Bacillus Calmette Research Articles

Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis.

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

Childhood Lupus Vulgaris after Bacillus Calmette–Guérin Vaccine

Abstract Lupus vulgaris (LV) is a cutaneous mycobacterial tuberculosis infection that is transmitted through lymphatic routes, hematogenous routes, or exogenous inoculation. It is infrequently reported after the Bacillus Calmette–Guérin (BCG) vaccine. In this report, we present a young child with LV at her BCG vaccine injection site as well as distant lesions of the chin.

Assessment of quality of routine immunization in rural areas of Doiwala Block, Dehradun

ABSTRACT Background: India initiated Expanded Programme on Immunization (EPI) in 1978 and was renamed to Universal Immunization Programme (UIP) in 1985 and subsequently integrated with National Rural Health Mission (NRHM) in 2005. Many studies have shown that health workers involved in immunization are more concerned towards coverage than the quality of immunization services provided. Aims and Objectives: This study aimed to assess the quality of routine immunization services in rural areas of Doiwala Block of Dehradun, Uttarakhand. Material and Methods: It was a cross-sectional study conducted for a duration of one year. Study participants included Auxillary Nurse Midwives (ANMs), Accredited Social Health Activists (ASHAs), Anganwadi Workers (AWWs) and parents/caregivers of children aged 12–23 months residing in that area who had received immunization services on the day of the survey. Institutional ethics committee clearance was obtained before the start of the study. A P value of <0.05 was considered as statistically significant. Results: ASHAs at two centres in low-performing centres had never undergone any training for routine immunization but there was no statistically significant difference found between high and low-performing centres (P > 0.05). The most common vaccine not available was the Bacillus Calmette–Guérin (BCG) vaccine. The majority of clients at both high (92%) and low-performing centres (96%) said that they never waited for at least 30 min post-vaccination at the vaccination site for observation. Conclusion: The study highlights that most of the ANMs at the immunization centre were having good knowledge and were adequately trained for maintaining cold chains at session sites.

Bacillus Calmette Guerin Injection Improves Hindlimb Motor Function and Alleviates Inflammation through Upregulating Foxp3 Expression in Rats with Spinal Cord Injury

Background: Immune and inflammatory reactions are important factors leading to secondary spinal cord injury. Aim: This study aimed to investigate the effect of BCG on behavior after acute spinal cord injury in rats and its related mechanisms. Methods: Rats with spinal cord injury were generated according to modified Allen’s method. Rats were divided into the BCG group (rats with spinal cord injury intraperitoneally injecting with BCG), Model group (rats with spinal cord injury intraperitoneally injecting with normal saline), and Sham group (normal rats intraperitoneally injecting with normal saline). Basso, Beattie, and Bresnahan (BBB) scoring system was used for evaluating behavioral outcomes. Foxp3 expression in spinal cord tissues was evaluated using immunofluorescence analysis. HE staining was used for assessing the injury of spinal cord tissues. Results: BBB scores of the Model group were remarkably lower compared to that of the Sham group (P<0.05). Foxp3 expression was significantly downregulated in the Model group compared with that of the Sham group (P<0.05). BBB scores of the BCG group were significantly higher compared to that of the Model group at 3, 5, 7, and 14 days post-treatment (P<0.05). In the BCG group, there were fewer inflammatory cells, smaller cavities, and a complete structural arrangement than in the Model group. BCG treatment significantly reduced the spinal cord injury score compared to that of the Model group (P<0.05). Post BCG treatment, Foxp3 expression was predominantly enhanced compared with that of the Model group (P<0.05). Conclusion: BCG could affect inflammation after spinal cord injury through upregulating the expression of Foxp3 and further promote the recovery of hindlimb motor function in rats with spinal cord injury.

