Enhancing X-Ray Sensitization with Multifunctional Nanoparticles.

In the progression of X-ray-based radiotherapy for the treatment of cancer, the incorporation of nanoparticles (NPs) has a transformative impact. This study investigates the potential of NPs, particularly those comprised of high atomic number elements, as radiosensitizers. This aims to optimize localized radiation doses within tumors, thereby maximizing therapeutic efficacy while preserving surrounding tissues. The multifaceted applications of NPs in radiotherapy encompass collaborative interactions with chemotherapeutic, immunotherapeutic, and targeted pharmaceuticals, along with contributions to photodynamic/photothermal therapy, imaging enhancement, and the integration of artificial intelligence technology. Despite promising preclinical outcomes, the paper acknowledges challenges in the clinical translation of these findings. The conclusion maintains an optimistic stance, emphasizing ongoing trials and technological advancements that bolster personalized treatment approaches. The paper advocates for continuous research and clinical validation, envisioning the integration of NPs as a revolutionary paradigm in cancer therapy, ultimately enhancing patient outcomes.

Biomechanical evaluation of flash-frozen and cryo-sectioned papillary muscle samples by using sinusoidal analysis: cross-bridge kinetics and the effect of partial Ca2+ activation.

We examined the integrity of flash-frozen and cryo-sectioned cardiac muscle preparations (introduced by Feng and Jin, 2020) by assessing tension transients in response to sinusoidal length changes at varying frequencies (1-100 Hz) at 25 °C. Using 70-µm-thick sections, we isolated fiber preparations to study cross-bridge (CB) kinetics: preparations were activated by saturating Ca2+ as well as varying concentrations of ATP and phosphate (Pi). Our results showed that, compared to ordinary skinned fibers, in-series stiffness decreased to 1/2, which resulted in a decrease of isometric tension to 62%, but CB kinetics and Ca2+ sensitivity were little affected. The pCa study demonstrated that the rate constant of the force generation step (2πb) is proportionate to [Ca2+] at < 5 µM, suggesting that the activation mechanism can be described by a simple second order reaction. We also found that tension, stiffness, and magnitude parameters are related to [Ca2+] by the Hill equation, with a cooperativity coefficient of 4-5, which is consistent with the fact that Ca2+ activation mechanisms involve cooperative multimolecular interactions. Our results support the long-held hypothesis that Process C (Phase 2) represents the CB detachment step, and Process B (Phase 3) represents the force generation step. Moreover, we discovered that constant H may represent the work-performing step in cardiac preparations. Our experiments demonstrate excellent CB kinetics with two well-defined exponentials that can be more distinguished than those found using ordinary skinned fibers. Flash-frozen and cryo-sectioned preparations are especially suitable for multi-institutional collaborations nationally and internationally because of their ease of transportation.

[Development and in vivo biomechanics of goat mobile artificial lumbar spine complex].

OBJECTIVE: Mobile artificial lumbar complex (MALC) which suitable for reconstruction after subtotal lumbar resection in goats was developed,and to test stability of the complex and postoperative lumbar segmental motor function. METHODS: Eighteen male boer goats aged from 1 to 2 years old (weighted from 35 to 45 kg) were selected and divided into control group,fusion group and non-fusion group,with 6 goats in each group. According to preoperative CT scans and MRI examinations of lumbar,the goat MALC was designed and performed by 3D printed for non-fusion group. Operation was performed on three groups respectively,and only vertebral body and disc were exposed in control group. In fusion group,L4 part of vertebral body and the upper and lower complete disc tissues were removed,and the lumbar spine bone plate fixation was performed with titanium mesh bone grafting. In non-fusion group,vertebral body and disc were removed in the same way,and MALC was implanted. AP and lateral X-rays of lumbar vertebrae in goat were taken at 6 months after surgery,in order to understand whether the plant was dislocated,displaced and fractured. Biomechanical tests were performed on the specimens by mechanical instrument to measure range of motion (ROM) of L2,3,L3,4,L4,5 intervertebral space and the overall ROM of L2-5 lumbar vertebrae. RESULTS: MALC of lumbar vertebra was designed by 3D printing,and its component artificial vertebrae and upper and lower artificial end plates were manufactured. The semi-spherical structure was fabricated by precision lathe using high-crosslinked polyethylene material,and the prosthesis was assembled. Postoperative AP and lateral X-rays of lumbar vertebra at 6 months showed the implant position of implant and MALC were good without displacement and dislocation. In vitro biomechanical test of lumbar vertebrae specimens:(1) There were no statistical significance in ROM of lumbar intervertebral space flexion and extension,lateral flexion and rotation on L3,4 and L4,5,between non-fusion group and control group (P>0.05),while ROM of fusion group was significantly reduced compared with the other two groups (P<0.05). There were no significant difference in ROM of L2,3 intervertebral flexion and extension,lateral flexion and rotation between non-fusion group and control group (P>0.05),while fusion group was significantly increased compared with the other two groups (P<0.001). (2) There was no significant difference in overall lumbar ROM of L2-5 (P> 0.05). CONCLUSION: The individual MALC could restore intervertebral height of lumbar vertebra while maintaining the stability of lumbar vertebra and re-establishing motor function of lumbar space.

