and invasion in a dose-dependent manner. The DEX-mediated inhibition of cell adhesion, migration, and invasion is partly through induction of microRNA-708 and subsequent Rap1B-mediated signaling in MDA-MB-231 cells. On the other hand, in MCF-7 cells, DEX-suppressed cell migration is independent from microRNA-708 mediated signaling. Overall, our data reveal that DEX acts as a double-edged sword during breast-cancer progression and metastasis: Lower concentrations inhibit breast cancer tumor growth and metastasis, whereas higher concentrations may play an undesired role to promote breast cancer progression.

Dysregulation of cystathionine γ-lyase promotes prostate cancer progression and metastasis.

Hydrogen sulfide (H2 S), an endogenous signaling gaseous molecule, is involved in various physiological activities, including vessel relaxation, regulation of cellular bioenergetics, inflammation, and angiogenesis. By using xenograft orthotopic implantation of prostate cancer PC3 cells and subsequently comparing bone metastatic with primary tumor-derived cancer cells, we find that H2 S-producing enzyme cystathionine γ-lyase (CTH) is upregulated in bone-metastatic PC3 cells. Clinical data further reveal that the expression of CTH is elevated in late-stage prostate cancer patients, and higher CTH expression correlates with poor survival from The Cancer Genome Atlas (TCGA) prostate cancer RNA-seq datasets. CTH promotes NF-κB nuclear translocation through H2 S-mediated sulfhydration on cysteine-38 of the NF-κB p65 subunit, resulting in increased IL-1ß expression and H2 S-induced cell invasion. Knockdown of CTH in PC3 cells results in the suppression of tumor growth and distant metastasis, while overexpression of CTH in DU145 cells promotes primary tumor growth and lymph node metastasis in the orthotopic implanted xenograft mouse model. Together, our findings provide evidence that CTH generated H2 S promotes prostate cancer progression and metastasis through IL-1ß/NF-κB signaling pathways.

Pulsed radiofrequency stimulation suppresses palmar hyperhidrosis in an animal study.

Objectives: Palmar hyperhidrosis (PH) exhibits excessive and unpredictable sweating. The most effective treatment for permanent cure is the ablation of thoracic sympathetic ganglia innervating hands. However, sympathectomy of T2 sympathetic ganglion by clipping or cauterization causes irreversible nerve damage, and results in a compensatory hyperhidrosis (CH). We herein used the pulsed radiofrequency (PRF) stimulation to reversibly block sympathetic ganglion to treat PH and avoid CH. Material and Methods: A bipolar electrode was implanted into the right T2 sympathetic trunk by endoscopic surgery and PRF was delivered through the electrode. The humidity (%) of right palm was measured to indicate sweating level. Results: Six out of 13 rats (46.2%) that received a 5-min PRF stimulation on the T2 sympathetic trunk showed a decrease in the right palm humidity during the surgery. PRF stimulation significantly reduced humidity from 69.17% ± 0.72% obtained from baseline condition to 66.93% ± 0.69%. The humidity reduction was also observed at 10 min after the PRF stimulation. We further evaluated the effect of PRF stimulation 1 week after surgery and found that the PRF stimuli reduced right hand humidity in 5 out of 8 rats (62.5%). PRF stimulation significantly reduced humidity from 66.11% ± 0.81% obtained from sham operation control to 63.62% ± 0.82%. The percentage of right hand humidity obtained 10 min after PRF stimulation was also reduced to 63.38% ± 0.80%. Anesthetics have no effect on humidity. Conclusions: These results indicate that PRF stimulation of T2 sympathetic trunk reduces palm sweating in rats.

A dual-mode highly efficient class-E stimulator controlled by a low-Q class-E power amplifier through duty cycle.

