Programmable and multi-targeted CARs: a new breakthrough in cancer CAR-T cell therapy

CAR-T cell therapy, as a novel immunotherapy approach, has indicated successful results in the treatment of hematological malignancies; however, distinct results have been achieved regarding solid tumors. Tumor immunosuppressive microenvironment has been identified as the most critical barrier in CAR-T cell therapy of solid tumors. Developing novel strategies to augment the safety and efficacy of CAR-T cells could be useful to overcome the solid tumor hurdles. Similar to other cancer treatments, CAR-T cell therapy can cause some side effects, which can disturb the healthy tissues. In the current review, we will discuss the practical breakthroughs in CAR-T cell therapy using the multi-targeted and programmable CARs instead of conventional types. These superior types of CAR-T cells have been developed to increase the function and safety of T cells in a controllable manner, which would diminish the incidence of relevant side effects. Moreover, we will describe the capability of these powerful CARs in targeting multiple tumor antigens, redirecting the CAR-T cells to specific target cells, incrementing the safety of CARs, and other advantages that lead to promising outcomes in cancer CAR-T cell therapy (AU)

Prognostic Role of Lymphovascular Invasion in Patients with Early Breast Cancer.

In this study, our aim was to evaluate the role of lymphovascular invasion (LVI) in the prognosis of patients with early stage breast cancer. The medical records of more than 7000 patients who suffered from invasive breast cancer and had undergone surgical treatment since December 1994 till December 2019, retrospectively. Patient's history, physical examination and the clinicopathological features, histopathology characteristics, immunohistochemical findings, adjuvant systemic therapy, recurrence rate, metastasis-free survival (MFS), disease-free survival (DFS), and overall survival (OS) were reviewed. A total of 5425 eligible patients were categorized into two groups based on the presence of LVI; 3031 (55.9%) patients had no LVI (group 1) and LVI was present in 2394 (44.1%) patients (group 2), then divided into LN-positive and -negative groups. Presence of LVI was significantly associated with patient age ≤ 40 years (p = 0.048), high histological grade (grades II and III, p < 0.001), tumor size between 2-5 cm and > 5 cm (p < 0.001), number of involved LN ≥ 4 (p < 0.001), and negative ER (p = 0.042) tumors. Five-year OS, MFS, and DFS were 93%, 88.9%, and 76.1% and 85.2%, 84.7%, and 73.6 in groups 1 and 2, respectively (P < 0.001). On multivariate analysis, LVI was an independent prognostic factor for DFS in all patients. Furthermore, histological grade II, histological grade III, and a higher number of involved LNs (≥ 4) were independent predictors in all patients. Thus, the presence of LVI can be considered as an independent prognostic factor for patients with operable breast cancer, irrespective of the LN status.

Programmable and multi-targeted CARs: a new breakthrough in cancer CAR-T cell therapy.

CAR-T cell therapy, as a novel immunotherapy approach, has indicated successful results in the treatment of hematological malignancies; however, distinct results have been achieved regarding solid tumors. Tumor immunosuppressive microenvironment has been identified as the most critical barrier in CAR-T cell therapy of solid tumors. Developing novel strategies to augment the safety and efficacy of CAR-T cells could be useful to overcome the solid tumor hurdles. Similar to other cancer treatments, CAR-T cell therapy can cause some side effects, which can disturb the healthy tissues. In the current review, we will discuss the practical breakthroughs in CAR-T cell therapy using the multi-targeted and programmable CARs instead of conventional types. These superior types of CAR-T cells have been developed to increase the function and safety of T cells in a controllable manner, which would diminish the incidence of relevant side effects. Moreover, we will describe the capability of these powerful CARs in targeting multiple tumor antigens, redirecting the CAR-T cells to specific target cells, incrementing the safety of CARs, and other advantages that lead to promising outcomes in cancer CAR-T cell therapy.

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.

The distinction of self from non-self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma-b (Cbl-b) is a newly identified component in the ubiquitin-dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co-ordinated by Cbl-b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl-b and the suppressive signaling mechanisms of Cbl-b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

Effect of arginine and threonine administered in ovo on digestive organ developments and subsequent growth performance of broiler chickens.

This trial was conducted to investigate the effect of arginine (Arg), threonine (Thr) and Arg + Thr administered in ovo on growth performance, digestive organs and intestinal morphology in broiler chickens. On day 14 of incubation, 400 fertile eggs were randomly allotted to five experimental treatments through injection in the amniotic fluid including: (i) control (none injected), (ii) sham (0.5 ml of 0.5% saline), (iii) Arg (35 mg/egg), (iv) Thr (25 mg/egg) and (v) Arg + Thr (35 + 25 mg/egg). After hatching, chicks were given a commercial corn-soya bean diet up to 42 days of age. Daily feed intake (FI) and body weight (BW) of chicks were measured during different periods of the trial. Digestive organs were measured for their relative weight and intestinal length on days 11 and 42 of age. Intestinal morphometric traits were evaluated on day 11 of the experiment. Supplementing amino acids affected the performance of broiler chicks as Thr significantly increased FI and BW across starter, grower and finisher periods compared with sham and control (p < 0.05). Furthermore, Arg + Thr injection increased jejunal weight compared with control on day 42 (p < 0.05). Moreover, Arg inclusion led to the greatest villus height and crypt depth among treatments in duodenum (p > 0.05); however, amino acid supplemented groups had lower villus height than control in jejunum (p < 0.05). Negative correlations found between digestive organs related to day 11 of age containing pancreas (r = -0.484; p = 0.030), duodenal (r = -0.577; p = 0.007) as well as ileal lengths (r = -0.471; p = 0.035) and FI of entire period. Otherwise, positive relationships were observed between duodenum (r = 0.580; p = 0.007) and ileum (r = 0.582; p = 0.007) weights on day 42 and FI of chickens across the entire phase. In conclusion, Arg and particularly Thr injection into amnion can improve FI and post-hatch growth performance of chickens which may be mediated by the development of digestive organs.

The effect of combined decongestive therapy and pneumatic compression pump on lymphedema indicators in patients with breast cancer related lymphedema.

BACKGROUND: Lymphedema treatment is difficult and there is no consensus on the best treatment. This study evaluated the effect of combined decongestive therapy (CDT) and pneumatic compression pump on lymphedema indicators in patients with breast cancer related lymphedema (BCRL). METHODS: Twenty one women with BCRL were enrolled. The volume difference of upper limbs, the circumference at 9 areas and shoulder joint range of motion were measured in all patients. CDT was done by an educated nurse in two phases. In first phase, CDT was accompanied by use of a compression pump for 4 weeks, 3 days per week. In second phase, CDT was performed daily without compression pump for 4 weeks by patients at home. At the end of each phase, the same primary measurements were done for patients. RESULTS: The mean volume difference of the upper limbs and mean difference in circumference in all areas at different phases decreased significantly. Mean flexion, extension, abduction and external rotation (in degrees) at different phases increased significantly. CONCLUSION: CDT significantly reduced mean volume and mean circumference of the affected limb, and significantly increased shoulder joint range of motion. The findings support the optimal effects of CDT in the treatment of secondary lymphedema of upper extremity. CLINICAL TRIAL REGISTRATION NUMBER: 138902212621N8.

Primary breast mucormycosis, a case report.

Mucormycosis is a rare fungal infection caused by organisms of the order Mucorales often occurring in diabetics or immunologically compromised patients. To date, only one case of primary mucormycosis of breast has been reported in the English literature. We describe a further case of mucormycosis that was localized to the breast in a patient with no underlying disease and was successfully treated with a simple mastectomy and intravenous antifungal therapy.

Excess costs associated with common healthcare-associated infections in an Iranian cardiac surgical unit.

