Auxiliary Treatments Research Articles

Functional Peptides from Yak Milk Casein: Biological Activities and Structural Characteristics.

The average content of casein in yak milk is 40.2 g/L. Casein can be degraded by enzymatic digestion or food processing to produce abundant degradation peptides. International researchers have studied the degradation peptides of yak milk casein by using multiple techniques and methods, such as in vitro activity tests, cellular experiments, proteomics, bioinformatics, etc., and found that the degradation peptides have a wide range of functional activities that are beneficial to the human body, such as angiotensin-converting enzyme (ACE) inhibitory, antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer, and immunomodulatory activities, etc., and it has been proved that the types and strengths of functional activities are closely related to the structural characteristics of the peptides. This paper describes the characteristics of yak milk proteins, the functional activities, and mechanism of action of degraded peptides. Based on the types of functional activities of yak milk casein degradation peptides, we classified and elucidated the effects of structural factors, such as peptide molecular weight, peptide length, amino acid sequence, physicochemical properties, electrical charge, hydrophobicity, spatial conformation, chain length, and the type of enzyme on these activities. It reveals the great potential of yak milk casein degradation peptides as functional active peptide resources and as auxiliary treatments for diseases. It also provides important insights for analyzing yak casein degradation peptide activity and exploring high-value utilization.

Acupuncture combined with gonadotropin-releasing hormone agonists improves endometrial receptivity and pregnancy outcome in patients with recurrent implantation failure of in vitro fertilization-embryo transfer.

Gonadotropin-releasing hormone agonists (GnRHa), combined with other auxiliary treatments, can improve pregnancy outcomes in in vitro fertilization-embryo transfer (IVF-ET). This research investigated the effect of acupuncture combined with GnRHa in patients with recurrent implantation failure (RIF) of IVF-ET. A total of 164 patients who intended to undergo frozen-thawed embryo transfer after RIF of IVF-ET were selected for experiments and then divided into the control (received conventional hormone replacement therapy (HRT) for endometrial preparation) and study groups (received a combination of acupuncture, GnRHa, and HRT for endometrial preparation) (n = 82). Endometrial thickness (EMT), endometrial morphological classification, submucosal uterine blood flow classification, clinical pregnancy rate, embryo implantation rate, and early abortion rate for each transfer cycle were compared between the two groups. EMT of the study group was higher than that of the control group 1 day before transfer. There were more patients with linear endometrium (A + B type) in the study group on the day of endometrial transformation than in the control group. The number of patients with type I submucosal uterine blood flow in the study group was decreased and the number of patients with type III was increased compared with the control group on the day of endometrial transformation. The clinical pregnancy rate and embryo implantation rate of the study group were higher than those of the control group. Acupuncture combined with GnRHa improves the endometrial receptivity of patients with RIF of IVF-ET, thereby increasing clinical pregnancy rates and improving pregnancy outcomes.

Economic burden assessment for the management of asthma patients at Mexico's National Institute for Respiratory Diseases

Determinar la carga económica anual del asma, desde una perspectiva institucional y con base en la clasificación recomendada por GINA, en una cohorte retrospectiva de adultos atendidos en el Instituto Nacional de Enfermedades Respiratorias (INER) de México. Estudio observacional, longitudinal y retrospectivo, llevado a cabo a partir de la información recabada de 247 pacientes femeninas con asma. Se estimaron los costos directos anuales: visitas, pruebas de laboratorio, tratamiento farmacológico y de las crisis o exacerbaciones, para determinar la carga anual de la enfermedad desde una perspectiva institucional, y según la clasificación de la Iniciativa Global para el Asma. El costo promedio anual fue de $43,813,92, que aumentó en relación con la necesidad de aumento de dosis de corticoides inhalados y beta-agonistas de acción prolongada. El costo promedio de la consulta médica fue de $2004.57, $982.82 por gestión de crisis y $2645.95 por pruebas de laboratorio. El tratamiento farmacológico representó la principal carga económica, con un costo promedio anual de $38,180.58. Los resultados resaltan una carga económica del asma estimada en un costo anual por paciente de $43,813.92 MXN (DE=93,348.85), en el contexto del tercer nivel de atención en el sistema de salud público mexicano. La gravedad del asma, los tratamientos y los biológicos fueron los principales factores que aumentaron los costos directos de la atención.

