CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Effects of Breathing Patterns on Amide Proton Transfer MRI in the Kidney: A Preliminary Comparative Study in Healthy Volunteers and Patients With Tumors.

BACKGROUND: The amide proton transfer-weighted (APTw) imaging for kidney diseases is important. However, the breathing patterns on APTw imaging remains unexplored. PURPOSE: This study aimed to investigate the effects of intermittent breath-hold (IBH) and free breathing (FB) on renal 3D-APTw imaging. STUDY TYPE: Healthy volunteers were enrolled prospectively, and renal clear cell carcinoma (RCCC) patients were included retrospectively. POPULATION: 58 healthy volunteers and 10 RCCC patients. FIELD STRENGTH/SEQUENCE: 3-T, turbo spin echo, and fast field echo. ASSESSMENT: 3D-APTw imaging was scanned using the IBH and FB methods in volunteers and using the IBH method in RCCC patients. The image quality was evaluated by three observers according to the 5-point Likert scale. Optimal images rated at three points or higher were used to measure the APT values. STATISTICAL ANALYSIS: The measurement repeatability was assessed using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. The APT values were analyzed using McNemar's test, one-way analysis of variance, and t test. RESULTS: 50 healthy volunteers and 8 RCCC patients were enrolled. Renal 3D-APTw imaging using the IBH method revealed a higher success rate (88% vs 78%). The ICCs were excellent in the IBH group (ICCs > 0.74) and were good in the FB group (ICCs < 0.74). No significant differences in the APT values among various zones using the IBH (P = 0.263) or FB method (P = 0.506). The mean APT value using the IBH method (2.091% ± 0.388%) was slightly lower than the FB method (2.176% ± 0.292%), but no significant difference (P = 0.233). The APT value of RCCC (4.832% ± 1.361%) was considerably higher than normal renal using the IBH method. CONCLUSIONS: The study demonstrated that the IBH method substantially increased the image quality of renal 3D-APTw imaging. Furthermore, APT values may vary between normal and tumor tissues. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Effects of high incubation temperature on tight junction proteins in the yolk sac and small intestine of embryonic broilers.

During the transition from incubation to hatch, the chicks shift from obtaining nutrients from the yolk sac to the intestine. The yolk sac tissue (YST) and small intestine serve as biological barriers between the yolk or gut contents and the blood circulation. These barriers must maintain structural integrity for optimal nutrient uptake as well as protection from pathogens. The objective of this study was to investigate the effect of high incubation temperature on mRNA abundance of the tight junction (TJ) proteins zona occludens 1 (ZO1), occludin (OCLN), claudin 1 (CLDN1), and junctional adhesion molecules A and 2 (JAMA, JAM2) and the heat shock proteins (HSP70 and HSP90) in the YST and small intestine of embryonic broilers. Broiler eggs were incubated at 37.5°C. On embryonic day 12 (E12), half of the eggs were switched to 39.5°C. YST samples were collected from E7 to day of hatch (DOH), while small intestinal samples were collected from E17 to DOH. The temporal expression of TJ protein mRNA from E7 to DOH at 37.5°C and the effect of incubation temperature from E13 to DOH were analyzed by one-way and two-way ANOVA, respectively and Tukey's test. Significance was set at P < 0.05. The temporal expression pattern of ZO1, OCLN, and CLDN1 mRNA showed a pattern of decreased expression from E7 to E13 followed by an increase to DOH. High incubation temperature caused an upregulation of ZO1 and JAM2 mRNA in the YST and small intestine. Using in situ hybridization, OCLN and JAMA mRNA were detected in the epithelial cells of the YST. In addition, JAMA mRNA was detected in epithelial cells of the small intestine, whereas JAM2 mRNA was detected in the vascular system of the villi and lamina propria. In conclusion, the YST expressed mRNA for TJ proteins and high incubation temperature increased ZO1 and JAM2 mRNA. This suggests that the TJ in the vasculature of the YST and intestine is affected by high incubation temperature.

