Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.

BACKGROUND: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. PATIENTS AND METHODS: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). RESULTS: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature. CONCLUSIONS: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

[A mechanistic study of radiotherapy on intratumoral NK cell infiltration augmentation by regulating the EZH2/CXCL10 pathway in hepatocellular carcinoma cells].

Objective: To investigate the effect and associated mechanism of tumor tissue-infiltrating NK cells after receiving radiotherapy for hepatocellular carcinoma (HCC). Methods: A HCC tumor-bearing mouse model was constructed using human hepatocellular carcinoma cell line (SK-Hep-1) and divided into four groups: control, radiotherapy, NK cell clearance, and NK clearance combined with radiotherapy. Tumor growth condition was simultaneously recorded. The NK cell ratio in peripheral blood and the NK cell intratumoral infiltration condition were detected by flow cytometry and immunohistochemistry. Lentiviral-constructed SK-Hep-1 cells was used to detect the effect of radiotherapy on the regulation of CXCL10 and NK cell chemotaxis following EZH2 overexpression. SK-Hep-1 cells were irradiated in vitro and in vivo. The expression levels of EZH2 and CXCL10 mRNA and protein in the two groups of cell lines and mouse tumor tissues were detected by reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and immunohistochemistry. The chemotaxis and blocking experiments were used to validate the chemotaxis effect of CXCL10 on NK cells. The independent sample t-test was used to compare the groups. P<0.05 was considered statistically significant. Results: The HCC tumor-bearing mouse model experiment showed that HCC tumor growth was most remarkable in the NK clearance combined with the radiotherapy group compared to the radiotherapy group (P<0.05). Compared with the control group, the number of NK cells in the peripheral blood of nude mice in the radiotherapy group was significantly reduced, while the NK cell intratumoral infiltration was significantly increased (P<0.05). Flow cytometry and immunohistochemistry showed in vitro and in vivo expressional alterations. The average expression levels of EZH2 mRNA and protein in hepatocellular carcinoma cell lines and tumor tissues were decreased in the radiotherapy group than the control group and mouse tumor tissues (P<0.05), while the mRNA and protein expression levels of CXCL10 increased (P<0.05). The cell supernatant following radiotherapy enhanced NK cell chemotaxis but inhibited CXCL10 neutralization. EZH2 overexpression validated that radiotherapy up-regulated CXCL10 mRNA and down-regulated protein expression levels in in vitro and in vivo experiments (P<0.05). The chemotactic effect on NK cells was significantly weakened with EZH2 overexpression following radiotherapy. Conclusion: NK cells, as immune effector cells, are directly involved in radiotherapy- activated anti-HCC immunity. Importantly, radiotherapy inhibits EZH2 expression in hepatocellular carcinoma, thereby upregulating CXCL10 expression and enhancing intratumoral NK cell invasion.

High accuracy measurement of the ground-state hyperfine splitting in a 113Cd+ microwave clock: erratum.

We present an erratum to our Letter [Opt. Lett.40, 4249 (2015)OPLEDP0146-959210.1364/OL.40.004249]. This erratum corrects the nuclear Lande factor gI in Eq. (2). After correcting the error, the final ground-state hyperfine splitting frequency of the 113Cd+ ion is determined to be 15199862855.0287(10) Hz.

Inhibition of carbonic anhydrase II by sulfonamide derivatives.

A series of sulfonamide derivatives were synthesized, and the enzyme inhibitory activity of the synthesized compounds on carbonic anhydrase II was evaluated. Through molecular docking studies, it was found that compounds 1b, 1e, 2a, 2b, 3a have a strong binding affinity to carbonic anhydrase II. The IC50 values of the four compounds 1e, 2b, 3a, and 3b were lower than that of the positive control drug acetazolamide. What's more, the compounds had a high inhibitory activity for A549 lung cancer cell growth, among them, 1e and 3a could inhibit both carbonic anhydrase II and lung cancer cell proliferation.

