Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

3-Bromopyruvate(3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase(LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells(oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione(GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level(4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions(1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.

Cellular preconditioning and mesenchymal stem cell ferroptosis

In this editorial,we comment on the article published in the recent issue of the World Journal of Stem Cells.They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionineγ-lyase/hydrogen sulfide(H_(2)S)pathway as a novel approach to treat vascular disorders,particularly pulmonary hypertension.Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh,unfavorable microenvironment of the injured tissue.They also secrete various paracrine factors against apoptosis,necrosis,and ferroptosis to enhance cell survival.Ferroptosis,a regulated form of cell death characterized by iron accumulation and oxidative stress,has been implicated in various pathologies encompassing dege-nerative disorders to cancer.The lipid peroxidation cascade initiates and sustains ferroptosis,generating many reactive oxygen species that attack and damage multiple cellular structures.Understanding these intertwined mechanisms provi-des significant insights into developing therapeutic modalities for ferroptosis-related diseases.This editorial primarily discusses stem cell preconditioning in modulating ferroptosis,focusing on the cystathionase gamma/H_(2)S ferroptosis pathway.Ferroptosis presents a significant challenge in mesenchymal stem cell(MSC)-based therapies;hence,the emerging role of H_(2)S/cystathionase gamma/H_(2) S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention.Further research into understanding the precise mechanisms of H_(2)S-mediated cytoprotection against ferroptosis is warranted to enhance the thera-peutic potential of MSCs in clinical settings,particularly vascular disorders.

Type 2 diabetes and thyroid cancer:Synergized risk with rising air pollution

Diabetes is a complex condition,and the causes are still not fully understood.However,a growing body of evidence suggests that exposure to air pollution could be linked to an increased risk of diabetes.Specifically,exposure to certain pollutants,such as particulate Matter and Ozone,has been associated with higher rates of diabetes.At the same time,air pollution has also been linked to an increased risk of thyroid cancer.While there is less evidence linking air pollution to thyroid cancer than to diabetes,it is clear that air pollution could have severe implications for thyroid health.Air pollution could increase the risk of diabetes and thyroid cancer through several mechanisms.For example,air pollution could increase inflammation in the body,which is linked to an increased risk of diabetes and thyroid cancer.Air pollution could also increase oxidative stress,which is linked to an increased risk of diabetes and thyroid cancer.Additionally,air pollution could increase the risk of diabetes and thyroid cancer by affecting the endocrine system.This review explores the link between diabetes and air pollution on thyroid cancer.We will discuss the evidence for an association between air pollution exposure and diabetes and thyroid cancer,as well as the potential implications of air pollution for thyroid health.Given the connections between diabetes,air pollution,and thyroid cancer,it is essential to take preventive measures to reduce the risk of developing the condition.

Circulating microRNA 9-3p and serum endocan as potential biomarkers for hepatitis C virus-related hepatocellular carcinoma

BACKGROUND The high mortality rate of hepatocellular carcinoma(HCC)in Egypt is due mainly to the increasing prevalence of hepatitis C virus infection(HCV)and late diagnosis of the carcinoma.MicroRNAs(miRNA),which regulate tumor proliferation and metastasis in HCC,may serve as a useful diagnostic approach for the early detection of HCC,thus decreasing its mortality.Meanwhile,endocan is a protein with angiogenic and inflammatory properties that are associated with tumor progression and poor outcomes.AIM To analyze the levels of miRNA 9-3p and endocan in HCV-infected HCC patients and correlate them with clinicopathological parameters.METHODS We compared levels of endocan and circulating miRNA 9-3p from 35 HCVrelated HCC patients to 33 patients with HCV-induced chronic liver disease and 32 age and gender matched healthy controls recruited from inpatient and outpatient clinics of the National Liver Institute,Menoufia University,Egypt in the period from January to March 2021 in a case-control study.Serum samples from all groups were analyzed for HCV.Endocan was measured by enzymelinked immunosorbent assays,and the expression levels of circulating miRNA 9-3p were measured by real-time quantitative reverse transcriptase PCR.RESULTS The levels of circulating miRNA 9-3p were significantly lower in the HCC group compared to the chronic liver disease(P<0.001)and control(P<0.001)groups,while levels in the chronic liver disease were significantly lower than those in the control group(P<0.001).The levels of serum endocan were significantly higher in the HCC group compared to the chronic liver disease(P<0.001)and control(P<0.001)groups.Moreover miRNA 9-3p and endocan performed better thanα-fetoprotein in discriminating HCC patients from cirrhosis and healthy patients.The levels of miRNA 9-3p were significantly inversely correlated to vascular invasion(P=0.002),stage of advancement of Barcelona Clinical Liver Cancer(P<0.001)and the metastatic site(P<0.001)of the HCC group.CONCLUSION Circulating miRNA 9-3p and endocan can be used as novel biomarkers for the early diagnosis of HCV-related HCC.

