Doses Of Inhibitors Research Articles

Abstract B027: Investigating NRF2-mediated radioresistance in HPV-negative head and neck squamous cell carcinoma preclinical models

Abstract Background: Head and neck squamous cell carcinomas (HNSCC) that are not driven by human papillomavirus (HPV) are associated with a higher likelihood of treatment resistance and recurrence compared to HPV-positive HNSCC. There are currently no genomic-guided treatments for HPV-negative HNSCC, meaning that patients do not benefit from precision medicine approaches. Thus, it is critical to understand the mechanisms underlying HNSCC progression to identify molecular targets and better stratify therapeutic options for patients. NFE2L2 encodes for nuclear erythroid 2-related factor 2 (NRF2), a transcription factor that plays a crucial role in responding to oxidative stress by regulating the expression of genes associated with cellular defense mechanisms. Mutations in NFE2L2 and its negative regulator, KEAP1, make up approximately 25% of HPV-negative HNSCCs. Additionally, constitutive activation of NRF2 confers a growth advantage and causes resistance to chemotherapy and radiotherapy. We will elucidate the role of NRF2, identifying novel radiosensitizers to better guide therapeutic strategies for HPV-negative HNSCC patients. Methods: Using clonogenic and long-term viability assays measuring radiation response, we identified radioresistant and radiosensitive cells in a panel of 19 HPV-negative SCC cell lines. An area-under-the-curve (AUC) metric was used to measure cellular response to multiple doses of ionizing radiation. Reactive oxygen species (ROS) and DNA double strand breaks (DSBs) were quantified using DCFDA and γH2AX assays, respectively. Radiosensitization was measured using the ∆AUC of varying drug doses of NRF2 inhibitor, ML385. NFE2L2 and KEAP1 were knocked down using RNA interference in radioresistant and radiosensitive cells, respectively. Results: We identified 13 radiosensitive and 6 radioresistant cell lines out of the 19 HPV-negative SCC cell lines. There was a strong correlation between AUCs of the clonogenic and long-term viability assays (Pearson r=0.74, p=3.0×10–4). Six cell lines were consistently radioresistant (AUC>3.5) in both assays. None of the cell lines contained mutations in the NRF2 pathway, and only 1/6 were radiosensitized by ML385 (∆AUC=2); this effect was not correlated with ROS or DSBs, yet was abrogated by NFE2L2 knockdown. KEAP1 knockdown cell lines were generated for ongoing functional characterization and for genetic screens to identify radiosensitizers in HPV-negative HNSCC. Conclusions: We aim to identify the role of NRF2 in the treatment response of HPV-negative HNSCC. Although NRF2 is an important pathway in driving a radioresistant phenotype, the majority of radioresistant cell lines were not sensitized by NRF2 inhibition. Therefore, elucidating the molecular underpinnings of NRF2-mediated therapeutic resistance will be critical to identifying novel radiosensitizers with activity in HPV-negative HNSCC. Citation Format: Aakshi Puri, Meghan Lambie, Scott V. Bratman. Investigating NRF2-mediated radioresistance in HPV-negative head and neck squamous cell carcinoma preclinical models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B027.

Outcome Predictors of Generalized Myasthenia Gravis: A Prospective Observational Study.

There is paucity of studies on long-term remission of autoimmune generalized myasthenia gravis (MG) from Southeast Asia. We report the outcome predictors of generalized MG and also evaluate the influence of high- versus low-dose prednisolone and prednisolone with or without azathioprine (AZA). Fifty-seven patients with generalized MG were included, who completed 2 years of follow-up. Demographic information, comorbidities, Myasthenia Gravis Foundation of America (MGFA) class at baseline and follow-up, acetylcholine receptor (AChR) and muscle-specific kinase antibodies, decremental response, thymectomy, and treatments were recorded. Maximum doses of prednisolone, AZA, and acetylcholinesterase inhibitors were noted. The predictors of MGFA 0 at 3 and 6 months and minimal manifestation (MM) status at 2 years were evaluated. MGFA 0 was achieved by 27 (47.4%) patients at 3 months, 35 (61.4%) patients at 6 months, and 46 (80.7%) patients at 12 months. At 2 years, 48 (84.2%) patients achieved the MM status and none achieved complete stable or pharmacologic remission. On multivariate analysis, AChR antibody titer (adjusted odds ratio [AOR] 1.08, 95% confidence interval [CI] 1.006-1.167; P = 0.03) and MG activity of daily living (MGADL) at 6 months (AOR 1.28, 95% CI 1.066-1.558; P = 0.01) predicted the MM status. Maximum dose of prednisolone and adjunctive AZA did not predict the MM status. About 84.2% of patients with generalized MG, especially those with a low AChR antibody titer and MGADL < 4 at 6 months, achieved the MM status at 2 years.

