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Abstract Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research.

Vaccination-route-dependent adjuvanticity was identified as being associated with the specific features of antigen-carrying nanoparticles (NPs) in the present work. Here, we demonstrated that the mechanical properties and the decomposability of NP adjuvants play key roles in determining the antigen accessibility and thus the overall vaccine efficacy in the immune system when different vaccination routes were employed. We showed that soft nano-vaccines were associated with more efficient antigen uptake when administering subcutaneous (S.C.) vaccination, while the slow decomposition of hard nano-vaccines promoted antigen uptake when intravenous (I.V.) vaccination was employed. In comparison to the clinically used aluminum (Alum) adjuvant, the NP adjuvants were found to stimulate both humoral and cellular immune responses efficiently, irrespective of the vaccination route. For vaccination via S.C. and I.V. alike, the NP-based vaccines show excellent protection for mice from Staphylococcus aureus (S. aureus) infection, and their survival rates are 100% after lethal challenge, being much superior to the clinically used Alum adjuvant.

Understanding the mutation landscape of cancer may enable the development of more targeted therapies. Here, the authors sequence a panel of genes in a large Asian cohort and compare to American cohorts and find 64% of the Asian patients have actionable mutations.

The aim of this study was to evaluate the effects of replacing fish meal (FM) or soy protein concentrate (SPC) with wheat gluten on growth performance, feed utilization, and nutrient digestibility and retention in Japanese seabass (Lateolabrax japonicus). Seven isonitrogenous (441–456 g kg−1 crude protein) and isocaloric (21.5–22.0 MJ kg−1 gross energy) diets were produced to replace 0%, 33.3%, 66.7% and 100% of FM or SPC with a mixture of wheat gluten, wheat, and taurine (GWT, 77.5% wheat gluten, 20.5% wheat and 2.0% taurine). The gradual replacement of protein in FM with GWT had no significant effects on feed intake, whole-body composition, and the hepatosomatic and viscerosomatic indices, but resulted in a linear decrease in the weight gain rate, feed efficiency, and retention of nitrogen, energy, and essential amino acids (Arg, His, Ile, Leu, Lys, Met, Phe, Thr, and Val). The apparent digestibility of most essential amino acids (Cys, His, Leu, Lys, and Phe) and total amino acids increased linearly. Replacement protein in SPC with GWT had no significant effects on feed intake, growth, the feed conversion ratio, whole-body composition, and the hepatosomatic index, but resulted in a linear decrease in nitrogen, energy, and Met retention; the digestibility of Cys and Met increased linearly. Overall, wheat gluten is a more effective alternative for replacing protein in SPC than FM.

Nanoparticles have been identified in numerous studies as effective antigen delivery systems that enhance immune responses. However, it remains unclear whether this enhancement is a result of increased antigen uptake when carried by nanoparticles or the adjuvanticity of the nanoparticle carriers. Consequently, it is important to quantify antigen uptake by dendritic cells in a manner that is free from artifacts in order to analyze the immune response when antigens are carried by nanoparticles. In this study, we demonstrated several scenarios (antigens on nanoparticles or inside cells) that are likely to contribute to the generation of artifacts in conventional fluorescence-based quantification. Furthermore, we developed the necessary assay for accurate uptake quantification. PLGA NPs were selected as the model carrier system to deliver EsxB protein (a Staphylococcus aureus antigen) in order to testify to the feasibility of the established method. The results showed that for the same antigen uptake amount, the antigen delivered by PLGA nanoparticles could elicit 3.6 times IL-2 secretion (representative of cellular immune response activation) and 1.5 times IL-12 secretion (representative of DC maturation level) compared with pure antigen feeding. The findings above give direct evidence of the extra adjuvanticity of PLGA nanoparticles, except for their delivery functions. The developed methodology allows for the evaluation of immune cell responses on an antigen uptake basis, thus providing a better understanding of the origin of the adjuvanticity of nanoparticle carriers. Ultimately, this research provides general guidelines for the formulation of nano-vaccines.

