Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy

Background Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions. Methods In this report, coactivated abnormal levels of signaling activity for c-Met and HER family receptors in live tumor cells were measured by a new clinical test to identify a subpopulation of breast cancer patients that could be responsive to combined targeted therapies. The CELsignia Multi-Pathway Signaling Function (CELsignia) Test uses an impedance biosensor to quantify an individual patient’s ex vivo live tumor cell signaling response in real-time to specific HER family and c-Met co-stimulation and targeted therapies. Results The test identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met coordinated signaling that express otherwise normal amounts of these receptors. The supporting data of the pre-clinical verification of this test included analyses of 79 breast cancer patients’ cell response to HER and c-Met agonists. The signaling results were confirmed using clinically approved matching targeted drugs, and combinations of targeted drugs in addition to correlative mouse xenograft tumor response to HER and c-Met targeted therapies. Conclusions The results of this study demonstrated the potential benefit of a functional test for identifying a subpopulation of breast cancer patients with coordinated abnormal HER and c-Met signaling for a clinical trial testing combination targeted therapy.

Dysregulated Cell Signaling in Pulmonary Emphysema

Pulmonary emphysema is characterized by the destruction of alveolar septa and irreversible airflow limitation. Cigarette smoking is the primary cause of this disease development. It induces oxidative stress and disturbs lung physiology and tissue homeostasis. Alveolar type II (ATII) cells have stem cell potential and can repair the denuded epithelium after injury; however, their dysfunction is evident in emphysema. There is no effective treatment available for this disease. Challenges in this field involve the large complexity of lung pathophysiological processes and gaps in our knowledge on the mechanisms of emphysema progression. It implicates dysregulation of various signaling pathways, including aberrant inflammatory and oxidative responses, defective antioxidant defense system, surfactant dysfunction, altered proteostasis, disrupted circadian rhythms, mitochondrial damage, increased cell senescence, apoptosis, and abnormal proliferation and differentiation. Also, genetic predispositions are involved in this disease development. Here, we comprehensively review studies regarding dysregulated cell signaling, especially in ATII cells, and their contribution to alveolar wall destruction in emphysema. Relevant preclinical and clinical interventions are also described.

Engineering Bacterial Surface Interactions Using DNA as a Programmable Material

The diverse surface interactions and functions of a bacterium play an important role in cell signaling, host infection, and colony formation. To understand and synthetically control biological functions of individual...

Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology—for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.

Effect of different concentrations of lithium chloride on p-GSK-3β content in a model of ischemic stroke

Введение. В современном мире проблема инсультов постепенно выходит на лидирующие позиции. Отсутствие эффективных медикаментозных методов коррекции острого нарушения мозгового кровообращения приводит к необходимости поиска новых препаратов с нейропротекторным потенциалом, способных если не предотвратить, то значимо минимизировать последствия и тяжесть ишемического инсульта. Цель исследования - оценка влияния различных доз хлорида лития на фосфорилирование GSK-3β и выживаемость животных на модели ишемического инсульта. Методика. В исследовании были использованы беспородные крысы - самцы, разделённые на 5 групп: ложнооперированные (n=9), контрольная группа (ишемический инсульт с введением раствора NaCl 0,9% в объеме, эквивалентном вводимым лекарственным средствам в других группах, n=5), и группы с введением хлорида лития в дозах 4,2 мг/кг (n=5), 21 мг/кг (n=5) и 63 мг/кг (n=5). Ишемический инсульт моделировали по методу Лонга. По истечении 7 сут от начала эксперимента животные подвергались гуманной эвтаназии с извлечением головного мозга и дальнейшим определением уровня фосфорилированной формы GSK-3β (p-GSK-3β) методом вестерн-блоттинга. Нейропротекторный эффект солей лития реализуется благодаря прямому ингибированию ключевой киназы аптотического механизма клеточной сигнализации - гликоген-синтазы киназы-3β (GSK-3β) с переводом её в фосфорилированую форму (p-GSK-3β). На 7-е сут также был проведен анализ показателей летальности в группах. Для множественных сравнений рассчитывали критический уровень значимости при использовании поправки Бонферрони. Результат. Хлорид лития в дозе 4,2 мг/кг оказывал минимальное влияние как на уровень p-GSK-3β (p=0,8), так и на летальность по отношению к контрольной группе (p>0,017). Доза 21 мг/кг, в свою очередь, значимо повышала уровень p-GSK-3β (p=0,008), но не снижала летальность (p>0,017) по отношению к группе контроля. При использовании дозировки 63 мг/кг уровень p-GSK-3β был максимально приближен к группе ложнооперированных животных (p=0,007), а летальность на 7 сут была значимо ниже (p>0,017). Заключение. Хлорид лития обладает отчётливым дозозависимым нейропротекторным эффектом. Нейропротекторный эффект солей лития реализуется благодаря прямому ингибированию ключевой киназы аптотического механизма клеточной сигнализации - гликоген-синтазы киназы-3β (GSK-3β) с переводом её в фосфорилированую форму (p-GSK-3β) Реализация нейропротекторного эффекта данного препарата потенциально способна улучшить прогнозы течения ишемического инсульта. Background. Ischemic stroke is becoming a major medical concern worldwide. Reasons for this include the aging population, which experiences an increasing frequency of cardiovascular problems. Additionally, social factors, e.g., smoking, fatigue, substance abuse, lead to strokes in young and middle-aged people. The lack of effective medical methods for correcting acute cerebral circulatory disorders underscores the need for new drugs whose neuroprotective potential can prevent or significantly minimize the consequences and severity of ischemic stroke. Aim. To evaluate the effect of different doses of lithium chloride on GSK-3ß phosphorylation and on animal survival in a model of ischemic stroke. Methods. 29 male rats were divided into five groups: Sham-operated (n=9); control, ischemic stroke with administration of a volume of 0.9% NaCl solution equivalent to the volume of the administered drugs in other groups (n=5); and groups with administration of lithium chloride at doses of 4.2 mg/kg (n=5), 21 mg/kg (n=5), and 63 mg/kg (n=5). Ischemic stroke was produced by the Long method. After 7 days, the animals were subjected to humane euthanasia. The brain was excised, and the phosphorylated form of GSK-3β (p-GSK-3β) was measured by Western blotting. The neuroprotective effect of lithium salts occurs due to a direct inhibition of the key kinase of the apoptotic mechanism of cell signaling, glycogen-synthase kinase (GSK-3β), that is transformed into a phosphorylated form. Also, the group mortality rates were analyzed on day 7. For multiple comparisons, a critical level of significance was calculated using the Bonferroni correction. Results. Lithium chloride, 4.2 mg/kg, had a minimal effect on both p-GSK-3ß (p=0.8) and mortality compared to the control group (p>0.017). A dose of 21 mg/kg significantly increased p-GSK-3ß (p=0.008), but did not reduce mortality (p>0.017), relative to the control group. At a dose of 63 mg/kg, p-GSK-3ß was similar to that of the sham operated animals (p=0.007), and the mortality on day 7 was significantly lower (p>0.017). Conclusion. Lithium chloride produces a dose-dependent, neuroprotective effect. This protective effect occurs due to a direct inhibition of the key kinase of the apoptotic mechanism of cell signaling, glycogen-synthase kinase (GSK-3β), that is transformed into a phosphorylated form. This neuroprotection is potentially able to improve the prognosis of ischemic stroke.