3-year experience of hyperthermic intravesical chemotherapy use in patients with high risk non-muscular-invasive bladder cancer

Cur rently, the search for additional organ-sparing methods of intravesical therapy for non-muscular-invasive bladder cancer (NMIBC) is actively continuing, which could become an effective alternative to standard treatment using the Bacillus Calmette-Guérin (BCG) vaccine. The aim of this work was to analyze the safety profile and long-term results of treatment of patients with the high-risk non-muscular-invasive bladder cancer who received adjuvant intravesical chemotherapy using the Combat BRS HIVEC® device for local hyperthermia (HIVEC® therapy group; n=53) in comparison with patients who received adjuvant therapy after transurethral resection of bladder performed with the Bacillus Calmette-Guérin vaccine (BCG therapy group; n=54). As a result, the median follow-up was 30 months (range 7-36). According to Common Terminology Criteria for Adverse Events (CTCAE) v 5.0, the most relevant side effects in HIVEC®/BCG therapy groups were adverse events grade 1-2: fever – 1%/8%; dysuria – 9%/13%; bladder spasms – 7%/12%; hematuria – 3%/4% and urinary tract infection – 3%/10%. Tumor recurrence was reported in 23 patients receiving intravesical BCG therapy and in 10 patients receiving intravesical hyperthermic chemotherapy (42.6% versus 18.9%, p=0.008). Tumor progression was recorded in 11 patients receiving intravesical BCG therapy and in 4 patients receiving intravesical hyperthermic chemotherapy (20.4% versus 7.5%, p=0.046). The study allows us to conclude that the method of hyperthermic intravesical chemotherapy has a better safety profile compared to intravesical Bacillus Calmette–Guérin vaccine therapy, while such indicators of oncological efficacy as 3-year recurrence-free survival and the incidence of progression were better in the HIVEC® therapy group.

BCG vaccine-induced mucosal humoral immunity in human nasal associated lymphoid tissue

ObjectivesMycobacterium tuberculosis (Mtb) is the causative pathogen of tuberculosis (TB). TB vaccine studies have long been conducted. Since the discovery of the successful intradermally administered Mycobacterium bovis Bacillus Calmette–Guérin (BCG) vaccine against TB, no licensed TB mucosal vaccine has yet been approved. Our research aims to investigate the suitability of human NALT-derived MNCs as an in vitro human cell culture model to explore the mucosal humoral immune responses to the BCG vaccine. Moreover, to assure that BCG vaccine able to induce the different antibody isotypes including IgG, IgM and IgA. MethodsTonsils from 20 patients who underwent elective tonsillectomies at Madinah Germany Hospital were recruited. Tonsillar mononuclear cells (MNCs) were separated and co-cultured in the presence and absence of the BCG vaccine. ELISA was used to measure BCG-induced IgG, IgM and IgA antibodies in the cell culture supernatants following stimulation and culture. ResultsNasal-associated lymphoid tissue (NALT) cell culture as an in vitro model was successfully used to evaluate the BCG-induced humoral immune response. Significant (p = 0.001, n = 20) levels of specific, anti-TB IgG, IgM, and IgA antibody responses were detected in MNCs stimulated with the BCG vaccine compared with unstimulated MNCs. Significant differences were found between anti-TB antibody classes. Anti-TB IgG antibody was significantly higher (mean = 2.33) than anti-TB IgM (mean = 1.37) antibody (p = 0.0001, n = 20). Anti-TB IgM antibody was significantly higher than IgA (mean = 0.93) antibody (p = 0.0018, n = 20). ConclusionsThe current human model will be beneficial for the future comprehensive study of other immune components such as cellular immune responses to the BCG vaccine. The model would be ideal to design, improve and study the possible intranasal use of the BCG vaccine.