[Analysis on survival time and influencing factors among reported HIV/AIDS in Yunnan Province, 1989-2021].

Objective: To analyze the survival time of reported HIV/AIDS and influencing factors of Yunnan Province from 1989 to 2021. Methods: The data were extracted from the Chinese HIV/AIDS comprehensive response information management system. The retrospective cohort study was conducted. The life table method was applied to calculate the survival probability. Kaplan-Meier was used to draw survival curves in different situations. Furthermore, the Cox proportion hazard regression model was constructed to identify the factors related to survival time. Results: Of the 174 510 HIV/AIDS, the all-cause mortality density was 4.23 per 100 person-years, the median survival time was 20.00 (95%CI:19.52-20.48) years, and the cumulative survival rates in 1, 10, 20, and 30 years were 90.75%, 67.50%, 47.93% and 30.85%. Multivariate Cox proportional risk regression model results showed that the risk of death among 0-14 and 15-49 years old groups were 0.44 (95%CI: 0.34-0.56) times and 0.51 (95%CI:0.50-0.52) times of ≥50 years old groups. The risk for death among the first CD4+T lymphocytes counts (CD4) counts levels of 200-349 cells/µl, 350-500 cells/µl and ≥501 cells/µl groups were 0.52 (95%CI: 0.50-0.53) times, 0.41 (95%CI: 0.40-0.42) times and 0.35 (95%CI: 0.34-0.36) times of 0-199 cells/µl groups. The risk of death among the cases that have not received antiretroviral therapy (ART) was 11.56 (95%CI: 11.26-11.87) times. The risk for death among the cases losing to ART, stopping to ART, both losing and stopping ART was 1.66 (95%CI:1.61-1.72) times, 2.49 (95%CI:2.39-2.60) times, and 1.65 (95%CI:1.53-1.78) times of the cases on ART. Conclusions: The influencing factors for the survival time of HIV/AIDS cases were age at diagnosis in Yunnan province from 1989 to 2021. The first CD4 counts levels, antiretroviral therapy, and ART compliance. Early diagnosis, early antiretroviral therapy, and increasing ART compliance could extend the survival time of HIV/AIDS cases.

[Pathological features of early gastric cancer and its background mucosa after eradication of Helicobacter pylori and their implications for biopsy diagnosis].

Objective: To investigate the clinicopathological changes of early gastric cancer, especially its background mucosa, after the eradication of Helicobacter pylori (H. pylori), and to investigate the causes of underdiagnosis in preoperative biopsy pathology. Methods: Ninety cases of early gastric cancer after H. pylori eradication and 120 cases of endoscopic submucosal dissection (ESD) specimens without H. pylori eradication and their corresponding biopsy specimens were collected from Beijing Friendship Hospital Affiliated to Capital Medical University during 2016-2021. The clinicopathological data of the patients were analyzed, and the histopathological characteristics and immunophenotypic results compared. Results: Compared with the early gastric cancer without H. pylori eradication history, the histopathological type of early gastric cancer after H. pylori eradication was differentiated adenocarcinoma, with staggered distribution of cancerous and non-cancerous epithelium in the tumor area. The morphologic characteristics of gastric mucosa in the background of early gastric cancer after H. pylori eradication, were distinctive, including widening of the opening of enterosylated glandular ducts, serrated change of luminal margin, eosinophilic and microvesicular cytoplasm of enterosylated epithelium. Low-grade atypia existed in gastric cancer epithelial cells after sterilization, which might lead to underdiagnosis or missed diagnosis in biopsy pathology. Conclusions: Early gastric cancer and its background mucosa after H. pylori eradication have unique morphological characteristics, which can be used as a clue for pathological diagnosis, improve the accuracy of biopsy pathology and reduce the underdiagnosis.

[The value of vaccines from the perspective of population medicine].

