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.

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.

Mechanochemical strategy assisted morphology recombination of COFs for promoted kinetics and LiPS transformation in Li-S batteries

A covalent organic frameworks(COFs)material with regular pores and stable structure can be used as the host of lithium-sulfur batteries to improve battery kinetics and polysulfides conversion.Herein,we designed and synthesized two kinds of rod-liked bulk COFs by adjusting different pore sizes(COF-BTD and COF-TFB),unfortunately,the active sites masking and sluggish kinetics have not met our expectations.Generally,the available layered COFs prepared from mechanochemical can expose abundant active sites and favorable kinetics than bulk COFs.Thus,simple mechanical ball milling is applied to activate the above COFs(M-COFs group).It is worth noting that layered R-COF-BTD is directly synthesized from rod-liked precursors by simple morphological reconstruction.A series of characterization methods are used to systematically explore the advantages of the group of M-COFs@S electrodes in the cycling process,including the effects of specific morphology on the kinetics and transformation of polysulfides.Our research provides a feasible plan for the development and selection of the host material of lithium-sulfur batteries.

Physico−mathematical model of the voltage−current characteristics of light-emitting diodes with quantum wells based on the Sah−Noyce−Shockley recombination mechanism

Herein,a physical and mathematical model of the voltage−current characteristics of a p−n heterostructure with quantum wells(QWs)is prepared using the Sah−Noyce−Shockley(SNS)recombination mechanism to show the SNS recombination rate of the correction function of the distribution of QWs in the space charge region of diode configuration.A comparison of the model voltage−current characteristics(VCCs)with the experimental ones reveals their adequacy.The technological parameters of the structure of the VCC model are determined experimentally using a nondestructive capacitive approach for determining the impurity distribution profile in the active region of the diode structure with a profile depth resolution of up to 10Å.The correction function in the expression of the recombination rate shows the possibility of determining the derivative of the VCCs of structures with QWs with a nonideality factor of up to 4.

Initial measurement of ultrafast charge exchange recombination spectroscopy on the EAST tokamak

Ultrafast charge exchange recombination spectroscopy(UF-CXRS)has been developed on the EAST tokamak(Yingying Li et al 2019 Fusion Eng.Des.146522)to measure fast evolutions of ion temperature and toroidal velocity.Here,we report the preliminary diagnostic measurements after relative sensitivity calibration.The measurement results show a much higher temporal resolution compared with conventional CXRS,benefiting from the usage of a prismcoupled,high-dispersion volume-phase holographic transmission grating and a high quantum efficiency,high-gain detector array.Utilizing the UF-CXRS diagnostic,the fast evolutions of the ion temperature and rotation velocity during a set of high-frequency small-amplitude edgelocalized modes(ELMs)are obtained on the EAST tokamak,which are then compared with the case of large-amplitude ELMs.

Features of Recombination Radiation of GaAs Type Semiconductors with the Participation of Fine Acceptor Levels in a Magnetic Field

Using the method of Picus and Beer invariants, general expressions are obtained for the total intensity I and the degree of circular polarization Рcirc.of the luminescence of GaAs-type semiconductors with the participation of shallow acceptor levels in a longitudinal magnetic field H. Special cases are analyzed depending on the value and direction of the magnetic field strength, as well as on the constants of the g-factor of the acceptor g1,g2and the conduction band electron ge. In the case of a strong magnetic field H// [100], [111], [110], a numerical calculation of the angular dependence of the quantities I and Рcirc.was performed for some critical values of g2/g1, at which Рcirc.exhibits a sharp anisotropy in the range from −100% to +100%, and the intensity of the crystal radiation along the magnetic field tends to a minimum value.

The p recombination layer in tunnel junctions for micromorph tandem solar cells

A new tunnel recombination junction is fabricated for n-i-p type micromorph tandem solar cells. We insert a thin heavily doped hydrogenated amorphous silicon （a-Si：H） p^＋ recombination layer between the n a-Si：H and the p hydrogenated nanocrystalline silicon （nc-Si：H） layers to improve the performance of the n-i-p tandem solar cells. The effects of the boron doping gas ratio and the deposition time of the p-a-Si：H recombination layer on the tunnel recombination junctions have been investigated. The current-voltage characteristic of the tunnel recombination junction shows a nearly ohmic characteristic, and the resistance of the tunnel recombination junction can be as low as 1.5 Ω-cm^2 by using the optimized p-a-Si：H recombination layer. We obtain tandem solar cells with open circuit voltage Voc = 1.4 V, which is nearly the sum of the Vocs of the two corresponding single cells, indicating no Voc losses at the tunnel recombination junction.

