Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.

Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.

Development of Real-Time Cuffless Blood Pressure Measurement Systems with ECG Electrodes and a Microphone Using Pulse Transit Time (PTT).

Research has shown that pulse transit time (PTT), which is the time delay between the electrocardiogram (ECG) signal and the signal from a photoplethysmogram (PPG) sensor, can be used to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) without the need for a cuff. However, the LED of the PPG sensor requires the precise adjustment of both light intensity and light absorption rates according to the contact status of the light-receiving element. This results in the need for regular calibration. In this study, we propose a cuffless blood pressure monitor that measures real-time blood pressure using a microphone instead of a PPG sensor. The blood pulse wave is measured in the radial artery of the wrist using a microphone that can directly measure the sound generated by a body rather than sending energy inside the body and receiving a returning signal. Our blood pressure monitor uses the PTT between the R-peak of the ECG signal and two feature points of the blood pulse wave in the radial artery of the wrist. ECG electrodes and circuits were fabricated, and a commercial microelectromechanical system (MEMS) microphone was used as the microphone to measure blood pulses. The peak points of the blood pulse from the microphone were clear, so the estimated SBP and DBP could be obtained from each ECG pulse in real time, and the resulting estimations were similar to those made by a commercial cuff blood pressure monitor. Since neither the ECG electrodes nor the microphone requires calibration over time, the real-time cuffless blood pressure monitor does not require calibration. Using the developed device, blood pressure was measured three times daily for five days, and the mean absolute error (MAE) and standard deviation (SD) of the SBP and DBP were found to be 2.72 ± 3.42 mmHg and 2.29 ± 3.53 mmHg, respectively. As a preliminary study for proof-of-concept, these results were obtained from one subject. The next step will be a pilot study on a large number of subjects.

Characteristics of an Implantable Blood Pressure Sensor Packaged by Ultrafast Laser Microwelding.

We propose a new packaging process for an implantable blood pressure sensor using ultrafast laser micro-welding. The sensor is a membrane type, passive device that uses the change in the capacitance caused by the membrane deformation due to applied pressure. Components of the sensor such as inductors and capacitors were fabricated on two glass (quartz) wafers and the two wafers were bonded into a single package. Conventional bonding methods such as adhesive bonding, thermal bonding, and anodic bonding require considerable effort and cost. Therefore CO2 laser cutting was used due to its fast and easy operation providing melting and bonding of the interface at the same time. However, a severe heat process leading to a large temperature gradient by rapid heating and quenching at the interface causes microcracks in brittle glass and results in low durability and production yield. In this paper, we introduce an ultrafast laser process for glass bonding because it can optimize the heat accumulation inside the glass by a short pulse width within a few picoseconds and a high pulse repetition rate. As a result, the ultrafast laser welding provides microscale bonding for glass pressure sensor packaging. The packaging process was performed with a minimized welding seam width of 100 µm with a minute. The minimized welding seam allows a drastic reduction of the sensor size, which is a significant benefit for implantable sensors. The fabricated pressure sensor was operated with resonance frequencies corresponding to applied pressures and there was no air leakage through the welded interface. In addition, in vitro cytotoxicity tests with the sensor showed that there was no elution of inner components and the ultrafast laser packaged sensor is non-toxic. The ultrafast laser welding provides a fast and robust glass chip packaging, which has advantages in hermeticity, bio-compatibility, and cost-effectiveness in the manufacturing of compact implantable sensors.

The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine.

BACKGROUND/AIMS: Bile acid is an important luminal factor that affects gastrointestinal motility and secretion. We investigated the effect of bile acid on secretion in the proximal and distal rat colon and coordination of bowel movements in the guinea pig colon. METHODS: The short-circuit current from the mucosal strip of the proximal and distal rat colon was compared under control conditions after induction of secretion with deoxycholic acid (DCA) as well as after inhibition of secretion with indomethacin, 1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid (an intracellular calcium chelator; BAPTA), and tetrodotoxin (TTX) using an Ussing chamber. Colonic pressure patterns were also evaluated in the extracted guinea pig colon during resting, DCA stimulation, and inhibition by TTX using a newly developed pressure-sensing artificial stool. RESULTS: The secretory response in the distal colon was proportionate to the concentration of DCA. Also, indomethacin, BAPTA, and TTX inhibited chloride secretion in response to DCA significantly (P < 0.05). However, these changes were not detected in the proximal colon. When we evaluated motility, we found that DCA induced an increase in luminal pressure at the proximal, middle, and distal sensors of an artificial stool simultaneously during the non-peristaltic period (P < 0.05). In contrast, during peristalsis, DCA induced an increase in luminal pressure at the proximal sensor and a decrease in pressure at the middle and distal sensors of the artificial stool (P < 0.05). CONCLUSIONS: DCA induced a clear segmental difference in electrogenic secretion. Also, DCA induced a more powerful peristaltic contraction only during the peristaltic period.