Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Human endogenous retrovirus type-W and multiple sclerosis–related smoldering neuroinflammation

Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

Elucidation of potential relationship between endogenous proteases and key flavor substances in dry-cured pork coppa

Dry-cured meat products are considerably popular around the world due to unique flavor.Proteolysis is one of the enzymatic reactions from which flavor substances are derived,which is affected by endogenous proteases.The purpose aimed to reveal the potential relationship between endogenous proteases and key flavor substances in dry-cured pork coppa in this paper.The dynamic changes of endogenous proteases activity,free amino acids,and volatiles during dry-cured pork coppa processing were characterized.The results showed that 5 kinds of free amino acids,Glu,Lys,Val,Ala,and Leu,were identified as significant contributors to taste.Meanwhile,key volatiles,such as hexanal,nonanal,octanal,benzaldehyde,3-methyl butanoic acid,2-methyl propanoic acid,and ethyl octanoate,greatly contributed to the flavor characteristics of dry-cured pork coppa.Further partial correlation analysis was performed to better elucidate the relationship among parameters.The results revealed that close relationship between endogenous proteases and key substances.RAP not only significantly affected the accumulation of key active-amino acids,but also affected the accumulation of ethyl octanoate,2,3-pentanedione,and 2,3-octanedione by regulating the accumulation of octanoic acid and Leu.In addition,cathepsin B and D,DPP II,DPP IV and RAP notably affected accumulation of hexanal.

Construction of CDKN2A-related competitive endogenous RNA network and identification of GAS5 as a prognostic indicator for hepatocellular carcinoma

BACKGROUND Competitive endogenous RNA(ceRNA)is an innovative way of gene expression modulation,which plays a crucial part in neoplasia.However,the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma(HCC)remain dismal.AIM To establish a cyclin dependent kinase inhibitor 2A(CDKN2A)-related ceRNA network and recognize potential prognostic indicators for HCC.METHODS The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal database.Differential expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC samples.The targeted microRNAs were predicted by lncBasev3.0,and the targeted mRNAs were predicted by miRDB,and Targetscan database.The univariate and multivariate analysis were utilized to identify independent prognostic indicators.RESULTS CDKN2A was frequently mutated and deleted in HCC.The single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle pathways.The CDKN2A-related ceRNA network-growth arrest specific 5(GAS5)/miR-25-3p/SRY-box transcription factor 11(SOX11)was successfully established.GAS5 was recognized as an independent prognostic biomarker,whose overexpression was correlated with a poor prognosis in HCC patients.The association between GAS5 expression and methylation,immune infilt-ration was explored.Besides,traditional Chinese medicine effective components targeting GAS5 were obtained.CONCLUSION This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and progression.Moreover,GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.

Correction: Long non-coding RNA LINC02163 accelerates malignant tumor behaviors in breast cancer by regulating the microRNA-511-3p/HMGA2 axis as a competing endogenous RNA

In the article“Long non-coding RNA LINC02163 accelerates malignant tumor behaviors in breast cancer by regulating the microRNA-511-3p/HMGA2 axis as a competing endogenous RNA”(Oncology Research,2020,Vol.28,No.5,pp.483–495.doi:10.3727/096504020X15928179818438),there was an error in the processing of data.To further confirm our observation,we repeated multiple experiments involving in this study,including Flow Cytometry,Transwell Cell Migration and Invasion Assays,Xenograft Tumor Model,and Western Blotting.We have revised the figures to correct these errors.Corrected versions of the Figs.2,4,5,6,and 7 are provided.The corrections do not change any results or conclusion of the article.We apologize for any inconvenience caused.

Endogenous Endophthalmitis as a Triggering Factor for Fatal Bacterial Meningitis Caused by Streptococcus pneumoniae: A Case Report

Endogenous endophthalmitis is a rare condition with a poor long-term visual prognosis and significant mortality, often associated with the hematogenous spread of intravitreal infections and subsequent disruption of the blood-ocular barrier. Its anatomical proximity to the central nervous system (CNS) poses a high risk of infection dissemination, although cases documented in the literature are rare, and endogenous endophthalmitis is typically described as secondary to neuroinfections. We report the case of an 82-year-old female patient with a history of hypertension who presented with fever, decreased visual acuity, severe headache, chemosis, and conjunctival injection. Endogenous endophthalmitis was diagnosed, and antimicrobial treatment was initiated alongside surgical intervention by the ophthalmology service. However, the patient’s condition worsened neurologically, and Streptococcus pneumoniae was identified in cerebrospinal fluid cultures. Despite intensive medical treatment, the patient’s clinical course was poor, leading to death.

Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes

Deciphering the context-specific relationship between sequence and function is a major challenge in genomics.Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited.Here we present a programmable platform for long-range,locus-specific hypermutation called helicase-assisted continuous editing(HACE).HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large(>1000-base pair)genomic intervals.We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1(MEK1)that confer kinase inhibitor resistance,to dissect the impact of individual variants in splicing factor 3B subunit 1(SF3B1)-dependent missplicing,and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69.HACE provides a powerful tool for investigating coding and noncoding variants,uncovering combinatorial sequence-to-function relationships,and evolving new biological functions.

Responses of Membrane Lipid Peroxidation and Endogenous Hormones of Soybean Seedlings to UV-B Radiation and Rare Earth

[ Objective] The aim was to provide strategies for development of rare earth and control of environmental pollution. [ Method] Responses of membrane lipid peroxidation and endogenous hormones of soybean seedlings to UV-B radiation and rare earth were studied through hydroponics in laboratory. [ Result] The results showed that under irradiation of UV-B（ T1-0.15 W/m^2 and T2-0.45 W/m^2）, chlorophyll and indole-3-acetic acid（IAA） contents firstly decreased during the stress phase （1 -5 d） and then increased during the restoration phase （6 -9 d） while contents of malonadialdehyde（MDA） and abscisic acid（ABA） gradually increased during the imposition of UV-B radiation （1 -5 d） and subsequently decreased during recovery from UV-B stress （6 -9 d） . With adding of La （III） with the concentration of 20 mg · L^-1 , the decline/dse trend of chlorophyll, IAA, MDA and ABA contents was slowed down during the stress period while the rise/decline speed was accelerated during the recovery period. [ Conclusion] It suggests that the regulation of La （ III ） on membrane lipid peroxidation and endogenous hormones could increase chlorophyll and IAA contents, improve the metabolism of reactive oxygen species （ ROS）, inhibit membrane lipid peroxidation, decrease the accumulation amount of ABA and alleviate injury of UV-B radiation to soybean seedlings. Further, the protective potential of La （ III ） was better under low UV-B radiation than under high one.

Changes in Levels of Endogenous Plant Hormones During Floret Development in Wheat Genotypes of Different Spike Sizes

The levels of endogenous plant hormones regulate floret development and degeneration, and thus grain set in flower crops. This study was undertaken to characterize the changes of endogenous hormone levels during floret development in three wheat ( Triticum aestivum L.) genotypes: “97J1' with the highest grain set and fertile florets per spike, “H8679' with the lowest grain set and fertile florets per spike, and a medium, “YM158'. The results showed that the peak level of ABA appeared between stamen and pistil differentiation and antherlobe formation of floret development, and the timing delayed with the size of spike (earliest in “H8679” and latest in “97J1”). From antherlobe formation to meiosis, the levels of ABA and GA 1+3 decreased sharply in the ears of “97J1”, while in the ears of “H8679” there was only a slight decrease in ABA, and even an increase in GA 1+3 . The ratio of isopentenyladenosine (iPA)/ABA and IAA/ABA in the ears of “97J1” increased sharply from antherlobe formation to meiosis, but changed only slightly in the ears of “H8679”. At antherlobe formation, IAA and GA 1+3 levels were higher in the ears of “97J1”, but lower in the ears of “H8679” than in the leaves. At meiosis, ABA, GA 1+3 and IAA levels in the “97J1” ears were much lower than in the leaves, but similar in “H8679”. These results indicated that the sharp decreases of ABA and GA 1+3 in ears from antherlobe formation to meiosis and the lowest maintenance at meiosis may be favorable for development of fertile florets and enhancement of grain set in wheat.