Background: Intervertebral disc degeneration (IDD) entails complex pathological changes and causes lower back pain (LBP). However, there is still a lack of understanding of the mechanisms involved in IDD, particularly regarding the roles of autophagy and ferroptosis. The current study used microarray data to investigate the pathogenesis of IDD and potential biomarkers related to autophagy and ferroptosis in IDD.Methods: Differentially expressed genes (DEGs) were identified by analyzing the mRNA and miRNA expression profiles of IDD patients from the Gene Expression Omnibus (GEO). The protein-protein interaction network, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were utilized. The Human Autophagy Database (HADb) and Ferroptosis Database were used in conjunction with hub genes to identify autophagy- and ferroptosis-related genes. The Transcription Factor -hub gene-miRNA network was constructed. Lastly, the expression of DEGs in normal and degenerated nucleus pulposus cells (NPCs) was investigated via the quantitative reverse transcription polymerase chain reaction (qRT-PCR).Results: A total of 362 DEGs associated with IDD were identified. GO and KEGG analyses indicated that oxidative stress, extracellular matrix, PI3K-AKT signaling pathway, and ferroptosis were key factors in IDD occurrence. GSEA indicated that IDD was associated with changes in autophagy, iron ion homeostasis, extracellular matrix, and oxidative stress. Eighty-nine hub genes were obtained, including five that were autophagy-related and three that were ferroptosis-related. Of these, TP53 and SESN2 were the intersections of autophagy- and ferroptosis-related genes. In qRT-PCR analysis, CANX, SLC38A1, and TP53 were downregulated in degenerative NPCs, whereas GNAI3, SESN2, and VAMP3 were upregulated.Conclusion: The current study revealed aspects of autophagy- and ferroptosis-related genes involved in IDD pathogenesis, warranting further investigation.

BackgroundTalaromycosis is an invasive endemic mycosis caused by the dimorphic fungus Talaromyces marneffei (T. marneffei, TM). It mainly affects immunodeficient patients, especially HIV-infected individuals, which causes significant morbidity and mortality. Culture-based diagnosis takes a long turnaround time with low sensitivity, leading to treatment delay. In this study, we aimed to evaluate the performance of Metagenomic Next-Generation Sequencing (mNGS) for the rapid diagnosis of talaromycosis in HIV-infected patients.MethodsRetrospectively analysis was conducted in HIV-infected cases at Changsha First Hospital (China) from January 2021 to March 2022. Patients who underwent routine microbiological examination and mNGS testing in parallel were enrolled. The clinical final diagnosis was used as a reference standard, and cases were classified into the TM group (60 cases) and the non-TM group (148 cases). The clinical performances of mNGS were compared with culture and serum Galactomannan (GM). The mixed infections detected by mNGS were analyzed. The impact of mNGS detection on treatment was also investigated.ResultsThe sensitivity of mNGS test reached 98.3% (95% CI, 89.8-99.9), which was significantly higher than culture (66.7% [95% CI, 53.2-77.9], P < 0.001) and serum GM (83.3% [95% CI, 71.0-91.2], P < 0.05). The specificity of 98.6% (95% CI, 94.7-99.7) was similar to culture (100.0% [95% CI, 96.8-100.0], P = 0.156), and superior to serum GM (91.9% [95% CI, 85.9-95.5], P < 0.05). In bronchoalveolar lavage fluid (BALF) samples, the positive rate of mNGS was 97.6%, which was significantly higher than culture (28.6%, P

Abstract Background Village clinic doctors (VCDs) are part of the health service force in rural China. VCDs’ job satisfaction (JS) is important to the stability of the three-tiered health service system. Since 2009, the Chinese government launched a new health care system reform (NHCSR) which affected VCDs significantly. This study aimed to analysing the effect of NHCSR on JS among VCDs. Methods All the data came from three surveys in Shandong Province conducted in 2012, 2015 and 2018. In 2012, an originally designed questionnaire was used to conduct a baseline survey of 405 VCDs from 27 townships in nine counties. In 2015 and 2018, 519 and 223 VCDs in the same counties were surveyed with the same questionnaire. Descriptive analysis and ANOVA were used to analyse the level and changes in VCDs’ JS. Results The mean scores of VCDs’ total JS were 2.664 ± 1.069, 3.121 ± 0.931 and 2.676 ± 1.044 in 2012, 2015 and 2018, respectively, with a significant difference (F = 28.732, P

