Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglia (DRGs) neurons via MNK-eIF4E signaling to promote pain sensitization in mice. Activation of stimulator of interferon response cGAMP interactor 1 (STING) signaling is pivotal for type I IFN induction. We hypothesized that vinorelbine, a chemotherapeutic and activator of STING, would cause a neuropathic pain-like state in mice via STING signaling in DRG neurons associated with IFN production. Vinorelbine caused tactile allodynia and grimacing in wild-type (WT) mice and increased p-IRF3, type I IFNs, and p-eIF4E in peripheral nerves. Supporting our hypothesis, vinorelbine failed to induce IRF3-IFNs-MNK-eIF4E in StingGt/Gt mice and, subsequently, failed to cause pain. The vinorelbine-elicited increase of p-eIF4E was not observed in Mknk1-/- (MNK1 knockout) mice in peripheral nerves consistent with the attenuated pro-nociceptive effect of vinorelbine in these mice. Our findings show that activation of STING signaling in the periphery causes a neuropathic pain-like state through type I IFN signaling to DRG nociceptors.

Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes.

Gene expression is influenced by chromatin architecture via controlled access of regulatory factors to DNA. To better understand gene regulation in the human dorsal root ganglion (hDRG) we used bulk and spatial transposase-accessible chromatin technology followed by sequencing (ATAC-seq). Using bulk ATAC-seq, we detected that in females diverse differentially accessible chromatin regions (DARs) mapped to the X chromosome and in males to autosomal genes. EGR1/3 and SP1/4 transcription factor binding motifs were abundant within DARs in females, and JUN, FOS and other AP-1 factors in males. To dissect the open chromatin profile in hDRG neurons, we used spatial ATAC-seq. The neuron cluster showed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in females, and in Ca2+- signaling-related genes in males. Sex differences in transcription factor binding sites in neuron-proximal barcodes were consistent with the trends observed in bulk ATAC-seq data. We validated that EGR1 expression is biased to female hDRG compared to male. Strikingly, XIST, the long-noncoding RNA responsible for X inactivation, hybridization signal was found to be highly dispersed in the female neuronal but not non-neuronal nuclei suggesting weak X inactivation in female hDRG neurons. Our findings point to baseline epigenomic sex differences in the hDRG that likely underlie divergent transcriptional responses that determine mechanistic sex differences in pain.

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female StingGt/Gt mice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in StingGt/Gt or Mknk1-/- (MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.

Assessment of Calibration Models for Cuff-Less Blood Pressure Measurement After One Year of Aging.

OBJECTIVE: Many calibration models for cuff-less blood pressure (BP) measurement must be periodically updated with cuff BP values to account for vascular aging. However, the time period required for these "cuff re-calibrations" is largely unknown. The impact of one year of aging on several calibration models was assessed. METHODS: Ten humans (6 males, 57±18 years, 3 hypertensives) were studied during multiple recording sessions that occurred one year apart. In each session, electrocardiography (ECG), ear photoplethysmography (PPG), finger PPG, and toe PPG waveforms and manual cuff BP were recorded before and after slow breathing, mental arithmetic, cold pressor, and nitroglycerin. Linear models based on each PPG waveform, which were previously shown to offer value in predicting the intervention-induced BP changes in a larger subject cohort, were employed. The model coefficients were determined for each subject via one session, and the fully-defined, subject-specific calibration models were then evaluated in the corresponding subjects via the session one year later. RESULTS: Only a linear model relating toe pulse arrival time (PAT) - time delay between ECG R-wave and toe PPG foot - to systolic BP (SBP) remained useful. After the year, this model changed little on average (root-mean-squared-error (RMSE) = 1.5 mmHg) and predicted the cuff BP values better than the average of the initial cuff BP values of the subject (RMSE = 9.6±0.8 mmHg vs. 12.7±1.0 mmHg; p < 0.05). CONCLUSION: These results suggest annual cuff recalibrations for the toe PAT-SBP model. SIGNIFICANCE: Toe PAT may offer a practical recalibration period that fosters user adherence.

Photoplethysmography Fast Upstroke Time Intervals Can Be Useful Features for Cuff-Less Measurement of Blood Pressure Changes in Humans.

OBJECTIVE: Photoplethysmography (PPG) waveform analysis is being increasingly investigated for continuous, non-invasive, and cuff-less blood pressure (BP) measurement. However, the efficacy of this approach and the useful features and models remain largely unclear. The objectives were to develop easy-to-understand models relating PPG waveform features to BP changes (after a cuff calibration) and to determine their value in BP measurement accuracy. METHODS: The study data comprised finger, toe, and ear PPG waveforms, an ECG waveform, and reference manual cuff BP measurements from 32 human subjects (25% hypertensive) before and after slow breathing, mental arithmetic, cold pressor, and nitroglycerin administration. Stepwise linear regression was employed to create parsimonious models for predicting the intervention-induced BP changes from popular PPG waveform features, pulse arrival time (PAT, time delay between ECG R-wave and PPG foot), and subject demographics. Leave-one-subject-out cross validation was applied to compare the BP change prediction root-mean-squared-errors (RMSEs) of the resulting models to reference models in which PPG waveform features were excluded. RESULTS: Finger b-time (PPG foot to minimum second derivative time interval) and ear "STT" (PPG amplitude divided by maximum derivative), when combined with PAT, reduced the systolic BP change prediction RMSE of reference models by 6-7% (p 0.022). Ear STT together with pulse width reduced the diastolic BP change prediction RMSE of the reference model by 13% (p = 0.003). CONCLUSION: The two PPG fast upstroke time intervals can offer some added value in cuff-less BP trending. SIGNIFICANCE: This study offers important information towards achieving non-invasive and passive BP monitoring without a cuff.