The problem associated with tuberculosis in cattle and how this is being addressed

Bovine tuberculosis (bTB) is a zoonotic disease caused by Mycobacterium bovis that primarily infects cattle but has a wide range of hosts. It represents a global health problem affecting the livestock industry tremendously, with economic losses of about 3 billion annually. Dairy cattle produce a decline of 10% in terms of liters of milk produced and 5% in the meat industry because of live weight loss and seized carcasses in abattoirs. The core of the current control measures implemented in most countries against bTB is based on the diagnosis with tuberculin skin test (TST) and culling of infected animals. Unfortunately, control programs have failed to eradicate the disease since no vaccine protects cattle from infection. Moreover, the strain of M. bovis Bacillus Calmette Guerin, BCG used as a vaccine for human tuberculosis, interferes with surveillance tools. Nowadays, most researchers have been working on improving the efficacy of BCG through a prime-boost strategy that involves a first immunization with BCG and a booster with different types of vaccines. A less explored approach by experts has been the development of a new vaccine that only includes some protective antigens of M. bovis that should be absent ot in low representation in TST. On the other hand, because TST precludes implementation of Bacille Calmette-Guérin (BCG) vaccine–based control programs, several investigations have been carried out to replace the TST with a DIVA test that allows to differentiation infected from vaccinated animals. In this review, most of the studies cited agree that without an effective vaccine and a compatible diagnosis, no program for eradication would be successful against tuberculosis in cattle. Keywords: bovine tuberculosis; bTB; Mycobacterium bovis; diagnosis; tuberculin skin test, TST, bPPD; vaccines, DIVA.

Electromotive Drug Administration Chemotherapy with Mitomycin C Versus Bacillus Calmette-Guerin for the Treatment of Non-Muscle Invasive Bladder Cancer.

Devices that increase the penetrance of intravesical chemotherapeutics are emerging as alternatives to classical Bacillus Calmette Guérin (BCG) treatment. To compare the efficacy of mitomycin C applied with the electromotive drug delivery device (MMC-EMDA) versus BCG in patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ (CIS). Prospective non-randomized study in which 47 patients received MMC-EMDA (40 mg of MMC diluted in 50 mg of distilled water at 20 mA for 30 min. Regimen of 6 weekly and then 6 monthly instillations) and 48 patients received BCG (50 mg of OncoCITE® diluted in 50 ml of normal saline for 60 min. Regimen of 6 weekly instillations and then 3 weekly instillations at months 3, 6 and 12). The primary endpoint was the recurrence-free rate (RFR) at 24 months. Secondary endpoints were time to recurrence and progression-free rate (PFR) at 24 months follow-up. Baseline patient assessment and mean follow-up time were similar in both groups (MMC-EMDA group: 26.4 months; BCG group: 28.4 months (p = 0.44)). The RFR at 24 months was 80.9% for the MMC-EMDA group and 77.1% for the BCG group (p = 0.969). The mean time to recurrence was 12.5 months in the MMC-EMDA group and 14 months in the BCG group (p = 0.681). At 24 months, PFR was 97.9% in the MMC-EMDA group and 93.8% in the BCG group (p = 0.419). No differences were found between MMC-EMDA and BCG treatments in patients with high-risk and intermediate-risk NMIBC without CIS.

Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies.

Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette-Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803.

Bacillus Calmette–Guérin osteomyelitis of the fifth metatarsal bone in a Japanese infant: a case report

Abstract Bacillus Calmette–Guérin osteomyelitis is a rare complication following Bacillus Calmette–Guérin vaccination. Here, we describe a rare case of Bacillus Calmette–Guérin osteomyelitis of the fifth metatarsal in a 21-month-old Japanese infant. A 21-month-old Japanese female infant presented with a swollen mass on the dorsolateral aspect of the left foot. Based on physical examination, radiological and histopathologic findings and laboratory results, a diagnosis of Bacillus Calmette–Guérin osteomyelitis of the fifth metatarsal bone was made, and an oral anti-tuberculosis treatment was initiated. However, the mass recurred 10 months after the start of the anti-tuberculosis treatment, so additional surgical debridement was performed. Six months after surgery, clinical findings and plain radiograph images revealed complete improvement of the affected area, and anti-tuberculosis treatment was stopped. Bacillus Calmette–Guérin osteomyelitis of the fifth metatarsal in a 21-month-old Japanese infant was successfully treated with oral anti-tuberculosis therapy and surgical debridement.