Genomic Epidemiology of Imported Cases of COVID-19 in Guangdong Province,China,October 2020–May 2021

Objective The pandemic of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2) has been engendering enormous hazards to the world. We obtained the complete genome sequences of SARSCo V-2 from imported cases admitted to the Guangzhou Eighth People’s Hospital, which was appointed by the Guangdong provincial government to treat coronavirus disease 2019(COVID-19). The SARS-Co V-2 diversity was analyzed, and the mutation characteristics, time, and regional trend of variant emergence were evaluated.Methods In total, 177 throat swab samples were obtained from COVID-19 patients(from October2020 to May 2021). High-throughput sequencing technology was used to detect the viral sequences of patients infected with SARS-Co V-2. Phylogenetic and molecular evolutionary analyses were used to evaluate the mutation characteristics and the time and regional trends of variants.Results We observed that the imported cases mainly occurred after January 2021, peaking in May2021, with the highest proportion observed from cases originating from the United States. The main lineages were found in Europe, Africa, and North America, and B.1.1.7 and B.1.351 were the two major sublineages. Sublineage B.1.618 was the Asian lineage(Indian) found in this study, and B.1.1.228 was not included in the lineage list of the Pangolin web. A reasonably high homology was observed among all samples. The total frequency of mutations showed that the open reading frame 1 a(ORF1 a) protein had the highest mutation density at the nucleotide level, and the D614 G mutation in the spike protein was the commonest at the amino acid level. Most importantly, we identified some amino acid mutations in positions S, ORF7 b, and ORF9 b, and they have neither been reported on the Global Initiative of Sharing All Influenza Data nor published in Pub Med among all missense mutations.Conclusion These results suggested the diversity of lineages and sublineages and the high homology at the amino acid level among imported cases infected with SARS-Co V-2 in Guangdong Province, China.

From identification of fluorescent flavoproteins to mitochondrial redox indicators in intact tissues

Development of the use of favin and nicotinamide-adenine nucleotide fluorescence in monitoringthe redox state of the free mitochondrial NADH/NAD+couple in cels,tissues and organs isreviewed.A break-through was the identification of dihydrolipoamide dehydrogenase(FpL)asthe major NAD-linked fluorescent fla voprotein of mitochondria.This mitochondrial matrix fla-voprotein is in equilibriwn with the fre NADH/NAD+pool and its mid-potential is suficientlynear to that of NADH/NAD+so that its percentage reduction follows that of the latter.Pos.sibilities of monitoring mitochondial and cytosolic NADH depend on the population density ofmitochondria and thus are tissue-dependent.Upon a shift toward reduction,fluorescenceintensitis of NADH and flavins swing to reciprocal directions,so that the NADH/favin fluo-rescence ratio can be used to increase the sensitivity of redox monitoring.This method is attainingwidening use in studies on metabolic regulation under normal and pathological conditions.

PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma

AIM To evaluate PIK3 CA gene mutational status in Northwest Chinese esophageal squamous cell carcinoma(ESCC) patients, and examine the associations of PIK3 CA gene mutations with clinicopathological characteristics and clinical outcome.METHODS A total of 210 patients with ESCC who underwent curative resection were enrolled in this study. Pyrosequencing was applied to investigate mutations in exons 9 and 20 of PIK3 CA gene in 210 Northwest Chinese ESCCs. The associations of PIK3 CA gene mutations with clinicopathological characteristics and clinical outcome were examined.RESULTS PIK3 CA gene mutations in exon 9 were detected in 48 cases(22.9%) of a non-biased database of 210 curatively resected Northwest Chinese ESCCs. PIK3 CA gene mutations were not associated with sex, tobacco use, alcohol use, tumor location, stage, or local recurrence. When compared with wild-type PIK3 CA gene cases, patients with PIK3 CA gene mutations in exons 9 experienced significantly better disease-free survival and overall survival rates.CONCLUSION The results of this study suggest that PIK3 CA gene mutations could act as a prognostic biomarker in Northwest Chinese ESCC patients.