Abstract Background Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. Methods Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. Results Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. Conclusions FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

Highly sensitive staphylococcal enterotoxin B (SEB) assay is of great importance for the prevention of toxic diseases caused by SEB. In this study, we present a gold nanoparticle (AuNP)-linked immunosorbent assay (ALISA) for detecting SEB in a sandwich format using a pair of SEB specific monoclonal antibodies (mAbs) performed in microplates. First, the detection mAb was labeled with AuNPs of different particle sizes (15, 40 and 60 nm). Then the sandwich immunosorbent assay for SEB detection was performed routinely in a microplate except for using AuNPs-labeled detection mAb. Next, the AuNPs adsorbed on the microplate were dissolved with aqua regia and the content of gold atoms was determined by graphite furnace atomic absorption spectrometry (GFAAS). Finally, a standard curve was drawn of the gold atomic content against the corresponding SEB concentration. The detection time of ALISA was about 2.5 h. AuNPs at 60 nm showed the highest sensitivity with an actual measured limit of detection (LOD) of 0.125 pg/mL and a dynamic range of 0.125–32 pg/mL. AuNPs at 40 nm had an actual measured LOD of 0.5 pg/mL and a dynamic range of 0.5 to 128 pg/mL. AuNPs at 15 nm had an actual measured LOD of 5 pg/mL, with a dynamic range of 5–1280 pg/mL. With detection mAb labeled with AuNPs at 60 nm, ALISA’s intra- and interassay coefficient variations (CV) at three concentrations (2, 8, and 20 pg/mL) were all lower than 12% and the average recovery level was ranged from 92.7% to 95.0%, indicating a high precision and accuracy of the ALISA method. Moreover, the ALISA method could be successfully applied to the detection of various food, environmental, and biological samples. Therefore, the successful establishment of the ALISA method for SEB detection might provide a powerful tool for food hygiene supervision, environmental management, and anti-terrorism procedures and this method might achieve detection and high-throughput analysis automatically in the near future, even though GFAAS testing remains costly at present.

Abstract Acidic pH of lysosomes is closely related to autophagy; thus, well known of the precise lysosomes, pH changes will give more information on the autophagy process and status. So far, however, only pH changes in a relatively broad range could be indicated, the exact lysosomes pH detection has never arrived. In our study, we established an endo/lysosome pH indicator based on the self-decomposable SiO2 nanoparticle system with specific synthesis parameters. The central concentrated methylene blue (MB) in the central-hollow structural nanoparticles presented sensitive release as a function of pH values from pH 4.0–4.8, which is exactly the pH range of lysosomes. The linear correlation of the optical density (OD) values and the pH values has been built up, which has been used for the detection of lysosomes pH in 6 different cell lines. Moreover, by this system, we succeeded in precisely detecting the pH average changes of lysosomes before and after black mesoporous silicon (BPSi) NP endocytosis, clarifying the mechanism of the autophagy termination after BPSi endocytosis. So, the self-decomposable nanoparticle-based luminal pH indicator may provide a new methodology and strategy to know better of the lysosome pH, then indicate more details on the autophagy process or other important signaling about metabolisms.

ABSTRACTCOVID-19 is caused by SARS-CoV-2 infection and was initially discovered in Wuhan. This outbreak quickly spread all over China and then to more than 20 other countries. SARS-CoV-2 fluorescent microsphere immunochromatographic test strips were prepared by the combination of time-resolved fluorescence immunoassay with a lateral flow assay. The analytical performance and clinical evaluation of this testing method was done and the clinical significance of the testing method was verified. The LLOD of SARS-CoV-2 antibody IgG and IgM was 0.121U/L and 0.366U/L. The specificity of IgM and IgG strips in healthy people and in patients with non-COVID-19 disease was 94%, 96.72% and 95.50%, 99.49%, respectively; and sensitivity of IgM and IgG strips for patients during treatment and follow-up was 63.02%, 37.61% and 87.28%, 90.17%, respectively. The SARS-CoV-2 antibody test strip can provide rapid, flexible and accurate testing, and is able to meet the clinical requirement for rapid on-site testing of virus. The ability to detect IgM and IgG provided a significant benefit for the detection and prediction of clinical course with COVID-19 patients.

