Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies.

BACKGROUND: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas. PATIENTS AND METHODS: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world. RESULTS: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance. CONCLUSION: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.

An SLE patient with prolactinoma and recurrent granulomatous mastitis successfully treated with hydroxychloroquine and bromocriptine.

Granulomatous mastitis (GM) is a rare benign mammary lesion in which autoimmunity and hyperprolactinemia are considered possible etiological factors. GM has a high frequency of relapse and may lead to chronic ulceration and fistula if not treated properly. Here we report a case of a 22-year-old systemic lupus erythematosus (SLE) patient with three years' disease duration, stable on prednisone and hydroxychloroquine, who was found to have prolactinoma and recurrent GM after she discontinued medication on her own accord. The patient subsequently recovered and remained free of GM relapse under treatment of prednisone, hydroxychloroquine and bromocriptine. Though autoimmune disorders and prolactinoma were reported in GM, a coexisting condition of SLE, prolactinoma, and granulomatous mastitis has rarely been observed in one patient. We suggest our case as an illustrative example of the complex interaction between autoimmunity, neuroendocrine dysfunction, and manifestations in the breast: Immunological disturbances in the background of SLE, coupled with elevated prolactin levels secondary to a prolactinoma, may have predisposed the patient to the development of GM. The mammary lesion recovered and maintained free of relapse under immunosuppressive and antiprolactinemic therapy.

Clinical characteristics and risk factors of intracranial hemorrhage in systemic lupus erythematosus.

We enrolled and reviewed 26 medical records of systemic lupus erythematosus (SLE) with intracranial hemorrhage (cases) and 104 randomly matched records of SLE without intracranial hemorrhage (controls) out of 6653 admitted patients at Peking Union Medical College Hospital from 1994 to 2012, to analyze the clinical characteristics and risk factors of intracranial hemorrhage in SLE. The incidence of SLE with intracranial hemorrhage was only 0.39% within the last 18 years at Peking Union Medical College Hospital. However, the in-hospital fatality rate was quite high (23.1%). Headache was the most common symptom (53.5%) in SLE patients with intracranial hemorrhage. The anatomical localization of the hemorrhages in the brain was predominantly located in the cerebrum. Intracranial hemorrhage could happen in either stable or active SLE patients. SLE patients with intracranial hemorrhage presented other neuropsychiatric syndromes defined by the American College of Rheumatology (ACR) in 1999, thrombocytopenia and antiphospholipid syndrome more frequently than controls. Thrombocytopenia was the independent risk factor for intracranial hemorrhage coexisting with SLE (OR=3.687, 95% CI 1.510-9.001, p=0.004).

Effects of reactive oxygen species from activated leucocytes on human sperm motility, viability and morphology.

The accumulated data suggest that inflammation can increase the level of reactive oxygen species (ROS), which contribute to impaired sperm function and male infertility. Therefore, we propose that inflammation-mediated production of ROS in male and female reproductive tracts hinder sperm fertilisation. To test this hypothesis, phorbol myristate acetate (PMA) with polymorphonuclear leucocytes (PMNs) was applied to generate endogenous ROS. We evaluated the time-dependent effects of ROS on human sperm motility, viability and mitochondrial membrane potential (MMP). The results showed that after treatment with PMA and PMNs, the motility of human spermatozoa significantly decreased to 50% on Day 1 and 15% on Day 4 compared with that of the, respectively, negative controls (P = 0.012). The viability of human spermatozoa decreased on Day 4 of PMA + PMNs treatment (P = 0.028). The MMP of human spermatozoa significantly decreased from Day 2 to Day 4 in the PMA + PMN group compared with that of the controls (P = 0.019). Taken together, the 4-day cultivation approach provided an accurate evaluation of sperm quality, especially sperm motility and MMP. Our findings indicated that endogenous inflammation increased ROS levels, which might induce sperm oxidative damage. Additionally, sperm motility might be one of the earliest and most sensitive indicators of this damage.