Survival impact of immune-related adverse events in extensive stage small cell lung cancer patients: a retrospective cohort study.

Prior research indicates a connection between immune-related adverse events (irAEs) and improved progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer. However, limited data exists for extensive stage small cell lung cancer (ES-SCLC). This study included all ES-SCLC patients who received at least one dose of an immune checkpoint inhibitor between 2 January 2011 and 4 July 2022 using a large retrospective registry from a single institution. PFS and OS were right-censored at the date of last follow-up and were estimated using the Kaplan-Meier method. Differences in PFS and OS between irAE groups were assessed using Cox proportional hazards models. Among 245 patients with ES-SCLC; 56 (23%) experienced irAEs, 24 (42.9%) of which were high-grade (3-4). High-grade irAEs occurred at a median of 1.2 months (interquartile range [IQR] 0.45-2.5), while low-grade irAE occurred at 2.8 months (1.3-5.2). PFS was significantly longer among any irAE vs none (HR = 0.49; [95%CI 0.32-0.77]) as was OS (HR = 0.49; [95%CI 0.34-0.72]). In ES-SCLC patients treated with immunotherapy, those who experienced any irAE demonstrated a two-fold increase in both PFS and OS compared to those without an irAE. This is consistent with other tumor primaries.

Case Report of Status Epilepticus in a Patient with Acute HAE

Introduction: Hereditary angioedema (HAE) is a genetic disorder associated with recurrent episodes of angioedema in the absence of urticaria and pruritus. Hereditary angioedema is inherited in an autosomal dominant pattern and results in a quantitative deficiency (HAE type I) or dysfunction (HAE type II) of the C1-esterase inhibitor (C1-INH) protein. A very rare third type of HAE which is associated with normal quantitative and functional levels of C1-INH (HAE-nl-C1-INH) has been described. Case Report: A 54-year-old female with past medical history significant for HAE-nl-C1-INH presented to the emergency department (ED) for an acute attack of HAE and seizures. The patient arrived postictal after experiencing a total of three witnessed seizures, each lasting approximately 30 seconds. After the initial seizure was witnessed in the ED, the patient received 4200 Units of recombinant C1-INH intravenously. The patient’s mental status did not return to baseline, and she experienced two additional seizures. She was given a dose of the kallikrein inhibitor, ecallantide, as well as standard dosing of lorazepam and levetiracetam. The patient returned to her baseline and had no subsequent seizures while in the ED. Inpatient work-up included continuous video electroencephalography monitoring and magnetic resonance imaging of the brain, both of which were normal. The remainder of the inpatient course wasuncomplicated, and the patient was discharged home neurologically intact. Conclusion: We present a case of status epilepticus in a patient with HAE-nl-C1-INH. The focus of emergent medical management of status epilepticus includes airway protection, respiratory support, and administration of abortive and prophylactic antiepileptic drugs. The emergency medicine physician should also consider and treat possible underlying etiologies. The treatment of an acute attack of HAE should focus on replacing C1-INH and preventing the formation and limiting the action of bradykinin.

Concomitant Usage of H1-Antihistamines and Immune Checkpoint Inhibitors on Cancer Patient Survival.

Recent research (Li etal. 2021) suggests an upregulated expression and activation of H1 receptors on macrophages in the tumor microenvironment, and concomitant H1-antihistamine use is associated with improved overall survival in patients with lung and skin cancers receiving immunotherapy. Therefore, we retrospectively evaluated the impacts of H1-antihistamine use in cancer patients during immunotherapy. All patients who had received at least one dose of immune checkpoint inhibitors (ICIs) from July 1, 2014 to October 31, 2019 were identified from Hong Kong's territory-wide database, with this date defined as the baseline. A 1-month landmark analysis was conducted with follow-for up to 6 months, including an exposure period of 1 month before and after the baseline date. Patients were grouped according to the types of primary cancer and the percentages of daily H1-antihistamine usage within the exposure period. The primary outcome was overall survival. A total of 1740 (65.1% male, mean age 61.9 years) were included in the landmark analysis, of which 529 (30.4%) and 307 (17.6%) had primary lung and liver malignancies. The multivariable Cox regression model estimated statistically significant improvement in overall survival of intermediate use in patients with primary lung malignancies (adjusted hazard ratio [aHR] 0.223, 95% confidence interval [CI] 0.052-0.958, p = 0.044), but not with primary liver maligancies. Similar frequency-dependent effects were identified in Kaplan-Meier analysis. The benefits of adjunctive use of H1-antihistamines may be generation- and tumor-dependent. Further clinical and mechanistic studies are required to confirm the findings.

