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Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse.

Rett syndrome (RTT, OMIM 312750), a severe neurodevelopmental disorder characterized by regression with loss of spoken language and hand skills, development of characteristic hand stereotypies, and gait dysfunction, is primarily caused by de novo mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2). Currently, treatment options are limited to symptomatic management, however, reversal of disease phenotype is possible in mouse models by restoration of normal MECP2 gene expression. A significant challenge is the lack of biomarkers of disease state, disease severity, or treatment response. Using a non-targeted metabolomic approach we evaluated metabolite profiles in plasma from thirty-four people with RTT compared to thirty-seven unaffected age- and gender-matched siblings. We identified sixty-six significantly altered metabolites that cluster broadly into amino acid, nitrogen handling, and exogenous substance pathways. RTT disease metabolite and metabolic pathways abnormalities point to evidence of oxidative stress, mitochondrial dysfunction, and alterations in gut microflora. These observed changes provide insight into underlying pathological mechanisms and the foundation for biomarker discovery of disease severity biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT, OMIM 312750), a severe neurodevelopmental disorder characterized by regression with loss of spoken language and hand skills, development of characteristic hand stereotypies, and gait dysfunction, is primarily caused by de novo mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2). Currently, treatment options are limited to symptomatic management, however, reversal of disease phenotype is possible in mouse models by restoration of normal MECP2 gene expression. A significant challenge is the lack of biomarkers of disease state, disease severity, or treatment response. Using a non-targeted metabolomic approach we evaluated metabolite profiles in plasma from thirty-four people with RTT compared to thirty-seven unaffected age- and gender-matched siblings. We identified sixty-six significantly altered metabolites that cluster broadly into amino acid, nitrogen handling, and exogenous substance pathways. RTT disease metabolite and metabolic pathways abnormalities point to evidence of oxidative stress, mitochondrial dysfunction, and alterations in gut microflora. These observed changes provide insight into underlying pathological mechanisms and the foundation for biomarker discovery of disease severity biomarkers. [ABSTRACT FROM AUTHOR]

Epilepsy is associated with numerous neurodevelopmental disorders. Transcranial magnetic stimulation (TMS) of the motor cortex coupled with electromyography (EMG) enables biomarkers that provide measures of cortical excitation and inhibition that are particularly relevant to epilepsy and related disorders. The motor threshold (MT), cortical silent period (CSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) are among TMS-derived metrics that are modulated by antiepileptic drugs. TMS may have a practical role in optimization of antiepileptic medication regimens, as studies demonstrate dose-dependent relationships between TMS metrics and acute medication administration. A close association between seizure freedom and normalization of cortical excitability with long-term antiepileptic drug use highlights a plausible utility of TMS in measures of anti-epileptic drug efficacy. Finally, TMS-derived biomarkers distinguish patients with various epilepsies from healthy controls and thus may enable development of disorder-specific biomarkers and therapies both within and outside of the epilepsy realm.

Leukocytosis is a common feature of malignancies. While controversial, there appears to be an association between the degree of tumor-related leukocytosis and prognosis. In this paper, we provide evidence supporting an untapped clinical paradigm linking G-CSF secretion to the induction of leukocytosis and expansion of myeloid-derived suppressor cells, providing an explanation for the association between leukocytosis, elevated neutrophil-to-lymphocyte ratios and prognosis in non-small cell lung cancer. Clinically validating this mechanism may identify MDSCs and G-CSF as dynamic markers of early disease progression and therapeutic response, and shed light onto novel therapeutic avenues for the treatment of patients with non-small cell lung cancer.

The term microbiome describes the genetic material encoding the various microbial populations that inhabit our body. Whilst colonization of various body niches (e.g., the gut) by dynamic communities of microorganisms is now universally accepted, the existence of microbial populations in other “classically sterile” locations, including the blood, is a relatively new concept. The presence of bacteria-specific DNA in the blood has been reported in the literature for some time, yet the true origin of this is still the subject of much deliberation. The aim of this study was to investigate the phenomenon of a “blood microbiome” by providing a comprehensive description of bacterially derived nucleic acids using a range of complementary molecular and classical microbiological techniques. For this purpose we utilized a set of plasma samples from healthy subjects (n = 5) and asthmatic subjects (n = 5). DNA-level analyses involved the amplification and sequencing of the 16S rRNA gene. RNA-level analyses were based upon the de novo assembly of unmapped mRNA reads and subsequent taxonomic identification. Molecular studies were complemented by viability data from classical aerobic and anaerobic microbial culture experiments. At the phylum level, the blood microbiome was predominated by Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. The key phyla detected were consistent irrespective of molecular method (DNA vs. RNA), and consistent with the results of other published studies. In silico comparison of our data with that of the Human Microbiome Project revealed that members of the blood microbiome were most likely to have originated from the oral or skin communities. To our surprise, aerobic and anaerobic cultures were positive in eight of out the ten donor samples investigated, and we reflect upon their source. Our data provide further evidence of a core blood microbiome, and provide insight into the potential source of the bacterial DNA/RNA detected in the blood. Further, data reveal the importance of robust experimental procedures, and identify areas for future consideration.

