Preparation of injectable hydrophilic dextran/AgNPs nanocomposite product: White light active biomolecules as an antitumor agent.

Incidence of various cancers including melanoma continues to rise worldwide. While treatment options have expanded in the recent years, the benefit of these treatments suffer from short period of duration for many patients. Hence, new treatment options are highly desired. Here, we propose a method combining a Dextran/reactive-copolymer/AgNPs nanocomposite and a harmless visible light approach to obtain a plasma substitute carbohydrate-based nanoproduct (D@AgNP) that shows strong antitumor activity. Light-driven polysaccharide-based nanocomposite provided essential conditions for extra small (8-12nm) AgNPs capping with subsequent specific self-assembly into spherical-like cloud nanostructures. Obtained biocompatible D@AgNP are stable over six months at room temperature and demonstrated absorbance peak at 406 nm. New formulated nanoproduct revealed efficient anticancer properties against A375 with IC50 0.0035 mg/mL following 24-h incubation; complete cell death is achieved at 0.001 mg/mL and 0.0005 mg/mL by 24- and 48-h time points, respectively. SEM examination shows that D@AgNP altered the shape of the cell structure and damaged the cell membrane. TEM finding shows that D@AgNP are mostly localized at vesicles such as the endosomes, lysosomes and mitochondria. It is anticipated that the introduced new method serves as the cornerstone for improving the generation of biocompatible hydrophilic carbohydrate-based anticancer drugs.

Exploration of esophagojejunostomy after totally laparoscopic total gastrectomy / 中华胃肠外科杂志

The advantages of lymph node dissection through total laparoscopic total gastrectomy (TLTG) seem to be more and more accepted by the academic community. However, reconstruction of digestive tract is challenging and remains a focus of debate and research. Which way is better for esophagojejunostomy, circular stapler or linear stapler,remains to be answered. The authors believe that, under the conditions of existing anastomosis instruments, using of linear stapler for esophagojejunal side-to-side anastomosis may be the most common choice, but it must be used with strict indications, because there are still many problems to be solved. It is believed that with the breakthrough in the development of the circular stapler suitable for esophagojejunostomy in TLTG, the application of circular stapler for digestive tract reconstruction will become the mainstream again in future. Thus, the current routine clinical practice of TLTG should be cautious and the surgical indications should be strictly evaluated.

Spatial distribution characteristics of the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province in 2020 / 中国血吸虫病防治杂志

OBJECTIVE@#To investigate the spatial distribution characteristics of the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody, and to examine the correlation between the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province in 2020, so as to provide insights into advanced schistosomiais control in the province.@*METHODS@#The epidemiological data of schistosomiasis in Hunan Province in 2020 were collected, including number of permanent residents in survey villages, number of advanced schistosomiasis patients, number of residents receiving serological tests and number of residents seropositive for anti-Schistosoma antibody, and the prevalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody were descriptively analyzed. Village-based spatial distribution characteristics of prevalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody were identified in Hunan Province in 2020, and the correlation between the revalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody was examined using Spearman correlation analysis.@*RESULTS@#The prevalence of advanced schistosomiasis was 0 to 2.72% and the seroprevalence of anti-Schistosoma antibody was 0 to 20.25% in 1 153 schistosomiasis-endemic villages in Hunan Province in 2020. Spatial clusters were identified in both the prevalence of advanced schistosomiasis (global Moran's I = 0.416, P < 0.01) and the seroprevalence of anti-Schistosoma antibody (global Moran's I = 0.711, P < 0.01) in Hunan Province. Local spatial autocorrelation analysis identified 98 schistosomiasis-endemic villages with high-high clusters of the prevalence of advanced schistosomiasis, 134 endemic villages with high-high clusters of the seroprevalence of anti-Schistosoma antibody and 36 endemic villages with high-high clusters of both the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province. In addition, spearman correlation analysis showed a positive correlation between the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody (rs = 0.235, P < 0.05).@*CONCLUSIONS@#There were spatial clusters of the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province in 2020, which were predominantly located in areas neighboring the Dongting Lake. These clusters should be given a high priority in the schistosomiasis control programs.

Molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against Oncomelania hupensis in hilly regions / 中国血吸虫病防治杂志

OBJECTIVE@#To establish a snail control approach for spraying chemicals with drones against Oncomelania hupensis in complex snail habitats in hilly regions, and to evaluate its molluscicidal effect.@*METHODS@#The protocol for evaluating the activity of spraying chemical molluscicides with drones against O. hupensis snails was formulated based on expert consultation and literature review. In August 2022, a pretest was conducted in a hillside field environment (12 000 m2) north of Dafengji Village, Dacang Township, Weishan County, Yunnan Province, which was assigned into four groups, of no less than 3 000 m2 in each group. In Group A, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with drones at a dose of 40 g/m2, and in Group B, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with drones at a dose of 40 g/m2, while in Group C, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with knapsack sprayers at a dose of 40 g/m2, and in Group D, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with knapsack sprayers at a dose of 40 g/m2. Then, each group was equally divided into six sections according to land area, with Section 1 for baseline surveys and sections 2 to 6 for snail surveys after chemical treatment. Snail surveys were conducted prior to chemical treatment and 1, 3, 5, 7 days post-treatment, and the mortality and corrected mortality of snails, density of living snails and costs of molluscicidal treatment were calculated in each group.@*RESULTS@#The mortality and corrected mortality of snails were 69.49%, 69.09%, 53.57% and 83.48%, and 68.58%, 68.17%, 52.19% and 82.99% in groups A, B, C and D 14 days post-treatment, and the density of living snails reduced by 58.40%, 63.94%, 68.91% and 83.25% 14 days post-treatment relative to pre-treatment in four groups, respectively. The median concentrations of chemical molluscicides were 37.08, 35.42, 42.50 g/m2 and 56.25 g/m2 in groups A, B, C and D, and the gross costs of chemical treatment were 0.93, 1.50, 0.46 Yuan per m2 and 1.03 Yuan per m2 in groups A, B, C and D, respectively.@*CONCLUSIONS@#The molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against O. hupensis snails is superior to manual chemical treatment without environmental cleaning, and chemical treatment with drones and manual chemical treatment show comparable molluscicidal effects following environmental cleaning in hilly regions. The cost of chemical treatment with drones is slightly higher than manual chemical treatment regardless of environmental cleaning. Spraying 5% niclosamide ethanolamine salt granules with drones is recommended in complex settings with difficulty in environmental cleaning to improve the molluscicidal activity and efficiency against O. hupensis snails.

Sequence analysis of Paragonimus internal transcribed spacer 2 and cyclooxygenase 1 genes in freshwater crabs in Henan Province / 中国血吸虫病防治杂志

OBJECTIVE@#To investigate the sequences of internal transcribed spacer 2 (ITS2) and cyclooxygenase 1 (COX1) genes of Paragonimus metacercariae in freshwater crabs in Henan Province, identify the species of Paragonimus and evaluate its genetic relationships with Paragonimus isolates from other provinces in China.@*METHODS@#Freshwater crabs were collected from 8 survey sites in Zhengzhou, Luoyang, Pingdingshan, Nanyang and Jiyuan cities of Henan Province from 2016 to 2021, and Paragonimus metacercariae were detected in freshwater crabs. Genomic DNA was extracted from Paragonimus metacercariae, and the ITS2 and COX1 genes were amplified using PCR assay, followed by sequencing of PCR amplification products. The gene sequences were spliced and aligned using the software DNASTAR, and aligned with the sequences of Paragonimus genes in the GenBank. Phylogenetic trees were created using the MEGA6 software with the Neighbor-Joining method based on ITS2 and COX1 gene sequences, with Fasciola hepatica as the outgroup.@*RESULTS@#The detection rates of Paragonimus metacercariae were 6.83% (11/161), 50.82% (31/61), 18.52% (5/26), 8.76% (12/137), 14.29% (9/63), 17.76% (19/105), 18.50% (32/173) and 42.71% (41/96) in freshwater crabs from 8 survey sites in Zhengzhou, Luoyang, Pingdingshan, Nanyang and Jiyuan cities of Henan Province, with a mean detection rate of 19.46% (160/822), and a mean infection intensity of 0.57 metacercariae/g. The amplified ITS2 and COX1 gene fragments of Paragonimus were approximately 500 bp and 450 bp in lengths, respectively. The ITS2 gene sequences of Paragonimus metacercariae from 8 survey sites of Henan Province showed the highest homology (99.8% to 100.0%) with the gene sequence of P. skrjabini (GenBank accession number: MW960209.1), and phylogenetic analysis showed that the Paragonimus in this study was clustered into the same clade with P. skrjabini from Sichuan Province (GenBank accession number: AY618747.1), Guangxi Zhuang Autonomous Region (GenBank accession number: AY618729.1) and Hubei Province (GenBank accession number: AY618751.1), and P. miyazaki from Fujian Province (GenBank accession number: AY618741.1) and Japan (GenBank accession number: AB713405.1). The COX1 gene sequences of Paragonimus metacercariae from 8 survey sites of Henan Province showed the highest homology (90.0% to 100.0%) with the gene sequence of P. skrjabini (GenBank accession number: AY618798.1), and phylogenetic analysis showed that the Paragonimus in this study was clustered into the same clade with all P. skrjabini and clustered into the same sub-clade with P. skrjabini from Hubei Province (GenBank accession numbers: AY618782.1 and AY618764.1).@*CONCLUSIONS@#Paragonimus species from freshwater crabs in Henan Province were all characterized as P. skrjabini, and the ITS2 and COX1 gene sequences had the highest homology to those of P. skrjabini from Hubei Province. The results provide insights into study of Paragonimus in Henan Province and China.