Effect of Paclobutrazol plus Ethephon Treatment on Endogenous Hormones and Carbon and Nitrogen Nutrients in Litchi Variety ‘Feizixiao'

[Objective] This study aimed to investigate the effect of spraying the mixture of paclobutrazol and ethephon on the endogenous hormones and carbon and nitrogen nutrients in litchi variety ＇Feizixiao＇.[Method] [Result] The results showed that foliar spraying of the mixture of paclobutrazol and ethephon could effectively inhibit litchi variety ＇Feizixiao＇ to produce winter shoots,promote the flower bud differentiation and improve flower formation rate; meanwhile,this treatment could also increase the contents of ABA and ZR,and the ratios of ABA/IAA,ABA/GA3,ZR/IAA,ZR/GA3,and decrease the contents of IAA and GA3; additionally,it could increase the contents of soluble sugar,starch and total nitrogen,and raise C/N ratio,thus improving the flower formation rate.[Conclusion] Foliar spraying of the mixture of paclobutrazol and ethephon is an effective pathway for solving warmth damage to litchi.

Dynamic Changes of Endogenous Hormone Content in Dangshansu Pear during Fruit Development

[Objective] The aim was to clear the relationship between fruit growth and development and endogenous hormones content in the pulp of Dangshansu pear.[Method] Choosing Dangshansu pear as material,the dynamic changes of endogenous hormones in pulp during various development stages were determined by means of enzyme linked immunosorbent assay（ELISA）.[Result] The results indicated that the content of endogenous hormones like ZR,GA and IAA promoting fruit growth showed increase trend within 15 d after pollination,and higher content of ZR,GA and IAA could promote ovary development and normal fruit setting of Dangshansu pear.The content of ZR in pulp had the highest value at the beginning of the first fast growth period,and then showed decrease trend until fruit became mature.The dynamic changes of IAA and GA were similar,namely their contents were higher in the first fast growth period,and decreased with fruit development,and then increased rapidly and was up to the maximum value in the second fast growth period,corresponding with the growth dynamic of fruit.The peaks of ABA content could be found on the 15th,45th and 120th day after pollination,which corresponded with the physiological fruit dropping and maturing period of Dangshansu pear.[Conclusion] The duration of various development periods and content of endogenous hormones of Dangshansu pear were different,and fruit growth and development were closely related to the content of endogenous hormones.

Changes of the Transcriptional Levels of Molecules Associated with Endogenous Antigen Processing and Presentation in Porcine Skin-derived Dendritic Cells Infected with PCV2 in vivo

[Objective] This study aimed to investigate the changes of the transcriptional levels of molecules associated with endogenous antigen processing and presenta- tion in porcine skin-derived dendritic cells infected with PCV2 in vivo. [Method] Healthy 40-day-old Landrace piglets were infected with porcine circovirus type 2 （PCV2） and euthanized on the 34, 7rd, 14th, 21st and 35th d post inoculation （DPI）. The porcine skin-derived dendritic cells （DCs） were collected to analyze the transcrip- tional levels of molecules （LMP7, UBP, MHC-I, calreticulin） associated with endogenous antigen processing and presentation by using real-time fluorescent quantitative PCR （real-time FQ-PCR）. [Result] The results showed that the level of LMP7 mR- NAs was reduced significantly on the 3DPI （P〈0.05）; the level of UBP mRNAs was consistently up-regulated, which increased significantly on the 21DPI and 35DPI （P〈 0.05）; the level of MHC-I mRNAs was significantly down-regulated on the 7DPI （P〈 0.05）; the level of calreticulin mRNAs was up-regulated slightly without significant dif- ference. [Conclusion] PCV2 can inhibit the endogenous antigen processing and presentation ability of porcine skin-derived DCs at early stages of infection.

Studies on Endogenous Hormones and Nutritional Physiology Related to the Premature Senescence of Super-hybrid Rice Liangyoupeijiu and Its Parents at Late Growth Stage

The amount of root bleeding sap, contents of chlorophyl , nutrients and hormones in flag leaves of a super-hybrid rice cultivar Liangyoupeijiu （LYPJ） and its parents 9311 and Pei’ai 64S after heading were measured in this study. The re-sults revealed that compared with 9311, the chlorophyl content of LYPJ reduced more quickly after heading, and then kept at a lower level, which was an obvious characteristic of premature senescence. The other physiological indices of LYPJ af-ter heading except abscisic acid （ABA） content in leaf and root also maintained at a lower level than 9311, while al the physiological indices of the sterile line Pei＇ai 64S were lower than LYPJ. So it was speculated that the early-aging characteristic of LYPJ may be inherited from Pei’ai 64S. Al the leaf and root early-aging traits reduced for LYPJ and its parent lines after heading, their leaf and root aged grad-ual y, which indicated that the above-ground （leaf） and under-ground （root） parts cor-related to each other closely, but there was not absolute correlations between them judged from the data.

