[Effect and safety of Burosumab in the treatment of 4 children with X-linked hypophosphatemia].

Objective: To evaluate the effectiveness and safety of treatment with Burosumab in pediatric X-linked hypophosphatemia (XLH) patients. Methods: In this retrospective case study, 4 children with pediatric XLH, who were treated with Burosumab in Beijing Children's Hospital, Capital Medical University and Shandong Provincial Hospital affiliated to Shandong First Medical University from July 2022 to December 2023, were selected as the study objects. We collected and analyzed their clinical characteristics, biochemical indicators, imaging results, and treatment. The children were followed up every 3 months until December 2023, and the clinical outcomes and adverse drug reactions after treatment were evaluated. Results: Of the 4 patients, 3 were males and 1 was female; they were aged 6.7, 2.9, 2.1, and 2.3 years, respectively. Three patients had previously received treatment with phosphate supplements and active vitamins, but their wadding gait and lower limb deformities did not improve significantly, neither did their imaging changes of active richets. The initial dose of Burosumab in the 4 patients was 0.8 mg/kg, administered subcutaneously every 2 weeks, with a treatment course of 0.8-1.3 years. The fasting serum phosphorus and tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) of the 4 patients before treatment were 0.72, 0.95, 0.81, 0.66 mmol/L and 0.67, 0.85, 0.87, 0.61 mmol/L, respectively. At the last follow-up, the fasting serum phosphorus and TmP/GFR levels were significantly increased (0.96, 1.09, 1.09, 0.90 mmol/L, and 0.85, 0.79, 1.03, 0.98 mmol/L, respectively). Among them, only the TmP/GFR level (1.17 mmol/L) in case 2 achieved normal values at 3 months post-therapy, while the rest did not reach the normal range for children of the same age. After treatment, the alkaline phosphatase levels of all patients gradually decreased (the values were 461, 240, 423, and 237 U/L, respectively), and the ALP levels in cases 2 and 4 returned to normal at the last visit. Case 4 showed a slight increase in parathyroid hormone (PTH) levels after 9 months of treatment, while the PTH levels in the rest 3 cases remained normal. Case 1 underwent a 6-minute walking test, and the walking distance increased from 245 m to 570 m. Abnormal gait, lower limb deformity, and the severity of rickets in the 4 patients had all improved. No adverse drug reactions such as nephrocalcinosis, local skin injection reaction, hyperphosphatemia, or vitamin D deficiency were observed. Conclusion: Burosumab can improve clinical symptoms in children with XLH with a good safety profile.

[Clinical characteristics and prognostic analysis of 34 patients with primary thyroid lymphoma].

Objective: To investigate the clinical characteristics, diagnosis, treatment, and prognosis of primary thyroid lymphoma (PTL) . Methods: A retrospective analysis was conducted on the clinical and pathological data of 34 newly diagnosed PTL patients admitted to Beijing Tongren Hospital from September 2010 to February 2023. The Kaplan-Meier survival curve and Log-rank test were used for survival analysis, and the Cox regression model was applied for univariate analysis of prognostic factors. Results: All 34 PTL patients presented with cervical mass as the initial clinical manifestation. There were 9 males and 25 females. The pathological diagnosis was diffuse large B-cell lymphoma (DLBCL) in 29 patients and mucosa-associated lymphoid tissue (MALT) lymphoma in 5 patients. Among the DLBCL patients, 6 had B symptoms, 17 had an Eastern Cooperative Oncology Group (ECOG) score of ≥2, the Ann Arbor staging was stage Ⅰ-Ⅱ in 21 cases and stage Ⅲ-Ⅳ in 8 cases, the tumor diameter was ≥10 cm in 4 cases, and 14 had concurrent Hashimoto thyroiditis; 27 cases received chemotherapy, with 21 cases achieving complete remission (CR), 2 cases partial remission (PR), and 6 cases of disease progression; the 5-year progression-free survival and overall survival rates were 78.9% and 77.4%, respectively; univariate survival analysis showed that B symptoms, tumor diameter ≥10 cm, and Ann Arbor stage Ⅲ-Ⅳ were significant factors affecting patient prognosis (P<0.05). MALT lymphoma patients were all in stages Ⅰ-Ⅱ, had an ECOG score of 0-1, and were without B symptoms. All patients underwent surgical resection, with 4 cases achieving CR and 1 case PR. Conclusion: PTL is more common in females with concurrent Hashimoto thyroiditis, with the majority of pathological types being B-cell lymphoma. The main treatment is chemotherapy, supplemented by radiotherapy and surgery, and the prognosis is relatively favorable.

Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings.

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data. MAIN BODY: The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities). CONCLUSION: Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

Beating the Standard Quantum Limit Electronic Field Sensing by Simultaneously Using Quantum Entanglement and Squeezing.

Quantum entanglement and quantum squeezing are two typical approaches to beat the standard quantum limit (SQL) for the sensitive phase estimations in quantum metrology. Each of them has already been utilized individually and sequentially to improve the sensitivity of electric field sensing with the trapped ion platform. However, the upper bound of the demonstrated sensitivity gain is still limited, i.e., the theoretical 6 dB and experimental 3 dB over the corresponding SQL, for electric field sensing. By simultaneously using the internal (spin)-external (oscillator) state entanglement and the oscillator squeezing to effectively amplify the accumulation phase, we show here that such a theoretical sensitivity gain upper bound can be significantly surpassed. The proposal provides a novel approach to implement the stronger beat of the SQL and even approach the Heisenberg limit, for the sensitive sensings of the desired electric field and also the other metrologies.

[Research progress on the role of imbalanced high and low molecular weight hyaluronic acid in respiratory system inflammation caused by atmospheric particulate matter].

Atmospheric particulate matter has an association with respiratory system inflammation, and low molecular weight hyaluronic acid (LMW-HA) is a key biomarker of inflammatory cascade reaction. This review summarized the possible pathways and biomarkers of atmospheric particulate matter causing respiratory system inflammation through high molecular weight hyaluronic acid (HMW-HA)/LMW-HA imbalance, including the synthesis and decomposition of HA, the reduction of particulate matter and HMW-HA, the increase of LMW-HA, and the relationship between LMW-HA and respiratory system inflammation. Furthermore, inhibitors and therapeutic drugs targeting certain biomarkers were further listed. This review could shed light on the mechanism of respiratory system inflammation caused by atmospheric particulate matter and the weak points that need attention in subsequent research.

[Analysis of sequential chemotherapy efficacy in ovarian epithelial carcinoma, fallopian tube carcinoma and primary peritoneal carcinoma].

Objective: To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. Methods: A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel's Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups. Results: (1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P>0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups (Z=-7.82, P<0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P<0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P>0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P<0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P<0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P<0.05). Conclusions: Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

Attitudes and behaviors regarding sun exposure in Japan compared to Europe and North America.

The objective of our study was to assess the attitudes and behaviors in Japan regarding sun exposure and compare them to those in Europe and North America. The study population was a representative sample of individuals aged >18 years from Ipsos panels in Japan (N = 1000), North America (N = 1000), and Europe (N = 6000) using the quota method. Questionnaires covered habits, practices, and perceptions regarding sun exposure. Results revealed that the majority of people (80.1%) believed that the sun gives them energy, and 61.1% considered that being tanned made them look healthier. However, there was a significant difference between men and women regarding the appeal of tanned skin, with 54.95% of men versus 34.67% (p < 0.001) of women seeing a tan as an aesthetic asset. People aged <40 years were less likely to find a tan attractive (30.3%) compared to those aged ≥40 years (48.9%) (p < 0.001). Of those questioned, 45.70% of used sunscreen with a much higher use among women (70.10%) than men (18.74%) (p < 0.001). Almost 54% of people said they stayed in the shade to protect themselves from the sun with this behavior being more prevalent among women (67.05%) and fair-skinned individuals (56.13%). Fear of the risks of sun exposure was more common among women, with 84.8% fearing premature skin aging, compared to 71.8% of men (p < 0.001). In Japan, 44.30% of those questioned said tanned skin was attractive (p < 0.001); for Europeans and North Americans the proportions were 81.1% and 77.6%, respectively. Only a quarter (25.80%) thought it essential to return from vacation with a tan. On the other hand, Europeans showed a strong recognition of the energy the sun brings (83.18%), and widely believed that tanned skin is attractive (82.32%) and healthy (73.15%). In North America, attitudes were similar to those in Europe regarding the attractiveness of tanned skin (77.65%) and the importance of returning tanned from vacation (48.15%). Compared to Europeans and North Americans, the Japanese seemed to be more cautious about sun-induced hazards and considered lighter skin to be more attractive.