This paper presents the design flow of two high-efficiency class-E amplifiers for the implantable electrical stimulation system. The implantable stimulator is a high-Q class-E driver that delivers a sine-wave pulsed radiofrequency (PRF) stimulation, which was verified to have a superior efficacy in pain relief to a square wave. The proposed duty-cycle-controlled class-E PRF driver designed with a high-Q factor has two operational modes that are able to achieve 100% DC-AC conversion, and involves only one switched series inductor and an unchanged parallel capacitor. The measured output amplitude under low-voltage (LV) mode using a 22% duty cycle was 0.98 V with 91% efficiency, and under high-voltage (HV) mode using a 47% duty cycle was 2.95 V with 92% efficiency. These modes were inductively controlled by a duty-cycle detector, which can detect the duty-cycle modulated signal generated from the external complementary low-Q class-E power amplifier (PA). The design methodology of the low-Q inductive interface for a non-50% duty cycle is presented. The experimental results exhibits that the 1.5-V PA that consumes DC power of 14.21 mW was able to deliver a 2.9-V sine wave to a 500 Ω load. The optimal 60% drain efficiency of the system from the PA to the load was obtained at a 10-mm coupling distance.

Axillary hyperhidrosis and osmidrosis treated by ultrasonic surgical aspiration compared with transthoracic endoscopic sympathectomy.

BACKGROUND: Axillary hyperhidrosis (AH) and/or osmidrosis (AO) are characterized by excessive sweating and/or malodor that originate from axillary sweat glands. The condition often causes emotional, social, and professional embarrassment. Although there have been various therapeutic modalities, none has proved entirely satisfactory. In this report, we compared the results of 2 minimally invasive therapeutic modalities (transthoracic endoscopic sympathectomy [TES] and ultrasonic surgical aspiration [USA]) in terms of efficacy and complications and demonstrated which is the better choice of treatment of AH and AO. METHODS: In the past years, we have treated patients of AH and/or AO with TES by electrocoagulation of T2 and T3 segment of the thoracic sympathetic trunk. On the other hand, we treated patients with AH and/or AO by using USA with endoscopic confirmation for adequate removal of axillary secretion glands and subcutaneous fat. RESULTS: During the past 7 years, 20 patients with AH and/or AO were treated with TES, in which AH obtained adequate relief but AO with only partial alleviation. Only 2 patients showed clinical significant recurrence in 2 years' follow-up. About one half of the patients were complicated with compensatory hyperhidrosis. From May 2005 to April 2006, 55 patients with AO and/or AH were treated with USA. Most patients (91%) obtained adequate relief of AH and AO with minimal wound complications. In the 1-year follow-up, no clinical recurrence was encountered except 2 patients who belonged to the early series of this study. CONCLUSION: Based on our clinical experience with the 2 therapeutic techniques (TES and USA), USA is direct removal of local target tissue (secretion glands) and can avoid major wound complications. It has been proven that USA is more logical and effective than TES, which is less effective and often complicated with unwanted compensatory hyperhidrosis. Ultrasonic surgical aspiration aided with endoscopic confirmation is a minimally invasive technique and is considered as the treatment of choice for AO and/or AH.

Clinical experience of hydroxyethyl starch (10% HES 200/0.5) in cerebral perfusion pressure protocol for severe head injury.

BACKGROUND: The present study was undertaken to evaluate 10% hydroxyethyl starch (HES 200/0.5) with regard to its clinical outcome and safety in the treatment of severe head injury. METHODS: Retrospective review of patient data from a prospectively designed standard treatment protocol for severe head injury. The standard protocol included (1) cerebral perfusion pressure higher than 60 mm Hg, (2) colloid solution (10% HES 200/0.5) 1000 mL/d in combination with crystalloid solution, (3) stepwise management of intracranial hypertension. Renal function, coagulation function, and electrolytes were evaluated every other day. The data of intracranial pressure, mean arterial pressure, cerebral perfusion pressure, intake, output, mannitol, complications, and outcome were recorded and analyzed. RESULTS: There were 78 patients, aged 45.61 +/- 21.80 years, in this study. The initial Glasgow Coma Scale score was 6.35 +/- 1.38. Seventy-three patients received operations with intracranial pressure monitoring. Blood transfusion was surgery related (days 1 and 2); otherwise, it was rarely used (P<.05). Prolonged prothrombin time was shown only 7 (2.65%) times of 234 of blood sampling. There was no anaphylactic reaction, pulmonary complications, or renal function deterioration in the course of our observation. The chart review of the patients at 6 months revealed the following: favorable outcome, 55.1%; unfavorable outcome, 33.3%; and mortality, 11.6%. CONCLUSIONS: The 10% HES (200/0.5) can be used in the treatment protocol of severe head injury. There is no definite bleeding complications documented by current dosage of HES. Besides, balanced fluid management can be achieved without causing serious pulmonary complications. However, a further randomized, prospective study is needed to define the actual benefit of HES in fluid management and clinical outcome.

