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Background: The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. The available data suggest that the histone variant mH2A participates in the regulation of transcription, maintenance of heterochromatin, NAD+ metabolism, and double-strand DNA repair. Results: Here, we describe a novel function of mH2A, namely its implication in DNA oxidative damage repair through PARP-1. The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin. Conclusions: Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation. [ABSTRACT FROM AUTHOR]

To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. Genome-wide association study. Not applicable. A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. Three genome-wide significant (<5.0 × 10−8) and 16 genome-wide suggestive (<5.0 × 10−6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): −0.484 (0.091). This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Alcohols are common alkylating agents and starting materials alternative to harmful alkyl halides. In this study, a simple, benign and efficient pathway was developed to synthesize 1,3‐diphenylpropan‐1‐ols via the β‐alkylation of 1‐phenylethanol with benzyl alcohols. Unlike conventional borrowing hydrogen processes in which alcohols were activated by transition‐metal catalyzed dehydrogenation, in this work, t‐BuONa was suggested to be a dual‐role reagent, namely, both base and radical initiator, for the radical coupling of aromatic alcohols. The cross‐coupling reaction readily proceeded under transition metal‐free conditions and an inert atmosphere, affording 1,3‐diphenylpropan‐1‐ol with an excellent yield. A good functional group tolerance in benzyl alcohols was observed, leading to the production of various phenyl‐substituted propan‐1‐ol derivatives in moderate‐to‐good yields. The mechanistic studies proposed that the reaction could involve the formation of reactive radical anions by base‐mediated deprotonation and single electron transfer. [ABSTRACT FROM AUTHOR]

Simple Summary: This article explores the impact of chemotherapy on ovarian function in female cancer survivors, emphasizing the importance of preserving fertility alongside cancer treatment. Chemotherapy-induced ovarian failure (CIOF) poses a significant concern, affecting patients' quality of life. The study aims to identify genetic markers predictive of CIOF through a systematic review of existing literature. The review identifies four relevant studies focusing on genetic factors associated with CIOF. Findings suggest potential associations between genetic variations, like CYP3A4*1B and GSTA1, and CIOF risk. Moreover, BRCA mutations may influence ovarian reserve recovery post-chemotherapy. While current assessment methods rely on biochemical tests and ultrasound imaging, genetic testing holds promise for personalized fertility preservation strategies. Integrating genetic markers into clinical practice could revolutionize decision making in fertility preservation for female cancer survivors, enhancing reproductive potential preservation. Background: Recent advances in cancer diagnosis and treatment have significantly improved survival rates among women of reproductive age facing cancer. However, the potential iatrogenic loss of fertility caused by chemotherapeutic agents underscores the need to understand and predict chemotherapy-induced ovarian damage. This study addresses this gap by systematically reviewing the literature to investigate genetic markers associated with chemotherapy-induced ovarian failure (CIOF). Objective: The primary objective is to identify genetic markers linked to CIOF, contributing to a comprehensive understanding of the factors influencing fertility preservation in female cancer survivors. Methods: A systematic review was conducted using PubMed, EMBASE, Web of Science, Scopus, and OVID electronic databases from inception through December 2023. Studies were included if they featured genomic assessments of genes or polymorphisms related to CIOF in women with histologically confirmed tumors. Exclusion criteria comprised in vitro and animal studies, reviews, and pilot studies. The resulting four human-based studies were scrutinized for insights into genetic influences on CIOF. Results: Of the 5179 articles initially identified, four studies met the inclusion criteria, focusing on alkylating agents, particularly cyclophosphamide, and anthracyclines. Su et al. explored CYP3A41B variants, revealing modified associations with CIOF based on age. Charo et al. investigated GSTA1 and CYP2C19 polymorphisms, emphasizing the need to consider age and tamoxifen therapy in assessing associations. Oktay et al. delved into the impact of BRCA mutations on anti-Müllerian hormone (AMH) levels post-chemotherapy, supported by in vitro assays. Van der Perk et al. focused on childhood cancer survivors and revealed significant associations of CYP3A43 and CYP2B6*2 SNPs with AMH levels. Conclusions: This systematic review analyzes evidence regarding genetic markers influencing CIOF, emphasizing the complex interplay of age, specific genetic variants, and chemotherapy regimens. The findings underscore the need for a personalized approach in assessing CIOF risk, integrating genetic markers with traditional ovarian reserve testing. The implications of this study extend to potential advancements in fertility preservation strategies, offering clinicians a comprehensive baseline assessment for tailored interventions based on each patient's unique genetic profile. Further research is essential to validate these findings and establish a robust framework for integrating genetic markers into clinical practice. [ABSTRACT FROM AUTHOR]

The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance toward SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1. [ABSTRACT FROM AUTHOR]