Study on the structure and behaviour of cavitation bubbles generated in a high-intensity focused ultrasound (HIFU) field.

In this study, structures and behaviours of acoustic cavitation bubbles induced by a high-intensity focused ultrasound (HIFU) transducer, operating at its resonance frequency of 250kHz, are experimentally explored with corresponding observations captured by a high-speed video camera system. The experiments were conducted in an open-top Perspex water tank with deionized water, and illumination was provided by a LED spotlight which is placed beside the water tank throughout the whole experiment. Experimental results show that the structure of ultrasonically generated bubbles forms in a conical shape with several concentric bubble rings above the transducer. The distance between the adjacent rings with equal spacing as determined by the driving frequency of the HIFU transducer is experimentally measured and compared with the theoretical value. Then, the distribution of acoustic pressure in the acoustically driven liquid is further studied to investigate the behaviours of cavitation bubbles generated in a HIFU field. Additionally, the analysis of Bjerknes forces on the bubble surface which are induced by the gradient of acoustic pressure and the adjacent oscillating bubbles is quantitatively carried out, and the radius and velocity of a typical larger bubble are measured to characterize the behaviours of ultrasonically induced bubbles. Particularly, the physical phenomena of large bubbles including the coalescence, attraction or repulsion between adjacent bubbles, as well as the jumping of an acoustic bubble from the lower concentric ring level to the higher level, are analysed. The moving trajectory of the bubble is next obtained, and some conclusions are summarized to provide a greater understanding of the complex behaviours of the ultrasonically generated bubbles.

High accuracy measurement of the ground-state hyperfine splitting in a ¹¹³Cd⁺ microwave clock.

A microwave frequency standard based on laser-cooled (113)Cd(+) ions has been developed in recent years, and the short-term frequency instability is measured to be 6.1×10(-13)/√τ. By comparing the Cd(+) clock to a superior frequency reference, the ground-state hyperfine splitting of (113)Cd(+) is measured precisely to be 15199862855.0192(10) Hz with a fractional precision of 6.6×10(-14). This result is consistent with previous results, and the measurement precision is improved by nearly one order more than the best result reported before.

Interface ferroelectric transition near the gap-opening temperature in a single-unit-cell FeSe film grown on Nb-Doped SrTiO3 substrate.

We report findings of strong anomalies in both mutual inductance and inelastic Raman spectroscopy measurements of single-unit-cell FeSe film grown on Nb-doped SrTiO3, which occur near the temperature where the superconductinglike energy gap opens. Analysis suggests that the anomaly is associated with a broadened ferroelectric transition in a thin layer near the FeSe/SrTiO3 interface. The coincidence of the ferroelectric transition and gap-opening temperatures adds credence to the central role played by the film-substrate interaction on the strong Cooper pairing in this system. We discuss scenarios that could explain such a coincidence.

Construction of a gene-gene interaction network with a combined score across multiple approaches.

Recent progress in computational methods for inves-tigating physical and functional gene interactions has provided new insights into the complexity of biological processes. An essential part of these methods is presented visually in the form of gene interaction networks that can be valuable in exploring the mechanisms of disease. Here, a combined network based on gene pairs with an extra layer of re-liability was constructed after converting and combining the gene pair scores using a novel algorithm across multiple approaches. Four groups of kidney cancer data sets from ArrayExpress were downloaded and analyzed to identify differentially expressed genes using a rank prod-ucts analysis tool. Gene co-expression network, protein-protein interac-tion, co-occurrence network and a combined network were constructed using empirical Bayesian meta-analysis approach, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, an odds ratio formula of the cBioPortal for Cancer Genomics and a novel rank algorithm with combined score, respectively. The topological features of these networks were then compared to evaluate their performances. The results indicated that the gene pairs and their relationship rank-ings were not uniform. The values of topological parameters, such as clustering coefficient and the fitting coefficient R(2) of interaction net-work constructed using our ranked based combination score, were much greater than the other networks. The combined network had a classic small world property which transferred information quickly and displayed great resilience to the dysfunction of low-degree hubs with high-clustering and short average path length. It also followed distinct-ly a scale-free network with a higher reliability.