[Exploration and contemplation of homogenized education of specialists in pulmonary and critical care medicine at member hospitals of a hospital consortium].

Talent construction is the cornerstone to the establishment of a high-quality, homogeneous healthcare system in a healthcare consortium. Pulmonary and critical care medicine (PCCM) as the first pilot specialty, the standardized training of PCCM specialists has started and achieved remarkable results. The consortium member hospitals' physician specialist education is an important complement to PCCM training. The establishment of the consortium provides a new form of the education of physicians in PCCM, with the advantages of high quality teaching, wide coverage of staff and throughout the career development process. This article summarized the current status of physician specialty education in the member hospitals of the consortium, and further proposes the goal of homogenized specialty education for physicians in the member hospitals. And it analyzed in depth the problems that existed in the practice of training for hospital consortium member hospitals specialists, such as non-uniform level of instruction, non-systematic content of training, limited sources of teaching cases, and lack of teaching materials and equipment. For the medical consortium member hospital physician specialty education of in-depth thinking, we put forward the corresponding countermeasures. The aim of this study is to explore the homogenization of the specialty education system of pulmonary and critical care medicine in the member hospitals, in order to comprehensively improve the medical level of respiratory specialists in the member hospitals of the medical consortium.

A nucleoid-associated protein is involved in the emergence of antibiotic resistance by promoting the frequent exchange of the replicative DNA polymerase in Mycobacterium smegmatis.

Antibiotic resistance in Mycobacterium tuberculosis exclusively originates from chromosomal mutations, either during normal DNA replication or under stress, when the expression of error-prone DNA polymerases increases to repair damaged DNA. To bypass DNA lesions and catalyze error-prone DNA synthesis, translesion polymerases must be able to access the DNA, temporarily replacing the high-fidelity replicative polymerase. The mechanisms that govern polymerase exchange are not well understood, especially in mycobacteria. Here, using a suite of quantitative fluorescence imaging techniques, we discover that in Mycobacterium smegmatis, as in other bacterial species, the replicative polymerase, DnaE1, exchanges at a timescale much faster than that of DNA replication. Interestingly, this fast exchange rate depends on an actinobacteria-specific nucleoid-associated protein (NAP), Lsr2. In cells missing lsr2, DnaE1 exchanges less frequently, and the chromosome is replicated more faithfully. Additionally, in conditions that damage DNA, cells lacking lsr2 load the complex needed to bypass DNA lesions less effectively and, consistently, replicate with higher fidelity but exhibit growth defects. Together, our results show that Lsr2 promotes dynamic flexibility of the mycobacterial replisome, which is critical for robust cell growth and lesion repair in conditions that damage DNA. IMPORTANCE: Unlike many other pathogens, Mycobacterium tuberculosis has limited ability for horizontal gene transfer, a major mechanism for developing antibiotic resistance. Thus, the mechanisms that facilitate chromosomal mutagenesis are of particular importance in mycobacteria. Here, we show that Lsr2, a nucleoid-associated protein, has a novel role in DNA replication and mutagenesis in the model mycobacterium Mycobacterium smegmatis. We find that Lsr2 promotes the fast exchange rate of the replicative DNA polymerase, DnaE1, at the replication fork and is important for the effective loading of the DnaE2-ImuA'-ImuB translesion complex. Without lsr2, M. smegmatis replicates its chromosome more faithfully and acquires resistance to rifampin at a lower rate, but at the cost of impaired survival to DNA damaging agents. Together, our work establishes Lsr2 as a potential factor in the emergence of mycobacterial antibiotic resistance.

[Research progress on pseudocirrhosis].