Control of the regioselectivity of nucleophiles toward alkylating agents is a fundamental problem in heterocyclic chemistry. Substrate-controlled TfOH-catalyzed alkylation of 4-hydroxycoumarin with diazo compounds has been developed to provide rapid access to the C3- or O-alkylated 4-hydroxycoumarins with high efficiency. The regioselectivity can be determined by varying the electronic nature of the diazo substrates, especially those bearing a methylthio group. [ABSTRACT FROM AUTHOR]

Gonadotoxicity resulting from systemic and locoregional cancer treatments significantly threatens women's reproductive health, often culminating in premature ovarian insufficiency. These therapies, particularly alkylating agents and ionizing radiation, induce DNA damage and apoptosis in ovarian follicles, leading to infertility, amenorrhea, and estrogen deficiency, which exacerbate risks of osteoporosis and cardiovascular diseases. Existing fertility preservation methods do not prevent immediate ovarian damage, underscoring the need for innovative protective strategies. Menstrual blood-derived stem cells (MenSC) and their extracellular vesicles (EV) present promising regenerative potential due to their therapeutic cargo delivery and pathway modulation capabilities. Preclinical studies demonstrate that MenSC-derived EV ameliorate premature ovarian insufficiency by inhibiting granulosa cell apoptosis, promoting angiogenesis, and activating pivotal pathways such as SMAD3/AKT/MDM2/P53. However, comprehensive research is imperative to ensure the safety, efficacy, and long-term effects of MenSC-derived EV in clinical practice. In this review, we update the current knowledge and research regarding the use of MenSC-derived EV as a novel therapeutic weapon for ovarian regeneration in the context of gonadotoxicity induced by systemic anticancer treatment. [ABSTRACT FROM AUTHOR]

In clinics, chemotherapy is often combined with surgery and radiation to increase the chances of curing cancers. In the case of glioblastoma (GBM), patients are treated with a combination of radiotherapy and TMZ over several weeks. Despite its common use, the mechanism of action of the alkylating agent TMZ has not been well understood when it comes to its cytotoxic effects in tumor cells that are mostly non-dividing. The cellular response to alkylating DNA damage is operated by an intricate protein network involving multiple DNA repair pathways and numerous checkpoint proteins that are dependent on the type of DNA lesion, the cell type, and the cellular proliferation state. Among the various alkylating damages, researchers have placed a special on O6-methylguanine (O6-mG). Indeed, this lesion is efficiently removed via direct reversal by O6-methylguanine-DNA methyltransferase (MGMT). As the level of MGMT expression was found to be directly correlated with TMZ efficiency, O6-mG was identified as the critical lesion for TMZ mode of action. Initially, the mode of action of TMZ was proposed as follows: when left on the genome, O6-mG lesions form O6-mG: T mispairs during replication as T is preferentially mis-inserted across O6-mG. These O6-mG: T mispairs are recognized and tentatively repaired by a post-replicative mismatched DNA correction system (i.e., the MMR system). There are two models (futile cycle and direct signaling models) to account for the cytotoxic effects of the O6-mG lesions, both depending upon the functional MMR system in replicating cells. Alternatively, to explain the cytotoxic effects of alkylating agents in non-replicating cells, we have proposed a "repair accident model" whose molecular mechanism is dependent upon crosstalk between the MMR and the base excision repair (BER) systems. The accidental encounter between these two repair systems will cause the formation of cytotoxic DNA double-strand breaks (DSBs). In this review, we summarize these non-exclusive models to explain the cytotoxic effects of alkylating agents and discuss potential strategies to improve the clinical use of alkylating agents. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? SUMMARY ANSWER Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. WHAT IS KNOWN ALREADY Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. STUDY DESIGN, SIZE, DURATION This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. LIMITATIONS, REASONS FOR CAUTION The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2–5 years post-diagnosis. WIDER IMPLICATIONS OF THE FINDINGS The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. STUDY FUNDING/COMPETING INTEREST(S) The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K. D.K. W.H.W. D.H. M.C. A.U. and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular membranes, proteins, chromosomes and genetic material. It is thought that compounds like hesperidin with high antioxidant and anticancer potential can reduce development of cancer induced by chemical carcinogens via neutralizing their oxidative damages. We investigated protective effect of hesperidin against N-Ethyl-N-Nitrosourea (ENU)-induced neurotoxicity, congenital abnormalities and possible brain cancer after exposure of mice during pregnancy as model of glioma. The mice were divided to four groups; control (normal saline), ENU (40 mg/kg daily for three consecutive days from the 17th to the 19th of pregnancy), hesperidin (pretreated with 25 mg/kg for 30 consecutive days, before mating) + ENU and hesperidin alone. Developmental toxicity parameters (the number of pregnant mice, stillbirths, abortion, live and dead offspring), behavioral tests (novel object recognition, open field and elevated plus maze) were performed. Moreover, the activity of butrylcholinesterase and acetylcholinesterase enzymes, oxidative markers and histopathological abnormalities were detected in brain tissue. Our data showed that conversely, the pretreatment of hesperidin reduces various degrees of developmental toxicity, neurobehavioral dysfunction, neurotoxicity, oxidative stress and histopathological abnormalities induced by ENU as a neurotoxic and carcinogenic agent in the next generation. In conclusion, pre-mating exposure with hesperidin may open new avenues for prevention of primary brain cancer in next generation and could be valuable for enhancing the antioxidant defense and minimizing the developmental and neurotoxicity of DNA alkylating agents. [ABSTRACT FROM AUTHOR]