Application value of multislice spiral computed tomography angiography in the evaluation of renal artery variation in living donor kidney transplantation.

This study aims to investigate the accuracy and value of multislice spiral computed tomography (MSCT) angiography in the evaluation of renal artery variation in living donor kidney transplantation. Two hundred seventy-three kidney transplantation donors underwent preoperative MSCT scanning. Two doctors determined the running direction and variation of the renal artery through joint analysis of the preoperative original MSCT image and the recombination image using the blind reading method, compared the imaging results with the intraoperative results, and evaluated the accuracy and application value of MSCT angiography in the evaluation of renal artery variation in living donor kidney transplantation. CT angiography (CTA) can better show the renal artery and its variation. A total of 52 accessory renal arteries were found in the 273 kidney transplant operations, whereas 55 accessory renal arteries were found in preoperative MSCT. Four accessory renal arteries indicated in the MSCT were not found during the operation, and one accessory renal artery found during the operation was not indicated in the preoperative MSCT. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MSCT in the diagnosis of accessory renal arteries were 98.1, 98.2, 92.7, 99.5, and 98.2%, respectively. MSCT angiography can sensitively and accurately show the renal artery and its variation in living donor kidney transplantation, and has important clinical value for the formulation of the operative scheme before the transplantation.

A simplified genomic DNA extraction protocol for pre-germination genotyping in rice.

Genotyping is a critical step for molecular marker-assisted selection in rice. Rice genomic DNA samples for genotyping are typically isolated from living tissues such as seedlings. This requires the germination of all candidate seeds and extraction of DNA from the seedlings. Currently, an ideal individual is selected from a very large number of plants, which is time- and labor-consuming, requiring several transplantations of materials and sampling processes. In this study, we developed a simplified genomic DNA extraction protocol in rice by using amylase to treat half-seeds. The yields of genomic DNA from a half-seed of Indica and Japonica rice were greater than 203.8 ± 32.5 and 143.2 ± 25.5 ng, respectively, and the 260/280 nm absorbance ratio was 1.75-2.10. The DNA was confirmed to be sufficient for polymerase chain reaction amplification and can be used in a marker-assisted selection program.

Tim-3 expression on peripheral monocytes and CD3+CD16/CD56+natural killer-like T cells in patients with chronic hepatitis B.

Hepatitis B virus (HBV) infection is one of the major causes of chronic liver inflammation. Tim-3 acts as a negative regulatory molecule and plays a critical role in immune tolerance. In the current study, we investigated Tim-3 expression on peripheral monocytes and CD3+CD16/CD56+ natural killer like T (NKT-like) cells in chronic hepatitis B (CHB) patients. Peripheral blood mononuclear cells (PBMCs) were isolated from 52 CHB patients and 60 healthy controls. Tim-3+CD14+ cells and Tim-3+CD3+CD16/CD56+ cells were analyzed by flow cytometry. Results showed that expression of Tim-3 was significantly increased on both the monocytes and NKT-like cells in CHB patients than in controls (P = 0.002 and P < 0.001, respectively). Tim-3 levels on monocytes and NKT-like cells were further upregulated in patients with acute-on-chronic liver failure (ACLF). In addition, we assessed the correlation of Tim-3 expression with levels of alanine aminotransferase (ALT) and tumor necrosis factor alpha (TNF-α). Data revealed that Tim-3 expression on both monocytes and NKT-like cells was positively correlated with level of ALT (r = 0.59, P < 0.001, and r = 0.60, P < 0.001, respectively), whereas Tim-3 expression on NKT-like cells was negatively correlated with serum level of TNF-α (r = -0.54, P < 0.001) in CHB patients. Our results suggest that Tim-3 may play important roles in the pathogenesis of CHB.

