Establishment of an Animal Model of Depression: The Serotonin Transporter Knockout Rat

10.26686/wgtn.17135999.v1 ◽

2021 ◽

Author(s):

◽

Meyrick Kidwell

Keyword(s):

Serotonin Transporter ◽

Cardiac Tissue ◽

Response Rate ◽

First Line ◽

Major Depressive ◽

Future Studies ◽

Animal Model Of Depression ◽

Model Components ◽

Biological Methods ◽

Physiological Correlate

<p>Major depressive disorder (MDD) is a serious and debilitating psychiatric illness found of increasing prevalence. Despite this, our current first line treatments have been shown to lack efficacy and possess a high non-response rate. Most new pharmacological developments have not shown efficacy in humans, likely due to our current models being outdated. This thesis attempts to use a range of novel approaches, integrating behavioural, physiological, and biological methods to provide support for the use of the serotonin transporter knockout (SERT-KO) rat to model components of MDD in humans. Social anhedonia is assessed through conditioned place preference and play behaviour analysis, demonstrating significantly reduced reward sensitivity in SERT-/- animals. Comorbid anxiety is assessed using a modified successive alleys test, whereby SERT-/- animals demonstrate increased anxiety behaviour, which persist over the course of the experiment. The assessment of heart rate variability, a physiological correlate of MDD was impacted by time constraints, however suggests a likely reduction to be present in the SERT-/- animals. Finally, neurogenesis was found to be significantly increased in SERT-/- animals during early development (PND7), demonstrating neurodevelopmental alterations associated with reduced SERT expression. These data demonstrate that the SERT knockout rat possesses many deficits associated with MDD, thus being a likely candidate for novel pharmacological development. A final pilot experiment was conducted using MALDI-TOF to provide a method of examining potentially thousands of compounds in brain and cardiac tissue with high spatial definition. Applications and implication of this research are discussed in detail with suggestions for future studies being presented.</p>

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Depression in Dementia or Dementia in Depression? Systematic Review of Studies and Hypotheses

Current Alzheimer Research ◽

10.2174/1567205017666200217104114 ◽

2020 ◽

Vol 17 (1) ◽

pp. 16-28 ◽

Cited By ~ 9

Author(s):

Agnieszka Brzezińska ◽

Julius Bourke ◽

Rayito Rivera-Hernández ◽

Magda Tsolaki ◽

Joanna Woźniak ◽

...

Keyword(s):

Cognitive Impairment ◽

Randomised Controlled Trials ◽

Late Onset ◽

Alternative Hypothesis ◽

Controlled Trials ◽

Major Depressive ◽

Future Studies ◽

Individual Vulnerability ◽

Current Review ◽

Randomised Controlled

The majority of research works to date suggest that Major Depressive Disorder (MDD) is a risk factor for dementia and may predispose to cognitive decline in both early and late onset variants. The presence of depression may not, however, reflect the cause, rather, an effect: it may be a response to cognitive impairment or alters the threshold at which cognitive impairment might manifest or be detected. An alternative hypothesis is that depression may be part of a prodrome to Alzheimer’s Disease (AD), suggesting a neurobiological association rather than one of psychological response alone. Genetic polymorphisms may explain some of the variances in shared phenomenology between the diagnoses, the instance, when the conditions arise comorbidly, the order in which they are detected that may depend on individual cognitive and physical reserves, as well as the medical history and individual vulnerability. This hypothesis is biologically sound but has not been systematically investigated to date. The current review highlights how genetic variations are involved in the development of both AD and MDD, and the risk conferred by these variations on the expression of these two disorders comorbidly is an important consideration for future studies of pathoaetiological mechanisms and in the stratification of study samples for randomised controlled trials.

