Histological Assessment of Bone Regeneration in the Maxilla with Homologous Bone Graft:A Feasible Option for Maxillary Bone Reconstruction

Bone biomaterials have been increasingly used to reconstruct maxillary atrophic ridges.Thus,the aim of this study was to evaluate bone reconstruction in the maxilla using a homologous cortico-cancellous FFB(lyophilized)graft and verify its reliability.Eight individuals were included from 2014 to 2018.The first surgery was performed to install homologous bone blocks in the maxilla.The period of the second intervention varied between 5 months and 15 days to 11 months(≈7.93 months).The biopsies were taken from the central region of the matured graft during the surgery for implant placement.All patients presented clinical and radiographic conditions for the installation of dental implants.There was a 100%of survival rate.The histological assessment showed that the homologous block bone graft was an osteoconductive biomaterial,with connective tissue present,and newly formed bone juxtaposed on its surface.There were bone trabeculae with osteocytes and active osteoblasts with connective tissue in the mineralization process;the remodeling process can be found through the reverse lines.A limited focus of necrosis with fibrosis was detected,with small resorption and areas of inflammatory infiltrate,but without clinical significance.The homologous block bone graft can be considered a feasible option to substitute the autogenous bone graft(gold standard),with predictable clinical and favorable histological results.The patients had a shorter surgical period,low morbidity,and an unlimited amount of biomaterial available at an accessible cost.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients

BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors

Background:The homologous recombination deficiency(HRD)score serves as a promising biomarker to iden-tify patients who are eligible for treatment with PARP inhibitors(PARPi).Previous studies have suggested a 3-biomarker Genomic Instability Score(GIS)threshold of≥42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer.However,the GIS threshold for prostate cancer(PCa)is still lacking.Here,we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients.Methods:A total of 181 patients with metastatic castration-resistant PCa were included in this study.Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair(HRR)genes and copy number variation(CNV)analysis.The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms(SNP)distributed across the human genome,incorporating three SNP-based as-says:loss of heterozygosity,telomeric allelic imbalance,and large-scale state transition.The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors.The relation-ship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed.Results:Genomic testing was succeeded in 162 patients.In our cohort,61 patients(37.7%)had HRR mutations(HRRm).BRCA mutations occurred in 15 patients(9.3%).The median HRD score was 4(ranged from 0 to 57)in the total cohort,which is much lower than that in breast and ovarian cancers.Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores.CNV occured more frequently in patients with HRRm.The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores≥43.In the 16 patients who received PARPi in our cohort,4 patients with a high HRD score achieved an objective response rate(ORR)of 100%while 12 patients with a low HRD score achieved an ORR of 8.3%.Progression-free survival(PFS)in HRD high patients was longer compared to HRD low patients,regardless of HRRm.Conclusions:A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study.Future studies are needed to further verify this threshold.

The Citron homology domain of MAP4Ks improves outcomes of traumatic brain injury

The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults.Whether targeting this pathway is beneficial to brain injury remains unclear.In this study,we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis,tauopathy,lesion size,and behavioral deficits.Pharmacological inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology domain.Mechanistically,the Citron homology domain acted as a dominant-negative mutant,impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin pathway.These findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.

Sine oculis homeobox homolog family function in gastrointestinal cancer:Progression and comprehensive analysis

The sine oculis homeobox homolog(SIX)family,a group of transcription factors characterized by a conserved DNA-binding homology domain,plays a critical role in orchestrating embryonic development and organogenesis across various organisms,including humans.Comprising six distinct members,from SIX1 to SIX6,each member contributes uniquely to the development and differentiation of diverse tissues and organs,underscoring the versatility of the SIX family.Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders,as well as in tumor initiation and progression,highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions.Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development.While the development of inhibitors targeting this gene family is still in its early stages,the significant potential of such interventions holds promise for future therapeutic advances.Therefore,this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers,focusing on its critical role in normal organ development and its implications in gastrointestinal cancers,including gastric,pancreatic,colorectal cancer,and hepatocellular carcinomas.In conclusion,this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis,prognosis,and treatment of gastrointestinal cancers.

Effects of Different Concentrations of Homologous Probiotics on Small Intestinal Mucosa Structure of 42-day-old Broilers

In the study, the methods of applied histology and histochemistry were used to determine intestinal villus length, crypt depth, the ratio of intestinal villus length to crypt depth, mucous membrane thickness and intestinal wall thickness of duodenum, jejunum and ileum of 42-day-old broilers, so as to study the effects of different conncentrations of homologous probiottcs on small intestinal mucosa struc- ture of the broilers. The results showed that the effect of 0.3% probiotics on small intestine mucosal structures was the best, such as the length of intestinal villus was the longest, the ratio of villus length to crypt depth was the largest, the thins of mucous membrane and intestinal wall was the thickest. These showed that 0,3% probiotics had best effect on improving and enhancing the digestion-absorption func- tion of the small intestine of the broilers.