Herein, we report an efficient and sustainable manganese‐catalyzed α‐C−H bond alkylation methodology to synthesize branched sulfones via a hydrogen borrowing pathway. The air‐stable and phosphine‐free Mn‐catalyst, (NNN)Mn(II)Cl2 was synthesized by using an earth‐abundant, commercially available, and inexpensive precursor MnCl2.4H2O, and a stable NNN pincer i. e. [N‐((benzimidazole‐2‐yl)methyl)quinoline‐8‐amine] ligand system. Taking benzyl phenyl sulfones as substrates, and benzyl alcohol derivatives as alkylating agents, a range of branched sulfones were synthesized in 40–82 % isolated yields using (NNN)Mn(II)Cl2 complex as the catalyst under open‐air conditions. Control experiments and deuterium incorporation studies have also been conducted to investigate the possible reaction mechanism and to provide evidence for the hydrogen borrowing pathway. [ABSTRACT FROM AUTHOR]

Pulmonary injury is one of the key restricting factors for the therapy of malignancies with chemotherapy or following radiotherapy for chest cancers. The lung is a sensitive organ to some severely toxic antitumor drugs, consisting of bleomycin and alkylating agents. Furthermore, treatment with radiotherapy may drive acute and late adverse impacts on the lung. The major consequences of radiotherapy and chemotherapy in the lung are pneumonitis and fibrosis. Pneumonitis may arise some months to a few years behind cancer therapy. However, fibrosis is a long‐term effect that appears years after chemo/or radiotherapy. Several mechanisms such as oxidative stress and severe immune reactions are implicated in the progression of pulmonary fibrosis. Epithelial–mesenchymal transition (EMT) is offered as a pivotal mechanism for lung fibrosis behind chemotherapy and radiotherapy. It seems that pulmonary fibrosis is the main consequence of EMT after chemo/radiotherapy. Several biological processes, consisting of the liberation of pro‐inflammatory and pro‐fibrosis molecules, oxidative stress, upregulation of nuclear factor of κB and Akt, epigenetic changes, and some others, may participate in EMT and pulmonary fibrosis behind cancer therapy. In this review, we aim to discuss how chemotherapy or radiotherapy may promote EMT and lung fibrosis. Furthermore, we review potential targets and effective agents to suppress EMT and lung fibrosis after cancer therapy. [ABSTRACT FROM AUTHOR]

A series of twenty alkyl derivatives (2–21) of 4-amino benzoic acid (1, PABA) have been prepared using potassium carbonate and opportune alkylating agents under simple and mild reaction conditions. Compounds (16–21) are reported for the first time. Electron impact mass spectrometry (EIMS), Fourier transform infrared (FTIR) and Proton nuclear magnetic resonance (1H-NMR) spectroscopic techniques were adopted for the characterization of these analogues. In the present study, the cytotoxic screening of sixteen compounds (3, 5–11, 13 and 15–21) was also achieved against lung (NCI-H460) and oral squamous carcinoma (CAL-27) cell lines. Compound 20 has shown magnificent inhibitory properties against NCI-H460 cell line (IC50 15.59 and 20.04 µM, respectively) at a lower dose than that of the control (cisplatin; IC50 21.00 µM). One-way analysis of variance (ANOVA), t-test and Pearson correlation coefficient (PCC) have been performed to determine the reliability of current data through statistical package for the social sciences (SPSS). [ABSTRACT FROM AUTHOR]

Currently, a significant percentage of patients with DLBCL are refractory or relapse after a first line of immunochemotherapy. Second relapses after autologous stem cell transplantation or chimeric antigen receptor T-cell therapies present few treatment options and do not yield good results. New molecules have entered the immunotherapy arsenal. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal conjugated antibody, which consists of an anti-CD19 antibody and cytotoxic alkylating agent, SG3199. Several studies have proven its efficacy in the treatment of refractory cases of DLBCL with a good safety profile, with the main adverse effects being neutropenia, thrombopenia, and liver enzyme involvement. In this review, we explain the mechanism of action of this molecule, the clinical data that have led to its acceptance by the FDA, and the new therapeutic options that are proposed in association with this drug. [ABSTRACT FROM AUTHOR]