Vaccination is one of the most effective, broad-reach, and cost-effective public health initiatives to fight against infectious diseases. From the perspective of population medicine, this article systematically elaborates on the value of vaccines in preventing infections, reducing disease incidence, decreasing disability and severe cases, lowering mortality rates, improving population health and life expectancy, reducing antibiotic use and resistance, as well as promoting fairness in public health services. Based on the current situation, the following recommendations are proposed: first, strengthen scientific research to provide a solid foundation for related policy-making; second, increase the coverage rate of non-national immunization program vaccines; third, promote the inclusion of more appropriate vaccines in the national immunization program; fourth, strengthen the research and development of new vaccines; and fifth, increase talent training in the field of vaccinology.

Temporal expression of avian ß defensin 10 and cathelicidins in the yolk sac tissue of broiler and layer embryos.

The yolk sac is a multifunctional organ, which not only participates in nutrient absorption, but also plays an important role in immune function. The objective of this study was to compare the mRNA abundance of avian ß-defensin 10 (AvBD10) and 3 cathelicidins (CATH1, CATH2, and CATH3) in the yolk sac tissue (YST) of commercial broilers and white egg and brown egg commercial layers. AvBD10 and CATH mRNA abundance was analyzed using two-way ANOVA and Tukey's test, with P < 0.05 being considered significant. AvBD10 and CATH mRNA showed similar temporal expression patterns in the YST of both broiler and layers, with an increase from embryonic day (E) 7 to E9 through E13 followed by a decrease to day of hatch. AvBD10 mRNA showed a breed × age interaction with greater expression in the YST of both layers compared to broilers at E9 and E11. CATH1 mRNA was greater in the YST of brown egg layers than broilers. CATH2 mRNA showed a breed × age interaction, with greater expression in the YST of brown egg layers than broilers at E11. CATH3 mRNA showed no difference in the YST between layers and broilers. Because broilers and brown egg layers are genetically related, these results show that selection for production parameters (broiler vs. layer) and not genetic relatedness (white egg layer vs. brown egg layer and broilers) is the basis for the differences in AvBD10, CATH1, and CATH2 mRNA in the YST of broilers and layers. The yolk-free body weights of broiler embryos were greater than that of both brown and white egg layers from E9 to 17. One possible explanation is that the reduced expression of AvBD10, CATH1 and CATH2 mRNA in the YST of broilers compared to layers at E9 and 11 may be due to faster embryonic growth at the expense of host defense peptide expression in broilers compared to layers.

[Application of pretrained model based on electronic medical record in recognition of acute respiratory infection].

Objective: To evaluate the recognition of acute respiratory infection (ARI) by a pretrained model based on electronic medical records (EMRs). Methods: 38 581 EMRs were obtained from Chongqing University Three Gorges Hospital in December 2021. Bidirectional encoder representation from transformers (BERT) pretrained model was used to identify ARI in EMRs. The results of medical professionals were considered as the gold standard to calculate the sensitivity, specificity, Kappa value, and area under the curve of the receiver operating characteristic (AUC). Results: There were 3 817 EMRs in the test set, with 1 200 ARIs. A total of 1 205 cases were determined as ARI by the model, with a sensitivity of 92.67% (1 112/1 200) and a specificity of 96.45% (2 524/2 617). The model identified ARI with similar accuracy in males and females (AUCs 0.95 and 0.94, respectively), and was more accurate in identifying ARI cases in those aged less than 18 than in adults 18-59 and adults 60 and older (AUCs 0.94, 0.89 and 0.94, respectively). The current model had a better identification of ARIs in outpatient patients than that in hospitalized patients, with AUCs of 0.74 and 0.95, respectively. Conclusion: The use of the BERT pretrained model based on EMRs has a good performance in the recognition of ARI cases, especially for the outpatients and juveniles. It shows a great potential to be applied to the monitoring of ARI cases in medical institutions.

Baicalin Induced Apoptosis of Human Cholangiocarcinoma Cell through Activating AMPK/mTORC1/p70S6K Signaling Pathway.