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Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy

British Journal of Cancer ◽

10.1038/sj.bjc.6604955 ◽

2009 ◽

Vol 100 (6) ◽

pp. 881-887 ◽

Cited By ~ 114

Author(s):

V Catalano ◽

F Loupakis ◽

F Graziano ◽

U Torresi ◽

R Bisonni ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Response Rate ◽

Poor Response ◽

First Line ◽

Mucinous Histology

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Longitudinal Monitoring of the Serotonin Transporter Gene Expression to Assess Major Depressive Episode Evolution

Neuropsychobiology ◽

10.1159/000368120 ◽

2014 ◽

Vol 70 (4) ◽

pp. 220-227 ◽

Cited By ~ 3

Author(s):

Raoul Belzeaux ◽

Anderson Loundou ◽

Jean-Michel Azorin ◽

Jean Naudin ◽

El Chérif Ibrahim

Keyword(s):

Gene Expression ◽

Serotonin Transporter ◽

Depressive Episode ◽

Major Depressive Episode ◽

Serotonin Transporter Gene ◽

Transporter Gene ◽

Major Depressive

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Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.446 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 446-446

Author(s):

Marc-Oliver Grimm ◽

Bernd Schmitz-Dräger ◽

Uwe Zimmermann ◽

Barbara Grün ◽

Gustavo Bruno Baretton ◽

...

Keyword(s):

Immune Checkpoint ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Transitional Cell ◽

Added Value ◽

Phase Iii ◽

First Line ◽

Third Line

446 Background: Several PD-1 immune-checkpoint inhibitors including Nivolumab (Nivo) are approved in urothelial cancer. Recently, in the front line setting, improved activity of combined PD-L1 and CTLA4 immune-checkpoint inhibition has been reported and a phase III trial with Nivolumab + Ipilimumab (Nivo+Ipi) is ongoing. Here we report a response-based tailored approach starting treatment with Nivo monotherapy using Nivo+Ipi as immunotherapeutic “boost”. Methods: Between July 2017 and April 2019 86 patients were enrolled and treated according to protocol version 3 (cohort 1). Patients started with Nivo 240 mg Q2W induction. After 4 dosings and tumor assessment at week 8 (i) responders (PR/CR) to Nivo monotherapy continued with maintenance while (ii) patients with stable (SD) or progressive disease (PD) received 2 cycles Nivo3+Ipi1 followed by another 2 cycles Nivo1+Ipi3 if not responding. Median follow-up is 8.7 months. The primary endpoint is confirmed investigator-assessed objective response rate (ORR) per RECIST1.1. Secondary endpoints include activity of Nivo monotherapy at week 8, remission rate with Nivo+Ipi “boosts”, safety, overall survival and quality of life. Results: Of the patients 42, 39 and 5 were first, second and third line, respectively. Median age was 67 years (range 45-84), 61 patients (71 %) were male and 25 female. ORR with Nivo monotherapy at first assessment (week 8) was 29 % and 23 % in first and second/third line, respectively. Of the patients 41 received Nivo+Ipi “boosts” after week 8 while 12 received later “boosts”. Best overall response (BOR) rate with Nivo induction ± Nivo+Ipi “boosts” was 48 % and 27 % in first and second/third line, respectively. In first line 7/17 (41 %) patients receiving Nivo+Ipi after week 8 had an improved response compared to 2/24 (8.3 %) in second/third line. Of the patients who continued with Nivo maintenance after week 8 and received later “boosts” 2/12 (17 %) had a PR and 2/12 (17 %) improved to SD. Treatment-related AEs will be presented. Conclusions: TITAN–TCC explores a response-driven use of Nivo+Ipi as an immunotherapeutic “boost”. In first line, this significantly improved ORR compared to the expected response rate of Nivo monotherapy, providing further evidence to the added value of Ipi in combination with Nivo. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial information: NCT03219775 . Research Sponsor: Bristol-Myers Squibb[Table: see text]

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Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel inHER2-Positive Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.6531 ◽

2010 ◽

Vol 28 (6) ◽

pp. 976-983 ◽

Cited By ~ 77

Author(s):