Evaluation of the Accuracy of Cuffless Blood Pressure Measurement Devices: Challenges and Proposals.

Several novel cuffless wearable devices and smartphone applications claiming that they can measure blood pressure (BP) are appearing on the market. These technologies are very attractive and promising, with increasing interest among health care professionals for their potential use. Moreover, they are becoming popular among patients with hypertension and healthy people. However, at the present time, there are serious issues about BP measurement accuracy of cuffless devices and the 2021 European Society of Hypertension Guidelines on BP measurement do not recommend them for clinical use. Cuffless devices have special validation issues, which have been recently recognized. It is important to note that the 2018 Universal Standard for the validation of automated BP measurement devices developed by the American Association for the Advancement of Medical Instrumentation, the European Society of Hypertension, and the International Organization for Standardization is inappropriate for the validation of cuffless devices. Unfortunately, there is an increasing number of publications presenting data on the accuracy of novel cuffless BP measurement devices, with inadequate methodology and potentially misleading conclusions. The objective of this review is to facilitate understanding of the capabilities and limitations of emerging cuffless BP measurement devices. First, the potential and the types of these devices are described. Then, the unique challenges in evaluating the BP measurement accuracy of cuffless devices are explained. Studies from the literature and computer simulations are employed to illustrate these challenges. Finally, proposals are given on how to evaluate cuffless devices including presenting and interpreting relevant study results.

Computational study on cross-talking cancer signalling mechanism of ring finger protein 146, AXIN and Tankyrase protein complex.

Cancer is distinguished by uncontrolled cell growth and it is regulated by several environmental and genetic factors. The Wnt ß-Catenin signaling pathway has been considered as the most significant colon cancer-targeted pathway. AXIN plays a major regulatory role in the Wnt signaling mechanism. The AXIN after PARsylated by TNKS is ubiqutinated by RNF146 through its WWE domain that leads to degradation of AXIN protein. Several studies have been proposed highlighting the inhibition of the PARsylation mechanism that mediates the degradation of AXIN and improves ß-catenin stability. The present study focused on the identification of potential inhibitors for the inhibition of RNF146-TNKS complex through identifying potential RNF146 inhibitors to prevent ubiquitination of AXIN, further to confirm the regulatory role and inhibition mechanism of RNF146-AXIN and RNF146-TNKS. The docked complex was then evaluated using various computational analysis. Molecular interactions analysis was performed to observe the interacting residues between the protein complex. The compounds from various databases were docked with the RNF146 and complex proteins. Both the protein complex and ligand were analyzed for the confirmation of structural stability using molecular dynamics simulations. Selected compounds' atomic configuration and electron profile were analyzed through DFT calculations and ADME/T (Physico-chemical) properties. As a result, we found several common lead compounds for RNF146, TNKS protein inhibition. Therefore, the docked compounds may act as a better antagonist molecule for RNF146, TNKS and associated signaling molecules. Further, experimental validations are required to prove the potency of the identified compounds.Communicated by Ramaswamy H. Sarma.

PPG Sensor Contact Pressure Should Be Taken Into Account for Cuff-Less Blood Pressure Measurement.

OBJECTIVE: Photo-plethysmography (PPG) sensors are often used to detect pulse transit time (PTT) for potential cuff-less blood pressure (BP) measurement. It is known that the contact pressure (CP) of the PPG sensor markedly alters the PPG waveform amplitude. The objective was to test the hypothesis that PTT detected via PPG sensors is likewise impacted by CP. METHODS: A device was built to measure the time delay between ECG and finger PPG waveforms (i.e., pulse arrival time (PAT) - a popular surrogate of PTT) and the PPG sensor CP at different CP levels. These measurements and finger cuff BP were recorded while the CP was slowly varied in 17 healthy subjects. RESULTS: Over a physiologic range of CP, the maximum deviations of PAT detected at the PPG foot and peak were 22±2 and 40±7 ms (p<0.05), which translate to ∼11 and ∼20 mmHg BP error based on the literature. The curve relating PAT detected at the PPG foot to CP was U-shaped with minimum near finger diastolic BP. A conceptual model accounting for finger artery viscoelasticity and nonlinearity explained this curve. CONCLUSION: Since the regulatory bias error for BP measurement is limited to 5 mmHg, PPG sensor CP should be taken into account for cuff-less BP measurement via PTT. SIGNIFICANCE: This study suggests that widely pursued PPG-based BP measurement devices including those that detect PTT should maintain the CP or include a CP measurement in the calibration equation for deriving BP.

