Intestinal microbes are an important system in the human body, with significant effects on behavior. An increasing body of research indicates that intestinal microbes affect brain function and ...neurogenesis, including sensitivity to stress. To investigate the effects of microbial colonization on behavior, we examined behavioral changes associated with hormones and hormone receptors in the hypothalamic-pituitary-adrenal (HPA) axis under stress. We tested germ-free (GF) mice and specific pathogen-free (SPF) mice, divided into four groups. A chronic restraint stress (CRS) protocol was utilized to induce external pressure in two stress groups by restraining mice in a conical centrifuge tube for 4 h per day for 21 days. After CRS, Initially, GF restraint-stressed mice explored more time than SPF restraint-stressed mice in the center and total distance of the OFT. Moreover, the CRH, ACTH, CORT, and ALD levels in HPA axis of GF restraint-stressed mice exhibited a significantly greater increase than those of SPF restraint-stressed mice. Finally, the Crhr1 mRNA levels of GF CRS mice were increased compared with SPF CRS mice. However, the Nr3c2 mRNA levels of GF CRS mice were decreased compared with SPF CRS mice. All results revealed that SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress. Moreover, we also found that GF mice exhibited significant differences in, hormones, and hormone receptors compared with SPF mice. In conclusion, Imbalances of the HPA axis caused by intestinal microbes could affect the neuroendocrine system in the brain, resulting in an anxiety-like behavioral phenotype. This study suggested that intervention into intestinal microflora may provide a new approach for treating stress-related diseases.
•CAR-T therapy is associated with potentially life-threatening toxicities.•Immunotoxicity (mainly CRS and ICANS) is common after CAR-T therapy.•CRS, ICANS and targeted treatment are risk factors for ...hematotoxicity and infections.•Infections are the most common cause of therapy-related mortality after CAR-T therapy.•A multidisciplinary team approach is recommended for toxicity management.
Chimeric antigen receptor T-cell (CAR-T) therapy has improved outcomes in patients with relapsed/refractory hematological malignancies. Research is also extending to other diseases, including solid tumors, infections and autoimmune disorders. As living drugs, CAR-T cells are associated with potentially life-threatening immunological toxicities, which frequently require a multidisciplinary team approach. Cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, infections and hematotoxicity (including cytopenias, immune reconstitution dysfunction and hypogammaglobulinemia) are associated with significant morbidity and mortality. This review takes a practical approach to summarize current knowledge on CAR-T toxicity, addressing pathogeny, risk factors, and prophylactic and therapeutic strategies.
Background
This review adds to a series of reviews looking at primary medical management options for patients with chronic rhinosinusitis.
Chronic rhinosinusitis is common and characterised by ...inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Antifungals have been suggested as a treatment for chronic rhinosinusitis.
Objectives
To assess the effects of systemic and topical antifungal agents in patients with chronic rhinosinusitis, including those with allergic fungal rhinosinusitis (AFRS) and, if possible, AFRS exclusively.
Search methods
The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 17 November 2017.
Selection criteria
Randomised controlled trials (RCTs) with at least a two‐week follow‐up period comparing topical or systemic antifungals with (a) placebo, (b) no treatment, (c) other pharmacological interventions or (d) a different antifungal agent. We did not include post‐surgical antifungal use.
Data collection and analysis
We used the standard Cochrane methodological procedures. Our primary outcomes were disease‐specific health‐related quality of life (HRQL), patient‐reported disease severity and the significant adverse effects of hepatic toxicity (systemic antifungals). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse effects of gastrointestinal disturbance (systemic antifungals) and epistaxis, headache or local discomfort (topical antifungals). We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.
Main results
We included eight studies (490 adult participants). The presence of nasal polyps on examination was an inclusion criterion in three studies, an exclusion criterion in one study and the remaining studies included a mixed population. No studies specifically investigated the effect of antifungals in patients with AFRS.
Topical antifungal treatment versus placebo or no intervention
We included seven studies (437 participants) that used amphotericin B (six studies; 383 participants) and one that used fluconazole (54 participants). Different delivery methods, volumes and concentrations were used.
