Regulation and Function of Neuronal Nicotinic Acetylcholine Receptors in Lung Cancer: A Dissertation

Lung cancer is the leading cause of cancer-related mortality worldwide. The main risk factor associated with lung cancer is cigarette smoking. Research through the years suggests that nicotine in cigarettes promotes lung cancer by activating signaling pathways that lead to cell proliferation, cell survival, angiogenesis, and metastasis. Nicotine’s cellular actions are mediated by its cognate receptors, nicotinic acetylcholine receptors (nAChRs). Here, I describe the expression levels of all known human nAChR subunit genes in both normal and lung cancer cells. Of note, the genes encoding the α5, α3, and β4 subunits (CHRNA5/A3/B4) are over-expressed in small cell lung carcinoma (SCLC), the most aggressive form of lung cancer. This over-expression is regulated by ASCL1, a transcription factor important in normal lung development and lung carcinogenesis. The CHRNA5/A3/B4 locus has recently been the focus of a series of genetic studies showing that polymorphisms in this region confer risk for both nicotine dependence and lung cancer. I show that CHRNA5/A3/B4 depletion results in decreased SCLC cell viability. Furthermore, while nicotine promotes SCLC cell viability and tumor growth, blockade of α3β4 nAChRs inhibits SCLC cell viability. These results suggest that increased expression and function of nAChRs, specifically the α3β4α5 subtype, potentiate the effects of nicotine in SCLC. This dual hit from the carcinogens in tobacco and the cancer-promoting effects of nicotine, may provide a possible mechanism for the increased aggressiveness of SCLC. In addition, nAChRs can be activated by the endogenous ligand, acetylcholine, which acts as an autocrine/paracrine growth factor in SCLC. Increased function of α3β4α5 nAChRs in SCLC could also potentiate acetylcholine’s mitogenic effects. This mechanism, combined with other known autocrine/paracrine growth loops in SCLC, may help explain the ineffectiveness of available therapies against SCLC. In an effort to add to the current arsenal against SCLC, I screened a 1280-compund library using a bioluminescence-based viability assay I developed for high-throughput applications. Primary screening, followed by secondary and tertiary verification, indicate that pharmacologically active compounds targeting neuroendocrine markers inhibit SCLC cell viability

Preservice Teachers as Extra Milers: Lived Experiences in Teaching Emergent Literacy and Numeracy in an Online Radio Program

The present study explored preservice teachers’ lived experiences in teaching emergent literacy and numeracy in an online radio program of a Philippine elementary public school to fill a lacuna in online practicum experiences. Utilizing phenomenology as a methodological framework, preservice teachers’ firsthand experiences as online radio teachers were explored to acquire a better grasp of what they went through in developing their learners’ emergent literacy and numeracy skills. The finding of this study revealed three themes that underscored three stages of their practicum experiences: (1) Tuning In, (2) From AM to FM, and (3) Don’t Switch the Channel. The essence of their lived experiences offered insights that they are extra milers suggesting that their online practicum journey is a fulfilling yet challenging accountability for personal, professional, and institutional growth. The study offers policy recommendations for strengthening technology integration in teacher education programs and institutionalization of teacher educators’ technopedagogical knowledge and skills, redounding to knowledge and skills development of preservice teachers

Stuck in a Lockdown: Filipino Students' Odyssey of Resilience

The COVID-19 outbreak in the Philippines forced schools to close. Many Filipino students were stranded in their dormitories and boarding houses due to government-imposed lockdowns. As the study's impetus, the researchers explored the phenomenon of stranded students during a pandemic. A transcendental phenomenological inquiry was conducted in Northern Mindanao, Philippines, to disclose the experiences of six stranded students. Stranded students' lifeworld throughout the lockdown was documented through phenomenological interviews. The phenomenological reduction technique was used to transcribe and analyze the data. Provisional codes were used to classify critical statements into themes for the initial analysis of the interview data. The research revealed the themes of (a) groping in the dark, (b) journeying towards the light, and (c) welcoming the breaking dawn. The various stages of reality in the life of the stranded students are shown in these topics. They relate the story of how their confinement experience taught them to be resilient, which covers resilience as a process. The paper discusses numerous pedagogical implications of the phenomenon