Conventional pulse transit times as markers of blood pressure changes in humans.

Pulse transit time (PTT) represents a potential approach for cuff-less blood pressure (BP) monitoring. Conventionally, PTT is determined by (1) measuring (a) ECG and ear, finger, or toe PPG waveforms or (b) two of these PPG waveforms and (2) detecting the time delay between the waveforms. The conventional PTTs (cPTTs) were compared in terms of correlation with BP in humans. Thirty-two volunteers [50% female; 52 (17) (mean (SD)) years; 25% hypertensive] were studied. The four waveforms and manual cuff BP were recorded before and after slow breathing, mental arithmetic, cold pressor, and sublingual nitroglycerin. Six cPTTs were detected as the time delays between the ECG R-wave and ear PPG foot, R-wave and finger PPG foot [finger pulse arrival time (PAT)], R-wave and toe PPG foot (toe PAT), ear and finger PPG feet, ear and toe PPG feet, and finger and toe PPG feet. These time delays were also detected via PPG peaks. The best correlation by a substantial extent was between toe PAT via the PPG foot and systolic BP [- 0.63 ± 0.05 (mean ± SE); p < 0.001 via one-way ANOVA]. Toe PAT is superior to other cPTTs including the popular finger PAT as a marker of changes in BP and systolic BP in particular.

An iPhone Application for Blood Pressure Monitoring via the Oscillometric Finger Pressing Method.

We developed an iPhone X application to measure blood pressure (BP) via the "oscillometric finger pressing method". The user presses her fingertip on both the front camera and screen to increase the external pressure of the underlying artery, while the application measures the resulting variable-amplitude blood volume oscillations via the camera and applied pressure via the strain gauge array under the screen. The application also visually guides the fingertip placement and actuation and then computes BP from the measurements just like many automatic cuff devices. We tested the application, along with a finger cuff device, against a standard cuff device. The application yielded bias and precision errors of -4.0 and 11.4 mmHg for systolic BP and -9.4 and 9.7 mmHg for diastolic BP (n = 18). These errors were near the finger cuff device errors. This proof-of-concept study surprisingly indicates that cuff-less and calibration-free BP monitoring may be feasible with many existing and forthcoming smartphones.

Smartphone-based blood pressure monitoring via the oscillometric finger-pressing method.

High blood pressure (BP) is a major cardiovascular risk factor that is treatable, yet hypertension awareness and control rates are low. Ubiquitous BP monitoring technology could improve hypertension management, but existing devices require an inflatable cuff and are not compatible with such anytime, anywhere measurement of BP. We extended the oscillometric principle, which is used by most automatic cuff devices, to develop a cuff-less BP monitoring device using a smartphone. As the user presses her/his finger against the smartphone, the external pressure of the underlying artery is steadily increased while the phone measures the applied pressure and resulting variable-amplitude blood volume oscillations. A smartphone application provides visual feedback to guide the amount of pressure applied over time via the finger pressing and computes systolic and diastolic BP from the measurements. We prospectively tested the smartphone-based device for real-time BP monitoring in human subjects to evaluate usability (n = 30) and accuracy against a standard automatic cuff-based device (n = 32). We likewise tested a finger cuff device, which uses the volume-clamp method of BP detection. About 90% of the users learned the finger actuation required by the smartphone-based device after one or two practice trials. The device yielded bias and precision errors of 3.3 and 8.8 mmHg for systolic BP and -5.6 and 7.7 mmHg for diastolic BP over a 40 to 50 mmHg range of BP. These errors were comparable to the finger cuff device. Cuff-less and calibration-free monitoring of systolic and diastolic BP may be feasible via a smartphone.

Central Blood Pressure Monitoring via a Standard Automatic Arm Cuff.

Current oscillometric devices for monitoring central blood pressure (BP) maintain the cuff pressure at a constant level to acquire a pulse volume plethysmography (PVP) waveform and calibrate it to brachial BP levels estimated with population average methods. A physiologic method was developed to further advance central BP measurement. A patient-specific method was applied to estimate brachial BP levels from a cuff pressure waveform obtained during conventional deflation via a nonlinear arterial compliance model. A physiologically-inspired method was then employed to extract the PVP waveform from the same waveform via ensemble averaging and calibrate it to the brachial BP levels. A method based on a wave reflection model was thereafter employed to define a variable transfer function, which was applied to the calibrated waveform to derive central BP. This method was evaluated against invasive central BP measurements from patients. The method yielded central systolic, diastolic, and pulse pressure bias and precision errors of -0.6 to 2.6 and 6.8 to 9.0 mmHg. The conventional oscillometric method produced similar bias errors but precision errors of 8.2 to 12.5 mmHg (p ≤ 0.01). The new method can derive central BP more reliably than some current non-invasive devices and in the same way as traditional cuff BP.