Coupling harmful algae derived nitrogen and sulfur co-doped carbon nanosheets with CeO2 to enhance the photocatalytic degradation of isothiazolinone biocide.

Removing the algae from water bodies is an effective treatment toward the worldwide frequently occurred harmful algae blooms (HAB), but processing the salvaged algae waste without secondary pollution places another burden on the economy and environment. Herein, a green hydrothermal process without any chemical addition was developed to resource the HAB algae (Microcystis sp.) into autogenous nitrogen and sulfur co-doped carbon nanosheet materials C-CNS and W-CNS, whose alga precursors were collected from pure culture and a wild bloom pond, respectively. After coupling with CeO2, the obtained optimal C-CNS/CeO2 and W-CNS/CeO2 composites photocatalytically degraded 95.4% and 88.2% of the marine pollutant 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) in 90 min, significantly higher than that of pure CeO2 (63.15%). DCOIT degradation on CNS/CeO2 was further conducted under different conditions, including pH value, coexisting cations and anions, and artificial seawater. Although different influences were observed, the removal efficiencies were all above 76%. Along with the ascertained good stability and reusability in five consecutive runs, the great potential of CNS/CeO2 for practical application was validated. UV-vis DRS showed the increased light absorption of CNS/CeO2 in comparison to pure CeO2. PL spectra and photoelectrochemical measurements suggested the lowered charge transfer resistance and thereby inhibited charge recombination of CNS/CeO2. Meanwhile, trapping experiments and electron paramagnetic resonance (EPR) detection verified the primary roles of hydroxyl radical (OH) and superoxide radical (O2-) in DCOIT degradation, as well as their notably augmented generation by CNS. Consequently, a mechanism of CNS enhanced photocatalytic degradation of DCOIT was proposed. The intermediates involved in the reaction were identified by LC-QTOF-MS, giving rise to a deduced degradation pathway for DCOIT. This study offers a new approach for resourceful utilization of the notorious HAB algae waste. Besides that, photocatalytic degradation has been explored as an effective measure to remove DCOIT from the ocean.

Increased level of exosomal miR-20b-5p derived from hypothermia-treated microglia promotes neurite outgrowth and synapse recovery after traumatic brain injury.

Mild hypothermia has been proven to inhibit microglia activation after TBI. Exosomal microRNA derived from microglia played a critical role in promoting neurite outgrowth and synapse recovery. Here, we aimed to investigate the role of microRNAs in microglial exosomes after hypothermia treatment on neuronal regeneration after TBI. For in vitro study, stretch-injured neurons were co-cultured with microglial exosomes. For in vivo study, C57BL/6 mice were under controlled cortical impact and injected with microglial exosomes. The results showed that MG-LPS-EXOHT increased the number of dendrite branches and total length of dendrites both in vitro and in vivo, elevated the expression levels of PSD-95 and GluR1 in stretch-injured neurons, and increased spine density in the pericontusion region. Moreover, MG-LPS-EXOHT improved motor function and motor coordination. A high-throughput sequencing showed that miR-20b-5p was upregulated in MG-LPS-EXOHT. Elevating miR-20b-5p promoted neurite outgrowth and synapse recovery of injured neurons both in vitro and in vivo. Following mechanistic study demonstrated that miR-20b-5p might promote neurite outgrowth and synapse recovery by directly targeting PTEN and activating PI3K-AKT pathway. In conclusion, mild hypothermia could modify the microRNA prolife of exosomes derived from LPS activated BV2 cells. Furthermore, high level of microglial exosomal miR-20b-5p induced by mild hypothermia could transfer into injured neurons and promote neurite outgrowth and synapse recovery after TBI via activating the PI3K-AKT pathway by suppressing PTEN expression.

Primary angioleiomyoma of right frontal cranial base with intracranial and extracranial communication.