PURPOSE: Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS: Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS: Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A , TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION: CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Discussion of the benefits of moderate alcohol consumption is ongoing. Broadly, research focusing on ethanol consumption tends to report no benefits. However, studies that distinguish between different types of alcoholic beverages, particularly beers, often reveal positive effects.The present study evaluated the genotoxic and mutagenic effects of moderate chronic consumption of India Pale Ale (IPA) craft beer. Sixty‐four adult male Swiss mice were used and divided into control and treatment groups receiving water, IPA beer with 55.23 g of ethanol per liter of beer, aqueous solution with 55.23 g of ethanol per liter, and hop infusion ad libitum for 30 days. After this period, the animals were genetically evaluated with a comet assay. For the ex vivo comet assay, blood was collected and exposed to hydrogen peroxide (H2O2). For the in vivo assay, the alkylating agent cyclophosphamide (CP) was administered to the groups after blood collection and sacrificed after 24 h. Brain, liver, and heart tissues were analyzed. Bone marrow was collected and submitted to the micronucleus test.The groups treated with IPA beer, ethanol, and hops did not show genotoxic and mutagenic action in the blood, brain, heart, or liver. The antigenotoxic action of IPA beer and hops was observed in both in vivo and ex vivo models, showing a similar reduction in DNA damage caused by CP. There was no significant difference between the groups with regard to the formation of micronuclei by CP.Moderate chronic consumption of IPA beer and hops infusion showed antigenotoxic effects in mice but no antimutagenic action. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints—including oxidative stress markers and transcriptional regulation—in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1–750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM. [ABSTRACT FROM AUTHOR]

Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2–99.3%) compared to 67.1% (95% CI: 55.2–81.6%) for all stage IC and 60.6% (95% CI: 40.3–91.0%) for stage II-IV (p <.001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99–305.85). Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection. • Most (92%, 175/191) ovarian Sertoli-Leydig cell tumors (SLCTs) present as FIGO stage I disease with a favorable prognosis. • FIGO stage I tumors with mesenchymal heterologous elements are at higher risk for recurrence when not receiving chemotherapy. • Somatic (tumor) DICER1 RNase IIIb hotspot variants were found in 97% of intermediately and poorly differentiated SLCTs. • More than half (58%, 91/156) of individuals were found to have a germline DICER1 pathogenic/likely pathogenic variant. • DICER1 surveillance recommendations facilitated detection of asymptomatic ovarian SLCT with nearly all resected as stage IA. [ABSTRACT FROM AUTHOR]

The most important application of anticancer drugs in various forms (alkylating agents, hormones agents, and antimetabolites) is the treatment of malignant diseases. Topological indices are widely used in the field of chemical and medical sciences, especially in studying the chemical, biological, clinical, and therapeutic aspects of drugs. In this article, the temperature indices in anticancer drugs molecular graphs such as Carmustine, Convolutamine F, Raloxifene, Tambjamine K, and Pterocellin B were calculated and then analyzed based on physical and chemical properties. The analysis was performed by identifying the best regression models based on temperature indices for six physical and chemical features of anticancer drugs. The results indicated that temperature indices were essential topological indices that predict the properties of anticancer drugs, such as boiling point, flash point, enthalpy, molar refractivity, molar volume, and polarizability. It was also observed that the r value of the regression model was more than 0.6, and the p value was less than 0.05. [ABSTRACT FROM AUTHOR]

Background and Aims: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum‐containing therapy. Methods: Multicentre real‐world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three‐weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). Results: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second‐ (83%, 38/46) or subsequent‐ (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high‐grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six‐month OS was 44% (95% confidence interval (CI): 29.0–57.1). Twelve‐month OS was 15% (95% CI: 6.5–26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8–2.9) and OS was 4.5 months (95% CI: 3.5–7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0–17.2). Individuals with a longer chemotherapy‐free interval prior to lurbinectedin had longer PFS and OS. Conclusion: This real‐world national experience of lurbinectedin post‐platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials. [ABSTRACT FROM AUTHOR]

Rising cure rates in pediatric cancer patients warrants an increased attention toward the long‐term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post‐survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure. [ABSTRACT FROM AUTHOR]

Abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential. Results: Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity. Conclusion: Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings. Plain Language Summary: People being treated for cancer will often receive more than one drug at a time, and the concept of combining cancer drugs is frequently investigated as a potential opportunity to improve outcomes for patients. We reviewed the published literature for clinical trials and work undertaken in laboratories to explore whether combining targeted agents that stop cancer cells from multiplying (known as checkpoint inhibitors) with traditional chemotherapy that kills cancer cells could be a useful approach. We looked at evidence in publications where checkpoint inhibitors were used at the same time as chemotherapy, or given immediately before or after chemotherapy. The most important evidence came from clinical trials where outcomes for patients receiving combinations of treatment were directly compared with those from patients receiving a single treatment. These studies showed superior outcomes for patients who were treated with a combination of cancer drugs compared with patients receiving monotherapy. We also found evidence that adding another class of cancer drug, called histone deacetylase inhibitors, might sensitize tumors to checkpoint inhibitors. These findings provide a rationale for examining alkylating agents and/or histone deacetylase inhibitors combined with checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies. [ABSTRACT FROM AUTHOR]

