Incomplete Blockade Research Articles

Erythrocyte‐Derived Bioactive Nanovesicles Reverse the Immunosuppressive Function of Adenosine for Tumor Photoimmunotherapy

AbstractAdenosine has garnered significant attention as a potential target for overcoming tumor immune evasion. It exacerbates the immunosuppressive tumor microenvironment (TME) by incapacitating various protective immune cells. However, inhibitors targeting adenosine receptors are limited by incomplete blockade effects and off‐target toxicity, necessitating the exploration of more effective strategies. Inspired by the native biologic function of adenosine deaminase (ADA) in hydrolyzing adenosine, a bioactive catalytic nanovesicle (ENV@FeS) is designed to reverse adenosine immunosuppressive function. The nanovesicle is constructed through the serial extrusion of erythrocytes abundant with ADA, coupled with the synthesis of FeS complex in situ using Fe2+ in erythrocytes via H2S gas introduction. Notably, the bioactive nanovesicles not only promote tumor targeting and induce immunogenic cell death by the FeS‐induced photothermal effect, but also hinder the adenosine pathway by metabolizing adenosine into immunopotentiator inosine, further boosting antitumor immunity. In vivo, ENV@FeS efficiently increases the infiltration of cytotoxic T lymphocytes and M1 macrophages while reducing the production of regulatory T cells and myeloid‐derived suppressor cells, resulting in significant inhibition of tumor growth. Together, the biomimetic nanovesicle‐mediated adenosine metabolic regulation, in synergy with photothermal therapy, leads to a marked improvement in the immunogenic TME and enhances the therapeutic efficacy of photoimmunotherapy.

Costoclavicular Brachial Plexus Block Facilitates Painless Upper Extremity Reduction: A Case Report.

The costoclavicular brachial plexus block (CCBPB) has emerged as a more effective approach to regional anesthesia of the upper extremity. The costoclavicular space is the anterior portion of the superior thoracic aperture, located between the clavicle and first rib. The brachial plexus cords traverse this space clustered together in a superficial location lateral to the axillary artery and share a consistent topographical relationship to one another. By targeting the brachial plexus at this specific anatomical location, the CCBPB offers a powerful, single-shot, sensorimotor block of the upper extremity below the shoulder. We present a novel application of the CCBPB to facilitate emergency department (ED) analgesia and closed reduction of an upper extremity fracture. A 25-year-old male presented to the ED with a traumatic Colles fracture sustained during a high-speed motor vehicle collision. Despite multimodal analgesia, the patient reported intractable severe pain with intolerance of radial manipulation. An ultrasound-guided CCBPB was performed to augment pain control and avoid procedural sedation, resulting in dense, surgical anesthesia of the upper extremity, and painless fracture reduction. Regional anesthesia is an effective component of multimodal pain management and another tool in the emergency physician's analgesic armamentarium. In acute orthopedic traumas necessitating emergent reduction, regional blocks serve as rescue pain control and can obviate the need for procedural sedation. In terms of targeted upper extremity analgesia, the CCBPB offers effective, single-shot, sensorimotor blockade below the shoulder, mitigating use of opioids and their deleterious side effects, while simultaneously avoiding incomplete blockade or phrenic nerve palsy associated with other approaches to brachial plexus blockade.

Costoclavicular Brachial Plexus Block Facilitates Painless Upper Extremity Reduction: A Case Report

Introduction: The costoclavicular brachial plexus block (CCBPB) has emerged as a more effective approach to regional anesthesia of the upper extremity. The costoclavicular space is the anterior portion of the superior thoracic aperture, located between the clavicle and first rib. The brachial plexus cords traverse this space clustered together in a superficial location lateral to the axillary artery and share a consistent topographical relationship to one another. By targeting the brachial plexus at this specific anatomical location, the CCBPB offers a powerful, single-shot, sensorimotor block of the upper extremity below the shoulder. We present a novel application of the CCBPB to facilitate emergency department (ED) analgesia and closed reduction of an upper extremity fracture.Case Report: A 25-year-old male presented to the ED with a traumatic Colles fracture sustained during a high-speed motor vehicle collision. Despite multimodal analgesia, the patient reported intractable severe pain with intolerance of radial manipulation. An ultrasound-guided CCBPB was performed to augment pain control and avoid procedural sedation, resulting in dense, surgical anesthesia of the upper extremity, and painless fracture reduction.Conclusion: Regional anesthesia is an effective component of multimodal pain management and another tool in the emergency physician’s analgesic armamentarium. In acute orthopedic traumas necessitating emergent reduction, regional blocks serve as rescue pain control and can obviate the need for procedural sedation. In terms of targeted upper extremity analgesia, the CCBPB offers effective, single-shot, sensorimotor blockade below the shoulder, mitigating use of opioids and their deleterious side effects, while simultaneously avoiding incomplete blockade or phrenic nerve palsy associated with other approaches to brachial plexus blockade.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

Comparison of paravertebral block vs. general anesthesia for percutaneous nephrolithotomy: A retrospective study.