Healthcare-associated infection (HCAI) following open heart surgery is not only a major cause of mortality and morbidity, but also carries higher costs. There are limited data on the additional costs due to HCAI in non-western countries. To estimate the direct cost of the four most common HCAIs in an Iranian sample, we studied 1191 patients admitted for elective open heart surgery. HCAIs were defined using the National Nosocomial Infections Surveillance criteria (Centers for Disease Control and Prevention, Atlanta, GA, USA). The financial costs of length of stay per day in hospital, paraclinical services, medications, instruments, and operating room were provided by the hospital's finance department. The contribution of HCAI to excess direct medical costs in patients with HCAI was assessed by multivariable linear regression. In the study population, the mean age was 57.3±11.9 years, 857 (72.0%) were men, and 64 (5.4%) developed HCAI. In total there were 73 infections of which the most common was surgical site infection (49.3%), followed by urinary tract infection (20.5%), bloodstream infection (16.5%), and pneumonia (13.7%). After adjustment for other confounders HCAI remained associated with excess direct medical costs (ß=1707.06, SE=90.84; P < 0.001). The medical costs in patients with HCAI were almost twice those in patients without HCAI. More than half of the excess cost was attributable to prolonged hospitalisation.

The effect of iron and zinc dietary restriction of pregnant rats on physical growth of litters.

Evidence suggests that micronutrient deficiencies may be associated with problems in early growth. Iron (Fe) and Zinc (Zn) deficiency (D) are prevalent during gestation in low-income countries. For pregnant dams, adequate amount of these micronutrients are needed in the diet to ensure the capacity for increased physical growth. In this study, the role of Fe and Zn dietary restriction of pregnant rats on physical growth of litters was investigated. Pregnant rats after to mating were divided to three groups. Control group fed a standard diet and a FeD group fed a diet deficient in Fe and a ZnD group fed a diet deficient in Zn. All the diets were exposed during the last third of pregnancy. The results showed serum Fe and Zn concentration after to exert dietary compared to before to exert dietary in FeD and ZnD groups was significant. There was a significant difference in the physical growth indexes (body weight, body length, tail length, and head length) between FeD and ZnD groups compared to the Control group, but a significant difference in head width and brain weight between FeD and ZnD groups compared to the Control group was not seen. The results of this study suggest that adequate Fe and Zn affect the physical growth of litters.

Analysis of smoking behaviour among Iranian population: a cohort and period analysis.

BACKGROUND: The patterns of smoking in ageing cohorts are important to public health authorities. The aim of this study is to describe the patterns of smoking among Iranian population. METHODS: Data from cross-sectional surveys of Health and Disease Survey (HDS) in Iran were utilized. Smoking was categorized as no smoker, light smoker (less than 10 cigarettes a day), moderate smokers (10 to 20 cigarettes a day), and heavy smoker (more than 20 cigarettes a day). Age group cohorts were constructed by following each age group to the next age group in two consecutive surveys. The change in smoking behavior was express as the difference of smoking prevalence and 95% confidence interval around the difference were constructed. Three birth cohorts of 1930, 1960, and 1975 were constructed among smoker and their age at initiation of smoking were assessed for the three cohorts. RESULTS: Smoking was more prevalent among age group 25-39 in males and age group 40-60 in females. Smoking prevalence increased in all categories of smoking behavior among male cohort of 15-25 year age-group and stayed stable afterward up to their 40's. After age 40, the prevalence of smoking decreased in heavy smokers and stayed stable in light and moderate smokers. A different pattern was seen among female smokers. Age at initiation of smoking decreased in the last decades. Among the male birth cohort of 1930, just 32.6% of smokers started smoking before age 20 compared with 48.7% in birth cohort of 1975, P value < 0.0001. Similar pattern was seen among the female smokers. CONCLUSIONS: The pattern of smoking in Iranian population high lights the fact that smoking behavior is highly age dependent.