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Background and aims: Resistance training is associated with certain cardiovascular adaptations. However, a lack of exercise may affect it. Thus, the aim of this study was to investigate the effect of a period of detraining followed by resistance training on the fibrosis, angiogenesis, and cardiac dimensions of male Wistar rats. Methods: In this experimental study, 20 male Wistar rats at the age of five weeks were randomly divided into control, training, control+detraining, and training+detraining groups. The control (8 weeks) and control+detraining (11 weeks) groups were placed in their respective cages with 24-hour free access to food and water and did not exercise for eight weeks. The resistance training+detraining and resistance training groups performed eight weeks of the resistance training protocol. The resistance training+detraining group did not do any type of training after the training period of 3 weeks. The results were analyzed by SPSS version 18. Results: In terms of fibrosis, there was a significant difference between the control and control+detraining groups (P=0.001), between control and training groups (P=0.001), and between control+detraining and training+detraining groups (P=0.001). In addition, a significant difference was found between the training and training+detraining groups in terms of fibrosis (P=0.001). In terms of angiogenesis, a significant difference was observed between the control and training groups (P=0.001) and between the training and training+detraining groups (P=0.007). Conclusion: Resistance training could reduce fibrosis and increase cardiac angiogenesis in rats. Based on the findings, fibrosis increased significantly in the detraining period compared to the active period, and angiogenesis was also reduced due to detraining.

Abstract Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

During our study (summer of 1994) twenty two Tatera indica were collected and two out of them (9.09%) were naturally infected with amastigote. Parasites were cultured in NNN+LIT medium and isolated promastigotes were sent to the Medical University of Montpellier in France for identification. The result of isoenzyme showed, the parasite was Leishmania major zymodem MON 26-(=LON 1), therefore Tatera Indica was known the main reservoir host of zoonotic cutaneous leishmaniasis in the west of Iran. This is the first report on the isolation and identification of L.major zymodem MON 26-(=LON 1) from this species of rodent. In the meantime, Rhombomys opimus was absent in these areas.

The aim of this study was to considering the correlation between the muscle fibronectin type III domain-containing protein 5 (FNDC5), blood and heart level of Irisin in exercise-trained rats with Nano selenium supplementation after intraperitoneal injection of cigarette smoke extract induced chronic obstructive pulmonary disease (COPD). To this end, 49 male Wistar rats (8 weeks old) were divided into seven groups: control, SeNPs (2.5 mg/kg b.w by oral gavage, 3 days/week, 6 weeks), AIT (49 min/day, 5 days/week for 6 weeks, interval), SeNPs+AIT, CSE (150 µL by IP injection, 1 day/week for 6 weeks), CSE+AIT, and CSE+SeNPs+AIT. The results of the present study showed that CSE injection caused inflammation and damage to lung tissue, especially alveoli, compared to the healthy group. In other words, based on the histological examination of cigarette smoke extract, it was able to cause lung tissue damage similar to COPD, and doing exercise and taking nanoselenium antioxidant supplement could control these lung tissue damage. Pearson's correlation method was used to investigate the relationship between muscle FNDC5, serum and heart Irisin, and the results of this correlation were not significant in different groups (p>0.05). It seems that exercising and taking nanoselenium supplements can increase Irisin levels in serum and heart tissue by expanding muscle contraction and increasing muscle FNDC5. However, the relationship of this factor in muscle and heart crosstalk should be investigated more closely.

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.