INTRODUCTION: Primary intracranial angioleiomyoma (ALM) is quite rare and ALM of the adolescent is even rarer. To date, only three cases of adolescents have been reported. MATERIAL AND METHODS: We carefully introduced a new location of intracranial ALM in an adolescent. The clinical, pathological and imaging features of intracranial ALM were described in detail and published literature was reviewed. RESULTS: To our best knowledge, we presented the fourth primary intracranial ALM of adolescent and the first ALM of the right frontal cranial base with intracranial and extracranial communication. We not only summarize the generalities of ALM but also illustrate the difference between adult and adolescent ALM in the aspects of gender and age predominance, etiology, common location and pathologic subtype. CONCLUSIONS: We reported the first ALM of the right frontal cranial base with intracranial and extracranial communication of an adolescent with a good prognosis. We also summarize the generalities of ALM and illustrate the difference between adult and adolescent ALM. Future investigation of control study with large patient cohorts is needed for both adult and adolescent ALM to compare the difference between them.

m6A regulator-mediated RNA methylation modification patterns are involved in immune microenvironment regulation of periodontitis.

The role of epigenetic regulation in immunity is emerging, especially for RNA N6-methyladenosine (m6A) modification. However, little is known about the role of m6A in the regulation of the immune microenvironment of periodontitis. Thus, we aim to investigate the impact of m6A modification in periodontitis immune microenvironment. The RNA modification patterns mediated by 23 m6A-regulators were systematically evaluated in 310 periodontitis samples. The impact of m6A modification on immune microenvironment characteristics was explored, including infiltrating immunocytes, immune reaction gene-sets and HLAs (human leukocyte antigen) gene. m6A phenotype-related immune genes were also identified. 17 m6A regulators were dysregulated and a 15-m6A regulator signature can well distinguish periodontitis and control samples. ALKBH5 and FMR1 are closely related to infiltrating monocyte abundance. ELAVL1 and CBLL1 are significant regulators in immune reaction of TNF_Family_Members_Receptors and Cytokine. The expression of HLA-B and HLA-DOA is affected by ALKBH5 and LRPPRC. 3 distinct RNA modification patterns mediated by 23 m6A regulators were identified. They differ from immunocyte abundance, immune reaction and HLA gene. 1631 m6A phenotype-related genes and 70 m6A-mediated immune genes were identified, and the biological functions of these were explored. Our finding demonstrated the m6A modification plays a crucial role in the diversity and complexity of the immune microenvironment of periodontitis.

N/OFQ modulates orofacial pain induced by tooth movement through CGRP-dependent pathways.

BACKGROUND: Nociceptin/orphanin FQ (N/OFQ) has been revealed to play bidirectional roles in orofacial pain modulation. Calcitonin gene-related peptide (CGRP) is a well-known pro-nociceptive molecule that participates in the modulation of orofacial pain. We aimed to determine the effects of N/OFQ on the modulation of orofacial pain and on the release of CGRP. METHODS: Orofacial pain model was established by ligating springs between incisors and molars in rats for the simulation of tooth movement. The expression level of N/OFQ was determined and pain level was scored in response to orofacial pain. Both agonist and antagonist of N/OFQ receptor were administered to examine their effects on pain and the expression of CGRP in trigeminal ganglia (TG). Moreover, gene therapy based on the overexpression of N/OFQ was delivered to validate the modulatory role of N/OFQ on pain and CGRP expression. RESULTS: Tooth movement elicited orofacial pain and an elevation in N/OFQ expression. N/OFQ exacerbated orofacial pain and upregulated CGRP expression in TG, while UFP-101 alleviated pain and downregulated CGRP expression. N/OFQ-based gene therapy was successful in overexpressing N/OFQ in TG, which resulted in pain exacerbation and elevation of CGRP expression in TG. CONCLUSIONS: N/OFQ exacerbated orofacial pain possibly through upregulating CGRP.

Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions.

Cullin-5 (Cul-5) was originally identified as an arginine vasopressin (AVP) receptor due to its homology to a vasopressin-activated calcium-mobilizing protein 1 (VACM-1). Cul-5 has subsequently gained much attention after being identified as the key component of CRL-5 (Cullin-RING ligase-5) that mediates ubiquitylation and degradation of several key cellular proteins associated with human cancers and viral infections. Structurally, Cul-5 interacts with the Elongin B/C complex, a RING finger protein (RBX2/SAG), and a SOCS protein to form a CRL-5 E3 ubiquitin ligase protein complex. CRL-5, by controlling turnover of a variety of substrates, is implicated in several biological processes and human diseases. Activation of CRL-5 requires Cul-5 neddylation, catalyzed by a neddylation enzyme cascade, consisting of the E1 NEDD8-activating enzyme (NAE), the E2 neddylation conjugating enzyme (UBE2F), and E3 neddylation ligase (RBX2/SAG). RBX2/SAG, therefore, serves as both Cul-5 neddylation E3 and CRL-5 ubiquitylation E3. Here, we review the current knowledge on CRL-5, its activation by the UBE2F-SAG, its regulation of various signaling pathways via substrate degradation, and its implications in human cancers.