Psychotherapy duration and work disability: A prospective Finnish register study.

The influence of psychotherapy duration on common mental disorder (CMD) outcomes remains a topic of ongoing debate. Whereas most research has focused on CMD symptom change, the evidence on the psychotherapy duration of subsequent CMD-related work disability and the change in psychotropic drug purchases is scarce. We used a register-based cohort representing 33% of the Finnish population. The participants included working-age individuals (N = 12,047, 76% women, mean age = 36) who initiated long-term psychotherapy, between 2014 and 2017. They were followed from 2011 to 2021 and psychotherapy duration ranged from less than a year to over 3 years. We used an interrupted time series design to analyze the psychotherapy duration-dependent changes in CMD-related work disability (primary outcome, operationalized as depression or anxiety-related sickness absence, SA, days) and the annual number of psychotropic drug purchases or distinct drugs purchased (secondary outcomes). There were no differences in the levels of work disability or drug purchases before the psychotherapy. We observed a decreasing level and trend in all outcomes across all psychotherapy duration groups. The largest decline in level was observed in the <1-year duration group (88% decline for SA and 43%-44% for drug purchases) while the smallest decline was in the 3+ years duration group (73% for SA and 27% for drug purchases). Work disability outcomes and duration varied among individuals, even with similar initial mental health-related work disability or use of auxiliary psychotropic treatments. Compared to longer psychotherapy, shorter psychotherapy was associated with sharper improvements.

Research progress and prospects of artificial intelligence in diagnosis and treatment of colorectal cancer

Colorectal cancer is one of the most common malignant tumors worldwide. Due to the heterogeneity in patient outcomes and treatment responses to standard therapy regimens, personalized diagnostic and therapeutic strategies have remained a focus of sustained interest in research. In recent years, with the rapid progression of artificial intelligence (AI) technology in the medical field, an abundance of phased research results has emerged in the decision-making for preoperative, intraoperative, and postoperative diagnostic and therapeutic plans for colorectal cancer, demonstrating great potential for application. This new and efficient solution provides for the personalized evaluations and auxiliary diagnoses and treatments of patients with colorectal cancer. In the future, AI systems may continue to advance towards multimodal, multi-omics, and real-time directions. This paper aims to explore the current state of research on the multi-faceted auxiliary applications of AI in the diagnosis and treatment of colorectal cancer, as well as to present a prospective view of the innovations that AI technology could bring to personalized colorectal cancer treatment in the future and the challenges it may face.

Advance in the mechanism and clinical research of myalgia in long COVID.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, mortality rates of coronavirus disease 2019 (COVID-19) have significantly decreased. However, a variable proportion of patients exhibit persistent prolonged symptoms of COVID-19 infection (long COVID). This virus primarily attacks respiratory system, but numerous individuals complain persistent skeletal muscle pain or worsening pre-existing muscle pain post COVID-19, which severely affects the quality of life and recovery. Currently, there is limited research on the skeletal muscle pain in long COVID. In this brief review, we review potential pathological mechanisms of skeletal muscle pain in long COVID, and summarize the various auxiliary examinations and treatments for skeletal muscle pain in long COVID. We consider abnormal activation of inflammatory response, myopathy, and neurological damages as pivotal pathological mechanisms of skeletal muscle pain in long COVID. A comprehensive examination is significantly important in order to work out effective treatment plans and relieve skeletal muscle pain. So far, rehabilitation interventions for myalgia in long COVID contain but are not limited to drug, nutraceutical therapy, gut microbiome-targeted therapy, interventional therapy and strength training. Our study provides a potential mechanism reference for clinical researches, highlighting the importance of comprehensive approach and management of skeletal muscle pain in long COVID. The relief of skeletal muscle pain will accelerate rehabilitation process, improve activities of daily living and enhance the quality of life, promoting individuals return to society with profound significance.

Physiological Barriers and Strategies of Lipid-Based Nanoparticles for Nucleic Acid Drug Delivery.