Abstract Background Cats in Iran are definitive hosts for several zoonotic intestinal helminths, such as Toxocara cati, Dipylidium caninum, Toxascaris leonina, Physaloptera praeputialis and Diplopylidium nolleri. Objective This study aimed to determine the prevalence of intestinal helminth infection in free‐roaming cats in southeast Iran, a region with a high free‐roaming cat population. Methods From January 2018 to December 2021, 153 cadavers of free‐roaming cats from Southeast Iran were necropsied for intestinal helminth infections. The carcasses were dissected, and the digestive systems were removed. The esophagus, stomach, small intestine, caecum and colon were tightly ligated. All adult helminths were collected, preserved and identified. Results The prevalence of gastrointestinal helminth infections was 80.39% (123/153). Of the cats from Kerman, 73% (73/100) were infected with at least one helminth, including D. caninum 70% (70/100), T. leonina 8% (8/100) and P. praeputialis 17% (17/100). Concurrent infection with two helminth species was found in 16% (16/100) and of three species infections was found in 3% (3/100) of the cats. Of the cats from Zabol, 94.33% (50/53) were infected with at least one of the helminths, including D. caninum 69.81% (37/53), T. leonina 11.32% (6/53), P. praeputialis 37.73% (20/53) and T. cati 5.66% (3/53). Concurrent infection with two helminth species was found in 28.3% (15/53), and three species were found in 1.88% (1/53) of the cats. Helminth infections were more prevalent in older cats. There was no association between sex and infection rate. Conclusion Based on the very high prevalence of zoonotic intestinal helminth infections in free‐roaming cats in southeast Iran, the potential public health risk emphasizes the need for intersectoral collaboration, particularly the provision of health and hygiene education to high‐risk populations, such as pre‐school and school‐age children.

Background: Exercise and dietary supplements can partially mitigate the negative effects of cadmium. The present study aimed to investigate the effect of swimming and silymarin on placental growth factor (PLGF) in pregnant mice exposed to cadmium. Methods: Seventy-two 8-week-old pregnant Wistar rats (weighing 20 ± 200 g) were divided into 9 groups, with 8 rats in each group. Cadmium chloride at a dose of 400 mg/kg body weight was fed to rats by drinking a water solution. Silymarin (100 mg/kg body weight) was injected subcutaneously 3 times a week. The exercise program during pregnancy consisted of 60 minutes of swimming per day, conducted for 5 days a week. The microscopic sections of samples were taken 2 days after birth using the usual method of tissue sectioning. A 1-way analysis of variance (ANOVA) and Tukey post hoc test at the error level of 0.05 were used to analyze the data. Results: The PLGF index in the cadmium group showed a significant decrease (P < 0.001) compared to the cadmium + silymarin and cadmium + silymarin and swimming groups. However, swimming training alone had no effect on PLGF index (P = 0.162). Conclusion: Cadmium significantly reduced PLGF levels in neonatal lung tissue, and regular swimming endurance exercises and silymarin supplementation inhibited the effects of cadmium chloride.

Triple-negative breast cancer (TNBC) presents a formidable challenge in oncology due to its aggressive phenotype and the immunosuppressive nature of its tumor microenvironment (TME). In this issue of the JCI, Zhu, Banerjee, and colleagues investigated the potential of targeting the OTU domain-containing protein 4 (OTUD4)/CD73 axis to mitigate immunosuppression in TNBC. They identified elevated CD73 expression as a hallmark of immunosuppression in TNBC. Notably, the CD73 expression was regulated by OTUD4-mediated posttranslational modifications. Using ST80, a pharmacologic inhibitor of OTUD4, the authors demonstrated the restoration of cytotoxic T cell function and enhanced efficacy of anti-PD-LI therapy in preclinical models. These findings underscore the therapeutic potential of targeting the OTUD4/CD73 axis in TNBC., Overcoming immunosuppressive tumor microenvironment in breast cancer Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human [...]

Commensal human papillomaviruses (HPVs) are responsible for persistent asymptomatic infection in the human population by maintaining low levels of the episomal genome in the stratified epithelia. Herein, we examined the immunogenicity of cutaneotropic HPVs that are commonly found in the skin. Using an in silico platform to determine human leukocyte antigen (HLA)–peptide complex binding affinity, we observed that early genes of cutaneotropic HPV types within the same species can generate multiple conserved, homologous peptides that bind with high affinity to HLA class I alleles. Interestingly, we discovered that commensal β, γ, μ, and ν HPVs contain significantly more immunogenic peptides compared with α-HPVs, which include high-risk, oncogenic HPV types. Our findings indicate that commensal HPV proteins have evolved to generate peptides that better complement their host’s HLA repertoire. Promoting higher control by host T cell immunity in this way could be a mechanism by which HPVs achieve widespread asymptomatic colonization in humans. This work supports the role of commensal HPVs as immunogenic targets within epithelial cells, which may contribute to the immune regulation of the skin and mucosa.