AbstractThe number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusion Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted.In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom‐PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom‐PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety.Patients were heavily pretreated with a median number of four prior therapies (range: 1–10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double‐class refractory, 40% were triple‐class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression‐free survival was 8.9 months (0.92–not reached [NR]) and median overall survival was 11.8 months (3–40.6). Pom‐PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed.Pomalidomide‐PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Hydrogen borrowing is an attractive and sustainable strategy for carbon–carbon bond formation that enables alcohols to be used as alkylating reagents in place of alkyl halides. However, despite intensive efforts, limited functional group tolerance is observed in this methodology, which we hypothesize is due to the high temperatures and harsh basic conditions often employed. Here we demonstrate that room temperature and functional group tolerant hydrogen borrowing can be achieved with a simple iridium catalyst in the presence of substoichiometric base without an excess of reagents. Achieving high yields necessitates the application of anaerobic conditions to counteract the oxygen sensitivity of the catalytic iridium hydride intermediate, which otherwise leads to catalyst degradation. Substrates containing heteroatoms capable of complexing the catalyst exhibit limited room temperature reactivity, but the application of moderately higher temperatures enables extension to a broad range of medicinally relevant nitrogen rich heterocycles. These newly developed conditions allow alcohols possessing functional groups that were previously incompatible with hydrogen borrowing reactions to be employed. Hydrogen borrowing is a method that allows common alcohols to serve as alkylating agents but is often associated with high temperatures and relatively harsh reaction conditions leading to limited scope. Here, the authors present a hydrogen borrowing method that proceeds at lower temperatures under iridium catalysis, enabling broad substrate scope. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) is one of many potential long-term consequences of childhood cancer treatment in females. Causes of POI in this patient population can include chemotherapy, especially alkylating agents, and radiation therapy. Rarely, ovarian tumors lead to ovarian dysfunction. POI can manifest as delayed pubertal development, irregular menses or amenorrhea, and infertility. This diagnosis often negatively impacts emotional health due to the implications of impaired ovarian function after already enduring treatment for a primary malignancy. The emerging adult may be challenged by the impact on energy level, quality of life, and fertility potential. POI can also lead to low bone density and compromised skeletal strength. This review discusses the health consequences of POI in childhood cancer survivors (CCS). We also explore the role of fertility preservation for CCS, including ovarian tissue cryopreservation and other available options. Lastly, knowledge gaps are identified that will drive a future research agenda. [ABSTRACT FROM AUTHOR]

Chemotherapy serves as a crucial treatment modality for various types of cancer and has made significant contributions to enhancing patient outcomes in recent decades. This abstract presents a comprehensive overview of chemotherapy, encompassing its progress, obstacles, and prospects for the future. The primary aim of chemotherapy is to selectively target and eradicate cancer cells throughout the body using cytotoxic drugs. Chemotherapeutic agents can be categorized into diverse groups, including alkylating agents, antimetabolites, anthracyclines, taxanes, and targeted therapies. Significant advancements have emerged in the field of chemotherapy, leading to the development of more efficient and personalized treatment strategies. The introduction of targeted therapies, such as monoclonal antibodies and small molecule inhibitors, has revolutionized cancer treatment by precisely attacking cancer cells while minimizing harm to healthy tissues. Additionally, the integration of immunotherapeutic agents, like immune checkpoint inhibitors, has displayed remarkable success in augmenting the immune system's ability to identify and eliminate cancer cells. Nevertheless, chemotherapy encounters several challenges. One of the primary limitations lies in its toxicity to normal cells, resulting in notable side effects. Efforts are underway to enhance the selectivity and specificity of chemotherapy drugs, aiming to reduce adverse effects on healthy tissues. Furthermore, drug resistance remains a critical concern in chemotherapy, as cancer cells can develop mechanisms to evade the cytotoxic impact of drugs. Despite these challenges, chemotherapy remains a crucial component of cancer treatment, and recent advancements have paved the way for more effective and personalized therapeutic approaches. Overcoming the obstacles associated with toxicity and drug resistance remains a priority, with future research focused on optimizing treatment strategies to improve patient outcomes. By harnessing the potential of emerging technologies and innovative approaches, chemotherapy holds promise for further advancements in the battle against cancer. Keywords: chemotherapy, cancer treatment, advancements, challenges, drug resistance, targeted therapies, immunotherapy, toxicity, drug delivery, personalized medicine. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is a common treatment for cancer, but it is associated with adverse drug reactions like oral mucositis. This condition destroys basal cells in the oral mucosal layer, causing inflammation and ulceration. This can impact the patient's physical, emotional, and psychological well‐being, affecting treatment outcomes and quality of life. This study aims to determine the prevalence, severity, and risk factors of chemotherapy‐induced oral mucositis among adult cancer patients. Methods: The study was a cross‐sectional study conducted among adult cancer patients receiving chemotherapy at the cancer unit of Mbarara Regional Referral Hospital in southwestern Uganda. Data was collected through patient interviews, oral examinations, and patient chart reviews. Results: Out of 268 patients, 115 (42.9%) experienced oral mucositis. Grade 2 oral mucositis was the most common (44.3%) followed by grade 1 (35.7%) and grade 3 (20.0%). Independent risk factors of chemotherapy‐induced oral mucositis were female gender (Adjusted Odds Ratio (AOR) = 2.19, 95% confidence interval [CI]: 1.27–3.78; p‐value = 0.005), poor oral hygiene (AOR = 3.70, 95% CI: 1.51–9.10; p‐value = 0.04), and receiving chemotherapy containing an alkylating agent (AOR = 3.17, 95% CI: 1.63–6.19; p‐value < 0.001). Conclusion: The study found that two out of five chemotherapy patients developed oral mucositis, with nearly half being grade 2. The risk factors identified in our study were comparable to those reported in previous studies. Therefore, identification and assessment of cancer patients at high risk for chemotherapy‐induced oral mucositis should be routinely done for proper and timely management. [ABSTRACT FROM AUTHOR]

