Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance.

The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.

B cells and T cells abnormalities in patients with selective IgA deficiency.

BACKGROUND: Selective IgA deficiency (SIgAD) is the most prevalent inborn errors of immunity with almost unknown etiology. This study aimed to investigate the clinical diagnostic and prognostic values of lymphocyte subsets and function in symptomatic SIgAD patients. METHODS: A total of 30 available SIgAD patients from the Iranian registry and 30 age-sex-matched healthy controls were included in the present study. We analyzed B and T cell peripheral subsets and T cell proliferation assay by flow cytometry in SIgAD patients with mild and severe clinical phenotypes. RESULTS: Our results indicated a significant increase in naïve and transitional B cells and a strong decrease in marginal zone-like and switched memory B-cells in SIgAD patients. We found that naïve and central memory CD4+ T cell subsets, as well as Th1, Th2 and regulatory T cells, have significantly decreased. On the other hand, there was a significant reduction in central and effector memory CD8+ T cell subsets, whereas proportions of both (CD4+ and CD8+) terminally differentiated effector memory T cells (TEMRA) were significantly elevated in our patients. Although some T cell subsets in severe SIgAD were similar, a decrease in marginal-zone and switched memory B cells and an increase in CD21low B cell of severe SIgAD patients were slightly prominent. Moreover, the proliferation activity of CD4+ T cells was strongly impaired in SIgAD patients with a severe phenotype. CONCLUSION: SIgAD patients have varied cellular and humoral deficiencies. Therefore, T cell and B cell assessment might help in better understanding the heterogeneous pathogenesis and prognosis estimation of the disease.

Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway.

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase.

Duodenal Web in an Elderly Patient with Abdominal Discomfort and Vomiting: A Rare Case.

Duodenal web is complete or incomplete obstruction of the duodenum due to a membranous web or intraluminal diverticulum. This abnormality is one of the main causes of intestinal obstruction in children. The symptoms of this disease may rarely appear in older age and cause gastric outlet obstruction in adults. In the present paper, we report a 69-year-old male patient with heartburn, abdominal discomfort, frequent non-bilious, non-bloody vomiting for the past 6 months. Furthermore, the patient had experienced a weight loss of 12 kg during this period. He had been taking aspirin daily for years due to his ischemic heart disease. After performing contrast-enhanced CT imaging, esophagogastroduodenoscopy and barium meal examination, the patient was diagnosed to suffer from duodenal web. Since surgery is currently the mainstay of treatment in the management of this disease, the patient finally underwent a gastrojejunostomy.

Evaluation of effective factors on IL-10 signaling in B cells in patients with selective IgA deficiency

Background: Selective IgA deficiency is the most prevalent form of primary immunodeficiencies. The pathogenesis of the disease is still unknown. Several studies have suggested a defect in B cell responses to IL-10; however, the main reason for this defect has not been reported. Elucidating IL-10 signaling defects and their correlation with clinical manifestations could be helpful for better understanding and treatment of the disease. Methods: In this study, 15 SIgAD patients and 15 age- and sex-matched healthy controls were included. Surface expression of transforming growth factor ß receptor II (TGF-ß RII), IL-10R and IgA was assessed by flow cytometry in human purified B cells before and after stimulation by IL-10. Protein expression of STAT3, p-STAT3 and SOCS3 was measured by Western blotting analysis. TGF-ß and IgA secretion was evaluated by ELISA. Finally, the measurement of B cell apoptosis was performed by flow cytometry. Results: The TGF-ßRII expression level was decreased after stimulation with IL-10 in patients compared with controls. Notably, the TGF-ß level were higher after stimulation with mCD40L and IL-10 in the control group as compared to stimulation with mCD40L alone. The IgA+ B cell percentage and IgA secretion levels were significantly increased in controls as compared with SIgAD patients. The relative concentration of the total STAT3 was decreased as compared with controls. Conclusion: The defect in IgA production in SIgAD patients could be due to inadequate B cell responses to IL-10 stimulation that probably originate from defective regulation of IL-10-mediated TGF-b 'symbol' production TGF-ß response by IL-10. Furthermore, it is suggested that the absence of STAT3 protein baseline expression could impair cytokine-mediated signaling such as thatinduced by IL-!0 and IL-21.

Innovative targets of the lncRNA-miR-mRNA network in response to low-dose aspirin in breast cancer patients.