Epilepsy is associated with numerous neurodevelopmental disorders. Transcranial magnetic stimulation (TMS) of the motor cortex coupled with electromyography (EMG) enables biomarkers that provide measures of cortical excitation and inhibition that are particularly relevant to epilepsy and related disorders. The motor threshold (MT), cortical silent period (CSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) are among TMS-derived metrics that are modulated by antiepileptic drugs. TMS may have a practical role in optimization of antiepileptic medication regimens, as studies demonstrate dose-dependent relationships between TMS metrics and acute medication administration. A close association between seizure freedom and normalization of cortical excitability with long-term antiepileptic drug use highlights a plausible utility of TMS in measures of anti-epileptic drug efficacy. Finally, TMS-derived biomarkers distinguish patients with various epilepsies from healthy controls and thus may enable development of disorder-specific biomarkers and therapies both within and outside of the epilepsy realm. [ABSTRACT FROM AUTHOR]

The term microbiome describes the genetic material encoding the various microbial populations that inhabit our body. Whilst colonization of various body niches (e.g., the gut) by dynamic communities of microorganisms is now universally accepted, the existence of microbial populations in other "classically sterile" locations, including the blood, is a relatively new concept. The presence of bacteria-specific DNA in the blood has been reported in the literature for some time, yet the true origin of this is still the subject of much deliberation. The aim of this study was to investigate the phenomenon of a "blood microbiome" by providing a comprehensive description of bacterially derived nucleic acids using a range of complementary molecular and classical microbiological techniques. For this purpose we utilized a set of plasma samples from healthy subjects (n = 5) and asthmatic subjects (n = 5). DNA-level analyses involved the amplification and sequencing of the 16S rRNA gene. RNA-level analyses were based upon the de novo assembly of unmapped mRNA reads and subsequent taxonomic identification. Molecular studies were complemented by viability data from classical aerobic and anaerobic microbial culture experiments. At the phylum level, the blood microbiome was predominated by Proteobacteria , Actinobacteria , Firmicutes , and Bacteroidetes. The key phyla detected were consistent irrespective of molecular method (DNA vs. RNA), and consistent with the results of other published studies. In silico comparison of our data with that of the Human Microbiome Project revealed that members of the blood microbiome were most likely to have originated from the oral or skin communities. To our surprise, aerobic and anaerobic cultures were positive in eight of out the ten donor samples investigated, and we reflect upon their source. Our data provide further evidence of a core blood microbiome, and provide insight into the potential source of the bacterial DNA/RNA detected in the blood. Further, data reveal the importance of robust experimental procedures, and identify areas for future consideration. [ABSTRACT FROM AUTHOR]

Assessing progression of disease or response to treatment remains a major challenge in the clinical management of nontuberculous mycobacterial (NTM) infections of the lungs. Serial assessments of validated measures of treatment response address whether the current therapeutic approach is on track toward clinical cure, which remains a fundamental question for clinicians and patients during the course of NTM disease treatment. The 2015 NTM Research Consortium Workshop, which included a patient advisory panel, identified treatment response biomarkers as a priority area for investigation. Limited progress in addressing this challenge also hampers drug development efforts. The Biomarker Qualification Program at the FDA supports the use of a validated treatment response biomarker across multiple drug development programs. Current approaches in clinical practice include microbiologic and radiographic monitoring, along with symptomatic and quality-of-life assessments. Blood-based monitoring, including assessments of humoral and cell-mediated NTM-driven immune responses, remain under investigation. Alignment of data collection schemes in prospective multicenter studies, including the support of biosample repositories, will support identification of treatment response biomarkers under standard-of-care and investigational therapeutic strategies. In this review, we outline the role of treatment monitoring biomarkers in both clinical practice and drug development frameworks.

Assessing progression of disease or response to treatment remains a major challenge in the clinical management of nontuberculous mycobacterial (NTM) infections of the lungs. Serial assessments of validated measures of treatment response address whether the current therapeutic approach is on track toward clinical cure, which remains a fundamental question for clinicians and patients during the course of NTM disease treatment. The 2015 NTM Research Consortium Workshop, which included a patient advisory panel, identified treatment response biomarkers as a priority area for investigation. Limited progress in addressing this challenge also hampers drug development efforts. The Biomarker Qualification Program at the FDA supports the use of a validated treatment response biomarker across multiple drug development programs. Current approaches in clinical practice include microbiologic and radiographic monitoring, along with symptomatic and quality-of-life assessments. Blood-based monitoring, including assessments of humoral and cell-mediated NTM-driven immune responses, remain under investigation. Alignment of data collection schemes in prospective multicenter studies, including the support of biosample repositories, will support identification of treatment response biomarkers under standard-of-care and investigational therapeutic strategies. In this review, we outline the role of treatment monitoring biomarkers in both clinical practice and drug development frameworks. [ABSTRACT FROM AUTHOR]

Leukocytosis is a common feature of malignancies. While controversial, there appears to be an association between the degree of tumor-related leukocytosis and prognosis. In this paper, we provide evidence supporting an untapped clinical paradigm linking G-CSF secretion to the induction of leukocytosis and expansion of myeloid-derived suppressor cells, providing an explanation for the association between leukocytosis, elevated neutrophil-to-lymphocyte ratios and prognosis in non-small cell lung cancer. Clinically validating this mechanism may identify MDSCs and G-CSF as dynamic markers of early disease progression and therapeutic response, and shed light onto novel therapeutic avenues for the treatment of patients with non-small cell lung cancer.