An adaptable, reusable, and light implant for chronic Neuropixels probes.

Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) be light enough for use in mice; (3) allow reuse of the probes after explantation. Here, we present the "Apollo Implant", an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a "payload" module that is attached to the probe and is recoverable, and a "docking" module that is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across seven labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.

Long-term familiarity promotes joining in neighbour nest defence.

Familiarity plays an important role in the evolution of sociality and cooperation. Familiar individuals may gain a reputation for participating in, or defecting from, cooperative tasks. Previous research suggests that long-term familiarity with territorial neighbours benefits breeders. We tested the hypothesis that great tits (Parus major) are more likely to join in neighbours' nest defence if those neighbours are familiar from the previous year. We show that neighbours that shared a territory boundary the previous year are more likely to join their neighbours' nest defence than neighbours that did not share a boundary before. Closer neighbours did not differ from distant neighbours in their latency to join. For familiar neighbours that joined, there was no difference in call rate in relation to whether one or both members of the focal pair were familiar. First-time breeders (by definition unfamiliar) did not join each other's nest defence. This is the first evidence of a relationship between familiarity and joining in nest defence. Such direct benefits of familiarity may have important implications in the evolution of sociality.

A clinical characteristics and genetic analysis of a case of Rubinstein-Taybi syndrome with glaucoma.

The aim of this study was to analyze the clinical features of a Rubinstein-Taybi syndrome (RSTS) case with neonatal glaucoma. We also wanted to explore the manifestation of the disease in combination with genotype-phenotype correlation. For DNA extraction we used 2 ml peripheral blood, collected from the child and parents. The extracted genomic DNA was used for clinical exome sequencing. A 38-day old baby boy was diagnosed with congenital glaucoma on the third day after birth with symptoms, including choking milk, feeding difficulties and slow weight gain. He was admitted to the neonatology department because of lung infection. The clinical exome sequencing showed that the child has a c.2368C>T heterozygous mutation in exome 13 in CREBBP (cAMP responsive element binding protein) while his parents have no such mutation. Combining genetic data with the clinical features, this infant was diagnosed with RSTS. This is the first report of RSTS caused by a c. 2368C>T mutation in CREBBP. RSTS is an extremely rare disease with extensive clinical manifestations. It is highly overlapped with other syndromes which makes the diagnosis difficult. RSTS is easy to be missed or misdiagnosed due to the lack of specific clinical manifestations during the neonatal period. Neonatal specialists need to enhance their awareness and recognition of this condition, and use genetic testing as an effective tool in order to finalize their diagnosis.

Expression analyses and antiviral properties of the Beijing-You and White Leghorn myxovirus resistance gene with different amino acids at position 631.

Influenza is a topic of wide public concern, particularly because of the recent emergence of avian flu. The myxovirus resistance (Mx) protein has been shown to have an inhibitory effect on influenza virus and is therefore of great interest. This study examines the Mx protein in 8 local Chinese chicken breeds and 2 exotic chicken breeds. Amino acid 631, found in the Mx GTPase effector domain, was examined in 534 individuals by comparing PCR results, and individuals were separated into the A/A genotype or the G/G genotype, depending on whether amino acid 631 is an Asn or Ser. In the native breed, the frequency of G/G homozygotes is 0.780 (294/377). The Mx expression levels in tissues and chicken embryo fibroblast cells with different genotypes were also studied. The A/A individuals from Beijing-You and White Leghorn breeds had higher Mx expression levels than G/G individuals. The liver, heart, and spleen had higher expression levels than muscle or kidney. The A/A chicken embryo fibroblast cells had higher antiviral activity against vesicular stomatitis virus and Newcastle disease. We provide the first report examining the expression level and antiviral activity of different Mx alleles of nucleotide 2216(S631N) genotypes. This study lays a good foundation for correlative studies examining genotype and antiviral function.