Systemic Immune-inflammation Index (SII) During Induction has Higher Predictive Value Than Preoperative SII in Non-muscle-invasive Bladder Cancer Patients Receiving Intravesical Bacillus Calmette -Guerin.

The prognostic value of the systemic immune-inflammation index during induction (ISII) remains unclear in non-muscle-invasive bladder cancer (NMIBC) patients receiving Bacillus Calmette-Guérin (BCG). We aimed to determine and compare the prognostic value of the ISII, preoperative systemic immune-inflammation index (PSII) and their dynamic changes (PISII). This study respectively collected data from 362 NMIBC patients receiving BCG treatment in our institution. The prognostic values of PSII, ISII and PISII were analyzed by the Kaplan-Meier method and Cox proportional hazard regression models. The concordance index and receiver operating characteristic curve analysis were employed to compare the prognostic value of these 3 factors. Our study enrolled 197 patients. These patients included 170 male patients, and the mean age was 64.17 years. During the follow-up time, 85 patients experienced recurrence and 55 patients found progression. According to the results of Cox multivariable analysis, PSII (P=.001) and ISII (P < .001) could independently predict the recurrence of NMIBC patients receiving BCG. Meanwhile, PSII (P=.025) and ISII (P < .001) were also independent prognostic factors of progression. Compared with PSII, ISII was associated with better accuracy for NMIBC patients receiving BCG. This study first found that ISII could independently predict the prognosis of NMIBC patients receiving BCG. Furthermore, we also identified that ISII was associated with higher prognostic value than PSII and PISII, which might help to select an optimal treatment schedule for patients with NMIBC.

EE383 Cost-Utility and Value of Information Analysis of Novel Treatments for BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

Nadofaragene firadenovec (awaiting regulatory approval) and pembrolizumab are bladder-sparing alternatives for treating Bacillus Calmette–Guérin (BCG)-unresponsive, high-risk non-muscle invasive bladder cancer (NMIBC). Cost-utility and value of information (VOI) analyses of these treatments, compared with a hypothetical treatment comparator based on approved and investigational therapies, were conducted from a United States health system perspective.

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones.

Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor.

18 - A multicentre pilot study on intravesical hyaluronic acid and chondroitin sulphate administration in the refractory Bacillus Calmette Guerin-induced chemical cystitis

18 - A multicentre pilot study on intravesical hyaluronic acid and chondroitin sulphate administration in the refractory Bacillus Calmette Guerin-induced chemical cystitis

Bacillus calmette gaurine vaccine ameliorates the neurotoxicity of quinolinic acid in rats via the modulation of antioxidant, inflammatory and apoptotic markers

A mutation in the Huntingtin gene causes ’Huntington's disease, which presents as a motor and behavioral impairment. Due to the limited drug therapy for this disease, scientists are constantly searching for newer and alternative drugs that may either retard or prevent the progress of the disease. This study aims to explore the neuroprotective potential of Bacillus Calmette Gaurine (BCG) vaccine against quinolinic acid-induced (QA) neurotoxicity in rats. QA (200 nmol/2 µl, i.s) was injected bilaterally into the rat striatum, after which a single dose of BCG (2 × 10^7, cfu) was given to the rats. Animals were assessed for behavioral parameters on the 14th and 21st days. On the 22nd day, animals were sacrificed, brains were harvested, and striatum was separated to evaluate biochemical, inflammatory, and apoptotic mediators. Histopathological studies were performed using Hematoxyline and Eosin staining to assess neuronal morphology. BCG treatment reversed motor abnormalities, reduced oxidative stress and neuroinflammatory markers, apoptotic mediators and striatal lesions induced by QA treatment. In conclusion, treat' 'ing rats with BCG vaccine (2 × 10^7, cfu) mitigated the quinolinic acid-induced Huntington's disease-like symptoms. Hence, BCG vaccine (2 ×10^7, cfu) could be used as an adjuvant in managing HD.

