Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P < 0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P < 0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB.     

Risk factors for severe and critically ill COVID-19 patients: A review

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1β, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.     

Monogenic lupus due to DNASE1L3 deficiency in a pediatric patient with urticarial rash,hypocomplementemia, pulmonary hemorrhage,and immune-complex glomerulonephritis

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease and usually involves the skin, musculoskeletal system, and kidneys. More than 30 genes have been to monogenic lupus, so far. Monogenic lupus is often characterized by an early-onset, similar family history, and syndromic appearance. Herein we present a pediatric patient with DNASE1L3 deficiency, suffering from both urticarial skin lesions, recurrent hemoptysis, and renal involvement, eventually diagnosed as this rare monogenic lupus.The patient suffered from recurrent urticarial rash and hemoptysis since the age of 15 months of age. He had microscopic hematuria, mild proteinuria, hypocomplementemia, and positive antinuclear antibody, anti-dsDNA, and antineutrophil cytoplasmic antibodies. Renal biopsy yielded immunocomplex glomerulonephritis. Due to early-onset, similar sibling history and consanguineous parents, we suspected monogenic lupus and performed whole-exome sequencing, which further revealed a homozygous T97Ifs*2 mutation (NM_004944.4: c.290_291delCA/p.Thr97Ilefs*2) in DNASE1L3 gene.In conclusion, DNASE1L3 deficiency should be thought when juvenile SLE occurs with early disease-onset, pulmonary hemorrhage, glomerulonephritis, and recurrent urticarial rash along with ANCA positivity.     

Paratracheal air cysts: prevalence and relevance to pulmonary emphysema and bronchiectasis using thoracic multidetector CT

PURPOSE

We aimed to determine the prevalence of paratracheal air cysts (PTACs) and the relationship of PTACs with emphysema and bronchiectasis through retrospective analysis of multidetector computed tomography (MDCT) findings.

METHODS

MDCT findings of 1027 consecutive patients who underwent routine thorax examination between January 2012 and January 2013 were evaluated retrospectively for the presence of PTACs. Localization of the PTACs, as well as their size, shape, and relationship with the trachea were examined. Presence of emphysema and bronchiectasis was recorded, and bronchiectasis severity index was calculated when present. We randomly selected 80 patients who had no visible PTACs as the control group. The findings of patients with and without PTACs were compared.

RESULTS

PTACs were determined in 82 of 1027 patients (8%), in 8.8% of females and 7.3% of males. The presence of PTACs was determined to be independent of gender (P = 0.361). Eighty-one PTACs (98.8%) were located in the right side of the trachea and 56.1% had a tracheal connection. The presence of PTACs significantly correlated with the presence and severity of bronchiectasis (P = 0.001 and P = 0.005 respectively). There was no significant relationship between the presence of PTACs and the presence of emphysema on CT images (P = 0.125).

CONCLUSION

The prevalence of PTACs was determined as 8% in this study. There was significant association between PTACs and bronchiectasis.Paratracheal air cysts (PTACs) are small collections of air adjacent to the trachea at the level of the thoracic inlet (1). Pathological diagnosis of PTACs in surgically confirmed cases includes tracheal diverticulum, lymphoepithelial cyst, and bronchogenic cyst (1–3). These cysts are covered with ciliary columnar epithelium and connected with the trachea (4). The majority of PTACs are reported as tracheal diverticula in the literature, due to their connection with the trachea (2). The thoracic inlet between the cartilage and muscle layers in right posterolateral wall of the trachea is the most common location for PTACs. A relationship may be seen between an isolated PTAC and the trachea l lumen (5). These lesions may cause recurrent infections by acting as a reservoir for secretions.Occasionally, PTACs can be confused with other causes of extraluminal air collections as laryngocele, pharyngocele, Zenker’s diverticulum, apical hernia of the lung, mediastinal air, apical paraseptal blebs, or bullae. To distinguish PTACs from other pathologies, its typical location in the right posterior paratracheal region at the thoracic inlet can be helpful: PTACs locate away from the lung pleura, communicate with the trachea and have rounded margins that can be differentiated from emphysematous changes (6).PTACs are usually discovered incidentally on thorax computed tomography (CT). They may be associated with a chronic cough or chronic obstructive pulmonary diseases (COPD). The reported prevalence of PTACs ranges from 0.75% to 8.1% (4, 6–8). There have been a limited number of studies reporting the incidence of PTACs related to COPD or emphysema as detected by CT, and the reported results are variable (4, 6, 8–11). The relationship between PTACs and pulmonary emphysema or bronchiectasis is still unclear. To our knowledge, no published study has evaluated the relationship between PTACs and bronchiectasis, using a bronchiectasis severity index and objective measures to determine the extent of bronchiectasis on CT images.The purpose of our study was to evaluate the prevalence and characteristics of PTACs, as well as their relationship with bronchiectasis and emphysema, on thorax CT scans.     

sparse inflorescence1 encodes a monocot-specific YUCCA-like gene required for vegetative and reproductive development in maize