Mitochondrial DNA haplogroup C4 can increase the risk of active tuberculosis disease in Southwest China.

Tuberculosis (TB) remains a serious health problem worldwide. Host genetic factors are reported to be correlated with tuberculous infection. However, few mitochondrial genetic studies of TB patients have been carried out. To investigate the role of mitochondrial DNA (mtDNA) in tuberculous infection. We recruited 243 TB patients and 261 normal controls (NCs) to compare their mtDNA haplogroups and copy numbers. The frequency of mtDNA haplogroup C4 was significantly higher in TB patients (7%) than in NCs (2.8%, P = 0.042). However, this difference disappeared when TB patients were separated into male and female groups and compared with sex-matched NCs. When TB patients were divided into five subgroups for further analyses, the mtDNA haplogroup C4 showed different frequencies among the five subgroups. The frequency of the haplogroup C4 was much lower in the pulmonary TB (pTB) and pleural TB (plTB) group (1.4%) than in the non-pTB and plTB group (9.3%, P = 0.027). mtDNA copy numbers were significantly higher in TB patients than in NCs (99.09 ± 54.54 vs. 73.90 ± 43.92; P < 0.0001); results in male/female/total TB patients and matched NCs were similar. mtDNA haplogroups and copy numbers were found to have an important role in active TB disease. .

[Application of Gene Xpert Mycobacterium tuberculosis DNA and resistance to rifampicin assay in the rapid detection of tuberculosis in children].

OBJECTIVE: To detect Mycobacterium tuberculosis (MTB) and rifampin resistance of the clinical specimens in children by Xpert MTB DNA and resistance to rifampicin(MTB/RIF) detection system, and evaluate the application value of this method in children with tuberculosis. METHOD: Data of 109 children cases of clinically suspected tuberculosis were collected (including 46 gastric lavage aspirate, 19 sputum, 10 fine needle aspiration biopsy, 4 pus, 14 cerebrospinal fluid, 11 Serous membrance fluid, 1 marrow, 3 stool, 1 urine specimens)between April 2014 and March 2015. All specimens were detected by smear fluorescence staining microscopy, MGIT 960 BACTEC liquid culture, Xpert MTB/RIF assay and T-SPOT.TB test respectively. The sensitivity and specificity of Xpert MTB/RIF assay were analyzed in those clinical specimens. RESULT: The sensitivity and specificity of the Xpert MTB/RIF assay for MTB detection in childhood tuberculosis clinical specimen were 28.6% and 87.5%. The sensitivity of 65 pulmonary tuberculosis(46 gastric lavage aspirate, 19 sputum) which included gastric lavage aspirates and sputum was 33.3% and 57.1%, the specificity of the two was 100.0%. In 44 extrapulmonary tuberculosis, the sensitivity of the pus and the puncture fluid was higher and approached 100.0%. The detection rate of the cerebrospinal fluid and serous cavity effusion was very low. The sensitivity was 100.0% in smear-positive and culture-positive samples and only 30.8% to 50.0% in smear-negative and culture-positive samples. The sensitivity and specificity of Xpert MTB/RIF assay to detect rifampin resistance were 100.0%. In clinical samples, the sensitivity of Xpert MTB/RIF assay was higher than that of smear fluorescence staining microscopy, but the difference was not statistically significant (χ(2)=0, P>0.05). The result was equivalent to that of MGIT 960 BACTEC liquid culture (28.6% vs. 27.3%, χ(2)=2.50, P>0.05), and far below that of T-SPOT.TB(28.6% vs 59.7%, χ(2)=13.92, P<0.05). CONCLUSION: Xpert MTB/RIF assay did not show obvious advantage in childhood tuberculosis, especially in serous cavity effusion and cerebrospinal fluid, but the advantages of detecting tuberculosis rapidly and resistance to rifampin can provide help for the clinical diagnosis and treatment in childrenhood tuberculosis.