Introduction: The study aimed to investigate the effects of deep neck flexor (DNF) and deep neck extensor (DNE) muscle exercises on pain, passive range of motion (PROM), craniovertebral angle (CVA), neck flexor endurance (NFE), neck extensor endurance (NEE), and the number of weekly painkiller usage (NWPKU) in chronic non-specific neck pain (CNNP) patients. Materials and Methods: A total of 27 CNNP patients, incuding intervention group (n=15) and control group (n=12), were recruited for this study. Patients in the intervention group participated in 6 weeks of DNF and DNE exercises plus traditional physiotherapy. After 10 sessions (3 weeks), the exercise protocol was followed for 3 weeks of the home-based exercise form. Control group patients received traditional physiotherapy alone. The numeric pain rating scale (NPRS), PROM, CVA, NFE, NEE, and NWPKU were examined and compared between groups, at the baseline and after six weeks. Results: Numeric pain rating scale, PROM, CVA, NFE, NEE, and NWPKU improved significantly in both groups after treatment (P

Introduction: Forward head posture (FHP) is one of the most common positional deviations. Frequent users often exhibit incorrect posture because of the rising popularity of media devices, such as smartphones and computers. This posture leads to changes in muscle activity in cervical flexion and extension. It is defined by hyperextension of the upper cervical vertebrae and forward translation of the cervical vertebrae. This study evaluates the effect of dry needles as a new method in the upper trapezius muscle on the neck’s angles and range of motion (ROM) in individuals with FHP. Materials and Methods: In this quasi-experimental interventional study, 18 women with FHP underwent a dry needle session. The photogrammetry of the cranio-vertebral angle measured the degree of FHP. Visual analog scale (VAS), pain pressure threshold (PPT), cranio-vertebral angle (CVA) and cranio-horizontal angles (CHA), ROM, scapular index (SI), and forward shoulder translation (FST) were assessed before and after the intervention. Results: The results demonstrated that after the intervention, right and left PPT, flexion, and proper neck rotation, right and left SI, CVA, and CHA were significantly improved (P

Our decisions are guided by how we perceive the value of an option, but this evaluation also affects how we move to acquire that option. Why should economic variables such as reward and effort alter the vigor of our movements? In theory, both the option that we choose and the vigor with which we move contribute to a measure of fitness in which the objective is to maximize rewards minus efforts, divided by time. To explore this idea, we engaged marmosets in a foraging task in which on each trial they decided whether to work by making saccades to visual targets, thus accumulating food, or to harvest by licking what they had earned. We varied the effort cost of harvest by moving the food tube with respect to the mouth. Theory predicted that the subjects should respond to the increased effort costs by choosing to work longer, stockpiling food before commencing harvest, but reduce their movement vigor to conserve energy. Indeed, in response to an increased effort cost of harvest, marmosets extended their work duration, but slowed their movements. These changes in decisions and movements coincided with changes in pupil size. As the effort cost of harvest declined, work duration decreased, the pupils dilated, and the vigor of licks and saccades increased. Thus, when acquisition of reward became effortful, the pupils constricted, the decisions exhibited delayed gratification, and the movements displayed reduced vigor.

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity., Introduction The advent of immune checkpoint blockade (ICB) therapy has greatly improved cancer treatment, especially for metastatic melanoma, non-small cell lung cancer and squamous cell carcinoma of the head and [...]