Lipid-based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, the NAD delivery efficiency and safety are still unsatisfactory, which are, to a large extent, due to the existence of multi-level physiological barriers in vivo. It is important to elucidate the interactions between these barriers and LBNPs, which will guide more rational design of efficient NAD vehicles with low adverse effects and facilitate broader applications of nucleic acid therapeutics. This review describes the obstacles and challenges of biological barriers to NAD delivery at systemic, organ, sub-organ, cellular, and subcellular levels. The strategies to overcome these barriers are comprehensively reviewed, mainly including physically/chemically engineering LBNPs and directly modifying physiological barriers by auxiliary treatments. Then the potentials and challenges for successful translation of these preclinical studies into the clinic are discussed. In the end, a forward look at the strategies on manipulating protein corona (PC) is addressed, which may pull off the trick of overcoming those physiological barriers and significantly improve the efficacy and safety of LBNP-based NADs delivery.

Efficacy and Safety of Treatment Options for Large Upper Ureteral Stone

Background: There are three minimally invasive methods for the treatment of large (&gt;1 cm) upper ureteral stones: ureteroscopic lithotripsy (URSL), percutaneous nephrolithotomy (PCNL) and laparoscopic ureterolithotomy (LUL). With multiple surgical options, the controversy of choosing the best option for a given patient lies. Objective: To compare efficacy and safety between URSL, PCNL and LUL to determine the best choice. Methodology: This study was conducted from March 2020 to February 2022 with 120 patients who had upper ureteral stones admitted at NIKDU. They were randomized into 3 equal URSL, PCNL &amp; LUL groups, 40 patients in each group. The primary outcome was a stone-free rate after 1 month of surgery, and the secondary outcomes were the duration of surgery, length of hospital stay, and complication rate postoperatively. Result: Eight patients needed auxiliary PCNL after URSL and 1 patient after LUL, but none after PCNL. The stone-free rate was 78.1% (25/32) in the URSL group, 95% (38/ 40) in the PCNL group and 100% (39/39) in the LUL group. Operation time was the shortest with URSL and the longest with LUL (all p &lt;0.05). Hospital stay was shorter in the URSL group compared with PCNL &amp; LUL group (p=0.0001). Operation-related complications were almost similar among the three groups. Conclusion: Laparoscopic ureterolithotomy followed by PCNL is the most efficacious modality for treating large upper ureteral stones with a superior stone-free rate and lesser need for auxiliary treatments compared to URSL. Bangladesh J. Urol. 2022; 25(2): 93-97

Deformation mechanisms and mechanical properties of the high-strength and ductile Al-Zn-Mg-Cu alloys processed by repetitive continuous extrusion forming process with different heat treatments

Continuous severe plastic deformation (SPD) processes, which overcome the limitations of economic efficiency and sample size for classical SPD approaches, are promising industry technologies for manufacturing aluminum alloy products with refined microstructures and enhanced properties. In the present work, the repetitive continuous extrusion forming (R-Conform) process combined with auxiliary thermal treatments was implemented in Al-Zn-Mg-Cu alloys, which had poor workability. By combining microstructural observation, mechanical testing and finite element simulation, the influence of auxiliary heat treatments on the mechanisms of grain refinement and strengthening for Al-Zn-Mg-Cu alloys processed by R-Conform were systematically investigated. The results indicated that the grains of Al-Zn-Mg-Cu alloys were significantly refined by a continuous dynamic recrystallization (CDRX) during the R-Conform process with special thermomechanical conditions. The increased supersaturated solid solution concentration and constituent precipitate fraction caused by prehomogenization were found to accelerate CDRX for grain refinement through the pinning effect on dislocation motion. Due to the simultaneous effect of shear deformation and online solution, the R-Conformed alloys contained massive lattice distortions and high concentrations of solute atoms. As a result, the processed Al-Zn-Mg-Cu alloys combined with prehomogenization and direct aging treatments possibly possess a good combination of strength and ductility due to the integrated functions of fine grains, massive lattice distortion, and evenly distributed nanosized precipitates.