Presently, pseudocirrhosis occurs in most patients with liver metastases from malignant tumors and can exhibit clinical manifestations related to portal hypertension, such as edema, ascites, and gastrointestinal bleeding. Imaging features include malignant tumor liver metastasis, the appearance of nodules accompanied with or without hepatic contour, segmental liver volume reduction, and caudate lobe enlargement. Histology shows the typical pathological manifestations of liver cirrhosis, such as diffuse tumor cell infiltration, fibrosis around the infiltrating lesion, hepatic sinus vascular thrombosis, nodular hyperplasia, non-accompanied bridging necrosis, bridging fibrosis, and pseudolobule formation. The possible pathogenesis of pseudocirrhosis is tumor cell infiltration and toxic reactions of tumor cells and liver cells to chemotherapy. The presence of pseudocirrhosis in patients diagnosed with malignant tumors is one of the challenges affecting their survival cycle and shortening the median survival time. The relationship between its onset, tumor type and metastasis, and the use of chemotherapy drugs is still unclear. The atypical clinical manifestations and imaging characteristics bring about great challenges for clinicians and patients. Thus, based on the existing case reports, observational studies, and meta-analysis results, this article reviews the research progress on the prevalence, etiology, pathogenesis, diagnosis, treatment, and prognosis of pseudocirrhosis.

[circDDX17 targets miR-223-3p / RIP3 to regulate the proliferation and apoptosis of non-small cell lung cancer cells].

Objective: To explore the molecular mechanism of circDDX17 regulating the proliferation and apoptosis of non-small cell lung cancer cells by targeting the miR-223-3p/RIP3 molecular axis. Methods: The expression levels of circDDX17, miR-223-3p, and RIP3 in human normal lung epithelial cell lines BEAS-2B and non-small cell lung cancer cells H1299, A549, and H446 were detected by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). The plasmids of pcDNA, pcDNA-circDDX17, anti-miR-con, anti-miR-223-3p, pcDNA-circDDX17 and miR-con, pcDNA-circDDX17 and miR-223-3p mimics were transfected into H1299 cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was used to detect the cell proliferation. Flow cytometry was used to detect the cell cycle and cell apoptosis. Plate cloning experiment was used to detect cell proliferation ability. The dual luciferase report experiment was applied to verify the targeting relationship between miR-223-3p with circDDX17 and RIP3. Western blot was used to detect the protein expression of cyclinD1, CDK2, cleaved caspase-3 and Bax. Results: The expression levels of circDDX17 and RIP3 mRNA in H1299, A549, and H446 cells were significantly reduced (P<0.05), the expression level of miR-223-3p mRNA was significantly increased (P<0.05) compared with BEAS-2B. The cell viability [(69.46±4.68)%], the number of cell clones (83.49±7.86), the proportion of cells in S phase [(22.52±1.41) %], the protein expression levels of cyclinD1 and CDK2 in PCDNa-CircDDX17 group were lower than those in pcDNA group [(97.54±7.72)%, 205.03±13.37, (28.69±1.49)%, respectively, P<0.05], while the percentage of G0/G1 phase cells [(64.45±3.56)%], apoptosis rate [(18.36±1.63)%], the protein expression levels of cleaved caspase-3 and Bax in pcDNA-circDDX17 group were higher than those of pcDNA group [(51.33±2.76) % and (5.21±0.54) %, respectively, P<0.05]. The viability [(72.64±5.44)%], the number of cell clones (78.16±8.23), the proportion of S-stage cells [(21.34±1.59) %], the protein expression levels of CyclinD1 and CDK2 in anti-miR-223-3p group were lower than those in anti-miR-con group [(103.47±6.25)%, 169.32±14.53, (28.43±1.26)%, respectively, P<0.05]. Percentage of G0/G1 phase cells [(62.86±3.28)%], apoptosis rate [(14.64±1.67)%], the protein expression levels of cleaved caspase-3 and Bax in the anti-miR-223-3p group were higher than those of anti-miR-con group [(51.33±2.71)% and (4.83±0.39)%, respectively, P<0.05]. MiR-223-3p has complementary sites with circDDX17 or RIP3. The viability [(135.45±9.28)%], the number of cell clones (174.64±10.68), the proportion of S-phase cells [(26.39±2.25)%], the protein expression levels of cyclinD1 and CDK2 in pcDNA-circDDX17+miR-223-3p group were higher than those in pcDNA-circDDX17+miR-con group [(101.56±6.68)%, 107.65±7.62, (21.64±1.72)%, P<0.05]. Percentage of G0/G1 phase cells [(56.64±2.76)%], apoptosis rate [(8.34±0.76)%], the protein expression levels of cleaved caspase-3 and Bax in pcDNA-circDDX17+miR-223-3p group were lower than those of pcDNA-circDDX17+miR-con group [(64.03±3.48)% and (15.21±1.18)%, respectively, P<0.05]. Conclusion: circDDX17 could inhibit the proliferation and induce apoptosis of non-small cell lung cancer cells via targeting the miR-223-3p / RIP3 molecular axis.