Global fungal-host interactome mapping identifies host targets of candidalysin.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.

Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

SIRT6 Reduces Rheumatoid Arthritis Injury by Inhibiting MyD88-ERK Signaling Pathway.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by destruction of synovial joints, abnormal immune responses and chronic inflammatory manifestations, which seriously affects patients' well-being. We explored this study to ascertain the effect and mechanism of silent information regulator 6 (SIRT6) on RA. METHODS: Genes of RA patients and normal volunteers were analyzed using Gene Expression Omnibus (GEO), Kyoto-Encyclopedia of Genes and Genomes (KEGG) and Disconet databases. Serum samples of RA patients and normal subjects were collected before detection of myeloid differentiation factor-88 (MyD88)-extracellular signal-regulated kinase (ERK) pathway proteins expression with Western blot. In vitro RA fibroblast-like synoviocytes (FLS) cell model (RA-FLS) was established by treating RSC-364 with recombinant rat IL-1ß (10 ng/mL) after which SIRT6 and MyD88 adenoviruses treatment was carried out. The enzyme linked immunoassay (ELISA), real time polymerase chain reaction (RT-PCR) and Western blot were respectively used to measure inflammatory factors, related messenger ribonucleic acid (mRNA) and protein expressions. Also, we constructed RA rat model with bovine type II collagen (BIIC) and complete Freund's adjuvant, before treatment with SIRT6 and MyD88 adenoviruses. RESULTS: Low expression of SIRT6 gene were detected in RA patients. Also, levels of MyD88, ERK and phosphorylated extracellular signal-regulated protein kinase (p-ERK) protein expressions in RA patients were increased, whilst that of SIRT6 protein decreased. Compared to FLS cells in Control group, inflammatory factors levels of rats in Model batch increased significantly. SIRT6 adenovirus treatment potentially and significantly inhibited inflammation including suppression of increased inflammatory factors induced by MyD88. In comparison with FLS cells in Control group, Model batch cells' MyD88, interleukin (IL)-1ß, IL-21, IL-22, IL-6, IL-17, tumor necrosis factor-alpha (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) mRNA expressions increased but SIRT6 gene treatment could reduce mRNA expression of the aforesaid factors, even after MyD88 adenovirus treatment. Besides, overpressed SIRT6 negatively regulated levels of MyD88, ERK and p-ERK proteins expressions. SIRT6 demonstrated anti-RA effect by regulating MyD88-ERK pathway and inhibiting inflammatory response in RA rats. CONCLUSIONS: SIRT6 could potentially inhibit the inflammatory response of RA via a regulatory mechanism mainly relating to MyD88-ERK signal pathway. Thus, SIRT6 and its agonists may serve as new targets for developing drugs that can potentially treat RA.

Functional fitness and risk factors of older patients with diabetes combined with sarcopenia and/or frailty: A cross-sectional study.

