BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment.

Approximately 50% of melanoma patients fail to respond to immune checkpoint blockade (ICB), and acquired resistance hampers long-term survival in about half of initially responding patients. Whether targeting BET reader proteins, implicated in epigenetic dysregulation, can enhance ICB response rates and durability, remains to be determined. Here we show elevated BET proteins correlate with poor survival and ICB responses in melanoma patients. The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models. Combination treatment response in the innate resistance model induced changes in tumor-infiltrating immune cells, reducing myeloid-derived suppressor cells (MDSCs). CD4+ and CD8+ T cells showed decreased expression of inhibitory receptors, with reduced TIM3, LAG3, and BTLA checkpoint expression. In human PBMCs in vitro, BET inhibition reduced expression of immune checkpoints in CD4+ and CD8+ T cells, restoring effector cytokines and downregulating the transcriptional driver TOX. BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

Maximizing microcalcification detectability in low-dose dedicated cone-beam breast CT: parallel cascades-based theoretical analysis.

Purpose: We aim to determine the combination of X-ray spectrum and detector scintillator thickness that maximizes the detectability of microcalcification clusters in dedicated cone-beam breast CT. Approach: A cascaded linear system analysis was implemented in the spatial frequency domain and was used to determine the detectability index using numerical observers for the imaging task of detecting a microcalcification cluster with 0.17 mm diameter calcium carbonate spheres. The analysis considered a thallium-doped cesium iodide scintillator coupled to a complementary metal-oxide semiconductor detector and an analytical filtered-back-projection reconstruction algorithm. Independent system parameters considered were the scintillator thickness, applied X-ray tube voltage, and X-ray beam filtration. The combination of these parameters that maximized the detectability index was considered optimal. Results: Prewhitening, nonprewhitening, and nonprewhitening with eye filter numerical observers indicate that the combination of 0.525 to 0.6 mm thick scintillator, 70 kV, and 0.25 to 0.4 mm added copper filtration maximized the detectability index at a mean glandular dose (MGD) of 4.5 mGy. Conclusion: Using parallel cascade systems' analysis, the combination of parameters that could maximize the detection of microcalcifications was identified. The analysis indicates that a harder beam than that used in current practice may be beneficial for the task of detecting microcalcifications at an MGD suitable for breast cancer screening.

Ochratoxin A detoxification potentials of basil, chan, and chia seeds.

The most toxic of the ochratoxins is ochratoxin A (OTA), which is primarily produced by species of Aspergillus and Penicillium that can be found in maize, wheat, coffee, red wine, and various grains. OTA induces immunotoxicity, nephrotoxicity, hepatotoxicity, teratogenicity, and carcinogenicity in both animals and humans. Thus, there is a need to identify mycotoxin detoxification agents that can effectively decontaminate OTA. Seeds of basil (Ocimum basilicum L.), chan (Hyptis suaveolens L.), and chia (Salvia hispanica L.) are functional foods capable of eliminating harmful substances. Despite this potential, the impact of these seeds on OTA detoxification remains unclear. This study reveals that milled basil, chan, and chia seeds adsorb significant levels of OTA, with chia demonstrating the highest adsorption capacity, followed by chan and basil seeds showing the least efficiency. Furthermore, milled basil, chan, and chia seeds effectively reduced OTA residues in artificial gastric and intestinal fluids, where they achieved up to 93% OTA adsorption in the former. In addition, these milled seeds were able to remove OTAs from canned, drip, and instant coffee. This study is the first to report the OTA elimination potential of basil, chan, and chia seeds.

Chemoenzymatic Synthesis of GAA-7 Glycan Analogues and Evaluation of Their Neuritogenic Activities.

Ganglioside GAA-7 exhibits higher neurite outgrowth than ganglioside GM1a and most echinodermatous gangliosides (EGs) when tested on neuron-like rat adrenal pheochromocytoma (PC12) cells in the presence of nerve growth factor (NGF). The unique structure of GAA-7 glycan, containing an uncommon sialic acid (8-O-methyl-N-glycolylneuraminic acid) and sialic acid-α-2,3-GalNAc linkage, makes it challenging to synthesize. We recently developed a streamlined method to chemoenzymatically synthesize GAA-7 glycan and employed this modular strategy to efficiently prepare a library of GAA-7 glycan analogues incorporating N-modified or 8-methoxyl sialic acids. Most of these synthetic glycans exhibited moderate efficacy in promoting neuronal differentiation of PC12 cells. Among them, the analogue containing common sialic acid shows greater potential than the GAA-7 glycan itself. This result reveals that methoxy modification is not essential for neurite outgrowth. Consequently, the readily available analogue presents a promising model for further biological investigations.