Baicalin (naturally bioactive flavone compound isolated from Scutellaria baicalensis) has been demonstrated to exert strong anticancer activity against various tumor cells. However, the possibility of using baicalin for the treatment of cholangiocarcinoma and its effectiveness remain unstudied. The effect of baicalin on QBC939 cholangiocarcinoma cell culture was studied by assessing cell viability (CCK-8 test) and expression of the key proteins (Western blotting). Baicalin induced apoptosis of QBC939 cells in culture in a dose- and time-dependent manner. The proapoptotic effect was attributed to inhibition of the mTORC1-p70S6K signaling pathway resulting from baicalin-induced AMPK activation. These findings provide a new approach for cholangiocarcinoma treatment and serve as a basis for developing baicalin-based combination cancer therapy strategies.

[Current status and research advances on drug sedation and analgesia in burn children].

Children are high-risk groups of burns, with unique physiological, psychological, and anatomical states, and the management of anxiety and pain for burn children are extremely challenging. Non-pharmacological interventions are very important for pain management in burn children, but are often inadequate for treating pain and anxiety, so pharmacological sedation and analgesia are necessary. This article reviewed the clinical treatment and research progress in this field in the past 10 years at home and abroad, including the pain assessment of burn children, monitoring in sedative and analgesic treatment, main therapeutic drugs and research progress, and some controversies in clinical practice. Besides, some suggestions have been put forward for clinical reference.

Diagnostic magnetic resonance imaging in synovial chondromatosis of the temporomandibular joint.

The aim of this paper was to investigate the clinical and magnetic resonance imaging (MRI) features of synovial chondromatosis (SC) of the temporomandibular joint (TMJ). Fourteen patients with SC of the TMJ were included in the study. Clinical and MRI features were analysed and divided into three types based on MRI classification: type I with loose bodies, type II with homogeneous masses, and type III with a mixture of loose bodies and homogeneous masses. All SCs occurred in the superior compartment of the TMJ. There were two patients (14%) categorised as type I, five (36%) as type II and seven (50%) as type III. Four patients (29%) had disc perforation, and nine had bone erosion; among those nine, seven (78%) had type III and two (22%) type II. Histological examination showed inflammation and calcification in the synovial membrane and, and cartilage of the hyaline type in all cases. MRI has advantages in the diagnosis of SC.

Successful use of tofacitinib in epidermolysis bullosa pruriginosa.

This case report describes 26-year-old woman who had multiple clusters of pale-pink lichenoid papules since childhood and the accompanying itching was intense. Skin biopsy revealed obvious fissures had formed under the epidermis. The patient was diagnosed with epidermolysis bullosa pruriginosa and was successfully treated with tofacitinib.

[Evaluation of demand of resources for laboratory testing and prevention and control of COVID-19 in the context of global pandemic].

Objective: To rapidly evaluate the level of healthcare resource demand for laboratory testing and prevention and control of corona virus disease 2019 (COVID-19) in different epidemic situation, and prepare for the capacity planning, stockpile distribution, and funding raising for infectious disease epidemic response. Methods: An susceptible, exposed, infectious, removed infectious disease dynamics model with confirmed asymptomatic infection cases and symptomatic hospitalized patients was introduced to simulate different COVID-19 epidemic situation and predict the numbers of hospitalized or isolated patients, and based on the current COVID-19 prevention and control measures in China, the demands of resources for laboratory testing and prevention and control of COVID-19 were evaluated. Results: When community or local transmission or outbreaks occur and total population nucleic acid testing is implemented, the need for human resources is 3.3-89.1 times higher than the reserved, and the current resources of medical personal protective equipment and instruments can meet the need. The surge in asymptomatic infections can also increase the human resource demand for laboratory testing and pose challenge to the prevention and control of the disease. When vaccine protection coverage reach ≥50%, appropriate adjustment of the prevention and control measures can reduce the need for laboratory and human resources. Conclusions: There is a great need in our country to reserve the human resources for laboratory testing and disease prevention and control for the response of the possible epidemic of COVID-19. Challenges to human resources resulted from total population nucleic acid testing and its necessity need to be considered. Conducting non-pharmaceutical interventions and encouraging more people to be vaccinated can mitigate the shock on healthcare resource demand in COVID-19 prevention and control.