The treatments for noninfectious uveitis (NIU) include topical steroids, local steroid injections, and systemic steroids or immunomodulatory agents. Over the last 20 years, there have been advancements in both conventional and alternative complementary therapies for uveitis. In this review, we will give an overview of the current conventional and alternative systemic treatments for NIU and discuss the possible risks and benefits to each. Conventional systemic therapies for NIU include corticosteroids, antimetabolites, biologics, calcineurin inhibitors, alkylating agents, janus kinase (JAK) inhibitors, and interferons. Alternative therapies include Ayurvedic medicine, berberine, glycosides, Traditional Chinese medicines, dietary changes, and vitamin supplementation. There are an expanding number of systemic treatments for NIU. Over the last 15 years, biologic agents in particular have expanded and improved treatment options for patients with NIU. [ABSTRACT FROM AUTHOR]

Herein we report a sustainable approach for the alkylation of ketones, 9H‐fluorene, oxindole, and indole using alcohols as the alkylating agent catalyzed by a well‐defined air‐stable zinc catalyst (1 a) of a tridentate redox non‐innocent arylazo ligand, 2‐((4‐chlorophenyl)diazenyl)‐1,10‐phenanthroline (La). 2–3 mol % of 1 a efficiently produces substituted α‐alkylated ketones, 9‐alkylated fluorenes, C3‐alkylated oxindoles, and C3‐alkylated indoles in moderate to good isolated yields. In aerial condition, the formation of bis(indolyl)methane (BIMs) derivatives were observed when indoles were subjected to alkylation by primary alcohols. A few drug molecules containing BIMs were prepared in good isolated yields. The catalyst 1 a exhibited good chemoselectivity during the functionalization of fluorene and indole with oleyl alcohol and β‐citronellol. A few control experiments, including deuterium labeling experiments, performed to unveil the reaction mechanism indicate that the one‐electron reduced azo‐anion radical species [1 a]‐formed in situ, acts as the active catalyst. All the redox events occur at the redox‐active aryl‐azo ligand, which acts as the reservoir of hydrogen and electrons throughout the catalytic cycle, keeping the Zn(II)‐center as a template. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is one of the leading causes of death worldwide. Among several therapeutic options available for patients, chemotherapy remains the most often used treatment strategy. Anticancer drugs known today are either substances isolated from plants and their derivatives or completely synthetic compounds. Some of them were discovered by accident, others as a result of long-term research. In this review, we present a brief history of the development of the main groups of anticancer drugs, focusing especially on their mode of action. This article also addresses the major side effects and limitations of currently available anticancer drugs and future perspectives in this area. Cancer is considered one of the leading causes of death in the 21st century. The intensive search for new anticancer drugs has been actively pursued by chemists and pharmacologists for decades, focusing either on the isolation of compounds with cytotoxic properties from plants or on screening thousands of synthetic molecules. Compounds that could potentially become candidates for new anticancer drugs must have the ability to inhibit proliferation and/or induce apoptosis in cancer cells without causing too much damage to normal cells. Some anticancer compounds were discovered by accident, others as a result of long-term research. In this review, we have presented a brief history of the development of the most important groups of anticancer drugs, pointing to the fact that they all have many side effects. [ABSTRACT FROM AUTHOR]