Formation and Prevention of Natural Gas Hydrates

Natural gas hydrate is formed under certain temperatures and pressures, which makes it an unavailable clean energy source. However, in industrial production, clogging occurring due to hydrate generation can cause a series of safety accidents and economic losses. In order to solve the hazards of natural gas hydrates in drilling, this paper reviews the formation conditions of natural gas hydrates and the prevention and control measures. In order to inhibit the formation of hydrates, the use of traditional well control measures and the addition of thermodynamic inhibitors have high costs, large dosages, an unfriendly environment, etc. The new type of kinetic inhibitor has a strong effect and low dosage and is considered to be the most promising chemical treatment for hydrate prevention and control in the industry. However, kinetic inhibitors are greatly affected by environmental factors, and compounding them with thermodynamic inhibitors and their synergistic effect can greatly reduce the dosage of thermodynamic inhibitors and improve inhibition performance. It is an important direction for laboratory research and has shown good results in field applications.

Assessing the feasibility of using a data-driven corrosion rate model for optimizing dosages of corrosion inhibitors

Optimizing dosages of corrosion inhibitors requires experimental data gathered from time-consuming methods. The current study examines the feasibility of optimizing inhibitor dosages using a model trained for predicting corrosion rates more easily measured using linear polarization resistance in a full-scale cooling water system. A comprehensive study on variable selection showed that linearly correlated variables are necessary to predict corrosion trends. The Sobol sensitivity of inhibitors is trivialized by variables linearly correlated to the corrosion rate. The study highlights the importance of achieving high model prediction accuracy and high Sobol sensitivity of inhibitors to the corrosion rate, for using the model for inhibitor dosage optimization.

Risk factors for gastric mucosa lesion in critically ill patients undergoing endoscopy for percutaneous gastrostomy: a case-control study

BackgroundPharmacologic prophylaxis for gastric ulcer is commonly prescribed in patients hospitalized in the intensive care unit (ICU). The aim of the study was to assess the current prevalence and risk factors for gastric mucosa lesion in ICU patients receiving standard pharmacologic prophylaxis undergoing endoscopy for percutaneous gastrostomy implantation.MethodsPatients hospitalized in the mixed medical-surgical ICU undergoing percutaneous endoscopic gastrostomy (PEG) were analyzed. We excluded patients receiving either no or high doses of intravenous proton pump inhibitor (PPI), only patients receiving standard doses of PPI were included. Data retrieved from the electronic medical records included: demographics, risk factors for gastric mucosa lesion (use of stimulants, comorbidities, medications, treatment methods in the ICU, laboratory derangements) and endoscopic findings. The study compared a group of patients with gastric mucosa lesions (cases) vs. patients without gastric mucosa lesions (controls). Inter-group comparisons between cases and controls were performed. Depending on the type of distribution continuous variables were assessed using two-sample t-test or Mann-Whitney test, whereas categorical variables with Chi-squared or Fisher exact test. Odds ratio (OR) with 95% confidence interval (95% CI) were calculated. Statistical significance was assumed at p < 0.05.ResultsPatients with no prophylaxis (n = 8) or receiving high doses (> 40 mg per day) of proton pump inhibitor (n = 2) were excluded. There were 182 patients receiving standard intravenous dose of PPI, 63 (34.6%) women and 119 (65.4%) men, with median age 61.5 (interquartile range IQR 46.0–70.0) years. Majority of patients (n = 169, 92.9%) were receiving pharmacological prophylaxis for venous thromboembolism. There were 53 (29.1%) patients with gastric mucosa lesion. The only risk factor that was significantly different between cases and controls was history of gastric ulcer (p = 0.04) with OR 3.8 (95% CI 1.1–12.5; p = 0.03).ConclusionsMajority of various risk factors for gastric ulceration may not predict gastric mucosa lesion in ICU patients receiving standard pharmacological prophylaxis undergoing endoscopy for PEG implantation. We found that history of gastric ulcer may be a risk factor for gastric ulceration in the ICU patients. Patients with history of gastric ulcer might benefit from higher than standard doses of anti-ulcer medication when hospitalized in the ICU.