The structure-properties relationships of native and debranched starch (DBS) were investigated by analyzing the results of DSC, XRD, NMR, HPAEC, FT-IR, SEM, hydrolysis, and digestibility properties. After debranching of starch in waxy rice, japonica rice, and indica rice, the linear short-chain molecules formed were easier to alignment and aggregation, and associate into a double helix. The crystalline structure of the rice starch after the pullulanase treatment was transformed from the type A to the type V crystalline by XRD measurement. Based on FT-IR and 13C NMR observations, molecular rearrangement and degree of order in starch granules increased. The DSC curve showed an increase in gelatinization temperature of debranched starch compared to native starch. Meanwhile, Solubility, water holding capacity and resistant starch content of DBS also raised. The study of structure- properties relationship provides a theoretical foundation for the development of foods or drugs with targeted functional properties. Abbreviations: WS: waxy rice starch; JS: Japonica rice starch; IS: Indica rice starch; DBWS: debranched waxy rice starch; DBJS: debranched Japonica rice starch; DBIS: debranched Indica rice starch; RDS: rapidly digestible starch; SDS: slowly digestible starch; RS: resistant starch; DP: degree of polymerization; DSC: differential scanning calorimertry; Gelatinization temperature at onset (To), peak (Tp), and end (Tc); ∆H: transition enthalpy; HPSEC: high-performance size-exclusion chromatography; ATR-FTIR: Attenuated total reflectance Fourier transform infrared spectroscopy; NMR: nuclear magnetic resonance; XRD: X-ray diffraction; SEM: Scanning electron microscopy; WHC: Water holding capacity.

Estimated glomerular filtration rate (EGFR)-sensitive mutations are extremely important for targeted treatment strategies in lung cancer. Osimertinib can effectively inhibit the activity of EGFR-sensitive mutations, including the T790M mutation. However, the efficiency of osimertinib for rare mutation types of T790 is unclear. Here, we report the case of a Chinese patient with lung adenocarcinoma (LADC) harboring a T790I mutation who achieved significant benefits from osimertinib treatment.

BackgroundThe COVID-19 outbreak has tremendously impacted the world. The number of confirmed cases has continued to increase, causing damage to society and the economy worldwide. The public pays close attention to information on the pandemic and learns about the disease through various media outlets. The dissemination of comprehensive and accurate COVID-19 information that the public needs helps to educate people so they can take preventive measures. ObjectiveThis study aimed to examine the dissemination of COVID-19 information by analyzing the information released by the official WeChat account of the People’s Daily during the pandemic. The most-read COVID-19 information in China was summarized, and the factors that influence information dissemination were studied to understand the characteristics that affect its dissemination. Moreover, this was conducted in order to identify how to effectively disseminate COVID-19 information and to provide suggestions on how to manage public opinion and information governance during a pandemic. MethodsThis was a retrospective study based on a WeChat official account. We collected all COVID-19–related information, starting with the first report about COVID-19 from the People’s Daily and ending with the last piece of information about lifting the first-level emergency response in 34 Chinese provinces. A descriptive analysis was then conducted on this information, as well as on Qingbo Big Data’s dissemination index. Multiple linear regression was utilized to study the factors that affected information dissemination based on various characteristics and the dissemination index. ResultsFrom January 19 to May 2, 2020, the People’s Daily released 1984 pieces of information; 1621 were related to COVID-19, which mainly included headline news items, items with emotional content, and issues related to the pandemic’s development. By analyzing the dissemination index, seven information dissemination peaks were discerned. Among the three dimensions of COVID-19 information—media salience, content, and format—eight factors affected the spread of COVID-19 information. ConclusionsDifferent types of pandemic-related information have varying dissemination power. To effectively disseminate information and prevent the spread of COVID-19, we should identify the factors that affect this dissemination. We should then disseminate the types of information the public is most concerned about, use information to educate people to improve their health literacy, and improve public opinion and information governance.