This study aimed to investigate innovative targets in breast cancer patients by considering the interaction of the lncRNA-miR-mRNA network in response to low-dose aspirin. The candidate miRs were first taken from the GEO and TCGA databases. Then, the candidate network was constructed using the high-throughput sequencing data. The expression levels of candidate targets were finally measured using Real-Time PCR in luminal A breast cancer patients undergoing aspirin (80 mg daily for three months) and non-aspirin groups during chemotherapy after surgery. The expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were measured using the ELISA technique. 5 lncRNAs, 12 miRs, and 10 genes were obtained in the bioinformatic phase. A significant expression increase of the candidate tumor suppressor lncRNAs, miRs, and genes and a substantial expression decrease of the candidate onco-lncRNAs, oncomiRs, and oncogenes were achieved after the aspirin consumption. Unlike the non-aspirin group, the expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were significantly decreased following aspirin consumption. The Kaplan-Meier analysis indicated a longer overall survival rate in the patients after aspirin consumption. Our results showed that the lncRNA-miR-mRNA network might be a significant target for aspirin; their expression changes may be a new strategy with potential efficacy for cancer therapy or prevention.

Mucocutaneous manifestations and nail changes in patients with end-stage renal disease on hemodialysis.

Mucocutaneous manifestations are common among patients on hemodialysis (HD). This study was undertaken to determine the prevalence of mucocutaneous manifestations in patients with end-stage renal disease (ESRD) who are on HD. In this cross-sectional, descriptive and analytic study conducted in 2009, 100 patients on HD at the Five Azar Hospital in Gorgan city were randomly selected. All the patients underwent detailed examination by a dermatologist to look for lesions in the skin, hair, nail and mucous membranes; if felt necessary, biopsy was obtained from the lesions. The findings were statistically analyzed using SPSS-13 software. For evaluation of normality of distribution, Kolmogorov-Smirnov was used, for quantitative variables Mann-Whitney and T-test (abnormal distribution) were used and for qualitative variables, Chi-2 and Fisher were used. In this study, P-value less than 0.05 was considered significant. Fifty-one males and 49 females were enrolled. The mean age was 49 ± 12 years. Diabetes was the most common cause of ESRD. In 95% of the patients, at least one mucocutaneous manifestation was present. Xerosis (78.3%) was the most common lesion, followed by pruritus (39.1%), lentigo (34.8%), skin discoloration (32.6%), leukonychia (32%) and thinning of the nail bed (24%). Xerosis, scaling, lentigo, folliculitis, idiopathic guttate hypopigmentation, leukonychia and half and half nail were associated with age. A significant relationship was seen between duration on dialysis and skin discoloration and leukonychia. Clubbing had a significant association with calcium-phosphorus product (Ca × P). There was a significant association between serum ferritin level and pruritus and tinea versicolor lesions. Our study shows that mucocutaneous manifestations are common among patients with ESRD. Identification of these manifestations and their association with causative factors are useful for preventing the lesions.

Single-dose oral fluconazole versus topical clotrimazole in patients with pityriasis versicolor: A double-blind randomized controlled trial.

This study was designed to compare the therapeutic effects of topical clotrimazole and systemic fluconazole in pityriasis versicolor. A double-blind randomized controlled trial was carried out in the dermatological clinic of Gorgan, northern Iran, between April 2006 and May 2007. All consecutive patients with pityriasis versicolor were included and randomly divided into two groups. In the first group (G1), patients underwent treatment with a single dose of fluconazole capsule (400 mg) and placebo cream. In the second group (G2), patients underwent treatment with clotrimazole cream (twice daily) and placebo capsule. The course of treatment was 2 weeks. All subjects were re-evaluated 2, 4 and 12 weeks after the end of the therapeutic course. After 2 weeks, the rate of complete resolution of disease was significantly higher in G2 than G1 (49.1% vs 30%). After 4 weeks, 41 patients (81.2%) of G1 and 52 patients (94.9%) of G2 showed complete resolution. After 12 weeks, 46 patients (92%) in G1 and 45 patients (81.8%) in G2 showed complete resolution. Recurrence rate in G1 and G2 were 6% and 18.2%, respectively. No complications were seen in either group. In this study, clinical response at week 4 was greater in the clotrimazole group than the fluconazole group. Recurrence at week 12 after treatment was less with oral fluconazole than clotrimazole cream. So, for better evaluation, more studies need to be done.