SIAP: an intelligent algorithm for multiple prescription pattern recognition based on weighted similarity distances

BackgroundClinical practices have demonstrated that disease treatment can be very complex. Patients with chronic diseases often suffer from more than one disease. Complex diseases are often treated with a variety of drugs, including both primary and auxiliary treatments. This complexity and multidimensionality increase the difficulty of extracting knowledge from clinical data.MethodsIn this study, we proposed a subgroup identification algorithm for complex prescriptions (SIAP). We applied the SIAP algorithm to identify the importance level of each drug in complex prescriptions. The algorithm quickly classified and determined valid prescription combinations for patients. The algorithm was validated through classification matching of classical prescriptions in traditional Chinese medicine. We collected 376 formulas and their compositions from a formulary to construct a database of standard prescriptions. We also collected 1438 herbal prescriptions from clinical data for automated prescription identification. The prescriptions were divided into training and test sets. Finally, the parameters of the two sub-algorithms of SIAP and SIAP-All, as well as those of the combination algorithm SIAP + All, were optimized on the training set. A comparison analysis was performed against the baseline intersection set rate (ISR) algorithm. The algorithm for this study was implemented with Python 3.6.ResultsThe SIAP-All and SIAP + All algorithms outperformed the benchmark ISR algorithm in terms of accuracy, recall, and F1 value. The F1 values were 0.7568 for SIAP-All and 0.7799 for SIAP + All, showing improvements of 8.73% and 11.04% over the existing ISR algorithm, respectively.ConclusionWe developed an algorithm, SIAP, to automatically match sub-prescriptions of complex drugs with corresponding standard or classic prescriptions. The matching algorithm weights the drugs in the prescription according to their importance level. The results of this study can help to classify and analyse the drug compositions of complex prescriptions.

Constant Force-Tracking Control Based on Deep Reinforcement Learning in Dynamic Auscultation Environment.

Intelligent medical robots can effectively help doctors carry out a series of medical diagnoses and auxiliary treatments and alleviate the current shortage of social personnel. Therefore, this paper investigates how to use deep reinforcement learning to solve dynamic medical auscultation tasks. We propose a constant force-tracking control method for dynamic environments and a modeling method that satisfies physical characteristics to simulate the dynamic breathing process and design an optimal reward function for the task of achieving efficient learning of the control strategy. We have carried out a large number of simulation experiments, and the error between the tracking of normal force and expected force is basically within ±0.5 N. The control strategy is tested in a real environment. The preliminary results show that the control strategy performs well in the constant force-tracking of medical auscultation tasks. The contact force is always within a safe and stable range, and the average contact force is about 5.2 N.

A comparison among RIRS and MiniPerc for renal stones between 10 and 20 mm using thulium fiber laser (Fiber Dust): a randomized controlled trial

We performed a prospective randomized comparison among Retrograde IntraRenal Surgery (RIRS) and MiniPerc (MP) for stones between 10 and 20mm to evaluate outcomes with the same laser device: Fiber Dust. Patients with a single renal stone between 10 and 20mm were randomized to RIRS (Group A) versus MP (Group B). Exclusion criteria were age < 18 or > 75, presence of acute infection, coagulation impairments, cardiovascular or pulmonary comorbidities. In both groups, the Fiber Dust laser was used. A CT scan after 3months was performed. A negative CT scan or asymptomatic patients with stone fragments < 3mm and a negative urinary culture were the criteria to assess the stone-free status. A statistical analysis was carried out to assess success, complication and retreatment rates and need for auxiliary treatments. Between January 2021 and January 2022, 186 patients were enrolled (90 in Group A and 96 in Group B). Mean stone size was 15.8mm and 14.9mm in Group A and B, respectively (p = 0.23). The overall stone-free rate (SFR) was 73.3% for Group A and 84.4% for Group B. A higher SFR was reached for upper calyceal stones in Group A (90.4%) lower calyceal stones in Group B (91.6%). Retreatment rate (p = 0.31) and auxiliary procedure rate (p = 0.18) were comparable. Complication rate was 5.5% and 5.2% for Groups A and B, respectively. RIRS and MP are both effective to obtain a postoperative SFR with Fiber Dust. According to the stone position one treatment is superior to the other one.