Abstract High‐grade serous ovarian carcinoma (HGSOC) is a major form of ovarian epithelial tumor that is often diagnosed only at an advanced stage when it is already highly aggressive. We performed comprehensive genomic profiling using an analytically validated clinical next‐generation sequencing assay to identify genomic alterations in 450 cancer‐related genes in a cohort of 88 Chinese HGSOC patients. Overall, we detected 547 genomic alterations with an average of 6.2 alterations per tumor. Most of these HGSOC tumors had low tumor mutation burden and were microsatellite stable. Consistent with earlier studies, TP53 mutations were present in the majority (96.6%) of the tumors studied, and mutations in BRCA1/2 that affect DNA repair were also detected frequently in 20.5% of the tumors. However, we observed a 10.2% of mutated genes in the Ras/Raf pathway, all co‐occurring with TP53 mutations in the same tumor, which was unrecognized previously. Our results show that in HGSOC patients, there may be an unrecognized co‐occurrence of TP53 mutations with mutations in Ras/Raf pathway.

Abstract Background JS001, a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy. Patients and methods In the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28 days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria. Results Thirty-six subjects diagnosed with advanced melanoma (n = 22), urothelial cancer (UC) (n = 8), or renal cell cancer (RCC) (n = 6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3− CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB). Conclusion JS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology. Trial registration Clinical Trial ID: NCT02836795, registered July 19, 2016, retrospectively registered.

The novel coronavirus disease 2019 (COVID-19) pandemic has changed the medical education platform for students in the United States of America (USA). In that light, medical schools had to rapidly rearrange the dynamics of their educational curricula from the traditional platforms, to incorporate telemedicine. The telemedicine platform is supported in many specialties, allowing students various options to continue their education without interruption during the COVID-19 pandemic, and beyond. Telemedicine platforms are projected to grow exponentially due to the COVID-19 pandemic, allowing a segue for medical schools to modify their curricula by incorporating telemedicine programs. These distant-, e-learning (tele-education) programs align with the recommendations and guidelines for practicing social distancing. In this article, we surveyed fourth-year medical students to better understand their views on multiple aspects of e-learning, and its impact on their medical education during the COVID-19 pandemic. We assessed the medical students’ experiences, satisfaction, insight and knowledge with e-learning, tele-education, telehealth, and their related modalities during COVID-19. We provide an organized overview and analysis of the main factors that influence medical education during the COVID-19 pandemic, while bringing forth the main challenges, limitations, and emerging approaches in the field of telemedicine and its application as it relates to medical education and e-learning across medical specialties. We outline the main themes and ideas that the medical students voiced, as to how their medical education is being impacted by the COVID-19 pandemic and how they will incorporate telemedicine and tele-education in their future career. A cross-sectional, mixed-method survey was developed and distributed via Google Surveys to 181 University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, United States of America, 4th year medical students, in December 2020. Results were compiled and analyzed after a 6-day open period for responses to be submitted. The survey instrument consisted of questions that inquire about the students’ perspectives as it relates to their rapid switch from their traditional method of learning to the on-line version of medical education during the COVID-19 pandemic. A total of 65 students responded to the survey, of which 63 completed the survey. More than half of the students (n = 63, 57%) indicated that both their specialty of interest, and (n = 21, 33%) their sub-internships were impacted by the temporary lockdown, due to the COVID-19 pandemic. Students also indicated that the top three specialties that were affected included surgery, internal medicine and obstetrics and gynecology. When the students were asked if they were satisfied with the use of aquifer for their health care e-learning, only 35% of the students were satisfied. The students expressed that the school’s administration team did a good job in developing the new tele-education curriculum for those in clinical training. In addition, responses indicated that students were open to case-based video learning and readings, when combined with the abbreviated clinical exposure during the make-up “clinical immersions periods” allowed for adequate learning. Overall, the survey responses show that more than half, approximately 54% of the medical students utilized telemedicine platforms during their clerkships that were impacted by COVID-19. The 4th-year medical students did not find tele-education and e-learning to be as effective as traditional medical education that combines in-person didactic classroom instructions and in-person face-to-face in hospital clerkships. Students felt that the telemedicine program that was rapidly set up due to the COVID-19 ‘lockdown’ was fragmented, since it was not a formal integration of a telemedicine E-learning program. Students would have preferred more ‘real’ cases to follow, instead of the ready-made, aquifer type of cases. Telemedicine has significant potential to address many of the challenges facing the medical education environment today. We believe now that people have become comfortable with this method of teaching, that even after the pandemic ends, we will continue to see tele-education used as a platform for medical education.