Post-transplant complications in alcohol- and metabolic-associated steatotic liver disease

Alcohol-associated liver disease (ALD) and metabolic-associated steatotic liver disease (MASLD)/metabolic-associated steatohepatitis (MASH) are severe liver diseases, with liver transplant being the primary curative treatment option. Transplant recipients with ALD suffer from alcohol use disorder (AUD) and poor drug compliance, which can result in graft injury and even graft loss. Relapse of alcohol consumption, lack of drug compliance, and smoking negatively impact the graft and clinical outcome of ALD-related transplantation patients. Furthermore, these patients are at a higher risk of developing non-hepatic complications such as malignancies, cardiovascular diseases, and other metabolic conditions. The management of these conditions requires pharmacological and behavioral strategies to manage complications as soon as they arise. Critical monitoring of these conditions is also advocated. In patients undergoing transplants for MASLD/MASH, early complications arise in obese and diabetic patients. Late post-transplant complications such as cardiovascular diseases, chronic kidney disease, recurring MASLD/MASH, immunosuppression, and arterial hypertension are reported. Integrating behavioral strategies with diet modification and physical activity is crucial to balance underlying metabolic disorders and improve clinical outcomes. Early steroid withdrawal and low calcineurin inhibitor doses can decrease the risk of post-transplant diabetes, hypertension, and dyslipidemia. Lifestyle modifications and tailored immunosuppression are helpful in the prevention and management of post-transplant recurrent MASLD/MASH.

Study on CO2 Corrosion Behavior of Underground Gas Storage Pipe Columns and Establishment of Corrosion Inhibition System

Herein, we take an underground natural gas storage in the Ordos Basin as an example to explore the influence of temperature, CO2 flow rate, CO2 partial pressure, and chloride ion concentration on the corrosion rate of N80 and P110 steels in CaCl2 brine type. Meanwhile, in order to reduce the amount of chemical corrosion inhibitors and improve performance, a novel corrosion inhibitor with a quinoline quaternary ammonium structure named YS-QB was synthesized from 1-methyl-1,2,3,4-tetrahydroisoquinoline, epichlorohydrin, and oleic acid amide propyl dimethylamine. Under normal and high-pressure environments, YS-QB exhibits a superior corrosion inhibition effect to the market product of CX-1. In order to further reduce the amount of corrosion inhibitor and improve the corrosion inhibition effect, orthogonal experiments were conducted to optimize the formula system, and the optimal composite system was finally obtained by forming YS-QB, propargyl alcohol, hexamethylenetetramine, and isopropanol in a mass ratio of 12:1:1:2. At 80 °C, a dosage of 30 mg/L can suppress the CO2 corrosion rate below 0.076 mm/a, while a dosage of 60 mg/L can suppress the CO2 corrosion rate below 0.076 mm/a at a high-pressure environment of 120 °C. Combining weightlessness and electrochemical experiments, it is found that the composite corrosion inhibitor performs best when the dosage reached 100 mg/L, and a further increase in the dosage weakens the corrosion inhibition capacity. Based on the polarization curve changes with the dosage of the composite corrosion inhibitor, it can be determined that the final obtained composite corrosion inhibitor system was a cathodic corrosion inhibitor.

Second-step strategies in antidepressant pharmacotherapy : Results of current meta-analyses

Antidepressant pharmacotherapy often does not result in the desired effect despite adequate duration and dose. Better evidence on second-step strategies is needed. Overview of the current evidence for various pharmacological second-step strategies after nonresponse to antidepressant monotherapy. Summary of recent systematic reviews with meta-analyses of the group of authors on pharmacological second-step treatment. Ameta-analysis showed no advantage of switching to asecond antidepressant compared with continuing the previously ineffective monotherapy. Another two meta-analyses showed no benefit of increasing the dose of selective serotonin reuptake inhibitors (SSRI). For serotonin and noradrenaline reuptake inhibitors (SNRI) and tricyclic antidepressants (TCA) in each case ameta-analysis showed no clear advantage of increasing the dose. Another two meta-analyses showed asuperiority of acombination therapy consisting of areuptake inhibitor (SSRI, SNRI, TCA) with apresynaptic alpha‑2 autoreceptor antagonist (e.g., mirtazapine) compared with an antidepressant monotherapy. In accordance with the recommendations of the German national treatment guideline, in the event of nonresponse to antidepressant monotherapy, the combination of two antidepressants is preferable to repeated switching of the antidepressant.