General anesthesia is used in the majority of patients undergoing percutaneous nephrolithotomy. To reduce the general anesthesia-related risks and complications, this study evaluated the efficacy and safety of the paravertebral block as a novel and alternative anesthetic method for percutaneous nephrolithotomy. This was a retrospective study. A total of 198 patients under percutaneous nephrolithotomy were included. Among them, 76 patients received paravertebral block and 122 received general anesthesia. Patients' characteristics, surgical outcomes, anesthetic outcomes, and perioperative complications and the visual analog scale (VAS) were recorded to evaluate the efficacy and safety of paravertebral block compared with general anesthesia. Intergroup differences of the parameters were analyzed using an independent t-test and χ2-tests appropriate. Seventy-six patients who underwent paravertebral block completed the surgery successfully, three patients were supplemented with propofol for discomfort during ureteroscopy, and two patients were supplemented with remifentanil for incomplete nerve blockade. Patients who underwent paravertebral block had a higher American Society of Anesthesiologists grade and heart function grade, including patients with contraindications to general anesthesia. Intraoperative and postoperative adverse events and the anesthesia costs were less in patients who underwent paravertebral block. VAS pain scores during the postoperative period in patients who underwent paravertebral block were lower than those in patients who underwent general anesthesia without the use of patient-controlled intravenous analgesia. In this retrospective study, paravertebral block was found to be effective and safe in providing intraoperative anesthesia for percutaneous nephrolithotomy, and had less adverse events and anesthesia costs. Paravertebral block is an attractive alternative anesthesia for patients at increased risk of comorbidities following general or neuraxial anesthesia.

ЭКГ-признаки транзиторного синдрома Бругада у пациента после COVID-19

The article presents a description of a clinical case of the appearance of characteristic ECG signs of Brugada syndrome type 1 in the form of incomplete blockade of the right bundle branch block, «convex» ST elevation of 2 mm and negative symmetrical T-wave inversion in V1-V2 in a practically healthy patient after a new coronavirus infection (COVID-19). On the control ECG performed a week later, these signs reduced to a latent form. However, there is an assumption that the Brugada syndrome in a woman had existed in a latent form, and against the background of COVID-19, it transformed into its active variant. Unfortunately, we do not have data on how long these signs were present on the ECG, as the ECG was recorded a week after COVID-19. The clinical case we demonstrate shows a possible relationship between the transient nature of type 1 Brugada syndrome and COVID-19, which requires further study. The article also provides examples of other clinical cases of the appearance of signs of Brugada syndrome on the ECG in patients with COVID-19 according to various literature data.

Persistent cardiac organ damage in surgically and medically treated primary aldosteronism.

We compared persistent cardiac organ damage in patients treated surgically or medically for primary aldosteronism. Eighty-four patients (age 57 ± 11 years, 27% women) with primary aldosteronism underwent echocardiography at time of diagnosis and after one year of treatment (49% adrenalectomy, 51% medical treatment). Persistent cardiac organ damage was defined as presence of left ventricle (LV) hypertrophy, low LV midwall shortening, global longitudinal strain and/or enlarged left atrium both at baseline and at follow-up. At one year, a significant regression of LV hypertrophy was observed in surgically (44 vs. 22%, P = 0.039), but not in medically treated patients (60 vs. 51%, P = 0.206). The prevalence of enlarged left atrium was reduced in both groups (both P < 0.001), whereas systolic myocardial function remained unchanged. In multivariable logistic regression analysis, medical treatment [odds ratio (OR) 4.88 (95% confidence interval (CI) 1.26-18.88)] was a strong predictor of persistent LV hypertrophy independent of higher BMI [OR 1.20 (95% CI 1.04-1.38)] and presence of diabetes [OR 6.48 (95% CI 1.20-34.83), all P < 0.05]. Persistently low midwall shortening was associated with suppressed plasma renin after one year [OR 6.11 (95% CI 1.39-26.7)] and lower renal function [OR 0.96 (95% CI 0.94-0.99), both P < 0.05]. The strongest predictor of persistently low global longitudinal strain was higher HbA1c [OR 2.37 (95% CI 1.12-5.02), P = 0.024]. Persistent cardiac organ damage was more common in the medical treatment group and associated with incomplete aldosterone blockade, impaired renal function and presence of metabolic comorbidities.