This review provides a comprehensive overview of mono‐alkylation methodologies targeting crucial nitrogen moieties – amines, amides, and sulfonamides – found in organic building blocks and pharmaceuticals. Emphasizing the intersection of chemical precision with drug discovery, the central challenge addressed is achieving one‐pot mono‐selective short‐chain N‐alkylations (methylations, ethylations, and n‐propylations), preventing undesired overalkylation. Additionally, sustainable, safe, and benign alternatives to traditional alkylating agents, including alcohols, carbon dioxide, carboxylic acids, nitriles, alkyl phosphates, quaternary ammonium salts, and alkyl carbonates, are explored. This review, categorized by the nature of the alkylating agent, aids researchers in selecting suitable methods for mono‐selective N‐alkylation. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy represents the most prevalent cause of glomerulonephritis worldwide and may lead to renal failure in a relevant number of cases in both paediatric and adult subjects. Although their pathogenesis is still largely unclear, evidence of immune abnormalities provides the background for the use of immunosuppressive drugs, such as corticosteroids, calcineurin inhibitors, and antiproliferative and alkylating agents. Unfortunately, these treatments fail to achieve a sustained remission in a significant percentage of affected patients and are burdened by significant toxicities. Recent developments of new biologics, including anti-BAFF/APRIL inhibitors and molecules targeting complement components, offered the opportunity to selectively target immune cell subsets or activation pathways, leading to more effective and safer hypothesis-driven treatments. However, studies testing new biologic agents in IgAN should also consider paediatric populations to address the unique needs of children and close the therapeutic gap between adult and paediatric care. [ABSTRACT FROM AUTHOR]

Objective: Aplastic anemia is a rare condition characterized by bone marrow failure due to various etiologies including Fanconi anemia. Mitomycin C is an alkylating agent inducing chromosome breaks in. aplastic anemia. The clastogenic effect of mitomycin C is most marked in Fanconi anemia. This study aims to demonstrate mitomycin C induced chromosomal breaks in patients with aplastic anemia and distinguish Fanconi anemia patients among them. Material and Method: Clastogenicity test was applied to 147 patients with aplastic anemia, four siblings and 30 healthy controls. Both simultaneous and mitomycin C (MMC) treated lymphocyte cultures were prepared. Chromosome breaks per metaphase were calculated and cytogenetic abnormalities were analyzed. Results: The mean number of chromosome breaks per metaphase increased from 0.02 to 0.37 after MMC treatment in patients with aplastic anemia. This number changed only from 0.01 to 0.16 in the healthy controls. In 25 patients (16.6%), the number of chromosome breaks per metaphase was > 1 in MMC treated cultures, and MMC treatment induced a significant increase compared to spontaneous culture (2.88 vs 0.35), which assured the diagnosis of Fanconi anemia. We observed various multiple chromosomal aberrations in all of them and accompanying phenotypic features in 20. Conclusion: Mitomycin C induced chromosomal breaks and cytogenetic abnormalities enable the diagnostic differentiation between aplastic anemia and Fanconi anemia. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumours (NETs) are predominantly from digestive (75%) or thoracic (25%) origin. Chemotherapy remains the reference treatment for aggressive pancreatic NETs or grade 3 NETs and is an option for certain selected cases of NETs from thoracic or digestive tract origin. Alkylating agents (ALKY) are the gold standard for pancreatic NETs, but oxaliplatin-based therapy appears to be of interest, particularly in cases where the enzyme O(6)-methylguanine-methyltransferase (MGMT), which repairs ALKY-induced DNA damage, is deficient. The first studies focused on glioblastoma, where MGMT methylation by pyrosequencing is now used to predict the efficacy of temozolomide. There are still a number of questions concerning its use in NETs. The first is the technique and the threshold to be used to obtain MGMT status (deficient (d) or proficient (p)), whether assessed by immunohistochemistry (protein expression) or by pyrosequencing, for which there are currently no recommendations. The second concerns the frequency of dMGMT status, which varies according to the primary site: the majority of dMGMTs are found in pancreatic NETs, but very few in gastrointestinal or thoracic NETs, which could partly explain their lower chemosensitivity to ALKYs. In this article, we present the results of 3 recently reported prospective studies which shed light on the value of using MGMT status to guide the management of NETs and the choice of chemotherapy, with a preference for an ALKY (such as temozolomide/dacarbazine or streptozotocin) in dMGMT NETs and oxaliplatin in pMGMT NETs. [ABSTRACT FROM AUTHOR]

Persulfides (RSSH/RSS−) participate in sulfur metabolism and are proposed to transduce hydrogen sulfide (H2S) signaling. Their biochemical properties are poorly understood. Herein, we studied the acidity and nucleophilicity of several low molecular weight persulfides using the alkylating agent, monobromobimane. The different persulfides presented similar pKa values (4.6–6.3) and pH-independent rate constants (3.2–9.0 × 10³ M−1 s−1), indicating that the substituents in persulfides affect properties to a lesser extent than in thiols because of the larger distance to the outer sulfur. The persulfides had higher reactivity with monobromobimane than analogous thiols and putative thiols with the same pKa, providing evidence for the alpha effect (enhanced nucleophilicity by the presence of a contiguous atom with high electron density). Additionally, we investigated two enzymes from the human mitochondrial H2S oxidation pathway that form catalytic persulfide intermediates, sulfide quinone oxidoreductase and thiosulfate sulfurtransferase (TST, rhodanese). The pH dependence of the activities of both enzymes was measured using sulfite and/or cyanide as sulfur acceptors. The TST half-reactions were also studied by stopped-flow fluorescence spectroscopy. Both persulfidated enzymes relied on protonated groups for reaction with the acceptors. Persulfidated sulfide quinone oxidoreductase appeared to have a pKa of 7.8 ± 0.2. Persulfidated TST presented a pKa of 9.38 ± 0.04, probably due to a critical active site residue rather than the persulfide itself. The TST thiol reacted in the anionic state with thiosulfate, with an apparent pKa of 6.5 ± 0.1. Overall, our study contributes to a fundamental understanding of persulfide properties and their modulation by protein environments. [ABSTRACT FROM AUTHOR]