Laser Doppler scanning study of palmar skin perfusion for patients with hyperhidrosis before and after thoracic sympathectomy.

BACKGROUND: Palmar hyperhidrosis is effectively treated by thoracic sympathectomy. Previous reports revealed that palmar skin temperature and perfusion increased on focal palmar regions after treatment. This study aimed to investigate the blood flow change over the whole palmar surface after the procedure. METHODS: Thirty patients with severe palmar hyperhidrosis were included for study. Each participant received measurement of palmar skin perfusion by a laser Doppler image scanner 1 day before and 1 day after surgery. Concomitantly, palmar skin temperature was recorded by a contact thermometer probe. One patient underwent intraoperative recording of palmar skin perfusion. RESULTS: Palmar skin perfusion and temperature increased significantly after thoracic sympathectomy. Intraoperative measurement performed for a patient showed a similar trend of increment of palmar skin blood flow. CONCLUSIONS: The global skin perfusion of palms can be analyzed in real time by the laser Doppler image scanner. This technique could be useful for analysis of blood flow changes in other body surface regions after thoracic sympathectomy.

Comparison of the applicability of rule-based and self-organizing fuzzy logic controllers for sedation control of intracranial pressure pattern in a neurosurgical intensive care unit.

This paper assesses the controller performance of a self-organizing fuzzy logic controller (SOFLC) in comparison with a routine clinical rule-base controller (RBC) for sedation control of intracranial pressure (ICP) pattern. Eleven patients with severe head injury undergoing different neurosurgeries in a neurosurgical intensive care unit (NICU) were divided into two groups. In all cases the sedation control periods lasted 1 h and assessments of propofol infusion rates were made at a frequency of once per 30 s. In the control group of 10 cases selected from 5 patients, a RBC was used, and in the experimental group of 10 cases selected from 6 patients, a self-organizing fuzzy logic controller was used. A SOFLC was derived from a fuzzy logic controller and allowed to generate new rules via self-learning beyond the initial fuzzy rule-base obtained from experts (i.e., neurosurgeons). The performance of the controllers was analyzed using the ICP pattern of sedation for 1 h of control. The results show that a SOFLC can provide a more stable ICP pattern by administering more propofol and changing the rate of delivery more often when rule-base modifications have been considered.

Fuzzy logic control for intracranial pressure via continuous propofol sedation in a neurosurgical intensive care unit.

The major goal of this paper is to provide automatically continuous propofol sedation for patients with severe head injury, unconsciousness, and mechanical ventilation in order to reduce the effect of agitation on intracranial pressure (ICP) using fuzzy logic control in a neurosurgical intensive care unit (NICU). Seventeen patients were divided into three groups in which control was provided with three different controllers. Experimental control periods were of 60min duration in all cases. Group A used a conventional rule-based controller (RBC), Group B a fuzzy logic controller (FLC), and Group C a self-organizing fuzzy logic controller (SOFLC). The performance of the controllers was analyzed by ICP pattern of sedation. The ICP pattern of errors was analyzed for mean and root mean square deviation (RMSD) for the entire duration of control (i.e., 1h). The results indicate that FLC can easily mimic the rule-base of human experts (i.e., neurosurgeons) to achieve stable sedation similar to the RBC group. Furthermore, the results also show that a SOFLC can provide more stable sedation of ICP pattern because it can modify the fuzzy rule-base to compensate for inter-patient variations.

Intracranial metastasis of hepatocellular carcinoma: review of 45 cases.

