Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer's disease.

BACKGROUND: Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. METHODS: We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aß42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. RESULTS: Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). CONCLUSIONS: Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging.

There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

Clinical Value of Patient-Specific Three-Dimensional Printing of Kidney Before Partial Nephrectomy: A Qualitative Assessment.

Objectives: To qualitatively assess the clinical usefulness of patient-specific high-fidelity three-dimensional (3D) print model of kidney before partial nephrectomy (PN) and to identify subset domains where it may help in clinical terms. Materials and Methods: Thirteen 3D models were printed for tumors having RENAL nephrometry score of ≥8. Their usage for PN was assessed prospectively using a qualitative questionnaire to be answered on a Likert scale of 1-10. The questions focused on realistic resemblance, preoperative dry surgical run, intertest comparison, surgical impact, and overall beneficence domains as perceived by primary surgeons with respect to surgical conduct during PN. Results: Mean RENAL score was 9.15 (8-11). Models were rated high (9.07 ± 0.86) for realistic resemblance domain and were rated better than contrast-enhanced computed tomography (CECT) (8.38 ± 0.87) and intraoperative ultrasonography (8.07 ± 1.26) for orientation regarding resection margins. A further marginal improvement to 8.2 ± 0.84 was noted against ultrasound where surgeon did a dry cut preoperatively. Use of superselective arterial approach in four, precise awareness about dissection of a major vessel in four, retroperitoneoscopic approach in one, and surgical margin awareness in three were directly attributed to the model. Overall utility of having a model printed was rated high (8.23 ± 1.3). Conclusion: The 3D print models of complex renal tumors have high realistic resemblance to actual patient's anatomy. They were rated better than preoperative CECT or intraoperative ultrasonography for orientation regarding surgical resection margins. It may also help change or modify the surgical plan in a subset of patients with a potential to improve overall outcomes in these complex cases.

A Novel Anterior Bladder Tube for Traumatic Bladder Neck Contracture in Females: Initial Results.

OBJECTIVE: To describe a novel tubularized bladder flap technique for repair of post-traumatic obliterate bladder neck and urethral stricture in women. Traumatic genitourinary injury in females is rare, and generally associated with pelvic fracture. Obliterate bladder neck is frequent in such cases. The options for obliterate strictures are limited with Tanagho's repair as one option. Limitations of Tanagho's repair include bladder neck being shifted anterosuperiorly posing voiding issues, posteriorly directed suture-line risking fistula formation with vagina and rotational tug of bladder putting tension at suture line. Here we present our initial results with our novel technique. METHODS: The young females with bladder neck obliteration with or without associated urogenital fistula were operated. A novel U-shaped anterior bladder wall flap was used to fashion a urethral tube and bladder neck. Native bladder neck fibres remained at bladder neck itself after reconstruction without limitation of length of urethral tube and continence outcome. Urogenital fistula was also repaired with omental interposition. RESULTS: Three tubes 3.5, 3, and 3.5 cm tubes were fashioned in the 3 cases, respectively. No perioperative complications were reported. Catheter was removed at 3 weeks. All cases had normal voiding and continence at follow-up of 15, 7, and 3 months, respectively. CONCLUSION: Our novel flap technique has provided good early results and aims to overcome the limitations of Tanagho's repair.

Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis.

The nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce apoptosis via TP53 (Tumor protein p53) or ERK1/2 (Extracellular signal-regulated kinases 1/2) (EPHB2) pathways. However, the exact mechanism is not known. PPAR, a type II nuclear hormone receptor deserves attention as a selective target for radiotherapy. Our study examines the potential of selective agonism of PPARG for radiation therapy in non-small cell lung carcinoma (NSCLC). We found that the overexpression of PPARG protein as well as its induction using the agonist, rosiglitazone was able to stimulate radiation-induced cell death in otherwise radio resistant NSCLC A549 cell line. This cell death was apoptotic and was found to be BAX (BCL2 associated X) mediated. The treatment also inhibited radiation-induced AKT (Protein Kinase B) phosphorylation. Interestingly, the ionising radiation (IR) induced apoptosis was found to be inversely related to TP53 levels. A relatively significant increase in the levels of radiation induced apoptosis was observed in H1299 cells (TP53 null) under PPARG overexpression condition further supporting the inverse relationship between apoptosis and TP53 levels. The combination of PPARG agonist and radiation was able to induce apoptosis at a radiation dose at which A549 and H1299 are radioresistant, thus confirming the potential of the combinatorial strategy. Taken together, PPARG agonism was found to invigorate the radiosensitising effect and hence its use in combination with radiotherapy is expected to enhance sensitivity in otherwise resistant cancer types.

Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy.