Inactivating the ubiquitin ligase Parkin suppresses cell proliferation and induces apoptosis in human keloids.

Keloids are a common type of pathological skin healing, characterized by the destruction of the vascular network. Thus, keloids often exhibit anoxic conditions. Hypoxia-inducible factor-1α (HIF-1α) is a core factor that mediates hypoxia stress responses and allows the cells to adapt to low-oxygen conditions. In the current study, we identified that Parkin acted as an E3 ubiquitin ligase, contributing to the degradation of HIF-1α in keloid fibroblasts (KFs). Silencing of Parkin in KFs upregulated HIF-1α expression and prolonged its protein half-life. Furthermore, Parkin influenced transforming growth factor ß (TGF-ß)/Smad signaling by targeting HIF-1α. Under hypoxic conditions, silencing Parkin enhanced KF proliferation and inhibited apoptosis through the TGF-ß/Smad signaling pathway. Notably, metformin, an antidiabetic drug, could significantly induce Parkin expression and enhance the interaction between Parkin and HIF-1α. As a result, we revealed an important mechanism for Parkin in keloid development and suggested that targeting Parkin could be an alternative method for keloid treatment.

Metformin Inhibits Epithelial-to-Mesenchymal Transition of Keloid Fibroblasts via the HIF-1α/PKM2 Signaling Pathway.

Background: Epithelial-to-mesenchymal transition (EMT) is a process whereby epithelial cells lose cell-cell contacts and acquire expression of mesenchymal components and manifest a migratory phenotype. Recent studies indicated that EMT is involved in the development of keloids. Therefore, this study aims to investigate the mechanisms of the effects of metformin in hypoxia-induced EMT in keloid fibroblasts (KFs). Methods: KFs were cultured in a hypoxia incubator to induce EMT and were treated with or without metformin. Cell viability was evaluated by a cell counting kit 8 (CCK-8), and cell migration was measured by the transwell assay. The expression levels of HIF-1α, E-cadherin, vimentin, phosphorylated p70s6k (p-p70s6k) and pyruvate kinase M2 (PKM2) were evaluated by western blotting. Results: Hypoxia promoted EMT in KFs. Metformin significantly inhibited the expression of HIF-1α and partially abolished hypoxia-induced EMT. PKM2 is involved in hypoxia-induced EMT of KFs and metformin decreased the expression of p-p70s6k and PKM2. Conclusions: Metformin abolishes hypoxia-induced EMT in KFs by inhibiting the HIF-1α/PKM2 signaling pathway. Our study provides a novel mechanistic insight into potential use of metformin for treatment of keloids.

The Suitability of Different Subtypes and Dimensions of Obsessive-Compulsive Disorder for Treatment with Anterior Capsulotomy: A Long-Term Follow-Up Study.

