Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade

KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers.     

Student feedback on the use of paintings in Sparshanam,the Medical Humanities module at KIST Medical College,Nepal

Background  

Paintings have been used in Medical Humanities modules in Nepal at Manipal College of Medical Sciences and KIST Medical College. Detailed participant feedback about the paintings used, the activities carried out, problems with using paintings and the role of paintings in future modules has not been previously done. Hence the present study was carried out.     

Spatial control of adult stem cell fate using nanotopographic cues

Adult stem cells hold great promise as a source of diverse terminally differentiated cell types for tissue engineering applications. However, due to the complexity of chemical and mechanical cues specifying differentiation outcomes, development of arbitrarily complex geometric and structural arrangements of cells, adopting multiple fates from the same initial stem cell population, has been difficult. Here, we show that the topography of the cell adhesion substratum can be an instructive cue to adult stem cells and topographical variations can strongly bias the differentiation outcome of the cells towards adipocyte or osteocyte fates. Switches in cell fate decision from adipogenic to osteogenic lineages were accompanied by changes in cytoskeletal stiffness, spanning a considerable range in the cell softness/rigidity spectrum. Our findings suggest that human mesenchymal stem cells (hMSC) can respond to the varying density of nanotopographical cues by regulating their internal cytoskeletal network and use these mechanical changes to guide them toward making cell fate decisions. We used this finding to design a complex two-dimensional pattern of co-localized cells preferentially adopting two alternative fates, thus paving the road for designing and building more complex tissue constructs with diverse biomedical applications.     

Hypoxia-inducible factor–dependent breast cancer–mesenchymal stem cell bidirectional signaling promotes metastasis

Metastasis involves critical interactions between cancer and stromal cells. Intratumoral hypoxia promotes metastasis through activation of hypoxia-inducible factors (HIFs). We demonstrate that HIFs mediate paracrine signaling between breast cancer cells (BCCs) and mesenchymal stem cells (MSCs) to promote metastasis. In a mouse orthotopic implantation model, MSCs were recruited to primary breast tumors and promoted BCC metastasis to LNs and lungs in a HIF-dependent manner. Coculture of MSCs with BCCs augmented HIF activity in BCCs. Additionally, coculture induced expression of the chemokine CXCL10 in MSCs and the cognate receptor CXCR3 in BCCs, which was augmented by hypoxia. CXCR3 expression was blocked in cocultures treated with neutralizing antibody against CXCL10. Conversely, CXCL10 expression was blocked in MSCs cocultured with BCCs that did not express CXCR3 or HIFs. MSC coculture did not enhance the metastasis of HIF-deficient BCCs. BCCs and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGFR1, respectively, in a HIF-dependent manner, and CXCL10 expression by MSCs was dependent on PGF expression by BCCs. PGF promoted metastasis of BCCs and also facilitated homing of MSCs to tumors. Thus, HIFs mediate complex and bidirectional paracrine signaling between BCCs and MSCs that stimulates breast cancer metastasis.     

Retinal Neovascularisation in Susac Syndrome: A Rare Complication

Purpose: To report a case of Susac syndrome with ocular complications in the chronic stage of the disease. Methods: Case report. Results: A 37-year-old male patient of Indian origin presented with painless blurring of vision in the right eye. Ophthalmoscopic examination revealed vitreous hemorrhage in the right eye and NVE in both eyes well-documented angiographically. Old medical records revealed a previous attack of bilateral BRAO as a complete triad of Susac syndrome 10 years before, with an uncomplicated clinical course. Panretinal photocoagulation helped in stabilization of the condition.

Conclusion: Ocular neovascularisation like NVE with vitreous hemorrhage can be a late manifestation of occlusive arteriolitis in Susac syndrome.     

Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia

Ischemia induces the production of angiogenic cytokines and the homing of bone-marrow-derived angiogenic cells (BMDACs), but these adaptive responses become impaired with aging because of reduced expression of hypoxia-inducible factor (HIF)-1α. In this study, we analyzed the effect of augmenting HIF-1α levels in ischemic limb by intramuscular injection of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, and intravenous administration of BMDACs that were cultured in the presence of the prolyl-4-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to induce HIF-1 expression. The combined therapy increased perfusion, motor function, and limb salvage in old mice subjected to femoral artery ligation. Homing of BMDACs to the ischemic limb was dramatically enhanced by intramuscular AdCA5 administration. DMOG treatment of BMDACs increased cell surface expression of β₂ integrins, which mediated increased adherence of BMDACs to endothelial cells. The effect of DMOG was abolished by coadministration of the HIF-1 inhibitor digoxin or by preincubation with a β₂ integrin-blocking antibody. Transduction of BMDACs with lentivirus LvCA5 induced effects similar to DMOG treatment. Thus, HIF-1α gene therapy increases homing of BMDACs to ischemic muscle, whereas HIF-1 induction in BMDACs enhances their adhesion to vascular endothelium, leading to synergistic effects of combined therapy on tissue perfusion.     

Different as night and day: Patterns of isolated seizures,clusters, and status epilepticus

Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient‐reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed‐effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions. In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36‐1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34‐1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79‐0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26‐1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44‐1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05‐1.39). With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults.