PD-1 antibody in combination with chemotherapy for the treatment of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum:Two case reports

BACKGROUND SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting(SWI/SNF)complexes and plays an essential role in oncogenesis.SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis.There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies.Programmed death 1(PD-1)antibodies,known as immune checkpoint inhibitor antibodies,potentially play a role in treating gastrointestinal tract malignancies.CASE SUMMARY We present two patients with SMARCA4 deficiency and TP53 gene mutation in advanced undifferentiated carcinomas of the duodenum.For both patients,SMARCA4 deficiency was confirmed by immunohistochemical staining for the BRG1 protein,while TP53 gene mutations were observed via next-generation sequencing.Both patients were administered chemotherapy in combination with an anti-PD-1 antibody.The two patients exhibited completely different responses to treatment and had different prognoses.Case 1 experienced rapid progression after PD-1 infusion and chemotherapy,case 2 experienced a remarkable response after treatment,and the progression-free survival was more than 6 months.CONCLUSION This study described our clinical and pathological observations of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum.PD-1 combined with chemotherapy showed a certain efficacy in select patients,providing options for treating these highly malignant tumors.Patients with liver metastases had a worse prognosis than did those with only lymph node metastasis.

Cause of over Water Quality Standard and Control Measures of State-controlled Sections in Northern Water-deficient Area of Jiangsu

Taking state-controlled section of Xuzhou Peiyan river as an example,the current water quality was monitored,and the cause of over water quality standard was analyzed.The results showed that the pollutants of Peiyan river were mainly from the urban river segment,and the immediate cause of over standard was tributary pollutants in urban river segment with the runoff into rivers.So we should strengthen the maintenance of drainage control and gate-han,accelerate the construction of urban wastewater treatment facilities and supporting pipe network,promote rural decentralized sewage treatment,prevent and control livestock and poultry pollution,pesticides and fertilizers pollution,and intercept non-point source pollution by using eco-technology.

STRUCTURAL REQUIREMENT FOR CLUSTERS TO BE RECONSTITUTED WITH THE FeMoCo DEFICIENT MOLYBDENUM IRON PROTEIN

By incubating the reduced MoFe protein from Azotobacter vinelandii with O phenanthroline under air and chromatographying the incubated solution on Sephadex G 25 column, inactive MoFe protein could be obtained. Its acetylene reduction activity was remarkably recovered not only by incubation with the reconstituent solution composed of KMnO 4,ferric homocitrate, Na 2S and dithiothreitol,Azotobacter vinelandii with O phenanthroline under air and chromatographying the incubated solution on Sephadex G 25 column, inactive MoFe protein could be obtained. Its acetylene reduction activity was remarkably recovered not only by incubation with the reconstituent solution composed of KMnO 4,ferric homocitrate, Na 2S and dithiothreitol, with O phenanthroline under air and chromatographying the incubated solution on Sephadex G 25 column, inactive MoFe protein could be obtained. Its acetylene reduction activity was remarkably recovered not only by incubation with the reconstituent solution composed of KMnO 4,ferric homocitrate, Na 2S and dithiothreitol, but also with a mixture of 4Fe∶4S clusters and another cluster which had two structure units of 1Mo∶3Fe∶4S bridged by three -OCH 3- at the Mo atoms. Neither the reconstituent solution nor the mixture could reactivate apo MoFe proteins from the mutants deleting nifE and nifH genes and from the mutant UW 45 , which could be reactivated by the FeMoco extracted from the MoFe protein. The results indicated that the FeMoco deficient MoFe proteins from these mutants seemed to be reconstituted only by the clusters which were probably structures only similar to FeMoco. The partially metallocluster deficient MoFe protein could be reconstituted by the clusters with a certain kind of structure and composition; and was changed into different nitrogenase proteins with the ability to fix nitrogen.

Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis(NASH) development in mice fed a methionine-choline-deficient(MCD) diet. METHODS Twenty-four male C57 BL/6 J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk(Control 2 w group,n = 6) or 4 wk(Control 4 w group,n = 6) or the MCD diet for 2 wk(MCD 2 w group,n = 6) or 4 wk(MCD 4 w group,n = 6). Liver injury,fibrosis,and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16 s r RNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet,however,the mice developed prominent NASH with liver fibrosis,and the intestinal barrier was more impaired. Compared with the control diet,the MCD diet induced gradual gut microbiota dysbiosis,as evidenced by a marked decrease in the abundance of Alistipes and the(Eubacterium) coprostanoligenes group(P < 0.001 and P < 0.05,respectively) and a significant increase in Ruminococcaceae UCG 014 abundance(P < 0.05) after 2 wk. At 4 wk,the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance(P < 0.05,and P < 0.01,respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk,arachidic acid,hexadecane,palmitic acid,and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group,and at 4 wk,cholic acid,cholesterol,arachidic acid,tetracosane,and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome.