Robotic Versus Conventional or Endoscopic-assisted Nipple-sparing Mastectomy and Immediate Prosthesis Breast Reconstruction in the Management of Breast Cancer: A Prospectively Designed Multicenter Trial Comparing Clinical Outcomes, Medical Cost, and Patient-reported Outcomes (RCENSM-P).

OBJECTIVE: To compare the clinical and patient-reported outcomes of minimal access and conventional nipple-sparing mastectomy (C-NSM). The secondary outcomes investigated included medical costs and oncological safety. BACKGROUND: Minimal-access NSM has been increasingly applied in the treatment of patients with breast cancer. However, prospective multicenter trials comparing robotic-assisted NSM (R-NSM) versus C-NSM or endoscopic-assisted NSM (E-NSM) are lacking. METHODS: A prospectively designed 3-arm multicenter, nonrandomized trial (NCT04037852) was conducted from October 1, 2019 to December 31, 2021, to compare R-NSM with C-NSM or E-NSM. RESULTS: A total of 73 R-NSM, 74 C-NSM, and 84 E-NSM procedures were enrolled. The median wound length and operation time of C-NSM was (9 cm, 175 minutes), (4 cm, and 195 minutes) in R-NSM, and (4 cm and 222 minutes) in E-NSM. Complications were comparable among the groups. Better wound healing was observed in the minimal-access NSM group. The R-NSM procedure was 4000 and 2600 United States Dollars more expensive than C-NSM and E-NSM, respectively. Wound/scar and postoperative acute pain evaluation favored the use of minimal access NSM over C-NSM. Quality of life in terms of chronic breast/chest pain, mobility, and range of motion of the upper extremity showed no significant differences. The preliminary oncologic results showed no differences among the 3 groups. CONCLUSIONS: R-NSM or E-NSM is a safe alternative if compared with C-NSM in terms of perioperative morbidities, especially with better wound healing. The advantage of minimal access groups was higher wound-related satisfaction. Higher costs remain one of the major limiting factors in the widespread adoption of R-NSM.

Dedicated Cone-Beam Breast CT: Reproducibility of Volumetric Glandular Fraction with Advanced Image Reconstruction Methods.

Dedicated cone-beam breast computed tomography (CBBCT) is an emerging modality and provides fully three-dimensional (3D) images of the uncompressed breast at an isotropic voxel resolution. In an effort to translate this modality to breast cancer screening, advanced image reconstruction methods are being pursued. Since radiographic breast density is an established risk factor for breast cancer and CBBCT provides volumetric data, this study investigates the reproducibility of the volumetric glandular fraction (VGF), defined as the proportion of fibroglandular tissue volume relative to the total breast volume excluding the skin. Four image reconstruction methods were investigated: the analytical Feldkamp-Davis-Kress (FDK), a compressed sensing-based fast, regularized, iterative statistical technique (FRIST), a fully supervised deep learning approach using a multi-scale residual dense network (MS-RDN), and a self-supervised approach based on Noise-to-Noise (N2N) learning. Projection datasets from 106 women who participated in a prior clinical trial were reconstructed using each of these algorithms at a fixed isotropic voxel size of (0.273 mm3). Each reconstructed breast volume was segmented into skin, adipose, and fibroglandular tissues, and the VGF was computed. The VGF did not differ among the four reconstruction methods (p = 0.167), and none of the three advanced image reconstruction algorithms differed from the standard FDK reconstruction (p > 0.862). Advanced reconstruction algorithms developed for low-dose CBBCT reproduce the VGF to provide quantitative breast density, which can be used for risk estimation.

Sex difference in the associations among risk factors with depression in a large Taiwanese population study.