Three first records of stick insects attacking plants (Inseect: Phasmida) in Tibet.

Except for a few stick insects that are economically valuable, most species be considered to be forest pests, so it is extremely important to obtain plant host-use information of more stick insects. In this paper, the plant hosts of three species of stick insects were recorded for the first time. We also discovered these stick insects can feed upon the flowers or leaves of plants. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) attacked Hypericum choisianum Wall. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) attacked Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) and Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae) attacked Debregeasia orientalis C. J. Chen, 1991 (Urticaceae). Finally, we were lucky enough to also obtain photographs of them mating and feeding.

Simvastatin relieves myocardial ischemia/reperfusion injury in rats through hedgehog signaling pathway.

OBJECTIVE: The aim of this study was to explore the effect of simvastatin (Sim) on myocardial ischemia/reperfusion (I/R) injury in rats and to elucidate the possible underlying mechanism. Our findings might help to provide a certain reference for the clinical prevention and treatment of myocardial I/R injury. MATERIALS AND METHODS: A total of 60 male Sprague-Dawley (SD) rats were randomized into three groups using a random number table, including: Sham group (n=20), I/R group (n=20) and I/R + Sim group (n=20). The I/R injury model was successfully established in rats via ligation of the left anterior descending coronary artery (LAD), followed by reperfusion. Before operation, the rats in I/R + Sim group were administered with Sim at 10 mg/kg/d through oral gavage for 7 d. Cardiac ejection fraction (EF) (%) and fractional shortening (FS) (%) of rats in each group were detected using echocardiography. 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to measure the myocardial infarction (MI) area in each group. Collagen deposition in myocardial tissues of rats in each group was detected by Masson's trichrome staining. The apoptosis level of myocardial cells and fibroblasts in myocardial tissues of rats in each group were evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The level of reactive oxygen species (ROS) in myocardial tissues of rats in each group was determined using fluorescent probes. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was conducted to measure the expression levels of pro-inflammatory cytokines interleukin (IL)-1ß and monocyte chemoattractant protein-1 (MCP-1) in myocardial tissues of rats in each group. Furthermore, the effects of Sim on the hedgehog signaling pathway-associated proteins were detected using Western blotting. RESULTS: Sim significantly alleviated I/R-induced cardiac dysfunction in rats and increased EF (%) and FS (%) (p<0.05). Meanwhile, it also evidently mitigated the MI caused by I/R and reduced the infarction area (p<0.05). According to the Masson's trichrome staining results, I/R + Sim group exhibited remarkably declined myocardial interstitial collagen deposition compared with I/R group (p<0.05). ROS-sensitive fluorescent staining showed that Sim notably reversed the increase of ROS expression and the decrease of myocardial oxidative stress induced by I/R (p<0.05). Finally, Western blotting results revealed that Sim dramatically restrained the protein expressions of sonic hedgehog (SHH), patched 1 (PTC1) and glioma-associated oncogene homolog 1 (GLI1) (p<0.05). CONCLUSIONS: Sim can significantly relieve myocardial I/R injury in rats. The possible underlying mechanism may be related to its inhibition on the hedgehog signaling pathway.

Transfected Eimeria tenella could complete its endogenous development in vitro.

Live attenuated coccidiosis vaccines could be used as powerful carriers, expressing exogenous viral and bacterial antigens, to induce protective immunity against pathogenic organisms. We investigated the ability of Eimeria tenella to express an exogenous gene in vitro. Eimeria tenella sporozoites were transfected with the plasmid pH4-2EYFP-Actin3 containing the yellow fluorescent protein gene (yfp) and inoculated into primary chicken kidney cells (PCKCs), followed by incubation at 41 C in a 5% CO2 chamber. Fluorescent sporozoites were observed as early as 15-20 hr post-inoculation (PI). Fluorescence displayed by the expressed YFP protein was visible throughout the schizogony and gametogony stages of the tranfected E. tenella. Fluorescent oocysts were found between 200-327 hr PI. Higher fluorescence intensity was observed in the nucleus than in other compartments of the transfectants, while little or no fluorescence was seen in the refractile globule. The diversity of schizonts, particularly of the first generation, was presented by fluorescent nuclei arranged in different patterns. Our results demonstrated the ability of E. tenella to express an exogenous gene throughout the endogenous development in vitro. Completion of the endogenous development of transfected E. tenella in cell cultures will facilitate the study of foreign antigen expression in Eimeria spp., paving the way for the development of an Eimeria spp. vector vaccine that also carries and delivers other vaccines by oral administration.