OBJECTIVE: Anterior capsulotomy (AC) is sometimes used as a life-saving treatment for patients with treatment-refractory obsessive-compulsive disorder (Tr-OCD). Most of the previous studies have assessed only total symptoms and have concluded that AC is a safe and effective procedure. Few of these studies have focused on meticulously investigating the variety of results obtained from patients with different subtypes of OCD. This study reviewed the long-term effects of AC on patients with OCD and analyzed the dissimilarity between particular subtypes of the disease in order to determine which groups are more suited to surgical treatment. METHODS: For this retrospective evaluation, we selected 54 consecutive patients from a total of 63 people with Tr-OCD between 2005 and 2014 who had undergone AC by thermocoagulation at our department. Preoperative and follow-up assessments were conducted at multiple time points (before surgery and 1, 3, 6, 12, and 36 months after surgery). The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) were used to quantify the symptoms of OCD. According to different elements (clinical manifestation, comorbidity, and whether a patient was more compulsive or more obsessive), we classified patients into various subtypes and analyzed the variation in symptom improvement and adverse effects. RESULTS: The mean Y-BOCS, HAMD, and HAMA scores were, respectively, 27.03, 23.30, and 21.46 preoperatively and 8.50, 7.07, and 7.42, respectively, at 36 months after surgery. Most patients (n = 43, 79.6%) were shown to have been at least partially responsive to surgical treatment at their long-term follow-up. Six patients demonstrated no obvious improvement (Y-BOCS score decreased by <35%), and 5 patients developed recurrences of their conditions. The following subtypes demonstrated better results: contamination/cleaning; obsessions/checking; compulsive behavior dominant; pure OCD; and OCD with Tourette's -syndrome. The subtypes of aggressive/sexual, obsessive thought dominant, compulsive behavior with obsessive thoughts, OCD comorbidity with bipolar disorder, OCD comorbid with severe depression, and OCD comorbid with psychiatric symptoms showed good outcomes. However, surgery was ineffective for patients with the subtypes of symmetry/ordering, hoarding, pure obsessive thoughts, and OCD with obsessive slowness. CONCLUSIONS: AC is effective in reducing symptoms of OCD. By comparing differently classified follow-up results, we found that patients with most subtypes/dimensions of OCD showed good outcomes. How-ever, patients categorized into the OCD subtypes of pure -obsessive thoughts, symmetry/ordering, hoarding, OCD with obsessive slowness, and OCD comorbid with psychiatric symptoms should take into account these results before undergoing AC.

Cervical Spinal Cord Stimulation for the Vegetative State: A Preliminary Result of 12 Cases.

OBJECTIVES: Data on the treatment of the vegetative state (VS) with cervical spinal cord stimulation (cSCS) are limited and prognostic factors are inconclusive. In this study, we present our experience of treating 12 VS patients with cSCS and discuss the prognostic factors. METHODS: Twelve VS patients were enrolled. Preoperative assessments included CT/MRI, PET, brainstem auditory evoked potentials (BAEPs), somatosensory evoked potentials (SEPs), and electroencephalogram (EEG). cSCS surgeries were performed at West China Hospital. The electrode was implanted in the epidural space of the C2-4 vertebrae. Levels of consciousness were evaluated based on the Coma Recovery Scale-Revised (CRS-R) at baseline and during follow-up. RESULTS: The average follow-up was 11.1 months. The average CRS-R score at the last evaluation was 10.8, which was significantly improved compared with the baseline score (6.25). Five patients achieved responsive outcomes (three recovered and two evolved to a minimally conscious state) and seven achieved unresponsive outcomes (six remained in VS and one died). Age, preoperative CRS-R score, the interval between acute comatose injury and cSCS, and the Vth wave of BAEPs did not differ significantly between the responsive group and the unresponsive group. Appearance of the N20 of SEPs and multifocal abnormalities on CT/MRI and PET were significantly associated with a better outcome, while the etiology of ischemia and anoxia (IAA) was significantly associated with a poor outcome. CONCLUSIONS: cSCS should be a glimmer of hope for VS patients. Patients whose N20 is elicited or whose CT/MRI or PET demonstrates multifocal abnormalities are more likely to benefit from cSCS, whereas those with an IAA etiology have a lower likelihood of recovery after cSCS.

Clinical features, radiologic findings, and treatment of pediatric germ cell tumors involving the basal ganglia and thalamus: a retrospective series of 15 cases at a single center.