Four studies reported disease‐specific health‐related quality of life using a range of instruments. We did not meta‐analyse the results due to differences in the instruments used, and measurement and reporting methods. At the end of treatment (one to six months) none of the studies reported statistically significant differences between the groups (low‐quality evidence ‐ we are uncertain about the result).
Two studies reported disease severity using patient‐reported symptom scores. Meta‐analysis was not possible. At the end of treatment (8 to 13 weeks) one study showed no difference and the second found that patients in the placebo group had less severe symptoms (very low‐quality evidence ‐ we are very uncertain about the result).
In terms of adverse effects, topical antifungals may lead to more local irritation compared with placebo (risk ratio (RR) 2.29, 95% confidence interval (CI) 0.61 to 8.62; 312 participants; 5 studies; low‐quality evidence) but little or no difference in epistaxis (RR 0.97, 95% CI 0.14 to 6.63; 225 participants; 4 studies, low‐quality evidence) or headache (RR 1.26, 95% CI 0.60 to 2.63; 195 participants; 3 studies; very low‐quality evidence).
None of the studies found a difference in generic health‐related quality of life (one study) or endoscopic score (five studies) between the treatment groups. Three studies investigated CT scan; two found no difference between the groups and one found a significant decrease in the mean percentage of air space occluded, favouring the antifungal group.
Systemic antifungal treatment versus placebo or no treatment
One study (53 participants) comparing terbinafine tablets against placebo reported that there may be little or no difference between the groups in disease‐specific health‐related quality of life or disease severity score (both low‐quality evidence). Systemic antifungals may lead to more hepatic toxicity events (RR 3.35, 95% CI 0.14 to 78.60) but fewer gastrointestinal disturbances (RR 0.37, 95% CI 0.04 to 3.36), compared to placebo, although the evidence was of low quality.
This study did not find a difference in CT scan score between the groups. Generic health‐related quality of life and endoscopic score were not measured.
Other comparisons
We found no studies that compared antifungal agents against other treatments for chronic rhinosinusitis.
Authors' conclusions
Due to the very low quality of the evidence, it is uncertain whether or not the use of topical or systemic antifungals has an impact on patient outcomes in adults with chronic rhinosinusitis compared with placebo or no treatment. Studies including specific subgroups (i.e. AFRS) are lacking.
Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address ...these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.
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•Uni-Vect combines constitutive and inducible expression in a single lentivirus•IL-12 delivered by Uni-Vect safely enhances the efficacy of CAR-T cells in vivo•Autonomous release of an IL-6R-blocking antibody in CAR-T cells ameliorates CRS•Transient transcription factor expression improves CAR-T cell expansion in vivo
Smole et al. develop a single-vector lentiviral system that combines constitutive and antigen-inducible transgene expression, called Uni-Vect. The therapeutic impact of Uni-Vect is demonstrated in CAR-T cells using an immunostimulatory cytokine that safely enhances efficacy, an antibody that ameliorates cytokine-release syndrome (CRS), and a transcription factor that enhances expansion.
Congenital Rubella Syndrome (CRS) adalah suatu kumpulan gejala penyakit terdiri dari katarak, penyakit jantung bawaan, gangguan pendengaran, dan keterlambatan perkembangan. Sindrom rubella kongenital ...disebabkan infeksi virus rubella pada janin selama masa kehamilan akibat ibu tidak mempunyai kekebalan terhadap virus rubella.. Virus rubella ditransmisikan melalui pernapasan yaitu melalui droplet yang dikeluarkan oleh seseorang yang terinfeksi rubella, setelah terkena droplet, virus ini akan mengalami replikasi di nasofaring dan di daerah kelenjar getah bening. Viremia terjadi antara hari ke-5 sampai hari ke-7 setelah terpajan virus rubella. Infeksi rubella menyebabkan kerusakan janin karena proses pembelahan terhambat. Diagnosis dari CRS bisa ditegakkan melalui anamnesis, pemeriksaan fisik dan pemeriksaan pebunjang. Pemeriksaan laboratorium untuk menunjang diagnosis CRS antara lain: isolasi virus, pemeriksaan serologik (ELISA) dan pemeriksaan terhadap RNA virus rubella. Terapi untuk CRS sendiri hanya bersifat suportif untuk defek-defek yang dialami. Penting untuk mencegah CRS adalah dengan vaksin MMR sebelum hami. Prognosis untuk CRS lebih buruk dibandingkan dengan rubella postnatal karena disertai kerusakan organ multiple yang berat.