BACKGROUND: Although extrahepatic metastasis of hepatocellular carcinoma (HCC) is not uncommon, intracranial metastasis is relatively rare. METHODS: We reviewed HCC cases admitted in our hospital in the past 16 years, and there were only 45 cases with clinically diagnosed intracranial metastasis. Their age ranged from 14 to 82 years with the peak in the 3rd and 4th decades, which is much younger than the average age of the HCC patients. RESULTS: Of the 45 patients, 39 (39/45, 86.7%) had hepatitis B related and 20 (20/45, 44.4%) had cirrhosis of the liver. Intracranial hemorrhage as the initial manifestation was common in our series (18/45, 40%). Hemiparesis was found in 14 cases, scalp mass in 9 cases, headache in 13 cases, diplopia in 3 cases (1 ultimately became totally blind), homonymous hemianopsia in 2 cases, dysarthria in 3 cases, gait disturbance in 1 case, seizure in 3 cases, and aphasia in 1 case. The modes of therapy for patients with intracranial metastasis included conservative medical treatment only or surgical excision and/or radiotherapy. In this series, elevated AFP was noted in 32 patients, and alpha fetoprotein higher than several thousands was even noted in 30 patients; extraordinary high level (>70000) was also seen in more than one-half of the patients. CONCLUSIONS: HCC patients with intracranial metastasis presented a very poor prognosis. In general, they deteriorated rapidly and expired without active treatment. Surgical excision of the intracranial metastatic mass, followed by radiotherapy, can improve the life quality and prolong survival time.

Cranioplasty for patients with severe depressed skull bone defect after cerebrospinal fluid shunting.

Cranioplasty is indicated for patients with a skull bone defect. Patients may achieve subjective and objective improvements after cranioplasty. Some patients with severe brain swelling treated with decompressive craniectomy may develop hydrocephalus associated with severe brain bulging or even herniation via the skull bone defect. Consequently, these patients require a ventriculoperitoneal (V-P) shunt to relieve hydrocephalus. However, after shunting for hydrocephalus, they may develop severe sinking at the skull defect. Subsequently, when doing a cranioplasty for such a depressed defect, it may result in the dysfunction of the underlying brain, or even hematoma formation due to the large dead space. In this study, we advocate a temporary procedure to occlude the V-P shunt tube to allow the expansion of a depressed scalp flap to facilitate the subsequent cranioplasty. We report four patients with severe depression of the skull defect resulting from previous traumatic brain swelling followed by decompressive craniectomy and V-P shunting for communicating hydrocephalus. A simple subcutaneous clipping of the shunt tube was performed to allow the expansion of the depressed scalp to obliterate the dead space before the cranioplasty. All four patients obtained a satisfactory result without complications and achieved good functional recovery. A temporary occlusion of the shunt tube with an aneurysm clip before cranioplasty for patients with a severely depressed scalp flap is a simple and useful procedure. This procedure can safely and effectively eliminate the dead space between the skull plate and the dura to facilitate the cranioplasty, and thus prevent the potential complication of intracranial hematoma.

Gamma knife surgery for trigeminal neuralgia.

OBJECT: Stereotactic radiosurgery is an increasingly used and the least invasive surgical option for patients with trigeminal neuralgia. In this study, the authors investigate the clinical outcomes in patients treated with this procedure. METHODS: Independently acquired data from 220 patients with idiopathic trigeminal neuralgia who underwent gamma knife radiosurgery were reviewed. The median age was 70 years (range 26-92 years). Most patients had typical features of trigeminal neuralgia, although 16 (7.3%) described additional atypical features. One hundred thirty-five patients (61.4%) had previously undergone surgery and 80 (36.4%) had some degree of sensory disturbance related to the earlier surgery. Patients were followed for a maximum of 6.5 years (median 2 years). Complete or partial relief was achieved in 85.6% of patients at 1 year. Complete pain relief was achieved in 64.9% of patients at 6 months, 70.3% at 1 year, and 75.4% at 33 months. Patients with an atypical pain component had a lower rate of pain relief (p = 0.025). Because of recurrences, only 55.8% of patients had complete or partial pain relief at 5 years. The absence of preoperative sensory disturbance (p = 0.02) or previous surgery (p = 0.01) correlated with an increased proportion of patients who experienced complete or partial pain relief over time. Thirty patients (13.6%) reported pain recurrence 2 to 58 months after initial relief (median 15.4 months). Only 17 patients (10.2% at 2 years) developed new or increased subjective facial paresthesia or numbness, including one who developed deaf-ferentation pain. CONCLUSIONS: Radiosurgery for idiopathic trigeminal neuralgia was safe and effective, and it provided benefit to a patient population with a high frequency of prior surgical intervention.