[Quality control of gastric resection range in laparoscopic locally advanced gastric cancer].

After nearly 30 years of exploration and practice, minimally invasive surgical techniques represented by laparoscopic technology have become an important means for the surgical treatment of gastric cancer. In China, laparoscopic radical resection for locally advanced gastric cancer has been extensively carried out. However, there are still controversies regarding the gastric resection range and methods for advanced gastric cancer. By reviewing relevant domestic and foreign guideline documents and combining team practice experience, this article elaborates on the key points of quality control of laparoscopic gastric resection range for locally advanced gastric cancer from aspects such as tumor localization and gastric resection range for upper, middle and lower gastric tumors. It aims to provide reference for carrying out and promoting laparoscopic radical gastrectomy more safely.

Exploring Recent Decreases in First Molar Sealants among US Children.

Analyses of National Health and Nutrition Examination Survey (NHANES) data suggested a significant decrease in sealant prevalence among children between 2011 to 2014 and 2015 to 2018. We explore whether this decrease could be associated with possible changes in 1) clinical sealant delivery, 2) dental materials (i.e., increased use of glass ionomer [GI] sealants resulting in an inability to detect sealant fragments that still provide preventive benefits or increased use of composite restorations leading to misclassifying sealants as restorations), and 3) examination sensitivity and specificity. We used NHANES data to estimate the prevalences of sealants, untreated caries, and restorations in ≥1 first permanent molar among children aged 7 to 10 y and used Medical Expenditure Panel Survey data to estimate the annual clinical delivery of sealants and fluoride treatments. We examined changes in outcomes between 2 periods (P < 0.05) controlling for selected sociodemographic characteristics. NHANES sealant examination quality was based on the reference examiner's replicate examinations. The adjusted prevalence of sealants decreased relatively by 27.5% (46.6% vs. 33.8%). Overall, untreated caries decreased. Untreated caries and restoration decreased among children without sealants. Annual clinical sealant delivery did not change, whereas fluoride treatment delivery increased. The decrease in sealant prevalence held when assessed for various age ranges and NHANES cycle combinations. While sealant examination specificity remained similar between the periods, sensitivity (weighted by the proportion of exams by each examiner) decreased relatively by 17.4% (0.92 vs. 0.76). These findings suggest that decreased sealant prevalence was not supported by decreased clinical sealant delivery nor increased use of composite restorations. Decreased examination sensitivity, which could be due to an increased use of GI sealants, could contribute to the decrease in sealant prevalence. The decrease in caries among children without sealants could suggest the increased use of GI sealants. However, we could not rule out that the decrease in caries could be attributable to increased fluoride treatment delivery.

A nucleoid-associated protein is involved in the emergence of antibiotic resistance by promoting the frequent exchange of the replicative DNA polymerase in M. smegmatis.

Antibiotic resistance in M. tuberculosis exclusively originates from chromosomal mutations, either during normal DNA replication or under stress, when the expression of error-prone DNA polymerases increases to repair damaged DNA. To bypass DNA lesions and catalyze error-prone DNA synthesis, translesion polymerases must be able to access the DNA, temporarily replacing the high-fidelity replicative polymerase. The mechanisms that govern polymerase exchange are not well understood, especially in mycobacteria. Here, using a suite of quantitative fluorescence imaging techniques, we discover that, as in other bacterial species, in M. smegmatis, the replicative polymerase, DnaE1, exchanges at a timescale much faster than that of DNA replication. Interestingly, this fast exchange rate depends on an actinobacteria-specific nucleoid-associated protein (NAP), Lsr2. In cells missing lsr2, DnaE1 exchanges less frequently, and the chromosome is replicated more faithfully. Additionally, in conditions that damage DNA, cells lacking lsr2 load the complex needed to bypass DNA lesions less effectively and, consistently, replicate with higher fidelity but exhibit growth defects. Together, our results show that Lsr2 promotes dynamic flexibility of the mycobacterial replisome, which is critical for robust cell growth and lesion repair in conditions that damage DNA.