A protective, single-visit TB vaccination regimen by co-administration of a subunit vaccine with BCG

The only licensed tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG), fails to reliably protect adolescents and adults from pulmonary TB, resulting in ~1.6 million deaths annually. Protein subunit vaccines have shown promise against TB in clinical studies. Unfortunately, most subunit vaccines require multiple administrations, which increases the risk of loss to follow-up and necessitates more complex and costly logistics. Given the well-documented adjuvant effect of BCG, we hypothesized that BCG co-administration could compensate for a reduced number of subunit vaccinations. To explore this, we developed an expression-optimized version of our H107 vaccine candidate (H107e), which does not cross-react with BCG. In the CAF®01 adjuvant, a single dose of H107e induced inferior protection compared to three H107e/CAF®01 administrations. However, co-administering a single dose of H107e/CAF®01 with BCG significantly improved protection, which was equal to BCG co-administered with three H107e/CAF®01 doses. Importantly, combining BCG with a single H107e/CAF®01 dose also increased protection in previously BCG-primed animals. Overall, a single dose of H107e/CAF®01 with BCG induced long-lived immunity and triggered BCG-specific Th17 responses. These data support co-administration of BCG and subunit vaccines in both BCG naïve and BCG-primed individuals as an improved TB vaccine strategy with reduced number of vaccination visits.

Effectiveness of BCG in recurrent non-muscle invasive bladder tumor: A 10 year retrospective study from a tertiary care centre

Abstract Introduction: Cancer-a term a word used to be so rare five decades back that people didn’t even know about this but now it has become so common and rampant and interestingly can be compared to a devil whose size seems to be increasing progressively. Even after so much advancement in medical science we have not been able to catch its tail. Urinary Bladder one of the very common cancer in our urological domain with its subtype non-muscle invasive bladder cancer (NMIBC) having high recurrence and progression rates has become very interesting subject for research. Such features led investigators to study the use of drugs to prevent this, out of which Bacillus Calmette–Guerin (BCG) has been successfully used as an intra vesical therapy to prevent recurrence and progression in NMIBC for more than four decades. Materials and Methods: In our study we have analyzed 111 patients retrospectively with only recurrent urinary bladder tumor irrespective of treatment received in the past. After completion Trans Urethral resection of bladder tumor (TURBT) and re-staging TURBT to substantiate the stage, induction and maintenance course of intravesical BCG was given according to Lamm protocol &amp; the impact of this therapy was studied in regards to recurrence free, progression free, cystectomy free &amp; overall survival rates. Result: Out of 111 patients, sixty percent of patient remained disease free, 19 patients had stage progression, nine patients underwent radical cystectomy and there was three cancer specific death. Conclusion: Despite BCG being the gold standard treatment for NMIBC, still intense research is required as there is a wide dark area of BCG failure.

Synthesis of plant-based, self-adjuvanted, dual antigen specific to Mycobacterium tuberculosis as a novel tuberculosis subunit vaccine that elicits immunogenicity in rabbit.

The only approved vaccine, Bacillus Calmette Guérin (BCG) used in global tuberculosis (TB) immunization programmes has been very effective in childhood TB but not in adult pulmonary and latent TB. Moreover, the emergence of multi-drug resistance-TB cases demands either to increase efficiency of BCG or replace it with the one with improved efficacy. A novel combination of two most effective secreted protein antigens specific for Mycobacterium tuberculosis (Mtb), ESAT-6 and MPT-64 (but not present in BCG strains) fused with a cholera toxin B subunit (CTB) and tagged with 6xHis was expressed for the first time in Escherichia coli as well as in transgenic cucumber plants developed using Agrobacterium tumefaciens-mediated transformation. The recombinant fusion protein (His6x.CTB-ESAT6-MPT64) expressed in E. coli was purified by a single-step affinity chromatography and used to produce polyclonal antibodies in rabbit. The transgenic cucumber lines were confirmed by polymerase chain reaction (PCR), Southern blot hybridization, reverse transcriptase PCR (RT-PCR), real-time PCR (qRT-PCR) and expression of recombinant fusion protein by western blot analysis and its quantification by enzyme-linked immunosorbent assay (ELISA). A maximum value of the fusion protein, 478ng.g-1 (0.030% of the total soluble protein) was obtained in a transgenic cucumber line. Rabbit immunized orally showed a significant increase in serum IgG levels against the fusion protein as compared to the non-immunized rabbit. Stable expression of Mtb antigens with CTB in edible cucumber plants (whose fruits are eaten raw) in sufficient amount possibly would facilitate development of a safe, affordable and orally delivered self-adjuvanted, novel dual antigen based subunit vaccine against TB.