Preparation and Characterization of Novel Ti-doped M-site Deficient Olivine LiFePO_4

A novel Ti-doped M-site deficient olivine LiFePO4, i.e. Li0.95Fe0.95Ti0.05PO4, was synthesized by a solid-state reaction method. XRD and VTR were used to characterize the as-prepared samples. As a cathode material for lithium-ion batteries, Li0.95Fe0.95Ti0.05PO4 exhibited improved rate capability.

Exogenous Nitric Oxide Alleviated the Inhibition of Photosynthesis and Antioxidant Enzyme Activities in Iron-Deficient Chinese Cabbage (Brassica chinensis L.)

The effects of exogenous nitric oxide （NO） on plant growth, chlorophyll contents, photosynthetic and chlorophyll fluorescence parameters as well as lipid peroxidation and activities of antioxidant enzymes were investigated in Chinese cabbage plants exposed to iron （Fe） deficiency. Iron deficiency led to serious chlorosis in Chinese cabbage leaves, and resulted in significant decrease in plant growth, photosynthetic pigments, net photosynthetic rate, Fv/Fm, Ф ps Ⅱ and activities of antioxidant enzymes, and increase in lipid peroxidation. While treatment with SNP, a NO donor, it could revert the iron deficiency symptoms, increased photosynthetic rate as well as activities of antioxidant enzymes, and protected membrane from lipid peroxidation, as a result, the growth inhibition of Chinese cabbage by Fe deficiency was alleviated.

Integrated transcriptomic and metabolomic analyses of a wax deficient citrus mutant exhibiting jasmonic acid-mediated defense against fungal pathogens

Naturally,resistant crop germplasms are important resources for managing the issues of agricultural product safety and environment deterioration.We found a spontaneous mutant of‘Newhall’navel orange(Citrus sinensis Osbeck)(MT)with broad-spectrum protections against fungal pathogens in the orchard,postharvest-storage,and artificial inoculation conditions.To understand the defense mechanism of MT fruit,we constructed a genome-scale metabolic network that integrated metabolome and transcriptome datasets.The coordinated transcriptomic and metabolic data were enriched in two sub-networks,showing the decrease in very long chain fatty acid(by 41.53%)and cuticular wax synthesis(by 81.34%),and increase in the synthesis of jasmonic acid(JA)(by 95.23%)and JA-induced metabolites such as 5-dimethylnobietin(by 28.37%)in MT.Furthermore,cytological and biochemical analyses confirmed that the response to fungal infection in MT was independent of wax deficiency and was correlated with the levels of jasmonates,and the expression of plant defensin gene PDF1.2.Results of exogenous application of MeJA and JA inhibitors such as propyl gallate proved that JA-mediated defense contributes to the strong tolerance against pathogens in MT.Our results indicated that jasmonate biosynthesis and signaling are stimulated by the fatty acid redirection of MT,and participate in the tolerance of pathogenic fungi.

Pathology of spleen in chickens fed on a diet deficient in methionine

The purpose of this 42-day study was to investigate the effects of methionine deficiency on spleen by determining the relative weight, morphological changes of spleen, cell cycle and apoptosis of splenocytes, and oxidative markers of serum and spleen. One hundred and twenty one-day-old avian broilers were randomly divided into two groups and fed on a control diet (starter diet, methionine 0.50%;grower diet, methionine 0.40%) and methionine deficient diet (starter diet, methionine 0.26%;grower diet, methionine 0.28%) for 6 weeks. The relative weight of spleen was lighter in methionine deficiency than control group. Histopathologically, lymphopenia and congestion were observed. Ultrastructurally, there were more apoptosis lymphocytes in spleen and the mitochondria of lymphocytes were swelled in methionine deficiency. By flow cytometry, the G0/G1 phase of the cell cycle of the spleen was much higher (P < 0.01), and the S, G2+M phases and proliferating index were lower (P < 0.01) in methionine deficiency than in control group. And the percentage of apoptotic cells in the spleen was significantly increased in methionine deficiency (P < 0.01).The superoxide dismutase and glutathione peroxidase activities, and abilities to inhibit hydroxyl radicals were greatly decreased while the malondialdehyde contents were markedly increased in methionine deficiency. It was concluded that methionine deficiency could restraine the development of the spleen by cell cycle arrest and increased apoptosis, cause splenic lesions and reduce splenic antioxidant function. The splenic function should be finally impaired and then the immune function could be impacted in chickens.