Enhanced recovery after surgery (ERAS) protocols have been shown to reduce length of stay (LOS) and complications. The impact of ERAS protocols on the cost of cytoreductive surgery and hyperthermic ...intraperitoneal chemotherapy (CRS-HIPEC) has not been studied.
We performed a retrospective cohort analysis of patients undergoing CRS-HIPEC from 2016-2022 at a single quaternary center. Propensity score matching was used to create pre-and post-ERAS cohorts. Cost, overall and serious complications, and intensive care unit (ICU) length of stay (LOS) between the two cohorts were compared using the Mann-Whitney U-test for continuous variables and χ2 test for categorical variables.
Our final matched cohort consisted of 100 patients, with 50 patients in both the pre- and post-ERAS groups. After adjusting for patient complexity and inflation, the median total cost $75,932 ($67,166-102,645) versus $92,992 ($80,720-116,710), p = 0.02 and operating room cost $26,817 ($23,378-33,121) versus $34,434 ($28,085-$41,379), p < 0.001 were significantly higher in the post-ERAS cohort. Overall morbidity (n = 22, 44% versus n = 17, 34%, p = 0.40) and ICU length of stay 2 days (IQR 1-3) versus 2 days (IQR 1-4), p = 0.70 were similar between the two cohorts. A total cost increase of $22,393 SE $13,047, 95% CI (-$3178 to $47,965), p = 0.086 was estimated after implementation of ERAS, with operating room cost significantly contributing to this increase $8419, SE $1628, 95% CI ($5228-11,609), p < 0.001.
CRS-HIPEC ERAS protocols were associated with higher total costs due to increased operating room costs at a single institution. There was no significant difference in ICU LOS and complications after the implementation of the ERAS protocol.
AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell-mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study ...evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day-1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.
The objective of this study is to assess the correlation between the pre-operative CA125 Elimination rate constant K(KELIM) score and the intraoperative chemo-response score (CRS) in patients with ...advanced high grade serous ovarian cancer(HGSC) treated with neoadjuvant chemotherapy(NACT).
This is a retrospective cohort study of patients with Stage III-IV HGSC treated with NACT from March 2010 to December 2019 at Princess Margaret Cancer Center, Toronto, Canada. KELIM scores were calculated based on the tool devised by You et al. available online. CRS was assessed using an established 3-tier scoring system. An association analysis was performed to determine if the KELIM score assessed during NACT can predict CRS score at the time of interval cytoreductive surgery(ICS).
172 patients were included in this analysis. Patients with CRS 1–2 had a lower median Platinum Free Interval(PFI) (9.24 vs 13.64 months, p = 0.005), lower median progression free survival(PFS) (14.99 vs 20.29 months, p = 0.003) and lower 5-year overall survival(OS) (63.8% vs 69.7%, p = 0.54) compared to patients with CRS3. Among patients with CRS 1–2(n = 115), 68.7% had KELIM <1, while 56.2% of patients with CRS3 had KELIM ≥1(56.2%), p = 0.0017, suggesting a correlation between the KELIM and CRS scores. Furthermore, patients with KELIM ≥1 and CRS3 had significantly higher PFS compared to other groups(median PFS 28.27 months vs 17.66 months for KELIM ≥1/CRS 1/2; 17.13 months for KELIM <1/CRS 3; and 14.53 months for KELIM <1/CRS 1–2, p = 0.003).
The biochemical KELIM score correlated with the surgical pathologic CRS score and may predict pathological response to chemotherapy. This information can be utilized to tailor and personalize treatment in patients with advanced ovarian malignancy.
•The KELIM score is predictive of chemotherapy response in patients with advanced ovarian cancer who are treated with NACT.•The KELIM score correlates with the pathologic CRS score.•The combination of the KELIM and CRS scores can be used to personalize treatment for patients with advanced ovarian cancer.
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