The Brown Alga Padina australis Total Extract and Depressive-like Behavior Following BCG Inoculation in Mice

Background: Depression is an important psychological disorder because it is a common mental illness that leads to morbidity and suicide. Although appropriate antidepressant drugs exist, they usually have unpleasant side effects and delayed onset. Objectives: Introducing new compounds such as medicinal plants and oceanic living organisms such as alga is appropriate. Here the depressive-like effects of Padina australis Hauck total extract (PAE) were evaluated following depression induced by Bacillus Calmette–Guérin (BCG) in mice. Methods: Male NMRI mice (average weight: 27±2 g) were used. A single BCG 0.2 mL/mouse was inoculated. PAE effective dose (40 mg/kg) and imipramine (10 mg/kg) were administered as the reference drug for 14 days. The control animals received normal saline. All treatments were administered intraperitoneally. After evaluating the locomotor activity, different depression criteria were assessed by forced swimming test (FST), sucrose preference (SP) test, and novelty-suppressed feeding test (NSFT). Results: Depression was induced by BCG. The selected PAE dose did not cause a significant change in the locomotor activity compared with the control (139±16.9 count), while the immobility time in FST reduced (45.1±11.4 s vs BCG, P&lt;0.001). During the NSFT, the latency decreased (94.7±18.5 s vs BCG, P=0.0365), food intake increased (17.4±2.11 mg/g body weight vs BCG, P=0.023), and SP up to 79.3±4.7%. These changes were similar to imipramine. Conclusion: PAE showed antidepressant-like effects as despair behavior reduced during FST. Based on NSFT, the stress declined, and animal appetite increased, while SP revealed remission of anhedonia. Further studies are suggested regarding the antidepressant effects of PAE different partitions.

Mutations in genes encoding innate immune molecules identified in bladder cancer samples as potential biomarkers for immunotherapy with BCG and agonists

Bacillus Calmette–Guérin (BCG) immunotherapy for the treatment of bladder cancer (BC) depends on the recognition of bacteria by extracellular toll-like receptors (TLRs) or the detection of mycobacterial DNA by endosomal TLRs or the cGAS-STING pathway. Agonists related to these innate immune pathways have been developed as adjuvants to potentiate the effects of immunotherapy. As innate immune pathways are important for the action of BCG and other agonists proposed for BC therapy, we decided to investigate the presence of mutations in the main receptors of these pathways. The Cancer Genome Atlas (TCGA) database was screened to identify BC-related mutations (apart from oncogenes), targeting, in particular, TLRs, the adaptor molecule MyD88, and the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) immune pathway. Among 1,724 BC entries, 103 mutations were identified in 80 affected cases in the cohort. TLR9 and TLR10 ranked among the most frequent mutated genes observed in the affected cases in our search (13 mutations each). Through all analyzed data, the search for MYD88 gene recovered only 1 mutation input in the database. Mutations in the STING and cGAS genes were found in one and four cases, respectively. We also evaluated clinical data, including the pathologic stage of BC, and gene expression from 103 mutations entries. This article attempts to highlight the relevance of mutations in genes coding for innate immune molecules in BC samples as potential biomarkers to predict individual disease outcome, and specifically to help find the appropriate treatment for each person in the future.