Clinicopathological analysis of benign mammary ductal cystic papillomatosis with loss of myoepithelial cells / 中华病理学杂志

Objective: To investigate the histopathological and immunohistochemical characteristics of benign apocrine cystic papillary hyperplasia of the breast with loss of myoepithelial cell layer. Methods: The clinical data, histopathological features and immunohistochemical profile of patients with benign apocrine cystic papillary hyperplasia of breast with loss of myoepithelial cell layer from January 2016 to December 2021 were examined, in which six patients were identified. Results: All six patients were female, aged 36-61 years (median 46 years), who presented with a breast mass; three cases were from the left breast and three cases were from the right breast. Microscopic examination of all cases showed breast hyperplasia with apocrine cysts, accompanied by different degrees of micropapillary and papillary hyperplasia of apocrine cells. One case was associated with lobular carcinoma in situ, and one case was associated with apocrine ductal carcinoma in situ with intraductal dissemination in adenosis. Immunohistochemical staining of CK5/6, p63, SMA, SMMHC, Calponin and CD10 showed complete absence of myoepithelial cell layer surrounding ducts in apocrine cystic papillary hyperplasia. Conclusions: The myoepithelial cells of apocrine cystic papillary hyperplasia of the breast may undergo abnormal changes and may even be completely lost. The diagnosis should be comprehensively considered along with cytomorphological and histological features to avoid overdiagnosis.

Values of ATX in predicting disease progression in patients with PBC and PBC related HCC / 中华肝脏病杂志

Objective: To clarify the values of autotaxin (ATX) in patients with primary biliary cholangitis (PBC) and PBC-related hepatocellular carcinoma (HCC). Methods: 179 patients with PBC were selected from prospective cohorts of autoimmune liver diseases at the time of first diagnosis of PBC in Department of Hepatology, the Fifth Medical Center of PLA General Hospital, from January 2016 to January 2018, all patients with PBC received UDCA therapy, primary endpoint was event of HCC, the follow-up period was censored at the date of HCC. The relationship between level of ATX and clinical features in patients with PBC and its potential value in predicting disease progression and PBC-related HCC were analyzed. Results: The ATX level in the peripheral blood of patients with PBC was significantly higher than that of alcoholic liver cirrhosis(ALC) (t = 3.278, P = 0.001) and healthy controls(HC) (t = 6.594, P < 0.001), however, when comparing PBC to non-PBC related HCC, no significant difference was found between the groups(t=-0.240, P = 0.811). Consistent with peripheral blood levels, histochemical staining indicated that ATX in the liver of patients with PBC was significantly higher than that of HC (Z=-3.633, P < 0.001) and ALC (Z=-3.283, P < 0.001), and the expression of ATX in PBC with advanced histological stage was significantly higher than PBC with early stage (Z=-2.018, P = 0.034). The baseline ATX level in PBC patients without developing to HCC during follow-up had significant difference to patients with developing to HCC (228.451 ± 124.093 ng/ml vs 301.583 ± 100.512 ng/ml, t = 2.339, P = 0.021). The result in multivariate logistic regression analysis showed that ATX were independent predictors of PBC related HCC(OR 1.245, 95%CI 1.097-1.413). The optimal critical value of peripheral blood ATX level at baseline for predicting HCC was 235.254 ng/ml, with the cut-off value of 0.714 in AUC of the ROC (95% CI was 0.597~ 0.857), sensitivity and specificity were 84.6% and 59.0%, respectively. Conclusion: ATX level was significantly higher in PBC patients over controls, and it's concentration was correlated with UDCA efficacy and fibrosis stage. ATX has potential values in predicting disease progression and PBC-related HCC.