The plant growth hormone auxin plays a critical role in the initiation of lateral organs and meristems. Here, we identify and characterize a mutant, sparse inflorescence1 (spi1), which has defects in the initiation of axillary meristems and lateral organs during vegetative and inflorescence development in maize. Positional cloning shows that spi1 encodes a flavin monooxygenase similar to the YUCCA (YUC) genes of Arabidopsis, which are involved in local auxin biosynthesis in various plant tissues. In Arabidopsis, loss of function of single members of the YUC family has no obvious effect, but in maize the mutation of a single yuc locus causes severe developmental defects. Phylogenetic analysis of the different members of the YUC family in moss, monocot, and eudicot species shows that there have been independent expansions of the family in monocots and eudicots. spi1 belongs to a monocot-specific clade, within which the role of individual YUC genes has diversified. These observations, together with expression and functional data, suggest that spi1 has evolved a dominant role in auxin biosynthesis that is essential for normal maize inflorescence development. Analysis of the interaction between spi1 and genes regulating auxin transport indicate that auxin transport and biosynthesis function synergistically to regulate the formation of axillary meristems and lateral organs in maize.     

Evaluation of salivary total oxidant-antioxidant status and DNA damage of children undergoing fixed orthodontic therapy

Objective:To determine the total oxidant status (TOS), total antioxidant status (TAS), and the 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels and their interrelationship in the saliva of children undergoing fixed orthodontic therapy.Materials and Methods:Thirty children were randomly divided into three groups. The attachments were bonded to all of the teeth using three different orthodontic composites: Transbond XT, Kurasper F, and GrenGloo. The salivary levels of TOS, TAS, and 8-OHdG were determined three times, as follows: before treatment (T₁) and at 1 month (T₂) and 3 months (T₃) following appliance placement. All data were statistically analyzed.Results:There were no significant differences in TOS, TAS, and 8-OHdG within the same time periods among the three different orthodontic composites (P > .05). TAS in all composite groups decreased over time. These decreases were found to be significant for Kurasper F and GrenGloo at the T₁–T₃ and T₂–T₃ time periods (P < .05). In all composite groups 8-OHdG decreased between T₁ and T₂ (P < .05). However, 8-OHdG in all composite groups increased from T₂ to T₃. These differences in 8-OHdG were significant in Kurasper F and GrenGloo (P < .05).Conclusions:Fixed orthodontic appliances bonded with the tested composites did not increase the cytotoxicity markers in saliva.     

The effects of aquatic,isometric strength-stretching and aerobic exercise on physical and psychological parameters of female patients with fibromyalgia syndrome

[Purpose] There are various treatment modalities for fibromyalgia syndrome (FMS), which is characterized by widespread pain and fatigue. The aim of this study was to investigate the effects of aquatic, aerobic and isometric strength-stretching exercises on the physical and psychological parameters of patients with FMS. [Subjects and Methods] Seventy five female patients with FMS were randomly selected and divided into three groups. Patients (18–50 years) were treated for 3 months using one of three methods: a home-based isometric strength and stretching exercise program (ISSEP), a gym-based aerobic exercise program (AEP), and a pool-based aquatic aerobic exercise program (AAEP). Items evaluated were: the number of tender points, Visual Analog Scale (VAS), Fibromyalgia Impact Questionnaire (FIQ), the Six-Minute Walk Test (6MWT), SF-36 physical and mental health scores, and the Beck Depression Inventory (BDI). [Results] The results revealed that AAEP was the most effective treatment of the three. All of the groups showed significant improvements in all variables between pre-and post-test, except the mean values of VAS and BDI in ISSEP. [Conclusion] The results suggest that aquatic aerobic exercise program is more effective than AEP and ISSEP in the treatment of FMS.Key words: Fibromyalgia, Exercise, Treatment     

A new silent germline mutation of the TSH receptor: coexpression in a hyperthyroid family member with a second activating somatic mutation.

BACKGROUND: Up to date, three thyroid-stimulating hormone receptor (TSHR) germline variants have been reported for which no functional consequences have been detected by in vitro characterizations. However, familial nonautoimmune hyperthyroidism and hot nodules are clearly associated with constitutively activating TSHR germline mutations. We describe a family with a new TSHR germline mutation that is associated with euthyroidism in 13 family members and hyperthyroidism in 1 family member. METHODS: Mutation analysis of the TSHR gene was performed by denaturing gradient gel electrophoresis. TSHR constructs were characterized by determination of cell surface expression, 3'-5'-cyclic adenosine monophosphate (cAMP) accumulation, and constitutive cAMP activity. RESULTS: A novel TSHR germline mutation (N372T) was found in a man who presented with thyrotoxicosis. The mutation was also detected in 13 family members, all of whom were euthyroid. Interestingly, an additional constitutively active somatic mutation (S281N) was identified on the second parental TSHR allele of the hyperthyroid index patient. Linear regression analysis showed a lack of constitutive activity for N372T. Moreover, coexpression studies of N372T with S281N did not reveal any evidence for a functional influence of N372T on the constitutively active mutation (CAM). CONCLUSIONS: N372T is unlikely to cause altered thyroid function. This is consistent with the finding that only the index patient with the additional somatic mutation S281N was hyperthyroid.