Nano-enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion.

Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the “Zn2+ interference”‐mediated glycolysis inhibition and Zn2+‐activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. It is discovered that ZIF‐8 (zinc imidazolate metal–organic frameworks ) can induce abrupt intracellular Zn2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through “Zn2+ interference”‐triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn2+‐activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up‐regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes are loaded in ZIF‐8 concurrently tethered by hyaluronic acid (HA), constructing a “nanoenabled energy interrupter ”. Such a rational design presents a preferential accumulation tendency to tumor sites due to the active CD44‐targeting mechanisms, specifically achieves remarkable systematic energy exhaustion in melanoma cells, and affords 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verifies a fascinating therapeutic platform enabling ion interference‐inductive starvation strategy for effective tumor therapy.

Left ventricular myocardial strain and electrocardiographic changes in children with hypertrophic cardiomyopathy

Abstract Introduction. Hypertrophic cardiomyopathy is one of the most common diseases of the myocardium in children. Meanwhile, the relationship between indicators of strain and electrocardiographic changes, their diagnostic significance for children with hypertrophic cardiomyopathy remains an insufficiently well-studied issue.Purpose.Тo analyze the relationship between indicators of strain of the left ventricular and ECG in children with hypertrophic cardiomyopathy (HCM).Materials and methods. Have been examined 61 patients with an asymmetric form of hypertrophic cardiomyopathy aged from 7 to 17 years. Of these, 45 (73.8%) children with nonobstructive form, 16 (26.2%) children with obstructive form. Electrocardiography (ECG) and 24-hour Holter monitoring ECG had performed. The parameters of global longitudinal, radial and circular of the left ventricular myocardial strain and their rates had determined by echocardiography in the 2D speckle tracking modeResults. In children with HCM, ECG signs of hypertrophy were studied (deviation of the electrical axis to the left, the predominance of the R wave in lead I, V6 over the S wave, the predominance of the S wave in lead V1 over the R wave) and myocardial ischemia (inversion of the T wave and a decrease in the ST segment in the leads I, II, V5, V6), rhythm and conduction disorders (ventricular extrasystole, degree I atrioventricular block, expansion of the QRS complex in leads V1-V3, incomplete blockade of the anterior left branch of the His bundle, increased duration of terminal activation), which significantly prevailed in obstructive form versus non-obstructive form. A decrease in the global longitudinal, radial, circular strain of the left ventricular myocardium and their rates had found, which had significantly more pronounced in the group with obstructive HCM. Inverse correlations had found between the parameters of strain and ECG-signs of hypertrophy and myocardial ischemia, conduction disorders, more pronounced between the parameters of longitudinal strain and ECG with a significant predominance in the obstructive form of the disease.Conclusions. In children with obstructive HCM, compared with the non-obstructive form, there have significantly more pronounced signs of myocardial hypertrophy and ischemia, rhythm and conduction disorders on the ECG and with 24-hour Holter monitoring ECG.

Atypical HUS and Crohn\u2019s disease\u2014interference of intestinal disease activity with complement-blocking treatment

BackgroundIn atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known.Case-diagnosis/treatmentWe present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn’s disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses.ConclusionIn aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.

Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.

Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway. We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with ×200 and ×10,000 folds improvement in binding affinity over wild-type PD-1 leading to superior inhibition of ligand-mediated PD-1 activities. Both in vitro and in vivo analyses performed in this study demonstrated that the high-affinity sPD-1 molecule is superior at blocking both PD-L1- and PD-L2-mediated immune evasion and reducing tumor growth in immune-competent murine models of ovarian cancer. The data presented in this study provide justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.