COVID-19 Contact Tracing Analysis with Bluetooth Technology Using Raspberry Pis

Contact tracing, a method for detecting and preventing the spread of a disease, can become more efficient by becoming automated, rather than being done manually. Bluetooth based contact tracing is a potential method for creating an automated method for contact tracing. However, Bluetooth signals cannot always predict something with complete accuracy due to many subtle obstructions. Received signal strength indicator (RSSI), a value produced when Bluetooth devices send and receive signals, generated from Raspberry Pis can predict the distance between the two devices. By running many experiments with variations of obstructions, I was able to successfully create models to correlate RSSI values and distance with a potential success rate of 91.973%. For my research, a success is determined to be anything but a false negative. Despite the limitations when conducting my research, the inaccuracies of my results prove Bluetooth based contact tracing to not be a reliable method for determining people who have been in contact with an index case in the real world.

Rotational alignment of the tibial component in total knee arthroplasty:a narrative review / 中华外科杂志

Component malrotation is one of the major causes of failure in total knee arthroplasty.Based on previous researches,Insall line has excessive external rotation tendency.Although Akagi line is the most recognized anatomical axis at present,it still has a certain tendency of internal rotation.The tibial posterior condylar axis is not suitable for symmetrical component and yet the Curve-on-Curve technique is not suitable for anatomic component.In addition,reference to any fixed anatomical markers cannot ensure the rotation consistency of tibiofemoral component in extension position.Although range of motion technique is beneficial to tibiofemoral rotation synchronization,its clinical effect seems to be unstable.Nevertheless,Patients can obtain good postoperative results with all major techniques.Before the recognized "gold standard" is defined,orthopedic surgeons can determine the rotation alignment of tibial component according to their most accustomed surgical method.With a deeper understanding of knee anatomy,biomechanics and kinematics,digital assistive technology may be expected to become a breakthrough in the tibial rotational alignment.

Proof of concept continuous event logging in living cells

Cells must detect and respond to molecular events such as the presence or absence of specific small molecules. To accomplish this, cells have evolved methods to measure the presence and concentration of these small molecules in their environment and enact changes in gene expression or behavior. However, cells dont usually change their DNA in response to such outside stimuli. In this work, we have engineered a genetic circuit that can enact specific and controlled genetic changes in response to changing small molecule concentrations. Known DNA sequences can be repeatedly integrated into a genomic array such that their identity and order encodes information about past small molecule concentrations that the cell has experienced. To accomplish this, we use catalytically inactive CRISPR-Cas9 (dCas9) to bind to and block attachment sites for the integrase Bxb1. Therefore, through the co-expression of dCas9 and guide RNA, Bxb1 can be directed to integrate one of two engineered plasmids, which correspond to two orthogonal small molecule inducers that can be recorded with this system. We identified the optimal location of guide RNA binding to the Bxb1 attP integrase attachment site, and characterized the detection limits of the system by measuring the minimal small molecule concentration and shortest induction time necessary to produce measurable differences in array composition as read out by Oxford Nanopore long read sequencing technology.