具有非线性homologous变形约束的桁架结构形态分析

研究了具有非线性homologous变形约束条件的桁架结构形态分析问题。在已有的线性homologous变形约束桁架形态分析的基础上,将结构的节点分成三类:homologous变形约束节点,形状可变节点和边界点。运用Moore-Penrose广义逆矩阵性质,将基础方程组解的存在条件表示为包含形状可变节点未知坐标的非线性方程组,为采用Newton-Raphson方法求解非线性方程组,对AA+(A为任意矩阵,A+为A的Moore-Penrose广义逆矩阵)求偏导数,找到了满足保型要求的形态,给出的桁架算例说明了本文方法的有效性。

具有Homologous变形约束立体桁架的形态分析

本文研究了具有Homologous位移约束的结构形状分析问题。文中第一部分把结点分成三类:表示Homologous变形点(自由度=h),形状可变点(自由度=f)和边界点。然后对于任意的桁架结构给出Homologous参数,n=h+f和m=1+f,引入具有n×m的系数矩阵的基础方程。在第二部分,利用广义逆矩阵导出基础方程的解存在条件。然后建立包含未知结点坐标的非线性方程组,并由Newton-Raphson法进行数值分析,以找出最终形状。最后一部分举了一个三维桁架的例子,以说明该方法的有效性,实用性。

基于广义逆的桁架结构非线性homologous设计方法

运用M-P广义逆理论,研究了桁架结构的非线性homologous设计问题。将homologous变形约束条件引入结构基本方程,运用M-P广义逆矩阵的性质,将基本方程解的存在条件表示为含可变节点坐标变量的非线性方程组,通过求解该非线性方程组找到了满足homologous变形约束要求的解,并为此推导了AA+(A为任意矩阵,A+为A的M-P广义逆矩阵)求偏导数的显式表达。最后的算例验证了本方法的正确性和有效性。

Double versus single homologous intrauterine insemination for male factor infertility： a systematic review and meta-analysis

Male factor infertility affects 30%-50% of infertile couples worldwide, and there is an increasing interest in the optimal management of these patients. In studies comparing double and single intrauterine insemination （IUI）, a trend towards higher pregnancy rates in couples with male factor infertility was observed. Therefore, we set out to perform a meta-analysis to examine the superiority of double versus single IUI with the male partner＇s sperm in couples with male factor infertility. An odds ratio （OR） of 95% confidence intervals （CIs） was calculated for the pregnancy rate. Outcomes were analysed by using the ManteI-Haesel or DerSimonian-Laird model accordingto the heterogeneity of the results. Overall, five trials involving 1125 IUI cycles were included in the meta-analysis. There was a two-fold increase in pregnancies after a cycle with a double IUI compared with a cycle with a single IUI （OR. 2.0; 95% CI. 1.07-3.75; P〈O.03）. Nevertheless, this result was mainly attributed to the presence of a large trial that weighted as almost 50% in the overall analysis. Sensitivity analysis, excluding this large trial, revealed only a trend towards higher pregnancy rates among double IUI cycles （OR. 1.58; 95% CI. 0.59-4.21）, but without statistical significance （P=0.20）. Our systematic review highlights that the available evidence regarding the use of double IUI in couples with male factor infertility is fragmentary and weak. Although there may be a trend towards higher pregnancy rates when the number of IUIs per cycle is increased, further large and well-designed randomized trials are needed to provide solid evidence toide current clinical practice.

C/EBP homologous protein deficiency aggravates acute pancreatitis and associated lung injury

