Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this ...study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.
Background and purpose
Elevated plasma total homocysteine level (tHcy) is associated with increased risk of dementia via increased white matter changes or reduction in cortical volume. Whether tHcy ...has an independent impact on regional perfusion and if it can predict a more rapid cognitive decline in mild Alzheimer dementia (AD) warrants investigation.
Methods
Eighty AD patients with a clinical dementia rating of 1 were enrolled. Their Cognitive Ability Screening Instrument (CASI) scores on enrolment and after 1 year of follow‐up as well as their perfusion index (PI) from single photon emission computed tomography upon enrolment were analyzed.
Results
In cross‐sectional analysis, elevated tHcy was associated with lower frontal PI independent of cerebrovascular risk factors (β = −0.35, P = 0.009). The CASI scores correlated with temporo‐parietal PI (Pearson r range 0.3–0.39, P < 0.01) but not with tHcy or frontal PI. By longitudinal analysis, only tHcy level was related to a more rapid cognitive decline (odds ratio for executive function score 1.82; odds ratio for total CASI score 1.74).
Conclusions
Cognitive performance in mild AD can be reflected by hypo‐perfusion of the temporo‐parietal region while frontal hypo‐perfusion may be mediated by tHcy. tHcy level is an independent risk factor for rapid cognitive decline, especially in the executive function.
In a warm and humid climate, increasing the temperature set point offers considerable energy benefits with low first costs. Elevated air movement generated by a personally controlled fan can ...compensate for the negative effects caused by an increased temperature set point. Fifty‐six tropically acclimatized persons in common Singaporean office attire (0.7 clo) were exposed for 90 minutes to each of five conditions: 23, 26, and 29°C and in the latter two cases with and without occupant‐controlled air movement. Relative humidity was maintained at 60%. We tested thermal comfort, perceived air quality, sick building syndrome symptoms, and cognitive performance. We found that thermal comfort, perceived air quality, and sick building syndrome symptoms are equal or better at 26°C and 29°C than at the common set point of 23°C if a personally controlled fan is available for use. The best cognitive performance (as indicated by task speed) was obtained at 26°C; at 29°C, the availability of an occupant‐controlled fan partially mitigated the negative effect of the elevated temperature. The typical Singaporean indoor air temperature set point of 23°C yielded the lowest cognitive performance. An elevated set point in air‐conditioned buildings augmented with personally controlled fans might yield benefits for reduced energy use and improved indoor environmental quality in tropical climates.
Despite optimal pharmacotherapy and cognitive-behavioral treatments, a proportion of patients with obsessive-compulsive disorder (OCD) remain refractory to treatment. Neurosurgical ablative or ...nondestructive stimulation procedures to treat these refractory patients have been investigated. However, despite the potential benefits of these surgical procedures, patients show significant surgery-related complications. This preliminary study investigated the use of bilateral thermal capsulotomy for patients with treatment-refractory OCD using magnetic resonance-guided focused ultrasound (MRgFUS) as a novel, minimally invasive, non-cranium-opening surgical technique. Between February and May 2013, four patients with medically refractory OCD were treated with MRgFUS to ablate the anterior limb of the internal capsule. Patients underwent comprehensive neuropsychological evaluations and imaging at baseline, 1 week, 1 month and 6 months following treatment. Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), and treatment-related adverse events were evaluated. The results showed gradual improvements in Y-BOCS scores (a mean improvement of 33%) over the 6-month follow-up period, and all patients showed almost immediate and sustained improvements in depression (a mean reduction of 61.1%) and anxiety (a mean reduction of 69.4%). No patients demonstrated any side effects (physical or neuropsychological) in relation to the procedure. In addition, there were no significant differences found in the comprehensive neuropsychological test scores between the baseline and 6-month time points. This study demonstrates that bilateral thermal capsulotomy with MRgFUS can be used without inducing side effects to treat patients with medically refractory OCD. If larger trials validate the safety, effectiveness and long-term durability of this new approach, this procedure could considerably change the clinical management of treatment-refractory OCD.
An increasing amount of research effort is being directed toward investigating the neural bases of social cognition from a systems neuroscience perspective. Evidence from multiple animal species is ...beginning to provide a mechanistic understanding of the substrates of social behaviors at multiple levels of neurobiology, ranging from those underlying high-level social constructs in humans and their more rudimentary underpinnings in monkeys to circuit-level and cell-type-specific instantiations of social behaviors in rodents. Here we review literature examining the neural mechanisms of social decision-making in humans, non-human primates and rodents, focusing on the amygdala and the medial and orbital prefrontal cortical regions and their functional interactions. We also discuss how the neuropeptide oxytocin impacts these circuits and their downstream effects on social behaviors. Overall, we conclude that regulated interactions of neuronal activity in the prefrontal-amygdala pathways critically contribute to social decision-making in the brains of primates and rodents.
Background
Use of polysomnography (PSG) is the gold standard of diagnosis and measurement of treatment effectiveness for paediatric obstructive sleep apnoea (OSA). Although adenotonsillectomy (T&A) ...is effective in diminishing the apnoea–hypopnoea index (AHI), a meta‐analysis of postoperative changes for all other PSG parameters and outcome comparisons between obese and non‐obese children following T&A have never been conducted.
Objective of review
To comprehensively review polysomnographic findings after surgery for obese and non‐obese children with OSA.
Search strategy
Study protocol was registered on PROSPERO (CRD42013004737). Two authors independently searched databases including PubMed, MEDLINE, EMBASE and Cochrane Review from January 1997 to July 2014. The keywords used included the following: sleep apnea, OSA, sleep apnea syndromes, tonsillectomy, adenoidectomy, infant, child, adolescent, and Humans.