Three first records of stick insects attacking plants (Inseect: Phasmida) in Tibet / Três primeiros registros de insetos-pau atacando plantas (Inseect: Phasmida) no Tibet

Except for a few stick insects that are economically valuable, most species be considered to be forest pests, so it is extremely important to obtain plant host-use information of more stick insects. In this paper, the plant hosts of three species of stick insects were recorded for the first time. We also discovered these stick insects can feed upon the flowers or leaves of plants. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) attacked Hypericum choisianum Wall. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) attacked Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) and Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae) attacked Debregeasia orientalis C. J. Chen, 1991 (Urticaceae). Finally, we were lucky enough to also obtain photographs of them mating and feeding.

Exceto por alguns insetos-pau que são economicamente valiosos, a maioria das espécies pode ser considerada praga florestal, por isso é extremamente importante obter informações sobre o uso de hospedeiros de plantas de mais insetos-pau. Neste artigo, as plantas hospedeiras de três espécies de bicho-pau foram registradas pela primeira vez. Também descobrimos que esses bichos-pau podem se alimentar de flores ou folhas de plantas. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) atacou a parede de Hypericum choisianum. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) atacou Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) e Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae orientaled) atacou Chen, 1991 (Urticaceae). Finalmente, tivemos a sorte de também obter fotos deles se acasalando e se alimentando.

Three first records of stick insects attacking plants (Inseect: Phasmida) in Tibet

Abstract Except for a few stick insects that are economically valuable, most species be considered to be forest pests, so it is extremely important to obtain plant host-use information of more stick insects. In this paper, the plant hosts of three species of stick insects were recorded for the first time. We also discovered these stick insects can feed upon the flowers or leaves of plants. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) attacked Hypericum choisianum Wall. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) attacked Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) and Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae) attacked Debregeasia orientalis C. J. Chen, 1991 (Urticaceae). Finally, we were lucky enough to also obtain photographs of them mating and feeding.

Resumo Exceto por alguns insetos-pau que são economicamente valiosos, a maioria das espécies pode ser considerada praga florestal, por isso é extremamente importante obter informações sobre o uso de hospedeiros de plantas de mais insetos-pau. Neste artigo, as plantas hospedeiras de três espécies de bicho-pau foram registradas pela primeira vez. Também descobrimos que esses bichos-pau podem se alimentar de flores ou folhas de plantas. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) atacou a parede de Hypericum choisianum. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) atacou Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) e Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae orientaled) atacou Chen, 1991 (Urticaceae). Finalmente, tivemos a sorte de também obter fotos deles se acasalando e se alimentando.

Three first records of stick insects attacking plants (Inseect: Phasmida) in Tibet / Três primeiros registros de insetos-pau atacando plantas (Inseect: Phasmida) no Tibet

Abstract Except for a few stick insects that are economically valuable, most species be considered to be forest pests, so it is extremely important to obtain plant host-use information of more stick insects. In this paper, the plant hosts of three species of stick insects were recorded for the first time. We also discovered these stick insects can feed upon the flowers or leaves of plants. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) attacked Hypericum choisianum Wall. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) attacked Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) and Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae) attacked Debregeasia orientalis C. J. Chen, 1991 (Urticaceae). Finally, we were lucky enough to also obtain photographs of them mating and feeding.