Relationship Between Heterosis and Endogenous Plant Hormones in Liriodendron

To investigate the possible involvement of endogenous plant hormones in heterosis of Liriodendron interspecific hybrid, growth traits and contents of endogenous GA 1/3 (gibberellin A 1, A 3), IAA (indole_3_acetic acid) and iPA (isopentenyl adenine) of tulip tree ( L. chinense (Hemsl.) Sarg.), yellow poplar ( L. tulipifera L.) and their interspecific hybrid ( L. chinense × L. tulipifera ) were examined. Results showed that: (1) the heterosis in height growth trait of the interspecific hybrid was mainly caused by the reletively greater elongation of internodes. Although the uppermost three internodes had the potential of elongation, the first one, which had the greatest elongation amount, contributed to the heterosis of the height growth trait; (2) the contents of endogenous GA 1/3 , IAA and iPA were greatly different among tulip tree, yellow poplar and their interspecific hybrid. All of the three interspecific hybrid families studied significantly contained higher amount of endogenous GA 1/3 and iPA in the uppermost first internode than their parental species. And thus, a correlation between the contents of endogenous GA 1/3 and iPA, and hybrid vigor for height growth trait in Liriodendron was observed; (3) the rankings of endogenous GA 1/3 and iPA contents in the uppermost first internode of three hybrid families studied were not similar to the ranking for height of 3_year_old trees. Therefore, the contents of endogenous GA 1/3 and iPA in the uppermost first internode could not be used in predicting hybrid vigor among hybrid families.

Relationship between Endogenous Hormones and Pod-length Development in Brassica napus L.

[Objective] The aim was to study the relationship between endogenous hormone levels and the pod lengths in Brassica napus L.[Method] Two specially-long pod lines H218 and H203,two normal pod length lines MSP334,Zhongyou 821 and two short pod lines ＂4101＂ and Zeng 11,were exploited as experimental materials,and the endogenous IAA,iPA,GA3 and ABA content in the pods of the materials were analyzed with the method of enzyme-linked immunosorbent assay（ELISA）.[Result] IAA contents in the specially-long pod lines were lower than those in the short pod lines on the 1st and 5th day after blossom.IAA contents on the 5th and 20th day were negatively correlated to the final pod length respectively.iPA contents in the specially-long pod lines were lower than those in the short pod lines on the 5th and 20th day.iPA content on the first day was positively correlated to the final pod length,but iPA content on the fifth day,the tenth day and the fifteenth day were negatively correlated to the final pod length.GA3 content on the 1st day was positively correlated to the final pod length.ABA content on the 1st day was negatively correlated to the final pod length.[Conclusion] It was shown that iPA and IAA played important roles in the development of pod length in the B.napus lines.

Effects of Drought Stress on Contents of Endogenous Hormones in Leaves of Different Clones of Liriodendron chinense×L. tulipifera

[Objective] The aim was to study the effects of drought stress on contents of endogenous hormones in leaves of different clones of Liriodendron chinense×L. tulipifera. Drought-resistant Liriodendron chinense×L. tulipifera clones NE25,NE78 and drought-sensitive Liriodendron chinense×L. tulipifera clones NE04,NE23 were selected as experimental materials to study the content changes of four kinds of endogenous hormones such as abscisic acid （ABA）,indoleacetic acid （IAA）,ribosylzeatin （ZR） and jasmonic acid （JA） in leaves of different clones under drought stress. [Result] Under drought stress,ABA was accumulated I leaves of different clones,however,the content changes in drought-resistant clones were not obvious; IAA content showed a decreasing trend,and the content changes n drought-resistant clones during later period of drought stress was decreased; JA content showed an increasing trend in leaves of drought-sensitive clones,indicating that drought-sensitive clones had to maintain higher contents of JA to resist drought stress. [Conclusion] The result of this study had provided scientific basis for the screening,planting and application of drougt-resistant clones of Liriodendron chinense×L. tulipifera.

Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain

Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2′-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen Neu N, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2′-deoxyuridine-positive ？ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.

Effect of Tong Xie Yao Fang on endogenous metabolites in urine of irritable bowel syndrome model rats

BACKGROUND Tong Xie Yao Fang is a representative traditional Chinese prescription for the treatment of liver and spleen deficiency,abdominal pain and diarrhea.It has a unique function in the treatment of gastrointestinal dysfunction including irritable bowel syndrome(IBS),is a common functional bowel disease.Its main symptoms are recurrent abdominal pain,diarrhea,constipation or alternations between diarrhea and constipation.There are obvious differences in metabolites between TCM syndromes.By comparing the body fluid metabolism maps of model animals,metabolomics can discover disease biomarkers,analyze the differences in metabolic pathways and understand the pathological process and the metabolic pathways of substances in the body.Thus,the evaluation of animal models tends to be comprehensive and objective.This may provide further understanding between the interaction between Tong Xie Yao Fang and the IBS model.AIM To evaluate the effect of Tong Xie Yao Fang on IBS rats by using metabolomics method.METHODS Wistar rats were used to establish IBS models,and then randomly divided into four groups:A model control group and three Tong Xie Yao Fang treatment groups(high,medium and low doses).A normal,non-IBS group was established.The rats were treated for 2 wk.On days 0 and 14 of the experimental model,urine was collected for 12 h and was analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry.Nine potential biomarkers were identified,and six major metabolic pathways were found to be related to IBS.RESULTS In the study of metabonomics,nine potential biomarkers including L-serine,4-methylgallic acid,L-threonine,succinylacetone,prolyl-hydroxyproline,valylserine,acetyl citrate,marmesin rutinoside and 5-hydroxy-L-tryptophan were identified in urine,which were assigned to amino acids,organic acids,succinyl and glycosides.Furthermore,the metabolic pathway of L-serine,L-threonine and 5-hydroxy-L-tryptophan was found in the Kyoto Encyclopedia of Genes and Genomes,which mainly involved the metabolism of cysteine and methionine,vitamin B6 metabolism,serotonin synapse,tryptophan metabolism,sphingolipid metabolism,digestion,absorption of protein and amino acid metabolism.These pathways are related to intestinal dysfunction,inflammatory syndrome,nervous system dysfunction and other diseases.CONCLUSION Tong Xie Yao Fang has pharmacological effects on IBS,and its mechanism may be related to the metabolism of the nine potential biomarkers identified above in urine.

Long noncoding RNA RP4 functions as a competing endogenous RNA through miR-7-5p sponge activity in colorectal cancer

AIM To investigate the role of long noncoding RNA(lnc RNA) RP4 in colorectal cancer.METHODS Lentivirus-mediated lnc RNA RP4 overexpression and knockdown were performed in the colorectal cancer cell line SW480. Cell proliferation, tumor growth, and early apoptosis were evaluated by a cell counting kit-8 assay, an in vivo xenograft tumor model, and annexin V/propidium iodide staining, respectively. Analysis of the lnc RNA RP4 mechanism involved assessment of the association of its expression with mi R-7-5 p and the SH3 GLB1 gene. Western blot analysis was also performed to assess the effect of lnc RNA RP4 on the autophagy-mediated cell death pathway and phosphatidylinositol-3-kinase(PI3 K)/Akt signaling.RESULTS Cell proliferation, tumor growth, and early apoptosis in SW480 cells were negatively regulated by lnc RNA RP4. Functional experiments indicated that lnc RNA RP4 directly upregulated SH3 GLB1 expression by acting as a competing endogenous RNA(ce RNA) for mi R-7-5 p. This interaction led to activation of the autophagy-mediated cell death pathway and de-repression of PI3 K and Akt phosphorylation in colorectal cancer cells in vivo.CONCLUSION Our results demonstrated that lnc RNA RP4 is a ce RNA that plays an important role in the pathogenesis of colorectal cancer, and could be a potential therapeutic target for colorectal cancer treatment.