Early detection of lung cancer using artificial intelligence-enhanced optical nanosensing of chromatin alterations in field carcinogenesis.

Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).

Measures of Information Content during Anesthesia and Emergence in the Caenorhabditis elegans Nervous System.

BACKGROUND: Suppression of behavioral and physical responses defines the anesthetized state. This is accompanied, in humans, by characteristic changes in electroencephalogram patterns. However, these measures reveal little about the neuron or circuit-level physiologic action of anesthetics nor how information is trafficked between neurons. This study assessed whether entropy-based metrics can differentiate between the awake and anesthetized state in Caenorhabditis elegans and characterize emergence from anesthesia at the level of interneuronal communication. METHODS: Volumetric fluorescence imaging measured neuronal activity across a large portion of the C. elegans nervous system at cellular resolution during distinct states of isoflurane anesthesia, as well as during emergence from the anesthetized state. Using a generalized model of interneuronal communication, new entropy metrics were empirically derived that can distinguish the awake and anesthetized states. RESULTS: This study derived three new entropy-based metrics that distinguish between stable awake and anesthetized states (isoflurane, n = 10) while possessing plausible physiologic interpretations. State decoupling is elevated in the anesthetized state (0%: 48.8 ± 3.50%; 4%: 66.9 ± 6.08%; 8%: 65.1 ± 5.16%; 0% vs. 4%, P < 0.001; 0% vs. 8%, P < 0.001), while internal predictability (0%: 46.0 ± 2.94%; 4%: 27.7 ± 5.13%; 8%: 30.5 ± 4.56%; 0% vs. 4%, P < 0.001; 0% vs. 8%, P < 0.001), and system consistency (0%: 2.64 ± 1.27%; 4%: 0.97 ± 1.38%; 8%: 1.14 ± 0.47%; 0% vs. 4%, P = 0.006; 0% vs. 8%, P = 0.015) are suppressed. These new metrics also resolve to baseline during gradual emergence of C. elegans from moderate levels of anesthesia to the awake state (n = 8). The results of this study show that early emergence from isoflurane anesthesia in C. elegans is characterized by the rapid resolution of an elevation in high frequency activity (n = 8, P = 0.032). The entropy-based metrics mutual information and transfer entropy, however, did not differentiate well between the awake and anesthetized states. CONCLUSIONS: Novel empirically derived entropy metrics better distinguish the awake and anesthetized states compared to extant metrics and reveal meaningful differences in information transfer characteristics between states.

Prospective use of descriptors of dyspnea to diagnose common respiratory diseases.

BACKGROUND: Although patients may find it difficult to describe their breathing discomfort, most are able to select statements among a list to describe their experience. The primary objective of this study was to examine sensitivity and specificity of descriptors of breathing discomfort prospectively in patients with common respiratory conditions as well as those patients who had refractory dyspnea. METHODS: Outpatients answered "Yes" or "No" for each of 15 statements describing breathing discomfort, next selected the best three that most closely applied, and then completed the Hospital Anxiety Depression Scale-Anxiety subscale. Sensitivity, specificity, and predictive values were calculated for the descriptors by diagnosis. RESULTS: "Work/effort" descriptors were selected as the best three by patients with COPD (n = 68), respiratory muscle weakness (n = 11), and refractory dyspnea (n = 17). Along with "work/effort" descriptors, "My chest feels tight" was among the best three in asthma (n = 22), with 38% sensitivity and 88% specificity. Along with "work/effort" descriptors, "My breathing is shallow" was among the best three in interstitial lung disease (n = 8), with 33% sensitivity and 84% specificity. Affective descriptors "frightening" (61% vs 31%, P = .002) and "awful" (66% vs 37%, P = .004) were reported more frequently in those with high anxiety scores compared with low anxiety scores. CONCLUSIONS: Although no descriptor achieved satisfactory sensitivity and specificity for identifying a particular condition, chest "tightness" was unique for asthma, whereas "shallow breathing" was unique for interstitial lung disease. Affective descriptors were associated with high anxiety scores.

Antagonism of substance P and perception of breathlessness in patients with chronic obstructive pulmonary disease.

The objective of this study was to investigate whether substance P, an excitatory neuropeptide, modulates the perception of breathlessness by administering aprepitant, a selective antagonist that blocks neurokinin (NK)-1 receptor signaling. Individual targeted resistive load breathing (RLB) was used to provoke breathlessness. In Study 1, sixteen patients (age, 70±6 years) with chronic obstructive pulmonary disease (COPD) reported similar ratings of breathlessness during RLB between oral aprepitant (125mg) and placebo. After aprepitant, but not with placebo, there were significant increases in blood levels of substance P (+54±39%) and beta-endorphin (+27±17%). A similar design was used in Study 2 except that naloxone (10mg) was administered intravenously prior to RLB to block any effect of endogenous opioids. Nine patients with COPD reported comparable breathlessness ratings during RLB between aprepitant and placebo. Our results do not support a role for the substance P-NK-1 pathway in the perception of breathlessness in patients with COPD. With selective antagonism of NK-1 signaling, there was co-transmission of substance P and beta-endorphin neuropeptides.