AIM: To learn the functional fitness levels in older adults with diabetes combined with sarcopenia and/or frailty. DESIGN: A cross-sectional investigation study. METHODS: A total of 205 participants with type 2 diabetes were recruited from September 2019 to August 2020. All patients underwent diagnostic screening for sarcopenia and frailty, and were divided into combined group (the patients who had sarcopenia and/or frailty) and non-combined group (the patient who had no sarcopenia and/or frailty). The diagnostic criteria for sarcopenia applied was proposed by the Asian Working Group on Sarcopenia in 2019 and frailty status was assessed using FRAIL Scale. Functional fitness was measured using the Senior Fitness Test and compared between combined and non-combined groups. Biochemical data of blood routine, glycolipid, and hepatorenal function tests were acquired from medical records. Logistic regression analysis was applied to explore the factors associated with the sarcopenia and/or frailty in the older adults with diabetes. RESULTS: Compared with non-combined group, the participants in combined group exhibited shorter 6-min walk distance, fewer repetitions of arm curls and chair stands, smaller back scratch and chair sit-and-reach values, and longer time in the 8-ft up-and-go test. The patients in the combined group had significantly lower level of red blood cell, haemoglobin, haematocrit, and higher level of platelet and blood urea nitrogen. Apart from calf circumference, physical activity, and insulin injection treatment, 6-min walk distance was the factor associated with diabetes combined with sarcopenia and/or frailty.

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

OBJECTIVE: Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. METHODS: Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. RESULTS: Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). CONCLUSION: HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Mechanical Evaluation of Frozen and Cryo-Sectioned Papillary Muscle Samples by Using Sinusoidal Analysis: Cross-bridge Kinetics and the Effect of Partial Ca2+ activation.

The use of frozen and cryo-sectioned cardiac muscle preparations, introduced recently by (Feng & Jin, 2020), offers promising advantages of easy transport and exchange of muscle samples among collaborating laboratories. In this report, we examined integrity of such preparation by studying tension transients in response to sinusoidal length changes and following concomitant amplitude and phase shift in tension time courses at varying frequencies. We used sections with 70 µm thickness, isolated fiber preparations, and studied cross-bridge (CB) kinetics: we activated the preparations with saturating Ca2+, and varying concentrations of ATP and phosphate (Pi). Our experiments have demonstrated that this preparation has the normal active tension and elementary steps of the CB cycle. Furthermore, we investigated the effect of Ca2+ on the rate constants and found that the rate constant r4 of the force generation step is proportionate to [Ca2+] when it is <5 µM. This observation suggests that the activation mechanism can be described by a simple second order reaction. As expected, we found that magnitude parameters including tension and stiffness are related to [Ca2+] by the Hill equation with cooperativity of 4-5, consistent to the fact that Ca2+ activation mechanisms involve cooperative multimolecular interactions. Our results are consistent with a long-held hypothesis that process C (phase 2 of step analysis) represents the CB detachment step, and process B (phase 3) represents the force generation step. In this report, we further found that constant H may also represent work performance step. Our experiments have demonstrated excellent CB kinetics with reduced noise and well-defined two exponentials, which are better than skinned fibers, and easier to handle and study than single myofibrils.

Redox signaling-driven modulation of microbial biosynthesis and biocatalysis.

Microbial communication can drive coordinated functions through sensing, analyzing and processing signal information, playing critical roles in biomanufacturing and life evolution. However, it is still a great challenge to develop effective methods to construct a microbial communication system with coordinated behaviors. Here, we report an electron transfer triggered redox communication network consisting of three building blocks including signal router, optical verifier and bio-actuator for microbial metabolism regulation and coordination. In the redox communication network, the Fe3+/Fe2+ redox signal can be dynamically and reversibly transduced, channeling electrons directly and specifically into bio-actuator cells through iron oxidation pathway. The redox communication network drives gene expression of electron transfer proteins and simultaneously facilitates the critical reducing power regeneration in the bio-actuator, thus enabling regulation of microbial metabolism. In this way, the redox communication system efficiently promotes the biomanufacturing yield and CO2 fixation rate of bio-actuator. Furthermore, the results demonstrate that this redox communication strategy is applicable both in co-culture and microbial consortia. The proposed electron transfer triggered redox communication strategy in this work could provide an approach for reducing power regeneration and metabolic optimization and could offer insights into improving biomanufacturing efficiency.

Genome-wide direct quantification of in vivo mutagenesis using high-accuracy paired-end and complementary consensus sequencing.

Error-corrected next-generation sequencing (ecNGS) is an emerging technology for accurately measuring somatic mutations. Here, we report paired-end and complementary consensus sequencing (PECC-Seq), a high-accuracy ecNGS approach for genome-wide somatic mutation detection. We characterize a novel 2-aminoimidazolone lesion besides 7,8-dihydro-8-oxoguanine and the resulting end-repair artifacts originating from NGS library preparation that obscure the sequencing accuracy of NGS. We modify library preparation protocol for the enzymatic removal of end-repair artifacts and improve the accuracy of our previously developed duplex consensus sequencing method. Optimized PECC-Seq shows an error rate of <5 × 10-8 with consensus bases compressed from approximately 25 Gb of raw sequencing data, enabling the accurate detection of low-abundance somatic mutations. We apply PECC-Seq to the quantification of in vivo mutagenesis. Compared with the classic gpt gene mutation assay using gpt delta transgenic mice, PECC-Seq exhibits high sensitivity in quantitatively measuring dose-dependent mutagenesis induced by Aristolochic acid I (AAI). Moreover, PECC-Seq specifically characterizes the distinct genome-wide mutational signatures of AAI, Benzo[a]pyrene, N-Nitroso-N-ethylurea and N-nitrosodiethylamine and reveals the mutational signature of Quinoline in common mouse models. Overall, our findings demonstrate that high-accuracy PECC-Seq is a promising tool for genome-wide somatic mutagenesis quantification and for in vivo mutagenicity testing.

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension.

BACKGROUND: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS). OBJECTIVE: Further characterize efficacy and safety of ofatumumab in RMS. METHODS: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021. RESULTS: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04-0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter "no evidence of disease activity" criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified. CONCLUSION: Ofatumumab has a favorable longer-term benefit-risk profile in RMS. TRIAL REGISTRY: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114.

[Hunyuan moxibustion for diarrhea-predominant irritable bowel syndrome of spleen and kidney yang deficiency: a randomized controlled trial].

OBJECTIVE: To compare the therapeutic effect between Hunyuan moxibustion and oral western medication on diarrhea-predominant irritable bowel syndrome（IBS-D）of spleen and kidney yang deficiency. METHODS: Sixty patients with IBS-D of spleen and kidney yang deficiency were randomly divided into a Hunyuan moxibustion group and a western medication group, 30 cases each group. The Hunyuan moxibustion group was treated with Hunyuan moxibustion at Guanyuan（CV 4），40 min each time, once a day; in the western medication group，loperamide hydrochloride capsules (2 mg each time, 3 times a day) and bacillus licheniformis live capsules (0.5 g each time, 3 times a day) were given orally.Both groups were treated for 20 days. The scores of irritable bowel syndrome（IBS）symptom severity scale（IBS-SSS）, IBS quality of life scale (IBS-QOL) and TCM symptom grading quantitative were observed before and after treatment, and the clinical efficacy and safety were evaluated in the two groups. RESULTS: After treatment，each item scores and total scores of IBS-SSS in the two groups were lower than those before treatment（P<0.05）, and the total scores of IBS-QOL were higher than those before treatment (P<0.05)；each item score and total score of IBS-SSS in the Hunyuan moxibustion group were lower than those in the western medication group (P<0.05), and the total score of IBS-QOL in the Hunyuan moxibustion group was higher than that in the western medication group (P<0.05).After treatment, each item score and total score of TCM symptom grading quantitative in the Hunyuan moxibustion group were lower than those before treatment (P<0.05), the abdominal pain, diarrhea, lack of appetite scores and total score in the western medication group were lower than those before treatment (P<0.05)；and the abdominal pain, soreness and weakness of waist and knees, fear to cold and cold limbs scores and total score in the Hunyuan moxibustion group were lower than those in the western medication group (P<0.05).The total effective rate was 90.0%（27/30）in the Hunyuan moxibustion group, which was higher than 73.3%（22/30）in the western medication group (P<0.05). No adverse reactions occurred in both groups during treatment. CONCLUSION: Hunyuan moxibustion can effectively improve the symptom severity and quality of life in patients with IBS-D of spleen and kidney yang deficiency, especially in improving the symptoms of abdominal pain, soreness and weakness of waist and knees, fear to cold and cold limbs.Its therapeutic effect is superior to western medication.

[Effects of Biogas Slurry Application on Soil Microbial Communities Structure and Function During Wheat-rice Stubble Period].

To reveal the effects of biogas slurry application on soil microbial community structure and function, a soil column experiment was constructed with three treatments[(no N addition, CM; conventional fertilization, SN; biogas slurry addition, SZ)]. The differences in composition, diversity, and structure of bacterial and fungal communities on day 1 and day 21 after soil flooding were evaluated, and their functions were predicted using Illumina high-throughput sequencing technology. The results of the analysis of α diversity showed that the fungal α-diversity indexes of CM, SN, and SZ treatments on day 1 were significantly higher than those on day 21, and there was no significant difference among the three treatments. However, the bacterial Simpson index differed among the three treatments on day 21, with SZ-21 showing a higher Simpson index but lower Chao1 index compared with those of SZ-21. The analysis of bacterial community structure showed that Firmicutes, Chloroflexi, and Actinobacteria in the SN-1 treatment were different from those in the other treatments on day 1, whereas the relative abundance of bacterial phyla in the SZ and SN treatments were similar on day 21. The analysis of fungal community structure showed that the relative abundance of Ascomycota and Zygomycota in the SZ-1 treatment were higher than those in the SN-1 and CM-1 treatments on day 1. The relative abundance of Ascomycota in the SN-21 and SZ-21 treatments were lower, whereas that of Zygomycota were higher compared with that in CM-21. The analysis of NMDS showed that the composition of bacterial and fungal communities in the SN and SZ treatments showed a gradually similar trend. The PICRUSt analysis showed that the function of the soil bacterial community was similar in the CM, SN, and SZ treatments. The FUNGuild function prediction reflected that the main differences in trophic type between the SN-21 and SZ-21 treatments occurred in saprotroph and pathotroph forms. Therefore, biogas slurry addition in the wheat-rice stubble stage could contribute to balancing soil nutrients and maintaining soil ecological function to a certain extent, but there may still be a risk of fungal disease.

PIG-A gene mutation as a mutagenicity biomarker among coke oven workers.

PIG-A gene mutations can be detected in humans, and PIG-A assays can potentially predict the risk of exposure to carcinogens. However, extensive, population-based studies to validate this are lacking. We studied a cohort of occupational coke oven workers with chronic high exposure to carcinogenic polycyclic aromatic hydrocarbons, which are well-studied genotoxins classified by the IARC as carcinogenic to humans. Peripheral blood erythrocytes of workers were assessed for gene mutations using a PIG-A assay, and chromosome damage using the cytokinesis-block micronucleus test with lymphocytes. Two sample populations from a non-industrialized city and new employees in industrial plants were selected as controls. We observed a significantly elevated PIG-A mutation frequency (MF) and increased frequencies of micronuclei (MN) and nuclear buds (NBUDs) in coke oven workers, compared with levels in the control groups. We found that the coke oven workers with different lengths of service had a relatively high mutation frequency. Overall, the study findings showed that occupational exposure of coke oven workers increases the genetic damage and the PIG-A MF could be a potential biomarker for risk assessment of carcinogen exposure.

Synthesis of Imidazole-Based Molecules under Ultrasonic Irradiation Approaches.

Imidazole-based compounds are a series of heterocyclic compounds that exhibit a wide range of biological and pharmaceutical activities. However, those extant syntheses using conventional protocols can be time-costly, require harsh conditions, and result in low yields. As a novel and green technique, sonochemistry has emerged as a promising method for organic synthesis with several advantages over conventional methods, including enhancing reaction rates, improving yields, and reducing the use of hazardous solvents. Contemporarily, a growing body of ultrasound-assisted reactions have been applied in the preparation of imidazole derivatives, which demonstrated greater benefits and provided a new strategy. Herein, we introduce the brief history of sonochemistry and focus on the discussion of the multifarious approaches for the synthesis of imidazole-based compounds under ultrasonic irradiation and its advantages in comparison with conventional protocols, including typical name-reactions and various sorts of catalysts in those reactions.

Glutathione S-Transferase Highly Expressed in Holotrichia parallela Antennae Inactivates the Odorant Unsaturated Aldehyde Volatiles.

