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.

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.

Immunotherapy in SMARCB1(INI-1)-deficient sinonasal carcinoma:Two case reports

BACKGROUND SMARCB1/INI-1 deficient sinonasal carcinoma(SDSC)is a rare subset of sinonasal undifferentiated carcinoma with a poor prognosis.Here,we present two case reports of SDSC patients.We also review the literature on this tumor.This is the first published report of SDSC treatment with immunotherapy.CASE SUMMARY Here we present two patient cases of SDSC in which initial consultation and diagnosis were complicated but SDSC was ultimately diagnosed.One patient received a traditional treatment of surgery and adjuvant chemoradiotherapy,while the other patient received additional immunotherapy;the prognoses of these two patients differed.We review previous diagnostic literature reports and SDSC treatments and provide a unique perspective on this rare type of tumor.CONCLUSION SDSC is a rare,diagnostically challenging carcinoma with a consistently poor prognosis,early distant metastases,and frequent recurrence.Timely diagnosis and intervention are critical for treatment,for which the standard of care is surgery followed by adjuvant chemoradiotherapy,though immunotherapy may be an effective new treatment for SDSC.

NaCl Facilitates Cell Wall Phosphorus Reutilization in Abscisic Acid Dependent Manner in Phosphorus Deficient Rice Root

Phosphorus(P) starvation in rice facilitates the reutilization of root cell wall P by enhancing the pectin content. NaCl modulates pectin content, however, it is still unknown whether NaCl is also involved in the process of pectin regulated cell wall P remobilization in rice under P starved conditions. In this study, we found that 10 mmol/L NaCl increased the shoot and root biomasses under P deficiency to a remarkable extent, in company with the elevated shoot and root soluble P contents in rice. Further analysis indicated that exogenous NaCl enhanced the root cell wall P mobilization by increasing the pectin methylesterase activity and uronic acid content in pectin suggesting the involvement of NaCl in the process of cell wall P reutilization in P starved rice roots. Additionally, exogenous NaCl up-regulated the expression of P transporter OsPT6, which was induced by P deficiency, suggesting that NaCl also facilitated the P translocation prominently from root to shoot in P starved rice. Moreover, exogenous abscisic acid(ABA) can reverse the NaCl-mediated mitigation under P deficiency, indicating the involvement of ABA in the NaCl regulated root cell wall P reutilization. Taken together, our results demonstrated that NaCl can activate the reutilization of root cell wall P in P starved rice, which is dependent on the ABA accumulation pathway.

Exosomes promote the invasion and metastasis of hepatocellular carcinoma cells via an integrin-dependent manner in the spleen-deficient state

Background:To investigate the detailed mechanism underlying the pro-metastatic effect of spleen deficiency(SD)syndrome on hepatocellular carcinoma(HCC).Methods:In the present study,our model was established based on an HCC mouse model induced by diethylnitrosamine using reserpine to induce SD.Exosomes were isolated and purified from mouse plasma samples using an exosome isolation kit.Subsequently,we verified the pro-metastatic effects of exosomes from the HCC mice with SD on HCC cells by transwell assays,wound healing assays,phalloidin staining in vitro,and lung metastasis assay of mice in vivo.Finally,we further explored the detailed mechanism underlying the pro-metastatic effect of exosomes from the HCC mice with SD on HCC cells.Results:We found that SD promoted the malignant progression of HCC in mice.Exosomes from HCC mice with SD enhanced the invasion and metastasis of HCC cells in vitro and in vivo.Mechanistically,upregulation of integrinα1,integrinβ1,and integrinβ5 seemed to play a key role in mediating the pro-metastatic effect of exosomes isolated from the HCC mice with SD,which was largely abrogated upon co-treatment with a broad-spectrum integrin inhibitor.Conclusion:Our findings demonstrated that exosomes promote the invasion and metastasis of HCC cells via an integrin-dependent manner in the spleen-deficient state that would contribute to our better understanding of the role of SD in HCC progression in traditional Chinese medicine,and thus management of the disease.

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.

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.

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.

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.

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.

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).

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.

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.

Biochemical and Morphological Changes in the Lenses of Selenium and/or Vitamin E Deficient Rats

The activities of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R),superoalde dismutase (SOD) and the contents of malondialdehyde (MDA) and free radicals were measured, and the morphological changes were observed in the lens of control rats, selenium-deficient (SeD) and/or vitamin E deficient (VED) rats. The activities of GSH-Px in the lens of SeD rats decreased significantly. The GSH-Px activities of lens were positively related to erythrocytes selenium level. There was a free radical at g = 2.0015 in the rat lens of all groupe, but the content of free radicals in the lens of SeD group was significantly higher than that of the control group. The free radical content of lens was negatively related to erythrocytes selenium level, as well as the GSH-Px activities in the lens. In vitro, ultraviolet radiation caused the generation of another kind of free radical (g = 2.0097) in the lens of all groups, but the amount of the free radical in the lens of the SeD group was also significantly higher than that of the control group. The activities of SoD and GSSG-R in VED rat lens were significantly decreased. The amount of MDA in the lens of SeD and/or VED rats were significantly increased. The results showed that the decrease of antioaldative capability in the lenses of SeD and/or VED rats accelerated the lipid peroxidation and generation of free radicals. Although only early morphological changes in SeD and/or VED rat lens were observed, it is considered that selenium and vitamin E deficiency may be involved in the occurrence of cataract

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.

Gene therapy for TH deficient mice through direct gene (PCI-hlL-2) transfer

Objective: The objective of research is to explorethe prospective for direct gene transfer to be applied as aform of gene therapy. Materials and methods: ①Experimental animals: Male BALB/c mice, 0 - 8 weeksold;②Preparations of plasmid: PCI-hIL-2 plasmid isexpression vector for human IL-2 containing cytome-galovirus immediate-early enhance/promoter region andT7 promoer;③Injection of plasmids: Male

The preparation and expression of replication- deficient human interleukin-2 recombinant adenoviruses

Interleukin-2(IL-2) has been demonstrated to beone of the most effective target genes in cancerimmunogene therapy. There are more than 20 clinicalprotocols of cancer gene therapy introducing IL-2 intotumor patients to treat melanoma, renal carcinoma,prostate carcinoma, colon carcinoma,