PURPOSE: Pediatric germ cell tumors (GCTs) involving the basal ganglia and thalamus are relatively rare neoplasms which have not been extensively described. We here summarize the clinical and radiological features of a series of such tumors and discuss optimal treatment strategies based upon our experience. METHODS: A total of 15 pediatric patients with basal ganglionic and thalamic GCTs were treated between 2011 and 2016 at West China Hospital. Epidemiological characteristics, clinical features, imaging findings, and treatment strategies were reviewed retrospectively. RESULTS: GCTs constituted 28% (15/53) of pediatric basal ganglionic and thalamic tumors in our institution between 2011 and 2016. There were 12 males and 3 females with mean age of 11.7 ± 2.8 years (range, 7-16 years). The most common initial manifestation was hemiparesis (n = 13, 86.7%), followed by headache (n = 5, 33.3%), vomiting (n = 3, 20.0%), cognitive disturbance (n = 2, 13.3%), and seizure (n = 1, 6.7%). No tumors were incidentally detected. The mean duration of the symptoms before diagnosis was 4.4 ± 3.9 months (range from 9 days to 13 months). The maximum diameters of the lesions ranged from 3.2 to 6.5 cm (mean 4.7 ± 1.1 cm). Cysts were seen in tumors in MRIs in 11 patients (73%), intratumoral hemorrhages in 3 (20%), calcification in 2 (13%), and there was obstructive hydrocephalus in 1 (7%). Of note, hemiatrophy was observed in 9 cases (60.0%). The mean follow-up for the 15 patients was 28 months (range, 9-54 months), and no patients were lost. During the follow-up period, all patients (9 cases) with germinomas responded well to radiotherapy, and no recurrence was observed. Among 4 patients with mixed nongerminomatous germ cell tumor, 2 suffered tumor recurrence after treatment. Neurological deficits improved or remained unchanged in 12 patients but 3 developed new dysfunction including significant cognitive disturbance and hemiparesis. CONCLUSIONS: Pediatric GCTs in the basal ganglia and thalamus are not as rare as previously considered. Tumor markers should be tested routinely for tumors in these sites in young patients. Optimal treatment strategy based on accurate diagnosis and comprehensive clinical assessment should be recommended.

Deep brain stimulation of the thalamic ventral intermediate nucleus for Benedikt's syndrome mainly present as tremor: a long-term case observation.

Benedikt's syndrome (BS) is caused by the lesion in the midbrain and specifically manifests a series of symptoms, including ipsilateral third nerve palsy, contralateral tremor, hemiataxia, and hyperactive tendon reflexes. Deep brain stimulation (DBS) for BS emerges as a new approach and achieves successfully results. We report a successful case report of thalamic ventral intermediate (VIM) nucleus DBS for a patient with BS. During follow-up of 3 years, DBS successfully control the tremor and greatly improve his living and working quality. We consider that VIM DBS may have sustained benefit for refractory BS that mainly presents as tremor.

Effect of radiation dose on the outcomes of gamma knife treatment for trigeminal neuralgia: a multi-factor analysis.

AIM: To analyze the effect of different radiation variables on the outcomes of treatment for trigeminal neuralgia (TN). MATERIALS AND METHODS: Seventy-three patients with refractory TN were treated with a maximum dose of 75-90 Gy using either one (n = 41) or two (n = 32) isocenters and were intensively followed up. The integrated dose delivered to the trigeminal nerve root within the prepontine cistern and the nerve root volume was calculated using the Gamma-Plan system. Relationships between the clinical outcomes and radiation variables were statistically analyzed using a combination of Fisher's exact test and multivariate analyses. RESULTS: At their last follow up, 21 patients (28.8%), 22 patients (30.1%), 19 patients (26%), 6 patients (8.2%), and 5 patients (6.8%) had Grade I-V pain outcomes, respectively, and the average mean dose delivered to the trigeminal nerve root, average integrated dose (mJ) and nerve root volume in prepontine cistern were 45.29 Gy, 4,26 mJ, and 98.47 mm 3 , respectively. The pain relief rate was not significantly improved by a higher amount of integrated dose received by the trigeminal nerve root in prepontine cistern, however, incidence of trigeminal nerve toxicity was increased (P = 0.005). CONCLUSIONS: Our limited results suggested that a higher integrated dose might increase the incidence of trigeminal nerve toxicity with no significant benefits in pain relief when the maximal doses were within 75-90 Gy. The protocol for increasing radiation variables such as longer nerve exposure length and higher maximal dose is not recommended as a routine approach and more randomized studies with large number of cases would be required to verify the best treatment strategy of gamma knife radiosurgery for TN.

Protein neddylation and its role in health and diseases.

NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation, catalyzed by the enzyme cascade, namely NEDD8 activating enzyme (E1), NEDD8 conjugating enzyme (E2), and NEDD8 ligase (E3). The substrates of neddylation are categorized into cullins and non-cullin proteins. Neddylation of cullins activates CRLs (cullin RING ligases), the largest family of E3 ligases, whereas neddylation of non-cullin substrates alters their stability and activity, as well as subcellular localization. Significantly, the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases, such as metabolic disorders, liver dysfunction, neurodegenerative disorders, and cancers, among others. Thus, targeting neddylation becomes an attractive strategy for the treatment of these diseases. In this review, we first provide a general introduction on the neddylation cascade, its biochemical process and regulation, and the crystal structures of neddylation enzymes in complex with cullin substrates; then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates. We further review the literature data on dysregulated neddylation in several human diseases, particularly cancer, followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach. Finally, few perspectives were proposed for extensive future investigations.