Clinical features and outcomes of leucine-rich glioma-inactivated protein 1 and contactin protein-like 2 antibody-associated autoimmune encephalitis in a Chinese cohort

The present study aimed to investigate the clinical manifestations, epidemiological characteristics, and outcomes of Chinese patients with voltage-gated potassium channel complex (VGKC) antibody–associated encephalitis. Patients diagnosed with VGKC antibody-associated encephalitis at our institution between January 2016 and December 2020 were included in this study. We retrospectively evaluated their clinical features, auxiliary examination results, treatments details, long-term outcomes, and risk factors for poor outcome. Of the 91 included patients, 61 (67.78%) were men and 30 (32.97%) were women. The most common clinical symptoms were seizures (n = 63, 69.23%), memory deficits (n = 62, 68.13%), mental behavioral disorders (n = 29, 31.87%), and hyponatremia (n = 57, 62.64%). Although patients with anti- leucine-rich glioma-inactivated 1 (LGI1) (n = 76) and anti- contactin-associated protein-like 2 (CASPR2) encephalitis (n = 15) had similar clinical manifestations, the former were more diverse. In total, 86 (94.51%) patients were treated with immunotherapy. Over a median follow-up period of 25 months, there were no mortalities and 14 (15.38%) patients experienced a relapse. Univariate analysis indicated differences in sex, modified Rankin Scale scores at onset, movement disorders, central hypoventilation, and intensive care unit occupancy between the good- and poor- outcome groups. Patients with anti-LGI1 and anti-CASPR2 encephalitis showed similar clinical manifestations while presenting delineating characteristics. Those with VGKC antibody-associated diseases generally responded well to immunotherapy and demonstrated favorable clinical outcomes. Several factors affected the prognosis, and a long-term follow-up examination is necessary.

DCAU-Net: dense convolutional attention U-Net for segmentation of intracranial aneurysm images

Segmentation of intracranial aneurysm images acquired using magnetic resonance angiography (MRA) is essential for medical auxiliary treatments, which can effectively prevent subarachnoid hemorrhages. This paper proposes an image segmentation model based on a dense convolutional attention U-Net, which fuses deep and rich semantic information with shallow-detail information for adaptive and accurate segmentation of MRA-acquired aneurysm images with large size differences. The U-Net model serves as a backbone, combining dense block and convolution block attention module (CBAM). The dense block is composed of a batch normalization layer, an randomly rectified linear unit activation function, and a convolutional layer, for mitigation of vanishing gradients, for multiplexing of aneurysm features, and for improving the network training efficiency. The CBAM is composed of a channel attention module and a spatial attention module, improving the segmentation performance of feature discrimination and enhancing the acquisition of key feature information. Owing to the large variation of aneurysm sizes, multi-scale fusion is performed during up-sampling, for adaptive segmentation of MRA-acquired aneurysm images. The model was tested on the MICCAI 2020 ADAM dataset, and its generalizability was validated on the clinical aneurysm dataset (aneurysm sizes: < 3 mm, 3–7 mm, and > 7 mm) supplied by the Affiliated Hospital of Qingdao University. A good clinical application segmentation performance was demonstrated.

Needle-perc-assisted endoscopic surgery for patients with complex renal stones: technique and outcomes.