Simulation study of the losses and influences of geminate and bimolecular recombination on the performances of bulk heterojunction organic solar cells

We use the method of device simulation to study the losses and influences of geminate and bimolecular recombinations on the performances and properties of the bulk heterojunction organic solar cells. We find that a fraction of electrons（holes）in the device are collected by anode（cathode）. The direction of the corresponding current is opposite to the direction of photocurrent. And the current density increases with the bias increasing but decreases as bimolecular recombination（BR）or geminate recombination（GR） intensity increases. The maximum power, short circuit current, and fill factor display a stronger dependence on GR than on BR. While the influences of GR and BR on open circuit voltage are about the same.Our studies shed a new light on the loss mechanism and may provide a new way of improving the efficiency of bulk heterojunction organic solar cells.

Effect of recombination process in femtosecond laser-induced modification on Ge crystal

The dynamics of produced excited carriers under the irradiation of Ge crystal is investigated theoretically by using femtosecond laser pulse.A two-temperature model combined with the Drude model is also used to study the nonequilibrium carrier density,carrier and lattice temperatures,and optical properties of the crystal.The properties of the surface plasmon wave when excited are also studied.The influences of non-radiation and radiative recombination process on the photoexcitation of the semiconductor during pulse and the relaxation after the pulse are described in detail.The results show that the effects of Auger recombination on the nonequilibrium carrier density and optical properties of the crystal and the properties of the surface plasmon polariton are great,whereas the effect of radiative recombination is extremely small.

Investigations of the dielectronic recombination of phosphorus-like tin at CSRm

The electron–ion recombination for phosphorus-like^（112） Sn^（35＋）has been measured at the main cooler storage ring of the Heavy Ion Research Facility in Lanzhou, China, employing an electron–ion merged-beams technique. The absolute total recombination rate coefficients for electron–ion collision energies from 0 e V–14 e V are presented. Theoretical calculations of recombination rate coefficients were performed using the Flexible Atomic Code to compare with the experimental results. The contributions of dielectronic recombination and trielectronic recombination on the experimental rate coefficients have been identified with the help of the theoretical calculation. The present results show that the trielectronic recombination has a substantial contribution to the measured electron–ion recombination spectrum of^（112）Sn^（35＋）. Although a reasonable agreement is found between the experimental and theoretical results the precise calculation of the electron–ion recombination rate coefficients for M-shell ions is still challengeable for the current theory.

Recombination-induced voltage-dependent photocurrent collection loss in CdTe thin film solar cell

Recently, the efficiency of CdTe thin film solar cell has been improved by using new type of window layer Mg_(x)Zn_(1-x)O(MZO). However, it is hard to achieve such a high efficiency as expected. In this report a comparative study is carried out between the MZO/CdTe and CdS/CdTe solar cells to investigate the factors affecting the device performance of MZO/CdTe solar cells. The efficiency loss quantified by voltage-dependent photocurrent collection efficiency(ηC(V′)) is 3.89% for MZO/CdTe and 1.53% for CdS/CdTe solar cells. The higher efficiency loss for the MZO/CdTe solar cell is induced by more severe carrier recombination at the MZO/CdTe p-n junction interface and in CdTe bulk region than that for the CdS/CdTe solar cell. Activation energy(Ea) of the reverse saturation current of the MZO/CdTe and CdS/CdTe solar cells are found to be 1.08 e V and 1.36 e V, respectively. These values indicate that for the CdS/CdTe solar cell the carrier recombination is dominated by bulk Shockley-Read-Hall(SRH) recombination and for the MZO/CdTe solar cell the carrier recombination is dominated by the p-n junction interface recombination. It is found that the tunneling-enhanced interface recombination is also involved in carrier recombination in the MZO/CdTe solar cell. This work demonstrates the poor device performance of the MZO/CdTe solar cell is induced by more severe interface and bulk recombination than that of the CdS/CdTe solar cell.

Recombination Efficiency and Width in Bilayer Organic Light-emitting Devices

A bilayer model with ohmic anode contact and injection limited cathode contact has been proposed to calculate the recombination efficiency and recombination zone width of the device. The effects of the thickness of hole transport layer and the barriers of organic/organic interface on the combination efficiency and recombination width have been discussed. It is found that： （1） When the electrons are blocked fully and the holes are not blocked significantly at the organic/organic interface, for a given Lh/L, the recombination efficiency increases with increasing the applied voltage, but at a higher applied voltage, the recombination efficiency decreases with increasing Lh/L; （2） The recombination efficiency increases with increasing applied voltage and Hh＇, and when applied voltage and Hh＇ exceed some value, the recombination efficiency appears as a plateau; （3） The recombination width decreases with increasing the applied voltage and Lh/L. This model might explain the relative experiment phenomena.