Hyperinsulinemia in Obesity, Inflammation, and Cancer

The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

Continuous Glucose Monitoring in the Hospital

Continuous glucose monitors (CGMs) have suddenly become part of routine care in many hospitals. The coronavirus disease 2019 (COVID-19) pandemic has necessitated the use of new technologies and new processes to care for hospitalized patients, including diabetes patients. The use of CGMs to automatically and remotely supplement or replace assisted monitoring of blood glucose by bedside nurses can decrease: the amount of necessary nursing exposure to COVID-19 patients with diabetes; the amount of time required for obtaining blood glucose measurements, and the amount of personal protective equipment necessary for interacting with patients during the blood glucose testing. The United States Food and Drug Administration (FDA) is now exercising enforcement discretion and not objecting to certain factory-calibrated CGMs being used in a hospital setting, both to facilitate patient care and to obtain performance data that can be used for future regulatory submissions. CGMs can be used in the hospital to decrease the frequency of fingerstick point of care capillary blood glucose testing, decrease hyperglycemic episodes, and decrease hypoglycemic episodes. Most of the research on CGMs in the hospital has focused on their accuracy and only recently outcomes data has been reported. A hospital CGM program requires cooperation of physicians, bedside nurses, diabetes educators, and hospital administrators to appropriately select and manage patients. Processes for collecting, reviewing, storing, and responding to CGM data must be established for such a program to be successful. CGM technology is advancing and we expect that CGMs will be increasingly used in the hospital for patients with diabetes.

Hyperinsulinemia in Obesity, Inflammation, and Cancer

The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

Continuous Glucose Monitoring in the Hospital

Continuous glucose monitors (CGMs) have suddenly become part of routine care in many hospitals. The coronavirus disease 2019 (COVID-19) pandemic has necessitated the use of new technologies and new processes to care for hospitalized patients, including diabetes patients. The use of CGMs to automatically and remotely supplement or replace assisted monitoring of blood glucose by bedside nurses can decrease: the amount of necessary nursing exposure to COVID-19 patients with diabetes; the amount of time required for obtaining blood glucose measurements, and the amount of personal protective equipment necessary for interacting with patients during the blood glucose testing. The United States Food and Drug Administration (FDA) is now exercising enforcement discretion and not objecting to certain factory-calibrated CGMs being used in a hospital setting, both to facilitate patient care and to obtain performance data that can be used for future regulatory submissions. CGMs can be used in the hospital to decrease the frequency of fingerstick point of care capillary blood glucose testing, decrease hyperglycemic episodes, and decrease hypoglycemic episodes. Most of the research on CGMs in the hospital has focused on their accuracy and only recently outcomes data has been reported. A hospital CGM program requires cooperation of physicians, bedside nurses, diabetes educators, and hospital administrators to appropriately select and manage patients. Processes for collecting, reviewing, storing, and responding to CGM data must be established for such a program to be successful. CGM technology is advancing and we expect that CGMs will be increasingly used in the hospital for patients with diabetes.

Learning during the pandemic: Perspectives of medical students in Singapore

The COVID-19 pandemic has significantly disrupted medical education, particularly affecting clinical-year students. Educational institutions often had to halt, shorten or impose significant restrictions on their hospital rotations due to strict infection control and social-distancing guidelines implemented in tertiary healthcare institutions, as well as manpower and logistical constraints amid the pandemic. Thus, distance-based learning platforms such as online lectures and case-based teaching were increasingly adopted in place of bedside and face-to-face tutorials. While interactive virtual case-based discussions are generally useful in imparting clinical reasoning skills to medical students, they are unfortunately not able to fully replicate the experience of clerking, examining and managing real patients in the wards, which is a quintessential process towards building clinical acumen and attaining core clinical competencies. Therefore, for final year medical students who are preparing for their Bachelor of Medicine and Bachelor of Surgery (MBBS) examinations, many are naturally concerned by how learning in this "new normal" may affect their ability to make the transition to become competent junior doctors. As such, we seek to share our learning experiences as the first batch of medical students to have completed our entire final year of clinical education amid the COVID-19 pandemic, and offer 4 practical suggestions to future batches of students on how to adapt and optimise clinical learning under these circumstances: actively engaging in virtual learning, making the most of every clinical encounter, learning how to construct peer teaching/practice sessions, and maintaining physical and psychological well-being.

Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S- enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) significantly more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. In addition, Mpro, as one of the critical enzymes for viral transcription and replication, also exhibited an enantioselective binding affinity toward the S-enantiomers. The most significant finding from this study is the pronounced difference of the two enantiomers of CQ and HCQ observed in hERG inhibition assay. The IC50 value of S-HCQ was higher than 20 M against hERG channel, which was much less active over all tested CQ and HCQ compounds. Moreover, S-HCQ alone did not prolong QT interval in guinea pigs after 3 days and 6 days of administration, indicating a much lower cardiac toxicity potential. With these and previous findings on the enantio-differentiated metabolism, we recommend that future clinical studies should employ S-HCQ, substantially free of the R-enantiomer, to potentially improve the therapeutic index for the treatment of COVID-19 over the racemic CQ and HCQ.

LncRNA MIR4435-2HG contributes into colorectal cancer development and predicts poor prognosis.

OBJECTIVE: Some studies have confirmed that long non-coding ribonucleic acids (lncRNAs) played a vital role in the pathophysiology of various diseases, especially in oncogenesis and progression of tumors. Dysexpressed lncRNAs regulate different cellular processes, including proliferation, invasion, and apoptosis. The aim of this study was to explore the clinical significance and function of lncRNA MIR4435-2HG in colorectal cancer. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to detect the expression of lncRNA MIR4435-2HG. The Kaplan-Meier method was used to evaluate the overall survival and disease-free survival of patients with colorectal cancer. The cell proliferation was measured by Methyl thiazolyl tetrazolium (MTT) assay. The cell apoptotic rate was measured via flow cytometry method. RESULTS: LncRNA MIR4435-2HG is a novel cancer-related lncRNA that was recently found to exhibit high expression in colorectal cancer. The dysregulation of lncRNA miR4435-2HG was significantly related to the tumor size (p<0.001), lymph node metastasis (p<0.001), and tumor node metastasis (TNM) staging (p=0.022). The patients with higher expression of lncRNA miR4435-2HG showed worse prognosis than those with low expression of lncRNA miR4435-2HG group. Besides, the downregulated lncRNA miR4435-2HG expression could repress cell proliferation and enhance cell apoptosis. CONCLUSIONS: LncRNA MIR4435-2HG functions as an oncogene that promotes colorectal cancer progression, and likely represents a biomarker or therapeutic target of colorectal cancer.

From the Lab to Patients: a Systematic Review and Meta-Analysis of Mesenchymal Stem Cell Therapy for Stroke.

There may be the potential to improve stroke recovery with mesenchymal stem cells (MSCs); however, questions about the efficacy and safety of this treatment remain. To address these issues and inform future studies, we performed a preclinical and clinical systematic review of MSC therapy for subacute and chronic ischemic stroke. MEDLINE, Embase, the Cochrane Register of Controlled Trials, and PubMed were searched. For the clinical review, interventional and observational studies of MSC therapy in ischemic stroke patients were included. For the preclinical review, interventional studies of MSC therapy using in vivo animal models of subacute or chronic stroke were included. Measures of safety and efficacy were assessed. Eleven clinical and 76 preclinical studies were included. Preclinically, MSC therapy was associated with significant benefits for multiple measures of motor and neurological function. Clinically, MSC therapy appeared to be safe, with no increase in adverse events reported (with the exception of self-limited fever immediately following injection). However, the efficacy of treatment was less apparent, with significant heterogeneity in both study design and effect size being observed. Additionally, in the only randomized phase II study to date, efficacy of MSC therapy was not observed. Preclinically, MSC therapy demonstrated considerable efficacy. Although MSC therapy demonstrated safety in the clinical setting, efficacy has yet to be determined. Future studies will need to address the discordance in the continuity of evidence as MSC therapy has been translated from "bench-to-bedside".

TheraP: a randomized phase 2 trial of 177 Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).

OBJECTIVE: To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment. PATIENTS AND METHODS: The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177 Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed 68 Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m2 ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177 Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening 68 Ga-PSMA-11 and Fluorine-18 (18 F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018. RESULTS AND CONCLUSIONS: 177 Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.