Our aim was to investigate the safety and efficacy of needle-perc-assisted percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS), namely, needle-perc-assisted endoscopic surgery (NAES), in a series of patients with large and/or complex renal stones. From May 2018 to August 2021, a total of 119 patients underwent NAES at our institute. Among them, 94 patients underwent needle-perc-assisted standard PCNL in prone position and 25 underwent needle-perc-assisted RIRS in the Galdakao-modified supine Valdivia position or prone split-leg position. Clinical factors including age, sex, medical history, and stone characteristics were collected. Intraoperative and postoperative outcomes were retrospectively evaluated. The patients' mean age ± standard deviation was 50.3 ± 14.3years. The mean stone size was 7.6 ± 3.7 and 1.7 ± 0.8cm for needle-perc-assisted PCNL and RIRS, respectively. Of the 119 patients, 51 had staghorn stones, 16 had solitary kidneys, 17 had a history of ipsilateral renal surgery, and 6 had calyceal diverticular stones. The mean operative time was 83.4 ± 25.9min for needle-perc-assisted PCNL and 66.3 ± 21.8min for needle-perc-assisted RIRS. The stone-free rate (SFR) for needle-perc-assisted PCNL was 77.7% after the first treatment and 88.3% after auxiliary treatments. The SFR for needle-perc-assisted RIRS was 88.0% and no auxiliary treatments were carried out in this group. Eleven (11.7%) patients who underwent needle-perc-assisted standard PCNL developed Clavien-Dindo grade I or II complications. Three (12.0%) patients who underwent needle-perc-assisted RIRS developed a fever (grade I). The overall complication rate for NAES was 11.8%, with no urosepsis, angioembolization, or other grade III to V complications. In conclusion, NAES is a safe and effective procedure for one-step complete resolution of large and/or complex renal stones with no additional procedure-related complications.

Clinical Manifestations of Inferior Vena Cava Injuries and the Progress of Emergency Treatment.

In this paper, clinical manifestations of inferior vena cava injuries and the progress of emergency treatment are presented. Inferior vena cava (IVC) is the large vein returning venous blood from the lower limbs and pelvic and abdominal cavities to the right atrium of the heart. The clinical manifestations of IVC injuries include shock, progressive hemorrhage, air embolism, retroperitoneal hematoma, active bleeding, and hemoperitoneum. The patients may be combined or not combined with injuries to other organs or even die. Routine examination methods for IVC injuries include general examination, color Doppler ultrasound, abdominal contrast-enhanced CT, magnetic resonance spectroscopic imaging (MRSI), and IVC angiography. These examinations are usually performed to confirm the diagnosis. Surgical treatment is the primary emergency treatment for this condition. Increasing the blood volume and symptomatic treatment are auxiliary treatments. The surgeries and repairs for IVC injuries are currently under investigation. Experimental results have verified the exceptional performance of the proposed scheme.

Volume should be used instead of diameter for kidney stones between 10 and 20mm to determine the type of surgery and increase success.

Aim of this study is to categorize stones between 10 and 20mm according to stone diameter or volume and compare mini percutaneous nephrolithotomy (mPNL) and retrograde intrarenal surgery (RIRS) outcomes. Files of 515 patients who underwent surgery for kidney stones with sizes 10-20mm were reviewed. Patients were divided into RIRS or mPNL groups. An attempt was made to find the diameter and volume threshold values above which the success of the operation, complication rates and the number of auxiliary treatments deteriorated. Subgroup analysis was performed below and above the threshold value to reveal the optimal treatment methods. RIRS complications increased with volumes above 1064 mm3, number of auxiliary interventions increased with volumes above 1256 mm3, and success of the operation decreased with volumes above 1416 mm3. A subgroup analysis under and over 1064 mm3 was performed in RIRS group. Complication and auxiliary treatment rates were higher, operative success was lower in patients with a stone volume greater than 1064 mm3. In patients who underwent RIRS, for every 1000 mm3 increase in stone volume success of the operation decreased by 2.1 times, while the probability of auxiliary treatment increased by 2.8 times. In patients with kidney stones between 10 and 20mm, it is more meaningful to use volume instead of diameter to determine the success rate. When mPNL is used instead of RIRS for volumes greater than 1064 mm3, the success rate will be higher, complication rate will be similar, and the need for auxiliary treatment will be lower.

Update on overview of pterygium and its surgical management.