[Elimination of infectious disease in China, past and future].

In the long history, infectious disease once caused huge disasters to human beings, not only resulting in serious impacts on public health, but even threatening socioeconomic development and national security. Since the founding of the People's Republic of China, China has attached great importance to the prevention and treatment of infectious disease and achieved remarkable achievements. This article mainly summarizes the historical progresses of the eradication of smallpox and the eliminations of polio, leprosy, filariasis, neonatal tetanus, blinding trachoma and malaria in China, and discusses the eliminations of the infectious diseases which can be conducted in the future.

[Clinical effect evaluation of high risk human papilloma virus E6/E7 mRNA in triaging women with atypical squamous cells of undetermined significance].

Objective: To evaluate the performance of high risk human papilloma virus (HR-HPV) E6/E7 mRNA in triaging women with atypical squamous cells of undetermined signification (ASCUS). Methods: The ASCUS cohort determined by liquid-based cytology test in the cervical cancer screening queue in Luoshan County, Xinyang City, Henan Province 2017 were selected. The population underwent colposcopy biopsy and pathological tests, combined with HPV16 or 18 (HPV16/18), HR-HPV DNA and HPV E6/E7 mRNA test. By using the pathological result as the gold standard, the sensitivity, specificity, positive predictor (PPV), negative prediction (NPV), referral rate and 95% confident interval (CI) of HPV E6/E7 mRNA, HR-HPV DNA, HPV16/18 were calculated, respectively. Results: The average age of 312 ASCUS women was 52.6±7.3 years old. Among the 290 women diagnosed as normal by pathology, 64 (22.1%) were HPV E6/E7 mRNA positive, 86 (29.7%) were HR-HPV DNA positive, and 19 (6.6%) were HPV16/18 positive. All of the cervical intraepithelial neoplasia (CIN) cases determined by pathology were both HPV E6/E7 mRNA and HR-HPV DNA positive. The sensitivity, specificity, PPV, NPV and referral rate of HPV E6/E7 mRNA for predicting CIN2+ lesion in women with ASCUS were 100.0% (95%CI: 72.3, 100.0), 77.8% (95%CI: 72.8, 82.1), 13.0% (95%CI: 7.2, 22.3), 100.0% (95%CI: 98.4, 100.0) and 24.7%. Compared with HPV E6/E7 mRNA, the sensitivity of HR-HPV DNA was similar with HPV E6/E7 mRNA, but with a lower specificity [70.2% (95%CI: 64.8, 75.1), P<0.05], a higher referral rate (32.1%, P<0.05); while HPV 16/18 had a high specificity (93.4%, 95%CI: 90.0, 95.7) and a low sensitivity (30.0%, 95%CI: 10.8, 60.3). Based on the age stratification by age 45, the sensitivity of HPV E6/E7 mRNA in both age groups was 100.0%. The specificity of HPV E6/E7 mRNA in group of ≥45 years was a little higher than that in group of <45 years [79.0% (95%CI: 73.7, 83.5) versus 68.3% (95% CI: 53.0, 80.4)], but the difference was not statistically significant (P>0.05). Conclusions: The ASCUS woman triaging effect of HPV E6/E7 mRNA detection is better than those of HR-HPV and HPV16/18 under certain conditions. The application of HPV E6/E7 mRNA detection to triage ASCUS population can avoid unnecessary colposcopy referral and reduce the missed diagnosis of cervical lesions.

High dose insulin promotes the proliferation of vascular smooth muscle cells via AP-1/SM-α pathway.