Background: Depression is a common psychiatric health issue affecting an estimated 5% of adults worldwide, and it can lead to disability and increased economic burden. Consequently, identifying the factors associated with depression as early as possible is a vital issue. The aim of this study was to explore these associations in a large cohort of 121,601 Taiwanese participants in the Taiwan Biobank, and also to identify sex differences in the associations. Methods: The study cohort included 77,902 women and 43,699 men (mean age, 49.9 ± 11.0 years), who were further classified into those with depression (n = 4,362; 3.6%) and those without depression (n = 117,239; 96.4%). Results: The results of multivariable analysis showed that female sex (vs. male sex; odds ratio = 2.578; 95% confidence interval = 2.319-2.866; p < 0.001) was significantly associated with depression. Older age, diabetes mellitus (DM), hypertension, low systolic blood pressure (SBP), smoking history, living alone, low glycated hemoglobin (HbA1c), high triglycerides, and low uric acid were significantly associated with depression in the men. In the women, older age, DM, hypertension, low SBP, smoking history, alcohol history, education level of middle and high school (vs. lower than elementary school), living alone, high body mass index (BMI), menopause, low HbA1c, high triglycerides, high total cholesterol, low estimated glomerular filtration rate (eGFR), and low uric acid were significantly associated with depression. Further, there were significant interactions between sex and DM (p = 0.047), smoking history (p < 0.001), alcohol use (p < 0.001), BMI (p = 0.022), triglyceride (p = 0.033), eGFR (p = 0.001), and uric acid (p = 0.004) on depression. Conclusion: In conclusion, our results showed sex differences in depression, and the women were significantly associated with depression compared to men. Furthermore, we also found sex differences among the risk factors associated with depression.

Palbociclib blocks neutrophilic phosphatidylinositol 3-kinase activity to alleviate psoriasiform dermatitis.

BACKGROUND AND PURPOSE: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. EXPERIMENTAL APPROACH: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. KEY RESULTS: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation. CONCLUSIONS AND IMPLICATIONS: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.

Dedicated cone-beam breast CT: Data acquisition strategies based on projection angle-dependent normalized glandular dose coefficients.

BACKGROUND: Dedicated cone-beam breast computed tomography (CBBCT) using short-scan acquisition is being actively investigated to potentially reduce the radiation dose to the breast. This would require determining the optimal x-ray source trajectory for such short-scan acquisition. PURPOSE: To quantify the projection angle-dependent normalized glandular dose coefficient ( D g N C T $Dg{N^{CT}}$ ) in CBBCT, referred to as angular D g N C T $Dg{N^{CT}}$ , so that the x-ray ray source trajectory that minimizes the radiation dose to the breast for short-scan acquisition can be determined. MATERIALS AND METHODS: A cohort of 75 CBBCT clinical datasets was segmented and used to generate three breast models - (I) patient-specific breast with heterogeneous fibroglandular tissue distribution and real breast shape, (II) patient-specific breast shape with homogeneous tissue distribution and matched fibroglandular weight fraction, and (III) homogeneous semi-ellipsoidal breast with patient-specific breast dimensions and matched fibroglandular weight fraction, which corresponds to the breast model used in current radiation dosimetry protocols. For each clinical dataset, the angular D g N C T $Dg{N^{CT}}$ was obtained at 10 discrete angles, spaced 36° apart, for full-scan, circular, x-ray source trajectory from Monte Carlo simulations. Model III is used for validating the Monte Carlo simulation results. Models II and III are used to determine if breast shape contributes to the observed trends in angular D g N C T $Dg{N^{CT}}$ . A geometry-based theory in conjunction with center-of-mass ( C O M $COM$ ) based distribution analysis is used to explain the projection angle-dependent variation in angular D g N C T $Dg{N^{CT}}$ . RESULTS: The theoretical model predicted that the angular D g N C T $Dg{N^{CT}}$ will follow a sinusoidal pattern and the amplitude of the sinusoid increases when the center-of-mass of fibroglandular tissue ( C O M f $CO{M_f}$ ) is farther from the center-of-mass of the breast ( C O M b $CO{M_b}$ ). It also predicted that the angular D g N C T $Dg{N^{CT}}$ will be minimized at x-ray source positions complementary to the C O M f $CO{M_f}$ . The C O M f $CO{M_f}$ was superior to the C O M b $CO{M_b}$ in 80% (60/75) of the breasts. From Monte Carlo simulations and for homogeneous breasts (models II and III), the deviation in breast shape from a semi-ellipsoid had minimal effect on angular D g N C T $Dg{N^{CT}}$ and showed less than 4% variation. From Monte Carlo simulations and for model I, as predicted by our theory, the angular D g N C T $Dg{N^{CT}}$ followed a sinusoidal pattern with maxima and minima at x-ray source positions superior and inferior to the breast, respectively. For model I, the projection angle-dependent variation in angular D g N C T $Dg{N^{CT}}$ was 16.4%. CONCLUSION: The heterogeneous tissue distribution affected the angular D g N C T $Dg{N^{CT}}$ more than the breast shape. For model I, the angular D g N C T $Dg{N^{CT}}$ was lowest when the x-ray source was inferior to the breast. Hence, for short-scan CBBCT acquisition with C O M b $CO{M_b}$ aligned with axis-of-rotation, an x-ray source trajectory inferior to the breast is preferable and such an acquisition spanning 205° can potentially reduce the mean glandular dose by up to 52%.