Introduction: Flexibility or the ability of a muscle to increase in length is an integral part of musculoskeletal characteristics and is essential in preventing musculoskeletal injuries and increasing functional levels. Hamstring muscles rupture is a common injury. One of the important factors in the occurrence of this injury is poor hamstring muscle flexibility, which because of its stiffened structure, has less ability to quickly increase in length. Some researchers have recently suggested that the dry needling technique could reduce the number of treatment sessions for hamstring muscle tightness and bring faster and more effective results. Accordingly, this study aims to investigate the effect of the application of dry needling through an acupuncture technique on hamstring muscle flexibility. Materials and Methods: The present study is a single-blinded randomized controlled trial in which 16 individuals with bilateral hamstring muscle shortness were randomly allocated into dry-needling and sham-needling groups. The sampling method was non-probability convenience. The outcome measures were the right and left active knee extension range of motion, assessed before and after the first, third, and fifth sessions of intervention. A 2-factor mixed analysis of variance was applied to determine the differences between and within the two groups. Results: Except for the group main effect, time main effect and interaction effect were statistically significant for the right and left active knee extension range of motion (P

Background: Carcinogen nitrosamine 4-(methyl-trosamino)−1-(3-pyridyl)−1-butanone (NNK) remarkably affects the actions of growth factors: EGFR, VEGFR-2, as well as the natural tumor suppressors: TGFβ-1 and TIMP-1. We propose that utilizing non-chemical interventions such as swimming and Nigella sativa nanocapsule play role in controlling cancer progression through direct effects on tumor-inherent factors. Material and methods: Male rats were randomly placed into seven groups: Control (C), Solvent (S), (NNK), NNK+N.sativa (NNK+NS), NNK+Exercise (NNK+E), N.sativa+Exercise (NS+E), NNK+N.sativa+Exercise (NNK+NS+E). The exercise program consisted of 12 weeks of submaximal swimming. NNK and NS groups received weekly doses of 12/5 mg/kg and 125 μg/kg of NNK and N.sativa, respectively. By the end of the protocol, the levels of VEGFR-2, and TIMP-1 were determined using immunohistochemistry method and EGFR, and TGFβ-1 levels were measured by RT-PCR assay. Results: In comparison with control group, there was a significant increase in the levels of VEGFR-2 in NNK, NNK+E, NNK+NS, NS+E, and NNK+NS+E groups (P ≤ 0.001), also TGFβ-1 levels of NNK+E and NS+E groups significantly increased (P ≤ 0.001). While EGFR levels did not change remarkably (P˃0.05), except in NNK group (P ≤ 0.001), TIMP-1 in NNK, NNK+E, NS+E, NNK+NS+E groups significantly decreased (P ≤ 0.001). Conclusion: We recommend 12 weeks of submaximal swimming and 125 μg/kg N.sativa nanocapsule are safe interventions to recover the balance of selected angiogenic/ angiostatic markers and to control tumor initiation, growth, and metastasis in lung carcinoma induced by 12/5 mg/kg of NNK injection.

Aim: Intracanal medicaments are often recommended during endodontic sessions to eliminate the necrotic debris and microorganisms. The aim of the present study was to observe the cytotoxicity of calcium hydroxide (CH) and colchicine (COL), at different concentrations, on human gingival fibroblast cells. Materials and Methods: Human gingival fibroblasts were cultured on plastic flasks containing RPMI 1640 media and fetal calf serum 10% supplemented with antibiotic agents. Trypsin/ethylenediaminetetraacetic acid 0.2% enzyme was used to isolate the cells, and the suspension was transferred to tubes for centrifuging. Conventional CH and COL were separately mixed with sterile saline solution to prepare a stock media. By serial dilution of stock media, desired concentrations were prepared at 2, 1.75, 1.5, and 1.25 mg/ml, separately. After considering a control group, the cells were exposed to test materials. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted at 24 h, 72 h, and 7 days later. Optical density (OD) was evaluated to attain cell viability percentage. Finally, the recorded data were analyzed by Kruskal–Wallis and Mann–Whitney tests using SPSS software version 19 at a significant level of 0.05. Results: The highest (1.40 ± 0.66) and lowest (0.15 ± 0.00) ODs were observed in CH 1.25 mg/ml and COL 1.5 mg/ml after 72 h, respectively. All of the concentrations of both CH and COL showed significant OD differences with the control group (all P = 0.001). Conclusion: Both CH and COL manifested similar cytotoxicity on human gingival fibroblast cells.