秩序·扰动·RECOMBINATION

这个事实我们知道了很久:一种生物,若遇到人为的物理、化学、生物方法引导,或者遗传因子得到重组,就可能在合适的新环境中发生多元突变。世界美术的古典风格、中世纪风格、文艺复兴风格、巴洛克风格,艺术设计的现代理念、后现代理念,手工艺的传统方式、"莫里斯方式"、"柳宗悦方式"……我们看到了,一部历史,就是传统秩序,经演进中的社会经济、政治、哲学、文化、生活方式等新生因子的扰动催化,最后产生复合变异的结果。

Influence of Recombination Centers on the Phase Portraits in Nanosized Semiconductor Films

Influence of recombination centers’ changes on the form of phase portraits has been studied. It has been shown that the shape of the phase portraits depends on the concentration of semiconductor materials’ recombination centers.

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.

Support vector machine for prediction of meiotic recombination hotspots and coldspots in Saccharomyces cerevisiae

A novel method for predicting hotspots and coldspots using support vector machine （SVM） based on statistical learning theory is developed. This method is applied to published 303 hot and 48 cold open reading frames （ORFs） in Saccharomyces cerevisiae. The sequence features of general dinucleotide abundance and dinucleotide abundance based on codon usage are extracted, and then the data sets are classified with different parameters and kernel functions combined with the method of two-fold cross validation. The result indicates that 87.47% accuracy can be reached when classifying hot and cold ORF sequences with the kernel of radial basis function combined with dinucleotide abundance based on codon usage.

The multi-factor recombination and processes superimposition model for hydrocarbon accumulation:application to the Silurian in the Tarim Basin

The multi-factor recombination and processes superimposition model for hydrocarbon accumulation is put forward in view of the hydrocarbon geological characteristics of multiple episodes of structural evolution, multiple sets of source-reservoir-seal assemblage, multiple cycles of hydrocarbon accumulation and multiple episodes of readjustment and reconstruction in the complex superimposed basins in China. It is a system including theories and methods that can help to predict favorable exploration regions. According to this model, the basic discipline for hydrocarbon generation, evolution and distribution in the superimposed basins can be summarized in multi-factor recombination, processes superimposition, multiple stages of oil filling and latest stage preservation. With the Silurian of the Tarim basin as an example, based on the reconstruction of the evolution history of the four factors （paleo-anticline, source rock, regional cap rock and kinematic equilibrium belt） controlling hydrocarbon accumulation, this model was adopted to predict favorable hydrocarbon accumulation areas and favorable exploration regions following structural destruction in three stages of oil filling, to provide guidance for further exploration ofoil and gas in the Silurian of the Tarim basin.

Vleiotic recombination and male infertility： from basic science to clinical reality？

Infertility is a common problem that affects approximately 15% of the population. Although many advances have been made in the treatment of infertility, the molecular and genetic causes of male infertility remain largely elusive. This review will present a summary of our current knowledge on the genetic origin of male infertility and the key events of male meiosis. It focuses on chromosome synapsis and meiotic recombination and the problems that arise when errors in these processes occur, specifically meiotic arrest and chromosome aneuploidy, the leading cause of pregnancy loss in humans. In addition, meiosis-specific candidate genes will be discussed, including a discussion on why we have been largely unsuccessful at identifying disease-causing mutations in infertile men. Finally clinical applications of sperm aneuploidy screening will be touched upon along with future prospective clinical tests to better characterize male infertility in a move towards personalized medicine.

Construction of recombinant industrial Saccharomyces cerevisiae strain with bglS gene insertion into PEP4 locus by homologous recombination

The bglS gene encoding endo-1,3-1,4-β-glucanase from Bacillus subtil＆ was cloned and sequenced in this study. The bglS expression cassette, including PGK1 promoter, bglS gene fused to the signal sequence of the yeast mating pheromone a-factor （MFals）, and ADH1 terminator with G418-resistance as the selected marker, was constructed. Then one of the PEP4 allele of Saccharomyces cerevisiae WZ65 strain was replaced by bglS expression cassette using chromosomal integration of polymerase chain reaction （PCR）-mediated homologous recombination, and the bglS gene was expressed simultaneously. The recombinant strain S. cerevisiae （SC-βG） was preliminarily screened by the clearing hydrolysis zone formed after the barley β-glucan was hydrolyzed in the plate and no proteinase A （PrA） activity was measured in fermenting liquor. The results of PCR analysis of genome DNA showed that one of the PEP4 allele had been replaced and bglS gene had been inserted into the locus of PEP4 gene in recombinant strains. Different endo-1,3-1,4-β-glucanase assay methods showed that the recombinant strain SC-βG had high endo-1,3-1,4-β-glucanase expression level with the maximum of 69.3 U/（h·ml） after 60 h of incubation. Meanwhile, the Congo Red method was suitable for the determination of endo-1,3-1,4-β-glucanase activity during the actual brewing process. The current research implies that the constructed yeast strain could be utilized to improve the industrial brewing property of beer.