Identification and validation of predictive factors for progression to severe COVID-19 pneumonia by proteomics

Dear Editor,Recent study showed that around 80%of coronavirus disease-19(COVID-19)patients are moderate cases who will recover with or without conventional treatment,while the remaining 20%developed severe disease requiring intensive care.1 Early and accurate screening of new COVID-19 patients to identify those who will develop severe disease will facilitate decision-making on appropriate treatment regimens and reasonable allocation of limited healthcare resources.Therefore,novel predictive factors for disease progress from moderate to severe are urgently needed.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17

Pulmonary hypertension(PH)is an extremely malignant pulmonary vascular disease of unknown etiology.ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine,thereby affecting RNA expression.However,the role of ADAR1 in PH development remains unclear.In the present study,we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling.Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells(PASMCs).Conversely,inhibition of ADAR1 produced opposite effects.High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH.CircCDK17 level was significantly lowered in the serum of PH patients.The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17.ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from mlA modification.We demonstrate for the first time that ADAR1 contributes to the PH development,at least partially,through m1A modification of circCDK17 and the subsequent PASMCs proliferation.Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Multisystem inflammatory syndrome in pediatric COVID-19 patients:a meta-analysis

Background We aimed to systematically review the clinical and laboratory features of patients with the multisystem inflam-matory syndrome in pediatrics diagnosed during the COVID-19 pandemic.Data sources A literature search in Web of Science,PubMed,Scopus,and Science Direct was made up to June 29,2020.Results Analysis of 15 articles(318 COVID-19 patients)revealed that although many patients presented with the typical multisystem inflammatory syndrome in pediatrics,Kawasaki-like features as fever(82.4%),polymorphous maculopapular exanthema(63.7%),oral mucosal changes(58.1%),conjunctival injections(56.0%),edematous extremities(40.7%),and cervical lymphadenopathy(28.5%),atypical gastrointestinal(79.4%)and neurocognitive symptoms(31.8%)were also com-mon.They had elevated serum lactic acid dehydrogenase,D-dimer,C-reactive protein,procalcitonin,interleukin-6,troponin I levels,and lymphopenia.Nearly 77.0%developed hypotension,and 68.1%went into shock,while 41.1%had acute kidney injury.Intensive care was needed in 73.7%of cases;13.2%were intubated,and 37.9%required mechanical ventilation.Intravenous immunoglobulins and steroids were given in 87.7%and 56.9%of the patients,respectively,and anticoagulants were utilized in 67.0%.Pediatric patients were discharged after a hospital stay of 6.77 days on average(95%CI 4.93-8.6).Conclusions Recognizing the typical and atypical presentation of the multisystem inflammatory syndrome in pediatric COVID-19 patients has important implications in identifying children at risk.Monitoring cardiac and renal decompensation and early interventions in patients with multisystem inflammatory syndrome is critical to prevent further morbidity.

High platelet distribution width can independently predict testicular survival in testicular torsion among patients with steady-state sickle cell anemia

Objective This study aimed to evaluate the predictive value of platelet volume indices(PVI),such as mean platelet volume(MPV),platelet distribution width(PDW),and plateletcrit(PCT),as prognostic indicators of testicular viability in torsion patients with steady-state sickle cell anemia(SCA)who underwent surgical exploration.Methods Forty-eight patients with SCA with testicular torsion and 46 male control subjects were enrolled in the study.All patients underwent scrotal color Doppler ultrasonography before surgery,and PVI(MPV,PDW,and PCT)values were measured in all participants.Symptom duration and testicular volume were also recorded.Results The testicular salvage rate in patients with SCA was 73%after surgery.Analyses showed that MPV,PDW,and PCT values were significantly higher in torsed SCA as compared with controls(p<0.05).Orchiectomy in patients with SCA showed significantly higher MPV,PDW,and PCT values than the orchiopexy group(p<0.05).The MPV values of orchiectomy patients showed a higher significant cut-off of≥11.5 fL,which is higher than in torsed patients without SCA,as an indicator of testis survival.PDW also demonstrated a higher significant cut-off of≥12.7 fL for detorsion outcomes in patients with SCA.Symptom duration of less than 7 hours was also significantly correlated with orchiopexy(p≤0.001).Univariate analysis showed that higher MPV,increased PDW,and symptom duration were indicative of the outcome of testicular detorsion in SCA.Multivariable analysis showed that increased PDW and symptom duration are prognostic parameters for testicular viability in SCA.Conclusion Increased PDW and symptom duration can be used as parameters for predicting testicular detorsion outcomes in patients with steady-state SCA.

Metabolon:a novel cellular structure that regulates specific metabolic pathways

Tumor cells exhibit several metabolic abnormalities,such as uptake disorders of glucose and amino acids,increased nutrient consumption rates,use of glycolysis/tricarboxylic acid(TCA)cycle intermediates for biosynthesis and NADPH production,and increased demand for nitrogen sources[1].As an increasing understanding of cancer cell metabolism has been gained in recent years,the metabolic changes and molecular mechanisms associated with tumors in different tumor stages have been gradually revealed.