Acid external and internal environment exchange the Oreochromis niloticus tissue immune gene expression compared to the mouse macrophage polarization model.

The water environment plays an important role in animal physiology. In this study, we sought to evaluate the effect of the acid environment on the Oreochromis niloticus (Nile tilapia) internal microenvironment immune response compare to the mouse macrophage model (J77A.1). The acid environment treated mouse macrophage J774A.1 model have shown that acidic treatment is able to polarize macrophages into M2-like macrophages via an increase in Ym1, Tgm2, Arg1, Fizz1, and IL-10 expression. Metabolic analysis of mouse macrophages (J774A.1) at pH 2 vs. pH 7 and pH 4 vs. pH 7 have been shown to promote the expression of intracellular acetylcholine, choline, prochlorperazine, L-leucine, and bisphenol A,2-amino-3-methylimidazo[4,5-f] quinolone metabolites in the M2-like macrophage. Immune gene expression of the O. niloticus spleen and liver treated at pH 2, 4, and 7 was shown to reduce TNF-α, IL-1 ß, IL-8, and IL-12 expression compared to pH 7 treatment. Immune gene was induced in O. niloticus following culture at pH 5, 6, and 7 fresh water environment. Taken together, we found that the acid internal environment polarizes tissues into an M2 macrophage developmental microenvironment. However, if the external environment is acid, tissues are exposed to an M1 macrophage developmental microenvironment.

Proposals for Standardization of Intraoperative Facial Nerve Monitoring during Parotid Surgery.

Intraoperative facial nerve monitoring (FNM) has been widely accepted as an adjunct during parotid surgery to facilitate identification of the facial nerve (FN) main trunk, dissection of FN branches, confirmation of FN function integrity, detection of FN injury and prognostication of facial expression after tumor resection. Although the use of FNM in parotidectomy is increasing, little uniformity exists in its application from the literature. Thus, not only are the results of many studies difficult to compare but the value of FNM technology is also limited. The article reviews the current literature and proposes our standardized FNM procedures during parotid surgery, such as standards in FNM setup, standards in general anesthesia, standards in FNM procedures and application of stimulus currents, interpretation of electrophysiologic signals and prediction of the facial expression outcome and pre-/post-operative assessment of facial expressions. We hope that the FNM standardized procedures will provide greater uniformity, improve the quality of applications and contribute to future research.

Investigation of the Electrophysiological and Thermographic Safety Parameters of Surgical Energy Devices during Thyroid and Parathyroid Surgery in a Porcine Model.

In thyroid and parathyroid surgery, surgical energy devices (SEDs) provide more efficient hemostasis than conventional clamp-and-tie hemostasis in areas with rich blood supply. However, when a SED is activated near the recurrent laryngeal nerve (RLN), the heat generated by the SED may injure the nerve irreversibly. To safely apply SEDs in thyroid/parathyroid surgery, this article introduces experimental porcine model studies to investigate the activation and cooling safety parameters of SEDs in standardized electrophysiological (EP) and thermographic (TG) procedures, respectively. In the EP safety parameter experiments, continuous intraoperative neuromonitoring (C-IONM) is applied to demonstrate the RLN function in real-time. The EP activation study evaluates the safe activation distance of SEDs; the EP cooling study evaluates the safe cooling time of SEDs. In the TG safety parameter experiment, a thermal imaging camera is used to record the temperature change after activating the SED. The TG activation study evaluates the lateral thermal spread distance after SED activation in a dry or humid environment and whether smoke and splashing are generated; the TG cooling study evaluates the cooling time. This will help establish the safety parameters of newly developed SEDs used in thyroid/parathyroid surgery and provide safety guidelines to avoid RLN injury and related complications.

Impact of common diseases and habits on daytime sleepiness in adults.