Incomplete Complement Inhibition in Patients with PNH on Eculizumab - 5 Year Experience from the National PNH Service Leeds

Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired disorder characterised by intravascular hemolysis and thrombosis. Patients with symptomatic PNH are commenced on the complement inhibitor eculizumab (600mg weekly for 5 weeks then 900mg 2 weekly). This monoclonal antibody targets C5 in the complement cascade, halting terminal complement activation thus inhibiting intravascular hemolysis. In some patients intravascular hemolysis is not adequately controlled on the standard regimen. Patient symptoms, transfusion requirements and raised Lactate dehydrogenase (LDH) levels are indicators for suboptimal control of PNH and review of eculizumab dosing. The 50% hemolytic complement (CH50) test is a functional assay assessing capability of serum complement components of the classical pathway to lyse sheep red blood cells pre-coated with rabbit anti-sheep red blood cell antibody. Patients with complement inhibited PNH should demonstrate absent lysis. As the test is expensive and difficult to organise, we tested if incomplete complete blockade as determined by CH50 activity would be better to confirm under-dosing than LDH value. Methods The Leeds (UK) PNH National Service reviewed patients who underwent CH50 assay between January 2015 and March 2020. All patients were on eculizumab with clinical concerns regarding suboptimal control of PNH. Patients receive eculizumab infusions intravenously every 14 days and routine follow up from the PNH Service. Serum samples were obtained 24 hours prior to infusions for CH50 assay; LDH values were routinely collected. Complete complement blockade was defined by &amp;lt;10% CH50 activity; intravascular hemolysis was indicated by LDH value &amp;gt;1.5x upper limit of normal (ULN). Confidence intervals were set at 95% and significance set at p&amp;lt;0.05. Results In the study period, 327 tests (median 2, range 1 - 8) were carried out in 146 patients (median age 54 years, range 16 - 89; 74 female). 81% (265) were successful; 19% (62) were unsuccessful due to processing errors. Of the successful tests, 74% (197 in 127 patients) indicated complete complement blockade and 26% (68 in 38 patients) indicated incomplete blockade. Of the patients with incomplete blockade, 68% (26) demonstrated complete blockade on repeat testing and 32% (12) had their eculizumab dose increased. Clinical symptoms of under-dosing in the 12 patients requiring a dose increase included increased transfusion requirements and/or breakthrough hemolysis (7), pregnancy (2; both returned to 900mg post pregnancy) and significant lethargy (3). Of the patients requiring a dose increase, 3 were on 1200mg before 2015; their dose was increased to 1500mg. Repeat testing was carried out in 10/12 patients after dose increase; 8 indicated complete blockade; 2 patients were incompletely blocked at 1200mg and received a further dose increase to 1500mg. Further testing indicated complete blockade in 1 patient; 1 required a 3rd dose increase to 1800mg due to incomplete blockade and ongoing transfusion requirement. Corresponding LDH values were analysed; median LDH for the complete blockade group was 1.16xULN (range 0.54 - 2.16) and 1.28xULN (range 0.76 - 2.38) for the incomplete blockade group. LDH values were not significantly higher in the incomplete blockade group compared to the complete blockade group, p=0.08. There was no significant difference in LDH values pre- and post-dose increase, p=0.38 (Figure 1); median pre-dose increase LDH 1.14xULN; median post-dose increase LDH 1.13xULN. Correlation coefficient shows that CH50 activity was positively correlated with LDH value, r(123)=0.18, p=0.04. Conclusion We report the effective utilisation of CH50 analysis where there is clinical concern of suboptimal control of PNH. All patients demonstrating hemolytic activity on CH50 assays indicated subsequent complement blockade following increase of eculizumab dose. Increasing eculizumab is costly requiring robust evidence of suboptimal complement inhibition; a positive correlation between CH50 activity and LDH values was shown however this is not sufficient to guide clinical decisions. LDH values of the incomplete blockade group were not significantly higher than those with complete blockade, suggesting the use of LDH values as an assessment of complement inhibition in patients with ongoing symptoms or transfusion requirements is not sufficient to guide eculizumab dose increases. Disclosures Munir: Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pike:Apellis: Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:AstraZeneca: Consultancy, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Straight to the X: Modeling Human X Chromosome Inactivation in hESCs by FGF Signal Blockade.

In this issue of Cell Stem Cell, An etal. (2020) provide a model to study human X chromosome inactivation. They followed X chromosome activity and traced cellular heterogeneity in naive hESCS, showed that it is caused by incomplete blockade of FGF-signaling, and in doing so isolated cells resembling pre-implantation epiblasts.