Why does HER2-positive breast cancer metastasize to the brain and what can we do about it?

Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain's anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

Diagnostic performance evaluation of urine HIV-1 antibody rapid test kits in a real-life routine care setting in China.

OBJECTIVES: To evaluate the diagnostic performance of urine HIV antibody rapid test kits in screening diverse populations and to analyse subjects' willingness regarding reagent types, purchase channels, acceptable prices, and self-testing. DESIGNS: Diagnostic accuracy studies PARTICIPANTS: A total of 2606 valid and eligible samples were collected in the study, including 202 samples from female sex workers (FSWs), 304 persons with injection drug use (IDU), 1000 pregnant women (PW), 100 subjects undergoing voluntary HIV counselling and testing (VCT) and 1000 students in higher education schools or colleges (STUs). Subjects should simultaneously meet the following inclusion criteria: (1) being at least 18 years old and in full civil capacity, (2) signing an informed consent form and (3) providing truthful identifying information to ensure that the subjects and their samples are unique. RESULTS: The sensitivity, specificity and area under the curve (AUC) of the urine HIV-1 antibody rapid test kits were 92.16%, 99.92% and 0.960 (95% CI: 0.952 to 0.968, p<0.001), respectively, among 2606 samples collected during on-site screenings. The kits showed good diagnostic performance in persons with IDU (AUC, 1.000; 95% CI, 1.000 to 1.000, p<0.001), PW (AUC, 0.999; 95% CI, 0.999 to 1.000, p<0.001) and FSWs (AUC, 1.000; 95% CI, 1.000 to 1.000, p<0.001). The AUC of the urine reagent kits in subjects undergoing VCT was 0.941 (95% CI: 0.876 to 0.978, p<0.001). The 'acceptable price' had the greatest influence on STUs (Pi=1.000) and PW (Pi=1.000), the 'purchase channel' had the greatest influence on subjects undergoing VCT (Pi=1.000) and persons with IDU (Pi=1.000) and the 'reagent types' had the greatest influence on FSWs (Pi=1.000). CONCLUSIONS: The rapid urine test kits showed good diagnostic validity in practical applications, despite a few cases involving misdiagnosis and underdiagnosis.

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination with Metformin in Patients with mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies.

BACKGROUND: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors. METHODS: Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks. RESULTS: A total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30-77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD. CONCLUSIONS: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations. SIGNIFICANCE: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.Clinical trial information: NCT03017833.

[Changes of glucose in the brains of monkeys with MPTP induced Parkinson's disease].

OBJECTIVE: To examine the metabolic and behavioral changes of monkeys with MPTP induced Parkinson's disease. METHODS: Four healthy monkeys were injected with diluted MPTP solution continuously through peripheral veins. The behavioral changes of the monkeys were monitored with the Parkinson disease scale for monkeys. 18FDG-PET-CT scans for the whole brain were obtained before and 3 months after the injection of MPTP. The pathological and glucose metabolic changes of the brains were examined. RESULTS: The animal model of Parkinson's disease was successfully established in all 4 monkeys, showing typical parkinsonian syndromes of bradykinesia, rigidity and hypokinesia. Changes in high nervous activities such as apathetic and less aggressive behaviors were also observed. Their scores of Parkinson disease scale exceeded 20. The parkinsonian syndromes were relieved after the administration of sinemet. The 18FDG-PET-CT scans showed significant glucose reduction after the MPTP injection within and outside of the basal ganglion area. CONCLUSION: The metabolic changes of brains in the monkeys with Parkinson's disease are not limited to the basal ganglion area, which may be an important mechanism for the non-motor symptoms.

The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells.

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo. Here we report that UBE2C was indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C was required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibited tumor formation and extended the lifespan of mice. Mechanistically, KrasG12D induced expression of UBE2C, which coupled with APC/CCDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of mTORC signaling. Importantly, DEPTOR levels fluctuated during cell cycle progression in a manner dependent on UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene and tumor suppressor cascade that regulates cell cycle progression and autophagy and validates UBE2C an attractive target for lung cancer associated with Kras mutations.