Small Molecule Myeloperoxidase (MPO) Inhibition Prevents Delayed Cerebral Injury (DCI) After Subarachnoid Hemorrhage (SAH) in a Murine Model.

Delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is a preventable injury that would improve patient outcomes if an effective treatment can be developed. The most common long-term disability in patients with SAH is cognitive dysfunction. Contrary to the common theory that damage from DCI originates solely from ischemia caused by cerebral vasospasm, inflammation has been shown to be an important independent mediator of DCI. Neutrophil infiltration of the meninges is a critical step in developing late spatial memory deficits in a murine model of SAH and may serve as a surrogate marker for disease progression. Importantly, myeloperoxidase (MPO) null mice do not develop meningeal neutrophilia and are protected from spatial memory deficits. In this study, wildtype mice administered a single dose of the MPO inhibitor (MPOi) AZD5904 at peak neutrophil entry day have a higher percentage of neutrophils that remain in the meningeal blood vessel 6days after the hemorrhage suggesting neutrophil extravasation into the meninges is inhibited (79 ± 20 vs. 28 ± 24, p < 0.01). Interestingly, the intraperitoneal route of administration has a larger effect than the intrathecal route suggesting that MPO inhibition is best administered systemically not in the central nervous system. Second, mice administered AZD5904 intraperitoneal for 4 consecutive days starting 2days after the hemorrhage do not develop delayed spatial memory dysfunction (two-way analysis of variance, p > 0.001 F [2, 22] = 10.11). Systemic MPOi prevents neutrophil entry into the meninges and prevents spatial memory dysfunction. MPOi is a promising strategy for translation to patients with aneurysmal SAH.

Estimating cancer risk in immune-mediated inflammatory diseases exposed to varying doses of tumour necrosis factor inhibitors.

The safety profile of high doses of tumour necrosis factor inhibitors (TNFi) therapy for cancer risk in immune-mediated inflammatory diseases (IMIDs) remains uncertain. We evaluated the risk of cancer development in patients with IMIDs exposed to standard and high doses of TNFi compared with those never exposed to TNFi. A cohort study was conducted using the Japanese claims database encompassing over 4.6 million individuals from 2013 to 2021. The study included patients aged 16years or older with new-onset IMIDs, such as inflammatory bowel disease, rheumatoid arthritis, or psoriasis, who had no cancer history. The subdistribution hazard ratios (SHR) for cancer risk in TNFi standard and high dose groups comparing with TNFi unexposed group were estimated using a Fine and Gray model that accounted for the competing risk of death unrelated to cancer. The high dose of TNFi was defined as either a dose escalation or shortening of the intervals during administrations from the standard dose treatment. We identified a total of 42,006 patients with new-onset IMIDs (40,573 in TNFi unexposed, 876 in TNFi standard dose, and 557 in TNFi high dose) and 1211 (2.8%) patients developed cancer, yielding an incidence rate of 787.8 (739.9-828.1) per 100,000 person-years. Neither the standard nor high doses of TNFi significantly increased the cancer risk (TNFi standard dose vs. TNFi unexposed, adjusted SHR, 0.65 [0.40-1.08]; TNF high dose vs. TNFi unexposed, adjusted SHR, 1.12 [0.67-1.87]). There is no association between varying doses of TNFi therapy and cancer risk in IMIDs.

First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors.

Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach. A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin-angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m² and a urine protein/creatinine ratio (UPCR) >0.75g/g. In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42mL/min/1.73m2 (32-63) and median baseline UPCR was 1.5g/g (0.9-1.8). After initiation of sparsentan, UPCR significantly decreased (P<0.0001) to a median of 0.85g/g (0.42-1.15) in the 2-week follow-up and further declined (P=0.001) to a median of 0.60g/g (0.32-0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45-74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported. In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.