[Overexpression of LncRNA MEG3 promotes ferroptosis and enhances chemotherapy sensitivity of hepatocellular carcinoma cells to cisplatin].

OBJECTIVE: To investigate the effect of overexpression of LncRNA MEG3 on proliferation, migration and cisplatin sensitivity of hepatoma cells HepG2 and LM3 and explore the underlying and mechanism. METHODS: The expression of MEG3 in healthy individuals and patients with hepatocellular carcinoma (HCC) was analyzed by online bioinformatics analysis, and Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect MEG3 expression in different HCC cell lines. A MEG3-overexpresing plasmid was transfected in HepG2 and LM3 cells, and the changes in cell proliferation and migration were examined using CCK8 assay and scratch assay. CCK8 assay was used to determine the inhibitory rate of cisplatin on the transfected cells. A reactive oxygen species (ROS) fluorescence probe (DCFH-DA) and malondialdehyde (MDA) kit were used to assess the changes in ROS production and MDA level in the cells. Western blotting was performed to detect the expression levels of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1). RESULTS: The expression of MEG3 was significantly lower in HCC cells than in LO2 cells, which was consistent with the results of bioinformatic analysis (P < 0.05). Overexpression of MEG3 in the HCC cell lines significantly suppressed cell proliferation and migration (P < 0.05), increased the cell inhibition rate of cisplatin (P < 0.05), enhanced cellular ROS production and increased MDA levels in the cells (P < 0.05). MEG3 overexpression significantly decreased the expressions of GPX4 and FTH1 in the HCC cell lines. CONCLUSION: The expression of MEG3 is decreased in HCC cells, and its overexpression inhibits proliferation and migration and enhances cisplatin sensitivity of HCC cells by promoting ferroptosis of the cells.

Josephson radiation threshold detector.

A Josephson radiation threshold detector (JRTD) that is based on the threshold behaviour of a current bias Josephson junction (CBJJ) is designed and fabricated for infrared radiation (IR@1550nm) detection at low temperatures. To achieve the optimal performance, we develop a binary hypothesis detection method to calibrate Josephson threshold behaviours (i.e. the switching current distributions of the CBJJ with the Al/AlOx/Al junction) in the absence and presence of radiation. In the absence of IR radiation, the junction transitioned with a measurable voltage drop across the junction, and this signal was treated as the events of hypothesis H0. The events of junction transition observed in the presence of the IR radiation served as hypothesis H1. Considering the usual Gaussian noise and based on statistical decision theory, the accumulated data of the measured switching current distributions are processed, and the threshold sensitivity of the demonstrated JRTD device is estimated. The minimum detectable IR radiation power of the proposed detector is approximately 0.74 pW, which corresponds to the photon rate of 5.692 × 106 photons/second. Further optimisation of JRTDs to implement the desired binary detection of a single photon is still a subject of argument, at least theoretically.

A revisit of drugs and potential therapeutic targets against non-alcoholic fatty liver disease: learning from clinical trials.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. Although numerous clinical trials have been conducted over the last few decades, an effective treatment has not been approved yet. Extensive research has accumulated a large amount of data and experience; however, the vast number of clinical trials and new therapeutic targets for NAFLD make it impossible to keep abreast of the relevant information. Therefore, a systematic analysis of the existing trials is necessary. METHODS: Here, we reviewed clinical trials on NAFLD registered in the mandated federal database, ClinicalTrials.gov, to generate a detailed overview of the trials related to drugs and therapeutic targets for NAFLD treatment. Following screening for pertinence to therapy, a total of 440 entries were identified that included active trials as well as those that have already been completed, suspended, terminated, or withdrawn. RESULTS: We summarize and systematically analyze the state, drug development pipeline, and discovery of treatment targets for NAFLD. We consider possible factors that may affect clinical outcomes. Furthermore, we discussed these results to explore the mechanisms responsible for clinical outcomes. CONCLUSION: We summarised the landscape of current clinical trials and suggested the directions for future NAFLD therapy to assist internal medicine specialists in treating the whole clinical spectrum of this highly prevalent liver disease.