We aimed to investigate the impact of common diseases and habits on daytime sleepiness in adults. We retrospectively collected the clinical and overnight polysomnographic data of 2829 adults. The impact of common diseases and habits on the Epworth Sleepiness Scale (ESS) score was analyzed by univariate and multivariate linear regression analyses. The mean ESS score was 6.2 (standard deviation = 4.3; range = 0-24) for all adults. Multivariate linear regression analysis showed that dyslipidemia, acute myocardial infarction (AMI), liver cirrhosis, alcohol drinking, and tea consumption had a significantly positive association with ESS score for all adults after adjusting for age, sex, body mass index, apnea-hypopnea index, sleep efficiency, percentage of sleep N3 stage, and depression. Subgroup analysis by sex showed that AMI, liver cirrhosis, alcohol drinking, and tea consumption had significantly positive association with ESS scores in males, whereas only dyslipidemia had significantly positive association with ESS scores in females. Subgroup analysis by age showed that alcohol drinking had a significantly positive association with ESS scores in young adults. AMI had a significantly positive association with ESS scores, but chronic kidney disease had a significantly negative association with ESS scores in middle-aged adults. Furthermore, dyslipidemia, chronic kidney disease, and cancers had a significantly positive association with ESS scores in older adults. Dyslipidemia, AMI, liver cirrhosis, alcohol drinking, and tea consumption had a significantly positive association with daytime sleepiness in adults but differed by sex and age.

Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade.

Precise maintenance of PTEN dosage is crucial for tumor suppression across a wide variety of cancers. Post-transcriptional regulation of Pten heavily relies on regulatory elements encoded by its 3'UTR. We previously reported the important diversity of 3'UTR isoforms of Pten mRNAs produced through alternative polyadenylation (APA). Here, we reveal the direct regulation of Pten APA by the mammalian cleavage factor I (CFIm) complex, which in turn contributes to PTEN protein dosage. CFIm consists of the UGUA-binding CFIm25 and APA regulatory subunits CFIm59 or CFIm68. Deep sequencing analyses of perturbed (KO and KD) cell lines uncovered the differential regulation of Pten APA by CFIm59 and CFIm68 and further revealed that their divergent functions have widespread impact for APA in transcriptomes. Differentially regulated genes include numerous factors within the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway that PTEN counter-regulates. We further reveal a stratification of APA dysregulation among a subset of PTEN-driven cancers, with recurrent alterations among PI3K/Akt pathway genes regulated by CFIm. Our results refine the transcriptome selectivity of the CFIm complex in APA regulation, and the breadth of its impact in PTEN-driven cancers.

A comparison between cisatracurium and rocuronium-induced neuromuscular block on laryngeal electromyography recovery after neostigmine reversal in a porcine model.

Background: Inducing and reversing neuromuscular block is essential to a positive outcome of thyroid surgery, with intraoperative neuromonitoring (IONM) being used to decrease recurrent and superior laryngeal nerve injuries and improve vocal outcome. Neostigmine is a non-specific broad-spectrum and inexpensive reversal agent for neuromuscular blocking agents (NMBAs). The aim of this porcine study was to explore the effect of neostigmine on electromyography (EMG) signal recovery profile following the commonly used NMBAs, cisatracurium and rocuronium. Methods: Twelve piglets were allocated into two groups with six piglets in each group. When stable baseline EMG signals were obtained, a neuromuscular block was induced by intravenous cisatracurium 0.2 mg/kg (group C) or rocuronium 0.6 mg/kg (group R) for each piglet. We compared laryngeal EMG tracing with spontaneous recovery (control) and neostigmine (0.04 mg/kg) reversal for each group. The time course of real-time laryngeal EMG signals was observed for 30 min from NMBA injection. Effects of neostigmine on EMG signal were assessed at 50% EMG recovery and by the maximum neuromuscular block recovery degree from the baseline value. Results: Neostigmine shortened the recovery time to 50% EMG amplitude in both group C (16.5 [2.5] vs. 29.0 [2.0] min, P<0.01) and group R (16.5[2.5] vs. 26.5 [1.5] min, P<0.05) compared to spontaneous recovery, respectively. Neostigmine reversal also enhanced the maximum degree of EMG amplitude recovery in both group C (83.6 [5.1] vs. 47.2 [6.1] %, P<0.01) and group R (85.6 [18.2]vs. 57.1 [6.3] %, P<0.05) compared to spontaneous recovery, respectively. The reversal effect of neostigmine did not differ significantly between cisatracurium and rocuronium. Conclusions: This porcine model demonstrated that neostigmine provides an adequate and timely IONM signal suppressed by both cisatracurium and rocuronium. These results can potentially expand the options for precision neuromuscular block management during IONM to improve vocal outcomes in thyroid surgery patients.