Functional deviations of the cardiovascular system in children of the Aral Sea

The study is devoted to the influence of disadvantages of the ecological disaster region Aral Sea on the state of the cardiovascular system in children. In 55.2% of cases, autonomic dysfunction was detected, mainly in girls of pre- and puberty age (80.8%). In 39.4% of children in the Aral Sea region hypotension was diagnosed as adaptive in 81.2% and pathological hypotension in 18.8% of cases with the initial vagotonic vegetative status according to cardiointervalography (94.6%). In children with arterial hypotension, there was a decline in the quality of life due to fatigue syndrome, cephalgia, reduced activity and deterioration of cognitive abilities. Cardiac pathology was manifested in 55.2% of cases in the form of impaired automatism of the sinus node (sinus arrhythmia, tachi and bradyarrhythmias) - 54.6%, conduction disorders (incomplete blockade of the right leg of the bundle of His) in 43.3% of cases. The identified pathology shows the need to provide comprehensive medical and social assistance to the children of the Aral Sea, along with solving environmental and economic problems of the region.

Short-term safety and effectiveness of sugammadex for surgical patients with end-stage renal disease: a two-centre retrospective study.

Sugammadex is a novel reversal agent for aminosteroid neuromuscular blocking drugs, especially rocuronium. Given its renal excretion, sugammadex is not recommended for patients with end-stage renal disease; however, reports exist of its use in this group of patients. This two-institutional retrospective observational study aimed to review the safety profile and effectiveness of sugammadex in surgical patients with end-stage renal disease who required pre-operative renal replacement therapy. Adult surgical patients with end-stage renal disease requiring pre-operative renal replacement therapy, who received sugammadex between April 2016 and January 2019, were studied. The primary outcome was the incidence of postoperative tracheal re-intubation within 48h. The secondary outcome was the incidence of deferred tracheal extubation in the operating theatre. One hundred and fifty-eight patients were identified from 125,653 surgical patients: 48 patients (30%) underwent renal transplantation and 110 (70%) underwent non-renal transplantation procedures. There were 22 instances (14%) of deferred tracheal extubation due to surgical and/or pre-existing medical conditions. Out of the 136 patients who had the tracheal tube removed at the end of the procedure, three patients had their trachea re-intubated within 48h: two patients developed pulmonary oedema resulting from volume overload; and one patient had worsening sepsis. No incidence of recurrence of neuromuscular blockade was observed. Of note, 24 (18%) patients were found to have incomplete neuromuscular blockade reversal with neostigmine but administration of sugammadex led to successful tracheal extubation. In conclusion, sugammadex appears to be safe and effective in adult patients with end-stage renal disease receiving pre-operative renal replacement therapy.

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

603P - A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

An Ex Vivo Test of Complement Activation on Endothelium for Individualized Eculizumab Therapy in Hemolytic Uremic Syndrome

Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role ofcomplement in secondary aHUS remains debatable. We evaluated the usefulness of an exvivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. Case series. 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced exvivo C5b-9 endothelial deposition test. Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate-activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of α-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs

IntroductionThis study examined whether the angiotensin II receptor blocker telmisartan had inhibitory effects on drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs. AnimalsFive healthy laboratory beagles were used in this study. MethodsEach dog received amlodipine (0.5 mg/kg, q12h, PO) alone for 14 days. Starting on the next day, animals received both amlodipine and telmisartan (1.0 mg/kg, q24h, PO) for 84 days. Systolic blood pressure, heart rate, plasma biochemical variables (blood urea nitrogen, creatinine, and electrolytes), plasma renin activity, and 24-h urinary aldosterone elimination (U-Aldo) were measured before amlodipine administration; at day 0; and at days 1, 7, 14, 28, 56, and 84 of telmisartan treatment. ResultsTelmisartan was associated with significant decreases in systolic blood pressure on day 56 (p=0.046), whereas heart rate did not significantly change during this treatment (p=0.061). Plasma renin activity was significantly increased on days 1, 7, 28, 56, and 84 during telmisartan administration (all p=0.04). No change in median U-Aldo was detected following telmisartan administration (p=0.241). When U-Aldo was evaluated in individual animals, two dogs displayed evidence of aldosterone breakthrough. ConclusionsTelmisartan administration did not suppress RAAS activation. The appearance of aldosterone breakthrough supports the incomplete blockade of RAAS activation.