Two Neuronal Nicotinic Acetylcholine Receptors, α4β4 and α7, Show Differential Agonist Binding Modes

Nicotinic acetylcholine receptors (nAChRs) are pentameric, neurotransmitter-gated ion channels responsible for rapid excitatory neurotransmission in the central and peripheral nervous systems, resulting in skeletal muscle tone and various cognitive effects in the brain. These complex proteins are activated by the endogenous neurotransmitter ACh as well as by nicotine and structurally related agonists. Activation and modulation of nAChRs has been implicated in the pathology of multiple neurological disorders, and as such, these proteins are established therapeutic targets. Here we use unnatural amino acid mutagenesis to examine the ligand binding mechanisms of two homologous neuronal nAChRs: the α4β4 and α7 receptors. Despite sequence identity among the residues that form the core of the agonist-binding site, we find that the α4β4 and α7 nAChRs employ different agonist-receptor binding interactions in this region. The α4β4 receptor utilizes a strong cation-π interaction to a conserved tryptophan (TrpB) of the receptor for both ACh and nicotine, and nicotine participates in a strong hydrogen bond with a backbone carbonyl contributed by TrpB. Interestingly, we find that the α7 receptor also employs a cation-π interaction for ligand recognition, but the site has moved to a different aromatic amino acid of the agonist-binding site depending on the agonist. ACh participates in a cation-π interaction with TyrA, whereas epibatidine participates in a cation-π interaction with TyrC2

Nicotinic acetylcholine receptors mediate lung cancer growth

Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an alpha3beta4-selective antagonist, alpha-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via alpha3/alpha5/beta4-containing nAChRs promotes lung carcinogenesis

Making Sense of Texts: a Meta-Analysis of College Students and Adults' Reading Strategies in a Hypermedia Environment

With the information influx from the hypermedia environment, queries have been made on the reading landscape, markedly related to college and adult readers, as they are perceived to have limited experience with the hypermedia environment. This environment calls on new literacies for a reader to cope with reading tasks inherent to its features. In this context, new challenges have been posed regarding online reading strategies of college and adult readers. With the dearth of literature about how college and adult readers navigate their way in their reading tasks in the hypermedia environment, this paper described their strategies in reading. The information gathered from the studies conducted before can contribute to the present plight of our readers who need to navigate their way through reading in a hypermedia environment. Eight studies that met the criteria on the variables of the study were included. The studies revealed the following reading strategies of college and adult readers: global, problem-solving, local, cognitive and metacognitive, and navigation strategies. This evidenced that print-based reading strategies are basics on which reading strategies in the hypermedia environment are built for strategic readers to be successful in their online reading tasks

Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer

Despite the known adverse health effects associated with tobacco use, over 45 million adults in the United States smoke. Cigarette smoking is the major etiologic factor associated with lung cancer. Cigarettes contain thousands of toxic chemicals, many of which are carcinogenic. Nicotine contributes directly to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels, expressed in both normal and lung cancer cells, which mediate the proliferative, pro-survival, angiogenic, and metastatic effects of nicotine and its nitrosamine derivatives. The underlying molecular mechanisms involve increases in intracellular calcium levels and activation of cancer signal transduction pathways. In addition, acetylcholine (ACh) acts as an autocrine or paracrine growth factor in lung cancer. Other neurotransmitters and neuropeptides also activate similar growth loops. Recent genetic studies further support a role for nAChRs in the development of lung cancer. Several nAChR antagonists have been shown to inhibit lung cancer growth, suggesting that nAChRs may serve as valuable targets for biomarker-guided lung cancer interventions