Andrew M. Wardley ◽

Xavier Pivot ◽

Flavia Morales-Vasquez ◽

Luis M. Zetina ◽

Maria de Fátima Dias Gaui ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Response Rate ◽

Performance Status ◽

Locally Advanced ◽

Metastatic Breast ◽

Progression Free Survival ◽

First Line ◽

Her2 Positive ◽

Grade 3

PurposeTo evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.Patients and MethodsPatients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m2in HTX arm, 100 mg/m2in HT arm, every 3 weeks) with or without X (950 mg/m2twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR).ResultsIn 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v < 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm.ConclusionHTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.

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Serotonin transporter binding as a possible predictor of one-year remission in major depressive disorder

Journal of Psychiatric Research ◽

10.1016/j.jpsychires.2008.01.012 ◽

2008 ◽

Vol 42 (14) ◽

pp. 1137-1144 ◽

Cited By ~ 40

Author(s):

Jeffrey M. Miller ◽

Maria A. Oquendo ◽

R. Todd Ogden ◽

J. John Mann ◽

Ramin V. Parsey

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Serotonin Transporter ◽

Major Depressive ◽

One Year

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Dual orexin receptor antagonist in treatment of insomnia

Engrami ◽

10.5937/engrami41-29093 ◽

2020 ◽

Vol 42 (2) ◽

pp. 57-68

Author(s):

Nikola Trajanović

Keyword(s):

Circadian Rhythm ◽

Side Effects ◽

Receptor Antagonist ◽

Safety Profile ◽

The Elderly ◽

First Line ◽

Future Studies ◽

Good Safety Profile ◽

Circadian Rhythm Disorders

A novel group of medications, dual orexin receptor antagonists, emerged as a competent group that challenges current first-line hypnotics. They have relatively infrequent and mostly well-tolerated side effects, primarily in the form of residual somnolence, fatigue and nightmares/disturbing dreams. The advantage over conventional hypnotics stems from the specifics of their target receptors, which translates into lack of tolerance after long term use and good safety profile. They are particularly favoured in some specific populations, including the elderly. Ongoing and future studies are set to explore their effect on selected conditions, such as addiction and psychiatric disorders, dementias, perimenopausal condition and circadian rhythm disorders, to name a few.

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The Efficacy of Ramucirumab in the Treatment of Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of RCTs

Gastroenterology Research and Practice ◽

10.1155/2021/8960315 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Hongqiong Yang ◽

Yaojun Zhou ◽

Liangzhi Wang ◽

Tianyi Gu ◽

Mengjia Lv ◽

...

Keyword(s):

Response Rate ◽

Meta Analysis ◽

Gastroesophageal Junction ◽

Objective Response ◽

Progression Free Survival ◽

Pooled Analysis ◽

First Line ◽

Free Survival ◽

Gastroesophageal Junction Cancer ◽

Line Chemotherapy

Five electronic databases were searched for eligible records. Outcomes were presented and analyzed according to the objective response rate (ORR), progression-free survival (PFS) rate, and overall survival (OS) rate. Five records involving 2,024 participants were included in the study. The pooled analysis of OS and PFS were longer with ramucirumab (RAM) therapy than without RAM for OS (odds ratio OR = 0.90 , 95% confidence interval CI = 0.82 – 1.00 , p = 0.05 ) and PFS ( OR = 0.74 , 95 % CI = 0.57 – 0.96 , p = 0.02 ). Moreover, compared with the current first-line chemotherapy, the OS ( OR = 0.93 , 95 % CI = 0.83 – 1.04 , p = 0.19 ) and PFS ( OR = 0.82 , 95 % CI = 0.64 – 1.06 , p = 0.13 ) results were not significantly higher with RAM. The ORRs of the patients in the RAM therapy groups were significantly higher than those in the groups without RAM ( OR = 1.40 , 95 % CI = 1.14 – 1.73 , p = 0.001 ).

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