Comparing the efficacy of different proton pump inhibitor dosing regimens for the treatment of gastroesophageal reflux disease: a systematic review and meta-analysis.

Several proton pump inhibitor (PPI) dosing regimens that vary by strength and frequency (once [Qday] or twice [BID] daily) are available to treat gastroesophageal reflux disease (GERD). We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the impact of various PPI regimens on esophageal healing and GERD and heartburn symptoms. To identify relevant studies, we searched EMBASE and PubMed in January 2023, which yielded 1381 records. Eligible RCTs included those that enrolled adults diagnosed with GERD and compared different dosing regimens within the same PPI. The outcomes were esophageal healing and resolution of GERD and heartburn symptoms within 12weeks (i.e. short-term) and > 12weeks (i.e. long-term). Meta-analysis pooling of the odds ratios with 95% confidence intervals were estimated using the random-effects inverse-variance model. Overall, a total of 38 RCTs across 20 countries (N = 15,540 patients, mean age 50years, 55% male) were included. Most PPI trials compared half standard dose Qday versus standard dose Qday or standard dose Qday versus double standard dose Qday. In general, when considering daily dosing, higher PPI strength significantly improved esophageal healing and relief of GERD symptoms both in the short- and long-term. Fewer trials compared Qday versus BID dosing; the impact of BID dosing on outcomes was inconsistent across the different PPI strength comparisons. In conclusion, this meta-analysis revealed that increasing PPI Qday dosages led to improved GERD outcomes. However, few studies compared Qday to BID dosing; as twice daily PPI usage is common in clinical practice, further studies are warranted to determine whether such dosing improves clinical outcomes.

Prediction of long‐term treatment outcome in Alzheimer's disease based on EEG connectivity

AbstractBackgroundIt is difficult to predict of long‐term treatment response of AD to medical treatment when starting medication. We explored EEG brain connectivity as a potential biomarker for long‐term medication outcomes in patients with AD.MethodsResting‐state EEG was recorded from a total of 56 AD patients (mean age = 73.23±6.39) when starting medication after diagnosis of AD. EEG was recorded in 32 channels. We divided the patients into two groups, good and poor respondent groups according to clinical evaluation after treatment and dosage changes of AD medication with MMSE score change. Starting dosage of AchE inhibitor, donepezil was 7.75±3.85mg and the mean treatment period is 104.05±57.93 weeks. The mean final medication dosages are donepezil 13.23±6.93mg and memantine 9.52±9.68mg. Initial MMSE scores of good respondent group (n=32, M=11, F=21) is 20.06±4.35 and poor respondent group (n=24, M=7, F=17) is 19.63±4.07. We analyzed brain EEG connectivity among the 246 cortical regions defined by the Brainnetome atlas.ResultsOur study found that the difference in brain EEG connectivity, especially intrahemispheric regional connectivity in gamma frequency bands, is increased at multiple regions of right hemisphere such as between Brodmann Area 44 and 39, such as DLFPC and hippocampal areas, DLFPC and caudate nucleus, middle frontal and inferior parietal areas in poor respondent group (p&lt;0.00001). In alpha frequency band, EEG connectivity between right DLPFC(BA 9/46) and right paracentral lobule of frontal lobe (BA 4) is increased in good respondent group (p&lt;0.0001). In theta frequency band, EEG connectivity in the areas of frontal lobe (BA 4 and 6) is decreased in good respondent group (p&lt;0.0001).ConclusionsThis study shows increased gamma bands EEG connectivity between right anterior and posterior areas in poor respondent group. In general cortical gamma‐band activity is increased by selective attention in normal populations and related to cholinergic system. Elevated gamma band power was observed in AD when compared to MCI and control subjects was reported in a previous study. Our results suggest the potential of the gamma EEG connectivity of initial EEG when starting treatment as a biomarker to predict long‐term medical treatment for AD medication.

Induction of IMPDH-Based Cytoophidia by a Probable IMP-Dependent ARL13B-IMPDH Interaction.