AIM:To investigate the pathophysiological role of C/EBP homologous protein(CHOP)in severe acute pancreatitis and associated lung injury.METHODS:A severe acute pancreatitis model was induced with 6 injections of cerulein(Cn,50μg/kg)at 1-h intervals,then intraperitoneal injection of lipopolysaccharide(LPS,7.5 mg/kg)in CHOP-deficient(Chop-/-)mice and wild-type(WT)mice.Animals were sacrificed under anesthesia,3 h or 18 h after LPS injection.Serum amylase,lipase,and cytokines[interleukin(IL)-6 and tumor necrosis factor(TNF)-α],pathological changes,acute lung injury,and apoptosis in the pancreas were evaluated.Serum amylase and lipase activities were detected using a medical automatic chemical analyzer.Enzyme-linked immunosorbent assay kits were used to evaluate TNF-αand IL-6 levels in mouse serum and lung tissue homogenates.Apoptotic cells in sections of pancreatic tissues were determined by terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick-end labeling(TUNEL)analysis.The mouse carotid arteries were cannulated and arterial blood samples were collected for PaO2analysis.The oxygenation index was expressed as PaO2/FiO2.RESULTS:Administration of Cn and LPS for 9 and 24 h induced severe acute pancreatitis in Chop-/-and WT mice.When comparing Chop-/-mice and WT mice,we observed that CHOP-deficient mice had greater increases in serum TNF-α(214.40±19.52 pg/mL vs 150.40±16.70 pg/mL;P=0.037),amylase(4236.40±646.32U/L vs 2535.30±81.83 U/L;P=0.041),lipase(1678.20±170.57 U/L vs 1046.21±35.37 U/L;P=0.008),and IL-6(2054.44±293.81 pg/mL vs 1316.10±108.74pg/mL;P=0.046)than WT mice.The histopathological changes in the pancreases and lungs,decreased PaO2/FiO2ratio,and increased TNF-αand IL-6 levels in the lungs were greater in Chop-/-mice than in WT mice(pancreas:Chop-/-vs WT mice,hemorrhage,P=0.005;edema,P=0.005;inflammatory cells infiltration,P=0.005;total scores,P=0.006;lung:hemorrhage,P=0.017;edema,P=0.017;congestion,P=0.017;neutrophil infiltration,P=0.005,total scores,P=0.001;PaO2/FiO2ratio:393±17.65 vs 453.8,P=0.041;TNF-α:P=0.043;IL-6,P=0.040).Results from TUNEL analysis indicated increased acinar cell apoptosis in mice following the induction of acute pancreatitis.However,Chop-/-mice displayed significantly reduced pancreatic apoptosis compared with the WT mice(201.50±31.43vs 367.00±47.88,P=0.016).CONCLUSION:These results suggest that CHOP can exert protective effects against acute pancreatitis and limit the spread of inflammatory damage to the lungs.

miR-506: a regulator of chemo-sensitivity through suppression of the RAD51-homologous recombination axis

Ovarian carcinoma is the most lethal gynecologic malignancy. Resistance to platinum is considered the major problem afecting prognosis. Our recent study established that micro RNA-506(mi R-506) expression was closely associated with progression-free survival and overall survival in two independent patient cohorts totaling 598 epithelial ovarian cancer cases. Further functional study demonstrated that mi R-506 could augment the response to cisplatin and olaparib through targeting RAD51 and suppressing homologous recombination in a panel of ovarian cancer cell lines. Systemic delivery of mi R-506 in an orthotopic ovarian cancer mouse model signiicantly augmented the cisplatin response, thus recapitulating the clinical observation. Therefore, mi R-506 plays a functionally important role in homologous recombination and has important therapeutic value for sensitizing cancer cells to chemotherapy, especially in chemo-resistant patients with attenuated expression of mi R-506.

Homologous fault monitoring technology of redundant INS in airborne avionics systems

Redundant technology plays an important role in improving the reliability and fault-tolerance of the airborne avionics systems. A Markov state transition model is introduced to the reliability analysis of the redundant inertial navigation system （RINS） in airborne navigation systems. An information processing mechanism based on difference filtering is put forward to strengthen the consistency between the outputs of the equal-precision inertial navigation system （INS）. On this basis, the homologous fault monitoring algorithm is designed to realize the homologous fault monitoring of RINS. The simulation is carried out based on the above algorithms, and the results verify the effectiveness of the proposed fault monitoring algorithm based on difference filtering. Research results have good reference value for the configuration and design of RINS in airborne integrated avionics systems.

Inhibition of KU70 and KU80 by CRISPR interference,not NgAgo interference,increases the efficiency of homologous recombination in pig fetal fibroblasts

Non-homologous end-joining(NHEJ) is a predominant pathway for the repair of DNA double-strand breaks(DSB). It inhibits the efficiency of homologous recombination(HR) by competing for DSB targets. To improve the efficiency of HR, multiple CRISPR interference(CRISPRi) and Natronobacterium gregoryi Argonaute(NgAgo) interference(NgAgoi) systems have been designed for the knockdown of NHEJ key molecules, KU70, KU80, polynucleotide kinase/phosphatase(PNKP), DNA ligase IV(LIG4), and NHEJ1. Suppression of KU70 and KU80 by CRISPRi dramatically promoted(P<0.05) the efficiency of HR to 1.85-and 1.58-fold, respectively, whereas knockdown of PNKP, LIG4, and NHEJ1 repair factors did not significantly increase(P>0.05) HR efficiency. Interestingly, although the NgAgoi system significantly suppressed(P<0.05) KU70, KU80, PNKP, LIG4, and NHEJ1 expression, it did not improve(P>0.05) HR efficiency in primary fetal fibroblasts. Our result showed that both NgAgo and catalytically inactive Cas9(dCas9) could interfere with the expression of target genes, but the downstream factors appear to be more active following CRISPR-mediated interference than that of NgAgo.