OBJECTIVES/SPECIFIC AIMS: I would like to make clinicians aware about prescription opioid use and glycemic control among patients with diabetes. This is a quality of care issue that increases the disease burden for two conditions opioid dependence and diabetic complications. Big data analytics can bring out this quality of care issue and help in changing clinical practice through precision medicine METHODS/STUDY POPULATION: This is a population health study of patients on prescription opioid pain medications in Erie county medical center and local out patient clinic. The electronic data from the hospital records and Outpatient were collected, merged and de identified. The database was saved in a protected environment and made accessible to researchers through a secure login. The data was queried for the number of patients with diabetes. The glycohemoglobin levels were collected and then the analysis was made RESULTS/ANTICIPATED RESULTS: It was found that only 63 of the 89 patients with DPN and 156 of the 570 patients without DPN had any measurement of HbA1c in our data. It was found that 86 out of 156 patients without DPN had suboptimal glycemic control with a glycohemoglobin level > 7% while 36 out of 63 patients with DPN had a glycohemoglobin > 6.7%. The odds of patients with DPN having poor glycemic control is 0.57 while the odds of having poor glycemic control without DPN is.55. The relative risk being 1.03. DISCUSSION/SIGNIFICANCE OF IMPACT: Our population study revealed suboptimal glycemic control among a large set of patients in Western New York with a diagnosis of diabetes mellitus and a concurrent prescription for an opioid pain medication. A significant percentage of patients in our study population with a diagnosis of DPN might benefit in terms of decreased painful symptoms of neuropathy from monitoring and attempting to improve glycemic control. Additionally, in our patient population, there were no patients with diabetic peripheral neuropathy prescribed pregabalin or duloxetine, the first-line FDA-approved medications for painful DPN, Based on our population study, the quality of care for diabetic patients with DPN who are prescribed opioid pain medications should be monitored closely. First-line, FDA approved anticonvulsants and antidepressants should be considered for the treatment of painful symptoms when necessary. Attention should be directed towards monitoring and improving glycemic control in patients without DPN receiving opioid pain medications to attempt to prevent or delay the microvascular complications of diabetes, including the onset of painful peripheral neuropathy.

The olive flounder (Paralichthys olivaceus) is an economically important flatfish in marine aquaculture with a broad thermal tolerance ranging from 14 to 23°C. Cold-tolerant flounder that can survive during the winter season at a temperature of less than 14°C might facilitate the understanding of the mechanisms underlying the response to cold stress. In this study, the transcriptional response of flounder to cold stress (0.7±0.05°C) was characterized using RNA sequencing. Transcriptome sequencing was performed using the Illumina MiSeq platform for the cold-tolerant (CT) group, which survived under the cold stress; the cold-sensitive (CS) group, which could barely survive at the low temperature; and control group, which was not subjected to cold treatment. In all, 29,021 unigenes were generated. Compared with the unigene expression profile of the control group, 410 unigenes were up-regulated and 255 unigenes were down-regulated in the CT group, whereas 593 unigenes were up-regulated and 289 unigenes were down-regulated in the CS group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that signal transduction, lipid metabolism, digestive system, and signaling molecules and interaction were the most highly enriched pathways for the genes that were differentially expressed under cold stress. All these pathways could be assigned to the following four biological functions for flounder that can survive under cold stress: signal response to cold stress, cell repair/regeneration, energy production, and cell membrane construction and fluidity.

Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p0.05).These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.