Inosine Monophosphate Dehydrogenase (IMPDH) catalyzes rate-limiting step of the reaction converting inosine monophosphate (IMP) to guanine nucleotides. IMPDH is up-regulated in the healthy proliferating cells and also in tumor cells to meet their elevated demand for guanine nucleotides. An exclusive regulatory mechanism for this enzyme is filamentation, through which IMPDH can resist allosteric inhibition by the end product, GTP. It has been proven that intracellular IMP, which rises during the proliferative state, potentially promotes IMPDH filamentation. On the other hand, interaction of IMPDH with ADP-ribosylation factor-like protein 13B (ARL13B) directs guanine biosynthesis toward the denovo pathway. However, ARL13B is not localized in the IMPDH-based cytoophidia, super structures composed of bundled IMPDH filaments and other proteins. Here, we hypothesized that ARL13B could increase availability of the denovo-produced IMP for IMPDH by interacting with the IMP-free IMPDH and microtubules adjacent to the purinosome. Following IMP-binding, IMPDH would be released from ARL13B and preferentially associated with its cytoophidia. Considering clinical side effects of catalytic inhibitors of IMPDH and their ability to induce IMPDH cytoophidia, we suggest that combination of proper doses of IMPDH catalytic inhibitors and inhibitors of the denovo IMP biosynthesis could be more effective in controlling cell proliferation.

Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth invitro and invivo and promotes chemosensitization.

By analyzing RNA datasets from rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people, we found upregulation of sterol regulatory element-binding protein 2 (SREBP2) and mevalonate pathway (MVP) genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival and predicted statin sensitivity. In human RD and RH30 lines, treatment with 0.01-1μM doses of fatostatin (SREBP2 inhibitor), lovastatin and simvastatin (HMGCR inhibitors), and zoledronic acid (FDPS inhibitor) impaired cell growth and migration, which were conversely stimulated by 50-100μM cholesterol (CHO) supplementation. Treatment of RMS lines with higher doses of SREBP2 and MVP inhibitors (5-50μM) promoted oxidative cell death and chemosensitization in combination with actinomycin D. Administration of lovastatin or fatostatin to RD and RH30 cells produced a rapid attenuation of Erk1/2 and Akt1 phosphorylation, detectable after 4h of treatment. Furthermore, tumor mass growth of xenografted RD cells in NOD/SCID mice was reduced by oral administration of lovastatin. Lastly, we found the forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression and enhance cell death susceptibility to MVP inhibitors. Taken together, these data suggest that the axis formed by Akt1, SREBP2 and MVP is critical for RMS tumor growth, migration, and oxidative stress protection mainly through the maintenance of CHO levels that ensure proper intracellular signaling. Therefore, targeting CHO levels by SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol in RMS.

Construct validity and responsiveness of ASAS Health Index assessed in two longitudinal studies of tumour necrosis factor alpha inhibitor initiation and dose reduction in patients with axial spondyloarthritis

BackgroundThe Assessment of SpondyloArthritis international Society Health Index (ASAS HI) is a novel questionnaire of global functioning for patients with axial spondyloarthritis (SpA).ObjectiveThe objective was to assess the construct validity,...

Effectiveness of acupuncture treatment in post-stroke depression and anxiety disorders: a prospective, randomized, controlled, single-blind study.

Our aim was to examine the effectiveness of acupuncture in post-stroke depression/anxiety disorders and to determine whether it reduces the need for anxiolytic and sedative drug use. This study included 54 stroke patients with depression and/or anxiety disorder. Patients were randomly assigned to the acupuncture treatment group (n = 27) or the control group (n = 27). A conventional rehabilitation program was applied to all patients and acupuncture was performed twice a week for 4 weeks. Patients were evaluated blindly by a psychiatrist at baseline (week 0), week 4 and week 8, using the Hamilton depression rating scale (HAM-D) and Hamilton anxiety rating scale (HAM-A), and drug doses were adjusted when necessary. The HAM-D and HAM-A scores at week 4 were pre-specified as the two primary outcome measures. Within each group, there was a significant decrease in the mean scores of HAM-D and HAM-A at weeks 4 and 8. No between-group differences in HAM-A or HAM-D scores were seen at 4 weeks but there was a significant decrease in HAM-D scores in favor of the acupuncture group at week 8 (p < 0.025). At week 4, the number of cases whose selective serotonin reuptake inhibitor (SSRI) dose was increased was found to be significantly higher in the control group. While the study was negative with respect to its primary outcomes, the findings with respect to certain secondary outcomes suggests further research is warranted to determine if acupuncture treatment is an effective/safe treatment to alleviate post-stroke depression/anxiety. NCT04283591 (ClinicalTrials.gov).