ON THE DISTRIBUTION OF VALUES AND DEFICIENT FUNCTION OF A GENERAL RANDOM INTEGRAL FUNCTION

Under suitable conditions on {X-n}, the author obtains the important results: it is almost sure that the random integral function f(w) = Sigma (infinity)(n=0) X(n)z(n) (of finite positive order) has no deficient function, and any direction is a Borel direction (without finite exceptional value) of f(w).

Facile Fabrication of Fe2O3/Nitrogen Deficient g-C3N4-x Composite Catalysts with Enhanced Photocatalytic Performances

The modification of graphitic carbon nitride can significantly improve the photocatalytic performance of graphitic carbon nitride(g-C3N4).Fe2O3/nitrogen-deficient g-C3N4-x composite catalysts were prepared with dicyandiamide as the precursor and Fe3+doped in this study.The composite catalysts were characterized by XRD,SEM,FT-IR,XPS and photocurrent measurements.Close interaction occurred between Fe2O3 and nitrogen deficient g-C3N4-x,more photogenerated electrons were created and effectively separated from the holes,resulting in a decrease of photocarrier recombination,and thus enhancing the photocurrent.Photocatalytic performance experiments showed that Fe2O3/nitrogen deficient g-C3N4-x could utilize lowenergy visible light more efficiently than pure g-C3N4,and the removal rate was 92%in 60 minutes.

Ototoxicity induced by kanamycin in iron-deficient young rats

Using auditory electrophysiological,histopathological,enzymehistochemical and scanning electron microscopic techniques,we observed thechanges of function and structure of cochlea in iron-deficient growing rats receiv-ing kanamycin intramuscularly.The results showed that at an equal dose ofkanamycin,hearing loss and hair cell damage were more serious,and incidence ofhearing loss was much higher in iron-deficient rats than in normal rats.Theinhibition of succinate dehydrogenase activity of cochlea induced by interaction ofkanamycin and iron deficiency was more obvious than that by either one of them.Iron deficiency can increase the sensitivity of cochlea to kanamycin.The resultsindicated that iron deficiency may be one of the reasons for high incidence ofototoxic deafness in children,and it should be cautious when using such drugs inchildren with iron-deficient anemia.

Enhanced Reversible Zinc Ion Intercalation in Deficient Ammonium Vanadate for High-Performance Aqueous Zinc-Ion Battery

Ammonium vanadate with bronze structure(NH_(4)V_(4)O_(10))is a promising cathode material for zinc-ion batteries due to its high specific capacity and low cost.However,the extraction of NH^(+)_(4) at a high voltage during charge/discharge processes leads to irreversible reaction and structure degradation.In this work,partial NH^(+)_(4) ions were pre-removed from NH_(4)V_(4)O_(10) through heat treatment;NH_(4)V_(4)O_(10) nanosheets were directly grown on carbon cloth through hydrothermal method.Defi-cient NH_(4)V_(4)O_(10)(denoted as NVO),with enlarged interlayer spacing,facilitated fast zinc ions transport and high storage capacity and ensured the highly reversible electrochemical reaction and the good stability of layered structure.The NVO nanosheets delivered a high specific capac-ity of 457 mAh g^(−1) at a current density of 100 mA g^(−1) and a capacity retention of 81%over 1000 cycles at 2 A g^(−1).The initial Coulombic efficiency of NVO could reach up to 97%compared to 85%of NH_(4)V_(4)O_(10) and maintain almost 100%during cycling,indicating the high reaction reversibility in NVO electrode.

In-vitro degradation behavior of Mg alloy coated by fluorine doped hydroxyapatite and calcium deficient hydroxyapatite