Pterygium is a bulbar conjunctival fibrovascular growth that crosses the limbus and extends onto the peripheral cornea, and in some cases leads to significant visual complications. The prevalence of this disease has been reported to be from 1.2% to about 40% in different parts of the world. Although there are various risk factors for pterygium, which include ultraviolet (UV) radiation, viral infection, hereditary factors, immune factors, aseptic inflammation, and environmental irritation, the pathogenesis of pterygium is mainly related to exposure to UV light. In addition to cosmetic problems, pterygium can lead to eye irritation, disrupt the transparency of cornea on the pupil area, and cause disorders such as corneal astigmatism and damage to the visual axis leading to vision impairment. In the last few years, the treatment of pterygium has been developed and various new solutions have been used. Surgery is the main treatment for pterygium. Various techniques such as Bare Sclera, Rotational Conjunctival Flap, Limbal Conjunctival Autograft, Amniotic Membrane Graft, and Free Conjunctival Autograft are used for the removal of pterygium. It also seems that the worrisome problem of recurrence has been significantly reduced with newer treatment methods. On the contrary, the use of auxiliary treatments such as mitomycin C, b-radiation, 5-fluorouracil, topical use of interferons, and Avastin are also effective in reducing the recurrence rate.

Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.

The discovery of immune checkpoints has been well known to provide novel clues for cancer treatments. Immunotherapy against the programmed cell death protein-1 (PD-1) /programmed death-ligand-1 (PD-L1), one of the most popular auxiliary treatments in recent years, has been applied in various tumor treatments, including non-small cell lung cancer (NSCLC). However, inevitable issues such as side effects and drug resistance emerge following the use of immune checkpoint inhibitors. The PI3K/AKT/mTOR pathway may participate in the regulation of PD-L1 expression. Abnormal PI3K/AKT/mTOR pathway activation results in increased PD-L1 protein translation, whereas PD-L1 overexpression can activate the PI3K/AKT/mTOR pathway inversely. Via downstream proteins, including 4E-BP1, STAT3, NF-κB, c-MYC, and AMPK in aberrant energy status, the PI3K/AKT/mTOR pathway can regulate PD-L1 post-transcription and translation. Besides, the regulation of the PI3K pathway by the PD-1/PD-L1 axis involves both tumor cells and the tumor immune microenvironment. Inhibitors targeting the PD-1/PD-L1 have been successfully applied in the treatment of gastrointestinal cancer and breast cancer. Meanwhile, drug resistance from alternative pathway activation also evidently affects clinical progress. To achieve a better therapeutic effect and quality of survival, the combination of multiple treatment modalities presents great research value. Here we reviewed the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in the progression and treatment of NSCLC and summarized its clinical implications. The intracellular interactions between PD-1/PD-L1 and the PI3K/AKT/mTOR pathway indicate that PD-1/PD-L1 inhibitors have a wide range of potential applications. And we presented the mechanism for combining therapy with monoclonal antibody PD-1/PD-L1 and PI3K/AKT/mTOR inhibitors in this review, to broaden the therapies for NSCLC.

Systematic review of drugs that modify the circadian system's phase-shifting responses to light exposure.

We searched PubMed for primary research quantifying drug modification of light-induced circadian phase-shifting in rodents. This search, conducted for work published between 1960 and 2018, yielded a total of 146 papers reporting results from 901 studies. Relevant articles were those with any extractable data on phase resetting in wildtype (non-trait selected) rodents administered a drug, alongside a vehicle/control group, near or at the time of exposure. Most circadian pharmacology experiments were done using drugs thought to act directly on either the brain's central pacemaker, the suprachiasmatic nucleus (SCN), the SCN's primary relay, the retinohypothalamic tract, secondary pathways originating from the medial/dorsal raphe nuclei and intergeniculate leaflet, or the brain's sleep-arousal centers. While the neurotransmitter systems underlying these circuits were of particular interest, including those involving glutamate, gamma-aminobutyric acid, serotonin, and acetylcholine, other signaling modalities have also been assessed, including agonists and antagonists of receptors linked to dopamine, histamine, endocannabinoids, adenosine, opioids, and second-messenger pathways downstream of glutamate receptor activation. In an effort to identify drugs that unduly influence circadian responses to light, we quantified the net effects of each drug class by ratioing the size of the phase-shift observed after administration to that observed with vehicle in a given experiment. This allowed us to organize data across the literature, compare the relative efficacy of one mechanism versus another, and clarify which drugs might best suppress or potentiate phase resetting. Aggregation of the available data in this manner suggested that several candidates might be clinically relevant as auxiliary treatments to suppress ectopic light responses during shiftwork or amplify the circadian effects of timed bright light therapy. Future empirical research will be necessary to validate these possibilities.