Proliferation of vascular smooth muscle cells (VSMCs) participates in multiple cardiovascular disorders, while the mechanism remains unclear. This study aims to investigate the effects of insulin on VSMC. Insulin was used to stimulate rat VSMCs, and the effects on cell cycle and proliferation were subsequently analyzed using flow cytometry. Furthermore, AP-1 and SM-α overexpression vectors were constructed and transfected into VSMCs. AP-1 and SM-α were inhibited by SR11302 and SM-α siRNA, respectively. The mRNA and protein expression levels were subsequently detected using the reversetranscription quantitative polymerase chain reaction and western blotting, respectively. AP-1 and SM-α gene promoter binding sites were determined using luciferase and chromatin immunoprecipitation assays. As a result, we found that high dose of insulin promoted proliferation of VSMCs and increased the percentage of cells in the S phase by downregulating AP-1. AP-1 was identified to bind to the SM-α gene promoter at locus 2-177 to upregulate SM-α gene expression. Inhibition of AP-1 led to the decrease of SM-α expression. Overexpression of SM-α directly suppressed proliferation of VSMCs, while knocking it down promoted the process. Therefore, this study revealed that insulin downregulated the expression of the SM-α gene by inhibiting AP-1, which in turn facilitated proliferation of VSMCs.

Research Note: Intestinal morphology and gene expression changes in broilers supplemented with lysolecithin.

Lysolecithin is used as a feed additive to aid fat digestion and absorption in broiler chickens. Previous research has shown that dietary fat source influences how broilers respond to lysolecithin supplementation. Therefore, the objective of this study was to investigate the effect of lysolecithin on a diet formulated with soybean oil on jejunum morphology and expression of selected genes in broiler chickens. Male Cobb 500 chickens were fed a Control diet or the Control diet supplemented with lysolecithin (TRT) from day of hatch to day 28. Jejunal samples were collected at day 10 for morphological and gene expression analysis. Feeding the TRT diet did not affect BW, villus height (VH), crypt depth (CD) or VH/CD ratio compared to Control fed chickens. Differential gene expression in the jejunum was analyzed using a custom microarray. Using a t test, 36 genes were found to be upregulated in TRT fed chickens compared to chickens fed the Control diet. The two most upregulated genes were carbonic anhydrase VII and interleukin 8-like 2, which are associated with healthy intestines. In summary, lysolecithin supplementation in a diet formulated with soybean oil caused no morphological changes but upregulated a number of genes in the jejunum.

Fluctuation in red cell distribution width predicts disseminated intravascular coagulation morbidity and mortality in sepsis: a retrospective single-center study.

BACKGROUND: Red cell distribution width (RDW) values increase in many diseases and conditions, including sepsis. However, the relationship between RDW fluctuation and prognosis in patients with sepsis or the likely morbidity associated with sepsis-induced disseminated intravascular coagulation (DIC) has not been previously investigated. This study examined the association between dynamic changes to RDW and DIC occurrence in sepsis, as well as the prognostic significance of changes to RDW during hospital stay in patients with sepsis. METHODS: We collected baseline emergency department admissions' data. All RDW values recorded during hospitalization of patients with sepsis were combined to calculate RDW standard deviation (RDW-SD) and the increase rate of RDW; we also collected data on coagulation indicators. The endpoints were 28-day mortality and sepsis-related DIC morbidity. RESULTS: Of 232 patients included in our analysis, 66 were diagnosed with DIC (28.4%), and 86 (37.1%) died within 28 days. The RDW-SD and the increase rate of RDW were independent risk factors for 28-day mortality and sepsis-associated DIC morbidity, respectively. The DIC occurrence and mortality rate increased continually with an increasing rate of RDW of at least 6%. CONCLUSIONS: The RDW-SD and RDW increase rate shown in the study as the indicators of RDW fluctuation can help predict sepsis-related DIC morbidity and prognosis in patients with sepsis.