Gene Sequence, Soluble Expression and Homologous Comparison of a D-Hydantoinase fromPseudomonas putida YZ-26

A 1440bp open-reading frame encoding D-hydantoinase from Pseudomonas putida YZ-26 was cloned and sequenced（ GenBank AY387829）. The DNA fragment was inserted into Nde and BamHI sites of vector pET-3a, yielding a recombinant plasmid, pET-HDT. After being transferred into the host strain, the artificial strain, pET-HDT/ E. coli BL21 can express the D-hydantoinase as the soluble form in the Lura-Bertani medium without addition of any inducers. The activity of the enzyme toward substrate DL-hydantoin can reach 3000-4000 IU per cells from one-liter bacterial culture incubated at 30 ℃ for 10-12 h. By the comparison of amino acid sequence homology, hydrophobic residues analysis and secondary structure prediction, it was found that D-hydantoinase reported herein is quite similar to that from Pseudomonas putdia CCRC12857, and alike to that from Pseudomonas putdia DSM84 or other bacteria. A rapid and efficient purification procedure of the enzyme was performed by a three-step procedure： ammonium sulfate fractionation, phenyl Sepharose hydrophobic interaction chromatography and Sephacryl S-200 gel filtration. The molecular mass of the monomeric enzyme is 52042 Da as determined by MALDI-TOF mass spectrometry.

Homologous recombination in DNA repair and DNA damage tolerance

Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR： homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.

Effects of serum containing natural cerebrolysin on glucose-regulated protein 78 and CCAAT enhancer-binding protein homologous protein expression in neuronal PC12 cells following tunicamycin-induced endoplasmic reticulum stress

BACKGROUND： Glucose-regulated protein 78 （GRP78）, a marker of endoplasmic reticulum stress, can prolong cell survival. Alternatively, CCAAT enhancer-binding protein homologous protein （CHOP）, a transcription factor specific for endoplasmic reticulum stress, can cause cell cycle arrest and cell apoptosis. OBJECTIVE： To study the protective effects of serum containing natural cerebrolysin on endoplasmic reticulum stress in tunicamycin-induced neuronal PC12 cells, and analyze the influence on GRP78 and CHOP expressions. DESIGN, TIME AND SETTING： A parallel controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, between March 2006 and August 2008. MATERIALS： Adult Sprague-Dawley rats were perfused with natural Cerebrolysin aqueous extract （0.185 g/kg/d） to produce serum containing natural Cerebrolysin. Physiological saline was used to produce blank serum. PC12 cell line was provided by Shanghai Institute of Cell Biology, Chinese Academy of Science. Tunicamycin was provided by Sigma （St. Louis, USA）, and natural Cerebrolysin, containing ginseng, rhizoma gastrodiae, and gingko leaf （1：2：2）, by Shengzhen Institute of Integrated Western and Traditional Chinese Medicine. METHODS： PC12 cells were treated with DMEM culture media containing 10% blank serum （normal control group）, tunicamycin （1 μg/mL; model group）, and 5%, 10%, and 15% serum containing natural cerebrolysin and tunicamycin （1 μ g/mL; low-, moderate-, and high-dose serum containing natural cerebrotysin groups）, for 2 hours. MAIN OUTCOME MEASURES： PC12 cells were treated with tunicamycin for 48 hours after which apoptosis was measured using the TUNEL method to calculate apoptotic index. GRP78 expression was detected using immunocytochemistry. After 24 hours of treatment with tunicamycin, GRP78 and CHOP mRNA expressions were measured using RT-PCR. RESULTS： The apoptotic index and CHOP mRNA expression were in the model group and three cerebrolysin groups were significantly increased when compared to the normal control group （P 〈 0.05）. In contrast, GRP78 mRNA and protein expressions were significantly decreased （P 〈 0.05）. CONCLUSION： Serum containing natural cerebrolysin significantly reduced apoptosis in neuronal PC12 cells following tunicamycin-induced endoplasmic reticulum stress. These results may be related to an up-regulation of GRP78 expression and down-regulation of CHOP expression, both of which displayed dose-dependent effects.

The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer

Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response.We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response.Methods:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC.Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese cohort.Mutations in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability status.In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy.

Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein

Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.