Resumo Exceto por alguns insetos-pau que são economicamente valiosos, a maioria das espécies pode ser considerada praga florestal, por isso é extremamente importante obter informações sobre o uso de hospedeiros de plantas de mais insetos-pau. Neste artigo, as plantas hospedeiras de três espécies de bicho-pau foram registradas pela primeira vez. Também descobrimos que esses bichos-pau podem se alimentar de flores ou folhas de plantas. Lopaphus unidentatus (Chen & He, 1995) (Phasmida: Lonchodidae) atacou a parede de Hypericum choisianum. ex N. Robson, 1973 (Hypericaceae), Leurophasma dolichocercum Bi, 1995 (Phasmida: Aschiphasmatidae) atacou Antenoron filiforme (Thunb.) Roberty & Vautier, 1964 (Polygonaceae) e Megalophasma granulatum Bi, 1995 (Phasmida: Lonchodidae orientaled) atacou Chen, 1991 (Urticaceae). Finalmente, tivemos a sorte de também obter fotos deles se acasalando e se alimentando.

Helicobacter pylori and nucleolar organizer regions in the gastric antral mucosa.

The association of Helicobacter pylori with an increased risk of gastric adenocarcinoma has been documented, but its mechanisms have not been elucidated. This study explored these mechanisms by addressing the relationship between H pylori and the silver-staining nucleolar organizer regions (AgNORs) in the gastric antrum. The number of AgNORs per nucleus has been correlated with proliferative rate and ploidy. The results of gastric biopsies performed before and after treatment for H pylori showed that only patients who cleared the H pylori infection had a significant decrease in the number of AgNORs per nucleus. A positive association between AgNOR counts and the severity of polymorphonuclear infiltrate could be demonstrated in patients who did not clear H pylori infection. The authors concluded that H pylori infection alters the replication cycle of the antral mucosa, inducing hyperproliferation and possibly ploidy abnormalities. Whether these alterations are induced directly by the bacterium or by the acute inflammatory infiltrate remains undecided; the data in this study suggest a possible direct effect of the polymorphonuclear leukocytes.

Double photoionization and transfer ionization of he: shakeoff theory revisited.

The shakeoff theory of Aberg [Phys. Rev. A 2, 1726 (1970)] is revisited. With the sudden approximation, we calculate the shakeoff probability when one of the electrons in He is ejected with a finite velocity. This theory is used to examine ratios of cross sections for double to single photoionization and transfer ionization to single electron capture. It is also shown that the momentum distribution of the shakeoff electron provides a means to measure the correlation of the ground state wave function directly.

Helicobacter pylori causes hyperproliferation of the gastric epithelium: pre- and post-eradication indices of proliferating cell nuclear antigen.

OBJECTIVE: To assess the effect of Helicobacter pylori (HP) eradication on the proliferation of the gastric epithelium by the expression of the proliferating cell nuclear antigen (PCNA). METHODS: Alcohol-fixed gastric biopsies taken before and after treatment for HP were immunostained with the PC-10 anti-PCNA monoclonal antibody and the labeling index was determined with an image analysis system. RESULTS: The mean PCNA-labeling index (LI) of 16 patients who remained HP positive did not change significantly (18.95 +/- 1.71 on first visit vs. 17.96 +/- 1.91 on second visit, mean +/- SEM). The mean PCNA LI of 31 patients who cleared HP was reduced significantly (19.95 +/- 1.77 on first visit vs. 14.13 +/- 1.29 on second visit, p < 0.001). Patients who were positive for HP at both first and second visit showed a significantly higher PCNA LI than normal control biopsies (13.05 +/- 1.70) (p < 0.05). CONCLUSIONS: These results indicate that the gastric mucosa infected with HP is in a state of hyperproliferation. Patients who cleared HP showed a significant histopathological improvement, reflected in the reduction in number of polymorphonuclear and mononuclear cell infiltrates, and a reduction in the amount of superficial mucosa damage. Prolonged hyperproliferation of the gastric epithelium exerted by HP infection could be a major factor for human gastric carcinogenesis.