Safety Parameters of Quantum Molecular Resonance Devices During Thyroid Surgery: Porcine Model Using Continuous Neuromonitoring.

Objectives: Quantum molecular resonance (QMR) devices have been applied as energy-based devices in many head and neck surgeries; however, research on their use in thyroid surgery is lacking. This study aimed to investigate the safety parameters of QMR devices during thyroidectomy when dissection was adjacent to the recurrent laryngeal nerve (RLN). Methods: This study included eight piglets with 16 RLNs, and real-time electromyography (EMG) signals were obtained from continuous intraoperative neuromonitoring (C-IONM). QMR bipolar scissor (BS) and monopolar unit (MU) were tested for safety parameters. In the activation study, QMR devices were activated at varying distances from the RLN. In the cooling study, QMR devices were cooled for varying time intervals, with or without muscle touch maneuver (MTM) before contacting with the RLN. Results: In the activation study, no adverse EMG change occurred when QMR BS and MU were activated at distances of 2 mm or longer from the RLNs. In the cooling study, no adverse EMG change occurred when QMR BS and MU were cooled in 2-second intervals or immediately after MTM. Conclusion: QMR devices should be carefully used when performing RLN dissection during thyroid surgery. According to the activation and cooling safety parameters in this study, surgeons can avoid RLN injury by following standard procedures when using QMR devices.

Nicotinamide Inhibits T Cell Exhaustion and Increases Differentiation of CD8 Effector T Cells.

One of the limitations of immunotherapy is the development of a state referred to as T cell exhaustion (TEx) whereby T cells express inhibitory receptors (IRs) and lose production of effectors involved in killing of their targets. In the present studies we have used the repeated stimulation model with anti CD3 and anti CD28 to understand the factors involved in TEx development and treatments that may reduce changes of TEx. The results show that addition of nicotinamide (NAM) involved in energy supply to cells prevented the development of inhibitory receptors (IRs). This was particularly evident for the IRs CD39, TIM3, and to a lesser extent LAG3 and PD1 expression. NAM also prevented the inhibition of IL-2 and TNFα expression in TEx and induced differentiation of CD4+ and CD8 T cells to effector memory and terminal effector T cells. The present results showed that effects of NAM were linked to regulation of reactive oxygen species (ROS) consistent with previous studies implicating ROS in upregulation of TOX transcription factors that induce TEx. These effects of NAM in reducing changes of TEx and in increasing the differentiation of T cells to effector states appears to have important implications for the use of NAM supplements in immunotherapy against cancers and viral infections and require further exploration in vivo.

Repurposing Melanoma Chemotherapy to Activate Inflammasomes in the Treatment of BRAF/MAPK Inhibitor Resistant Melanoma.

The development of resistance to treatments of melanoma is commonly associated with an upregulation of the MAPK pathway and the development of an undifferentiated state. Previous studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by the activation of inflammasomes. In this study, we have taken cell lines from patients before and after the development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in nonobese diabetic scid gamma mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2 or NLRP3 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome-targeted therapy.

Improving Voice Outcomes After Thyroid Surgery - Review of Safety Parameters for Using Energy-Based Devices Near the Recurrent Laryngeal Nerve.

Technological advances in thyroid surgery have rapidly increased in recent decades. Specifically, recently developed energy-based devices (EBDs) enable simultaneous dissection and sealing tissue. EBDs have many advantages in thyroid surgery, such as reduced blood loss, lower rate of post-operative hypocalcemia, and shorter operation time. However, the rate of recurrent laryngeal nerve (RLN) injury during EBD use has shown statistically inconsistent. EBDs generate high temperature that can cause iatrogenic thermal injury to the RLN by direct or indirect thermal spread. This article reviews relevant medical literatures of conventional electrocauteries and different mechanisms of current EBDs, and compares two safety parameters: safe distance and cooling time. In general, conventional electrocautery generates higher temperature and wider thermal spread range, but when applying EBDs near the RLN adequate activation distance and cooling time are still required to avoid inadvertent thermal injury. To improve voice outcomes in the quality-of-life era, surgeons should observe safety parameters and follow the standard procedures when using EBDs near the RLN in thyroid surgery.