Cellular effects of ionizing radiation include oxidative damage to macromolecules, unfolded protein response (UPR) and metabolic imbalances. Oxidative stress and UPR have been shown to induce macroautophagy/autophagy in a context-dependent manner and are crucial factors in determining the fate of irradiated cells. However, an in-depth analysis of the relationship between radiation-induced damage and autophagy has not been explored. In the present study, we investigated the relationship between radiation-induced oxidative stress, UPR and autophagy in murine macrophage cells. A close association was observed between radiation-induced oxidative burst, UPR and induction of autophagy, with the possible involvement of EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) and ERN1/IRE1 (endoplasmic reticulum [ER] to nucleus signaling 1). Inhibitors of either UPR or autophagy reduced the cell survival indicating the importance of these processes after radiation exposure. Moreover, modulation of autophagy affected lethality in the whole body irradiated C57BL/6 mouse. These findings indicate that radiation-induced autophagy is a pro-survival response initiated by oxidative stress and mediated by EIF2AK3 and ERN1. Abbreviations: ACTB: actin, beta; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; CQ: chloroquine; DBSA: 3,5-dibromosalicylaldehyde; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1: endoplasmic reticulum (ER) to nucleus signaling 1; IR: ionizing radiation; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; 3-MA: 3-methyladenine; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARP1: poly (ADP-ribose) polymerase family, member 1; 4-PBA: 4-phenylbutyrate; Rap: rapamycin; ROS: reactive oxygen species; UPR: unfolded protein response; XBP1: x-box binding protein 1.

Conventional digital subtractional vs non-invasive MR angiography in the assessment of brain arteriovenous malformation.

OBJECTIVES: Digital subtractional angiography (DSA) is the standard method for diagnosis, assessment and management of arteriovenous malformation in the brain. Conventional DSA (cDSA) is an invasive imaging modality that is often indicated before interventional treatments (embolization, open surgery, gamma knife). Here, we aimed to compare this technique with a non-invasive MR angiography (MRI DSA) for brain arteriovenous malformation (bAVM). PATIENTS AND METHODS: Fourteen patients with ruptured brain AVM underwent embolization treatment pre-operation. Imaging was performed for all patients using MRI (1.5 T). After injecting contrast Gadolinium, dynamic MRI was performed with 40 phases, each phase of a duration of 1.2 s and having 70 images. The MRI results were independently assessed by experienced radiologist blinded to the cDSA. RESULTS: The AVM nidus was depicted in all patients using cDSA and MRI DSA; there was an excellent correlation between these techniques in terms of the maximum diameter and Spetzler Martin grading. Of the fourteen patients, the drainage vein was depicted in 13 by both cDSA and MRI DSA showing excellent correlation between the techniques used. CONCLUSION: MRI DSA is a non-invasive imaging modality that can give the images in dynamic view. It can be considered as an adjunctive method with cDSA to plan the strategy treatment for bAVM.

PPARγ-targeting Potential for Radioprotection.

BACKGROUND: Peroxisomal proliferator receptor gamma (PPARγ) is a class of nuclear hormone receptor family involved in insulin sensitization. In addition, PPARγ has a key role in the protection against oxidative stress and inflammation through regulation of NFkappaB levels and crosstalk with the Nrf2 pathway. Also, its role in the modulation of immune response is substantial. OBJECTIVE: Radiation-induced oxidative stress is the sole determinant of damage to hematopoietic, gastrointestinal system and immune system suppression. Uncontrolled exposure to normal cells during radiotherapy raises the demand for novel and efficient radioprotectors. In this review, we will present an overview of the involvement of PPARγ in radiation-induced damage and inflammation with major emphasis on whether PPARγ can serve as a suitable radiomodification target. CONCLUSION: Through this review, we have justified that PPARγ having both radioprotective as wells as radiotherapeutic potential, may serve as an attractive target for the development of novel and more effective therapies.

Radiation-induced autophagy: mechanisms and consequences.

Autophagy is an evolutionary conserved, indispensable, lysosome-mediated degradation process, which helps in maintaining homeostasis during various cellular traumas. During stress, a context-dependent role of autophagy has been observed which drives the cell towards survival or death depending upon the type, time, and extent of the damage. The process of autophagy is stimulated during various cellular insults, e.g. oxidative stress, endoplasmic reticulum stress, imbalances in calcium homeostasis, and altered mitochondrial potential. Ionizing radiation causes ROS-dependent as well as ROS-independent damage in cells that involve macromolecular (mainly DNA) damage, as well as ER stress induction, both capable of inducing autophagy. This review summarizes the current understanding on the roles of oxidative stress, ER stress, DNA damage, altered mitochondrial potential, and calcium imbalance in radiation-induced autophagy as well as the merits and limitations of targeting autophagy as an approach for radioprotection and radiosensitization.

Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma.

Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti-apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy.

COX-2 signaling and cancer: new players in old arena.

Cancer is a leading cause of death worldwide. The expression of COX-2 and prostaglandins has not only been associated with various types of cancer but is also directly proportional to their aggressiveness including metastasis. Thus, inhibition of COX-2 activity has been one of the preferred targets for cancer reduction. Broad spectrum inhibition of all forms of COX (using NSAIDs) is associated with various side effects ranging from gastric ulceration to renal problems. Even specific COX-2 inhibitors (COXIBs) are associated with side effects like myocardial infarction. Alternative strategies including siRNA technology are also not very victorious due to their off-target associated problems. Thus, there is an urgent need for the development of strategies where COX-2 activity may be reduced without inducing any side effects. One of the approaches for designing novel inhibitors may be to target various molecules downstream of COX-2. In this review, we have tried to cover the basic biology of COX-2 and its association with different types of cancer. Various generations of COX-2 inhibitors have been covered with their merits and demerits. Possible exploitation of novel targets like EP receptors, mPGES and various other downstream molecules which can be utilized for a better COX-2 signaling inhibition and thus efficient cancer reduction with minimal side effects has been discussed.