Odorant-degrading enzymes in insects play a vital role in maintaining olfactory sensitivity. However, the role and molecular mechanism of glutathione S-transferases (GSTs) in odorant inactivation has been rarely studied. In the present study, 31 GSTs were identified from the antennal transcriptome of Holotrichia parallela. HpGSTd1 possesses the highest transcriptome expression level. Recombinant HpGSTd1 showed degradation activity toward various unsaturated aldehyde volatiles. Furthermore, the metabolite of cinnamaldehyde was identified by high-resolution mass spectrometry (HRMS). The molecular docking analysis and site-directed mutagenesis revealed the key residues of HpGSTd1 in degrading odorants. In addition, the unsaturated aldehyde volatiles elicited the behavioral and electrophysiological responses of H. parallela. Taken together, our findings suggest that HpGSTd1 may play an essential role in inactivating odorants in H. parallela, which provides new insights for identifying molecular targets and exploring effective olfactory regulators for this underground pest.

Experiences of visiting female sex workers, social interaction, support and HIV infection among elderly men from rural China.

OBJECTIVES: To make clear the roles of social interaction and social support in HIV infection among elderly men who visit female sex workers (FSW). METHODS: We conducted a case-control study: 106 newly HIV (+) vs. 87 HIV (-) elderly men who visited FSW with similar age, education levels, marital statuses, monthly expenses for entertainment and migration experiences. Experiences of visiting FSW, social interaction, and intimate social support were obtained. Backward binary logistic regression was applied. RESULTS: Cases' first visit to FSW happened at the age of 44.01 ± 12.25, older than controls (33.90 ± 13.43). 23.58% cases had gotten HIV-related health education (HRHE) before, less than controls (57.47%). More cases (48.91%) "always" got material support than controls (34.25%). Less cases gave "close" (38.04%) comments toward daily life, "satisfied" (34.78%) with their sexual life, "agree" being emotional fulfilled (46.74%) than controls (71.23% ,64.38%, and 61.64%). Risky factors for HIV infection among elderly men were having 3000 YUAN and above monthly income, visiting teahouse with friends, living without spouses, visiting different FSW, visiting FSW for other reason, receiving material support from most intimate sexual partner, older age of first visit to FSW. The protective factors were receiving HRHE, visiting FSW due to loneliness, and giving positive comments toward daily life with most intimate sexual partner. CONCLUSIONS: Elderly men's social interactions are mainly visiting teahouse which is a potential sexual venue. Getting HRHE is formal protective social interactions but very rare for cases (23.58%). Social support from sexual partner is not enough. Emotional support is protective meanwhile material support only is risky for becoming HIV-positive.

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression.

PURPOSE: For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression. METHODS: We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[-] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture. RESULTS: In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(-) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 (P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells. CONCLUSION: For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(-) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2- MBC.

Benchmark dose estimation for benzene-exposed workers in China: Based on quantitative and multi-endpoint genotoxicity assessments.

Based on previous exposure studies, benzene (BZ) has been classified as a human carcinogen and occupational exposure limit (OELs) for BZ has been set to be about 1 ppm around the world. However, health hazards have still been reported with exposure below the OEL. Thus, the OEL needs to be updated to reduce health risk. The overall aim of our study was therefore to generate new OEL for BZ via a benchmark dose (BMD) approach and based on quantitative and multi-endpoint genotoxicity assessments. Genotoxicities were determined using the novel human PIG-A gene mutation assay, the micronucleus (MN) test and the COMET assay in benzene-exposed workers. Among the 104 workers with below current OELs, they exhibited significantly higher PIG-A mutant frequencies (MFs) (15.96 ± 14.41 × 10-6) and MN frequencies (11.55 ± 6.83‰) than those among the controls (PIG-A MFs: 5.46 ± 4.56 × 10-6, MN frequencies: 4.51 ± 1.58 ‰), but no difference in the COMET assay. A significant association was also observed between BZ exposure doses and PIG-A MFs and MN frequencies (P < 0.001). Our results indicate that health hazards were induced among workers with below OEL exposures. Based on results from the PIG-A and MN assays, the lower confidence limit of the BMD (BMDL) were calculated to be 8.71 mg/m3-year and 0.44 mg/m3-year, respectively. Based on these calculations, the OEL for BZ was determined to be lower than 0.07 ppm. This value can be considered by regulatory agencies to set new exposure limits and to better protect workers.