Herein we report, the synthesis of single‐atom iron on nitrogen‐doped carbon as a catalyst for the direct formation of Csp3−S bond via borrowing hydrogen strategy using alcohols as the alkylating agent. The catalyst was synthesized by encapsulating ferrocene within the ZIF‐8 framework, followed by pyrolysis and characterized precisely by FE‐SEM, HR‐TEM, XPS, Raman, XRD and EXAFS. The catalyst is robust, displayed an excellent reactivity in borrowing hydrogen reaction and could be recycled five times without any appreciable loss in activity. [ABSTRACT FROM AUTHOR]

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines. [ABSTRACT FROM AUTHOR]

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapyrelated myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients. [ABSTRACT FROM AUTHOR]

Background: Temozolomide (TMZ) is an effective oral alkylating agent used in treating glioblastoma multiforme (GBM) and high-grade gliomas. It works by introducing methyl groups into DNA, inhibiting cell division. A case of blepharoconjunctivitis linked to the administration of TMZ is detailed in this report. Case presentation: We present a case of a 58-year-old African-American man diagnosed with GBM. Following adjuvant TMZ treatment, he developed blepharoconjunctivitis, characterized by eyelid and conjunctival inflammation. Symptoms included eyelid swelling, crusting, and conjunctival discharge, which were promptly resolved with topical steroid cream and eye drops. Conclusions: Reports specifically linking TMZ to blepharoconjunctivitis are limited. The exact mechanism remains unclear but may involve inflammation extending from blepharitis to the conjunctiva. Healthcare providers must recognize and manage ophthalmic complications promptly. This case report highlights blepharoconjunctivitis associated with TMZ use in a GBM patient. While TMZ is an effective treatment, ophthalmic side effects can occur. [ABSTRACT FROM AUTHOR]

In this work, a conceptually novel approach to diversely substituted 2‐(alkylsulfanyl)quinolines is described. The approach includes the assembly of the target molecules from allenic or acetylenic carbanions, aromatic isothiocyanates, and alkylating agents. The process proceeds in a single synthetic operation via the formation and 6π‐electrocyclization of N‐aryl‐1‐aza‐1,3,4‐trienes, R2R3C=C=C(R1)C(SAlk)=NAr, with the participation of the carbon‐carbon double bond of the phenyl group and the azadiene fragment of the azatrienic system. [ABSTRACT FROM AUTHOR]

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme's dysregulated activity has been implicated in a variety of pathologies (e.g., celiac disease, fibrosis, cancer), leading to the development of a wide range of inhibitors. Our group has primarily focused on the development of peptidomimetic targeted covalent inhibitors, the nature and size of which were thought to be important features to abolish TG2's conformational dynamism and ultimately inhibit both its activities. However, we recently demonstrated that the enzyme was unable to bind guanosine triphosphate (GTP) when catalytically inactivated by small molecule inhibitors. In this study, we designed a library of models targeting covalent inhibitors of progressively smaller sizes (15 to 4 atoms in length). We evaluated their ability to inactivate TG2 by measuring their respective kinetic parameters kinact and KI. Their impact on the enzyme's ability to bind GTP was then evaluated and subsequently correlated to the conformational state of the enzyme, as determined via native PAGE and capillary electrophoresis. All irreversible inhibitors evaluated herein locked TG2 in its open conformation and precluded GTP binding. Therefore, we conclude that steric bulk and structural complexity are not necessary factors to consider when designing TG2 inhibitors to abolish G-protein activity. [ABSTRACT FROM AUTHOR]

New nicotinamide derivatives have been synthesized by reactions of enamino ketones, aryl(hetaryl)-methylidenecyanothioacetamides, alkylating agents, formamide, and cycloalkanones. The structure of some of the synthesized compounds has been determined by X-ray analysis. [ABSTRACT FROM AUTHOR]

Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%–37% of patients. The impact of transplant‐ and patient‐specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir‐exposed, CMV‐free patients, treated with the same cyclophosphamide‐based graft‐versus‐host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC‐score including male gender, TBF conditioning, and HLA‐mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient‐related factors, chemotherapy‐related toxicities—especially due to alkylating agents—and immunological elements. [ABSTRACT FROM AUTHOR]

Purpose The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC. Materials and Methods Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment. Results In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively. Conclusion High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC. [ABSTRACT FROM AUTHOR]