Fluorine-doped hydroxyapatite(FHA) and calcium deficient hydroxyapatite(CDHA) were coated on the surface biodegradable magnesium alloy using electrochemical deposition(ED) technique. Coating characterization was investigated X-ray diffraction(XRD), Fourier-transformed infrared spectroscopy(FTIR), transmission electron microscopy(TEM), scanni electron microscopy(SEM) and energy dispersive X-ray spectroscopy(EDS). The result shows that nano-FHA coated samp presents nano needle-like structure, which is oriented perpendicular to the surface of the substrate with denser and more unifo layers compared to the nano-CDHA coated sample. The nano-FHA coating shows smaller crystallite size(65 nm) compared to t nano-CDHA coating(95 nm); however, CDHA presents thicker layer(19 μm in thickness) compared to the nano-FHA(15 μm thickness). The corrosion behaviour determined by polarization, immersion and hydrogen evolution tests indicates that the nano-FH and nano-CDHA coatings significantly decrease corrosion rate and induce passivation. The nano-FHA and nano-CDHA coatings c accelerate the formation of bone-like apatite layer and significantly decrease the dissolution rate as compared to the uncoated M alloy. The nano-FHA coating provides effective protection to Mg alloy and presents the highest corrosion resistance. Therefore, t nano-FHA coating on Mg alloy is suggested as a great candidate for orthopaedic applications.

Zinc-deficient diet aggravates ventilation-induced lung injury in rats

We investigated the effects of zinc deficiency on acute lung injury （ALI） induced by mechanical ventilation. Male Sprague-Dawley rats were fed with a zinc-deficient or zinc-proficient diet for 4 weeks, and then received mechanical ventilation at normal frequency and pressure for 30 min. Total protein, cell count, the number of poly- morphonuclear neutrophil （PMN） in the bronchoalveolar lavage （BAL）, and vascular endothelial growth factor （VEGF） expression in the lung were determined. Activation of nuclear factor-t^B （NF-~cB） was detected by exam- ining the phosphorylation of NF-kB （pNF-kB p65） and the expression of inhibitor of NF-kB （pI-kBa）. Compared to the controls, total cell count and the number of PMNs were significantly increased to 160% and 140%, respec- tively, in zinc-deficient rats treated with ventilation. Activation of NF-kB was significantly increased and VEGF was also increased to three-folds. Zinc deficiency aggravated the inflammatory response in rats and was associated with the overexpression of VEGF in response to mechanical ventilation. Zinc supplementation may be beneficial to zinc-deficient patients during mechanical ventilation.

Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation

Coffin–Lowry–Syndrome(CLS)is a X-linked mental retardation characterized by skeletal dysplasia and premature tooth loss.We and others have previously demonstrated that the ribosomal S6 kinase RSK2,mutated in CLS,is essential for bone and cementum formation;however,it remains to be established whether RSK2 plays also a role in mechanically induced bone remodeling during orthodontic tooth movement(OTM).We,therefore,performed OTM in wild-type(WT)mice and Rsk2-deficient mice using Nitinol tension springs that were fixed between the upper left molars and the incisors.The untreated contralateral molars served as internal controls.After 12 days of OTM,the jaws were removed and examined by micro-computed tomography(μCT),decalcified histology,and immunohistochemistry.Our analysis of the untreated teeth confirmed that the periodontal phenotype of Rsk2-deficient mice is characterized by alveolar bone loss and hypoplasia of root cementum.Quantification of OTM usingμCT revealed that OTM was more than two-fold faster in Rsk2-deficient mice as compared to WT.We also observed that OTM caused alveolar bone loss and root resorptions in WT and Rsk2-deficient mice.However,quantification of these orthodontic side effects revealed no differences between WT and Rsk2-deficient mice.Taken together,Rsk2 loss-of-function accelerates OTM in mice without causing more side effects.

SMARCA4-deficient undifferentiated thoracic tumor:A case report

BACKGROUND SMARCA4-deficient undifferentiated tumors(SMARCA4-DUTs)present with diverse clinical manifestations and progress to metastasis and even cause death within a few months.This novel subset of undifferentiated tumors occurs in the middle-aged population and is strongly associated with a smoking history.Distin-guishing it from other malignancies is challenging.CASE SUMMARY A 62-year-old man presented with chest pain for 7 d.The patient had no respiratory symptoms and normal pulmonary function test results.The patient had been a smoker for 8 years and quit smoking 2 years ago.Chest computed tomography revealed a huge mass involving the left upper and lower lung lobes with pericardial invasion and multiple metastases.Tumor samples were obtained using open frozen biopsy,after several unsuccessful attempts.The tumor was composed of sheets of undifferentiated disclosive cells with vesicular nuclei and prominent nucleoli.The differential diagnosis included high-grade lymphoma,germ cell tumor,NUT carcinoma,undifferentiated carcinoma,and sarcoma.The tumor cells were large,arranged in sheets,and did not exhibit glandular or squamous differentiation.Frequent foci of necrosis were noted.There was no evidence of epithelial differentiation on immunohistochemical staining.The SMARCA4 stain showed complete loss of expression of SMARCA4,which is diagnostic.CONCLUSION In the present case,thoracic SMARCA4-DUT was diagnosed based on clinical features,absence of epithelial differentiation,and negative SMARCA4 expression.