Evaluation method
A comprehensive systematic review and meta‐analysis for literature for OSA children treated by T&A with polysomnography data. Random‐effects model was applied to determine postoperative sleep parameter changes and the surgical success rate between obese and non‐obese groups. The quality of studies was assessed using the Newcastle–Ottawa Scale.
Results
In total, 51 studies with 3413 subjects were enrolled. After surgery, sleep architecture was altered by a significant decrease in sleep stage 1, and an increase in slow‐wave sleep and the rapid eye movement stage, and enhanced sleep efficiency. The mean difference between pre‐ and postoperative was a significant reduction of 12.4 event/h in AHI, along with a reduction of obstructive index, hypopnoea index, central index and arousal index. Mean and minimum oxygen saturation increased significantly after surgery. The overall success rate was 51% for postoperative AHI <1 (obese versus non‐obese versus combined, 34% versus 49% versus 56%), and 81% for AHI <5 (obese versus non‐obese versus combined, 61% versus 87% versus 84%). Meta‐regression analyses demonstrate that postoperative AHI was positively correlated with AHI and body mass index z score before surgery.
Conclusions
Meta‐analysis of current literature shows T&A offers prominent improvement in a variety of sleep parameters. Improvements in non‐obese children exceeded those for obese children. Postoperative residual OSA remained in roughly half of the children, especially those with severe disease and obesity, making additional treatment strategies and/or long‐term follow‐up highly desirable.
Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the ...efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.
To apply the RIFLE criteria "risk," "injury," and "failure" for severity of acute kidney injury to patients admitted to the intensive care unit and to evaluate the significance of other prognostic ...factors.
Retrospective analysis of the Riyadh Intensive Care Program database.
Riyadh Intensive Care Unit Program database of 41,972 patients admitted to 22 intensive care units in the United Kingdom and Germany between 1989 and 1999.
Acute kidney injury as defined by the RIFLE classification occurred in 15,019 (35.8%) patients; 7,207 (17.2%) patients were at risk, 4,613 (11%) had injury, and 3,199 (7.6%) had failure. It was found that 797 (2.3%) patients had end-stage dialysis-dependent renal failure when admitted to an intensive care unit.
None.
: Patients with risk, injury, and failure classifications had hospital mortality rates of 20.9%, 45.6%, and 56.8%, respectively, compared with 8.4% among patients without acute kidney injury. Independent risk factors for hospital mortality were age (odds ratio 1.02); Acute Physiology and Chronic Health Evaluation II score on admission to intensive care unit (odds ratio 1.10); presence of preexisting end-stage disease (odds ratio 1.17); mechanical ventilation (odds ratio 1.52); RIFLE categories risk (odds ratio 1.40), injury (odds ratio 1.96), and failure (odds ratio 1.59); maximum number of failed organs (odds ratio 2.13); admission after emergency surgery (odds ratio 3.08); and nonsurgical admission (odds ratio 3.92). Renal replacement therapy for acute kidney injury was not an independent risk factor for hospital mortality.
The RIFLE classification was suitable for the definition of acute kidney injury in intensive care units. There was an association between acute kidney injury and hospital outcome, but associated organ failure, nonsurgical admission, and admission after emergency surgery had a greater impact on prognosis than severity of acute kidney injury.
The authors prospectively evaluated the efficacy of lymphovenous bypass in patients with lymphedema secondary to cancer treatment.
The authors prospectively enrolled 100 consecutive patients with ...extremity lymphedema secondary to cancer treatment. Sixty-five patients underwent lymphovenous bypass with indocyanine green fluorescent lymphangiography. Evaluation included qualitative assessment and quantitative volumetric analysis before and 3, 6, and 12 months after bypass.
Lymphovenous bypass was performed in 89 upper extremities and 11 lower extremities. For upper extremity lymphedemas, the mean preoperative volume differential was 32 percent. Symptom improvement was reported by 96 percent of patients and quantitative improvement was noted by 74 percent. The overall mean volume differential reduction was 33 percent at 3 months, 36 percent at 6 months, and 42 percent at 12 months after surgery. The mean volume differential reductions at 3, 6, and 12 months after lymphovenous bypass in patients with stage 1 or 2 lymphedema (58, 52, and 61 percent, respectively) were significantly larger than those in the patients with stage 3 or 4 lymphedema (12, 16, and 17 percent, respectively). Eleven bypasses were performed in seven patients with lower extremity lymphedema, with a mean preoperative volume differential of 38 percent. Only four (57 percent) of these patients reported symptom improvement; postoperative volume measurements were available for only two of these four.
Lymphovenous bypass can be effective in reducing lymphedema severity, particularly in patients with early-stage upper extremity lymphedema. Indocyanine green lymphangiography accurately identified functional lymphatic vessels and may have a role in objectively assessing lymphedema severity and patient selection.
Therapeutic, IV.
There is accumulating anecdotal evidence that anosmia and dysgeusia are associated with the COVID-19 pandemic. To investigate their relationship to SARS-CoV2 infection, the American Academy of ...Otolaryngology-Head and Neck Surgery developed the COVID-19 Anosmia Reporting Tool for Clinicians for the basis of this pilot study. This tool allows health care providers to confidentially submit cases of anosmia and dysgeusia related to COVID-19. We analyzed the first 237 entries, which revealed that anosmia was noted in 73% of patients prior to COVID-19 diagnosis and was the initial symptom in 26.6%. Some improvement was noted in 27% of patients, with a mean time to improvement of 7.2 days in this group (85% of this group improved within 10 days). Our findings suggest that anomia can be a presenting symptom of COVID-19, consistent with other emerging international reports. Anosmia may be critical in timely identification of individuals infected with SARS-CoV2 who may be unwittingly transmitting the virus.
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