Highly surface electron-deficient Co_(9)S_(8) nanoarrays for enhanced oxygen evolution

Tailoring valence electron delocalization of transition metal center is of importance to achieve highly-active electrocatalysts for oxygen evolution reaction(OER).Herein,we demonstrate a“poor sulfur”route to synthesize surface electron-deficient Co_(9)S_(8) nanoarrays,where the binding energy(BE)of Co metal center is considerably higher than all reported Co_(9)S_(8)-based electrocatalysts.The resulting Co_(9)S_(8) electrocatalysts only require the overpotentials(h)of 265 and 326 mV at 10 and 100 mA cm^(-2) with a low Tafel slope of 56 mV dec^-(1) and a 60 hlasting stability in alkaline media.The OER kinetics are greatly expedited with a low reaction activation energy of 27.9 kJ mol^-(1) as well as abundant OOH*key intermediates(24%),thus exhibiting excellent catalytic performances.The surface electron-deficient engineering gives an available strategy to improve the catalytic activity of other advanced non-noble electrocatalysts.

Effect of N,N-Dimethylglycine on Homocysteine Metabolism in Rats Fed Folate-Sufficient and Folate-Deficient Diets

Objective This study aimed to investigate the effects of N,N-dimethylglycine(DMG) on the concentration and metabolism of plasma homocysteine(pHcy) in folate-sufficient and folate-deficient rats.Methods In this study, 0.1% DMG was supplemented in 20% casein diets that were either folatesufficient(20 C) or folate-deficient(20 CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system.Results Folate deprivation significantly increased pHcy concentration in rats fed 20 C diet(from 14.19 ±0.39 μmol/L to 28.49 ± 0.50 μmol/L;P < 0.05). When supplemented with DMG, pHcy concentration was significantly decreased(12.23 ± 0.18 μmol/L) in rats fed 20 C diet but significantly increased(31.56 ±0.59 μmol/L) in rats fed 20 CFD. The hepatic methionine synthase activity in the 20 CFD group was significantly lower than that in the 20 C group;enzyme activity was unaffected by DMG supplementation regardless of folate sufficiency. The activity of hepatic cystathionine β-synthase(CBS) in the 20 CFD group was decreased but not in the 20 C group;DMG supplementation enhanced hepatic CBS activity in both groups, in which the effect was significant in the 20 C group but not in the other group.Conclusion DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.

All-transRetinoic Acid Regulates Th1/Th2 Balance in CD4+T cells When GATA-3 is Deficient

The essential effect of vitamin A on immune function occurs through various mechanisms including direct effect on ThloTh2 balance modulation. However, it is unclear whether or not vitamin A can regulate Thl-Th2 balance under a strong Thl-polarizing condition. Therefore, the purpose of our study was to examine the effect of vitamin A metabolite allotrans retinoic acid （ATRA） on ThloTh2 differentiation in CD4~ T cells under GATA-3 deficiency, which can induce Thl-polarizing condition. In the present study, GATA-3 deficiency T cells were induced by siRNA and checked by real-time quantitative PCR and western blot. GATA-3 deficiency CD4＋ T cells and normal CD4＋ T were treated for 48 h with or without ATRA.

Deficient Developmental Planning Leading to Water Conflicts across Political Borders: The Way Forward

In this article, Turkey, Iran and Syria in the Middle East area are taken as examples for deficient planning and development of water resources shared with their downstream countries resulting in severe social, economic and political percussions to these neighbors. The current situation in the Middle East with wars against terrorism, uprising of population groups, and COVID-19 Pandemic have not allowed the affected countries Jordan, Iraq and Syria to properly react to the assaults of upstream water development and diversions on their fair shares in the transboundary waters. The rivers’ upstream developmental schemes have not taken advantages of recent advanced technological knowhow of water efficient development and use, seemingly because the arising water problems and catastrophes will not affect these upstream countries, but their downstream neighbors. Although, it is by now known that pressurized water conveyance system relative to canals saves 10% - 20% of the transmitted water, and drip and sprinkler irrigation require only 40% - 50% of the water used in surface and furrow irrigation, that is in addition to agricultural production increases when using advanced management strategies. As enhancing policies, tradeoffs between downstream and upstream countries are thought of as a strategic option to improve the water use efficiency in upstream countries in order to help downstream countries in obtaining their fair shares of the transboundary water resources.