Combined Germline and Mosaic SDHA Mutation Is Associated With a Multicancer Syndrome Including Neuroblastoma, Renal Cancer, and Multifocal GI Tumor.

Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.

Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging.

Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.

Markov models for clinical decision-making in radiation oncology: A systematic review.

The intrinsic stochasticity of patients' response to treatment is a major consideration for clinical decision-making in radiation therapy. Markov models are powerful tools to capture this stochasticity and render effective treatment decisions. This paper provides an overview of the Markov models for clinical decision analysis in radiation oncology. A comprehensive literature search was conducted within MEDLINE using PubMed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies published from 2000 to 2023 were considered. Selected publications were summarized in two categories: (i) studies that compare two (or more) fixed treatment policies using Monte Carlo simulation and (ii) studies that seek an optimal treatment policy through Markov Decision Processes (MDPs). Relevant to the scope of this study, 61 publications were selected for detailed review. The majority of these publications (n = 56) focused on comparative analysis of two or more fixed treatment policies using Monte Carlo simulation. Classifications based on cancer site, utility measures and the type of sensitivity analysis are presented. Five publications considered MDPs with the aim of computing an optimal treatment policy; a detailed statement of the analysis and results is provided for each work. As an extension of Markov model-based simulation analysis, MDP offers a flexible framework to identify an optimal treatment policy among a possibly large set of treatment policies. However, the applications of MDPs to oncological decision-making have been understudied, and the full capacity of this framework to render complex optimal treatment decisions warrants further consideration.

Skin assessment in congenital untreated isolated GH deficiency.

PURPOSE: The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. METHODS: Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. RESULTS: There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. CONCLUSION: IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Novel tetrapolar single-needle electrode for electrochemotherapy in bone cavities: Modeling, design and validation.

Electrochemotherapy is a cancer treatment in which local pulsed electric fields are delivered through electrodes. The effectiveness of the treatment depends on exposing the tumor to a threshold electric field. Electrode geometry plays an important role in the resulting electric field distribution, especially in hard-to-reach areas and deep-seated tumors. We designed and developed a novel tetrapolar single-needle electrode for proper treatment in bone cavities. In silico and in vitro experiments were performed to evaluate the electric field and electric current produced by the electrode. In addition, tomography images of a real case of nasal cavity tumor were segmented into a 3D simulation to evaluate the electrode performance in a bone cavity. The proposed electrode was validated and its operating range was set up to 650 V. In the nasal cavity tumor, we found that the electrode can produce a circular electric field of 3 mm with an electric current of 14.1 A at 500 V, which is compatible with electrochemotherapy standards and commercial equipment.

Hip Arthroplasty Outcomes in Patients with Metastatic Bone Disease.

Background/Objective: The hip is a common location for metastatic bone disease (MBD) and surgical intervention is often indicated to relieve pain and improve function. MBD of the hip is usually treated with hemiarthroplasty or with total hip arthroplasty if there are acetabular lesions. As treatment for metastatic disease evolves and patients may expect to live longer after diagnosis, further evaluation of the complications and functional outcomes associated with hip arthroplasty for MBD are necessary. Methods: This was a retrospective review of patients who underwent hip arthroplasty for MBD at a single institution between 2007 and 2021. Outcomes included rates of reoperation, complications, and overall survival. Results: Ninety-three cases in 91 patients were included. Total hip arthroplasty (THA) was performed in 52 cases (55.9%), hemiarthroplasty in 15 (16.1%), and complex arthroplasty, including proximal femur replacement or THA with complex acetabular reconstruction, was performed in 26 (28%). There were 11 reoperations in five patients and six dislocations. Median survival was 10.4 months and one-year overall survival was 53.3%. There was a significant increase in the proportion of patients who were able to ambulate independently (35.2% vs 17.6%; p=0.02) and a significant decrease in patients confined to a wheelchair (18.7% vs 3.3%; p=0.045) after surgery. Conclusions: Hip arthroplasty for MBD leads to relatively low rates of complications and reoperations in this population known to have high postoperative morbidity and mortality. Hip arthroplasty provides the majority of MBD patients with a durable reconstruction that exceeds their lifespan and enables them to return to an acceptable level of function.

Abdominal donor-site complications following autologous breast reconstruction: A multi-institutional multisurgeon study.

BACKGROUND: The deep inferior epigastric perforator (DIEP) free flap is the gold standard procedure for autologous breast reconstruction. Although breast-related complications have been well described, donor-site complications and contributing patient risk factors are poorly understood. METHODS: We examined a multi-institutional, prospectively maintained database of patients undergoing DIEP free flap breast reconstruction between 2015 and 2020. We evaluated patient demographics, operative details, and abdominal donor-site complications. Logistic regression modeling was used to predict donor-site outcomes based on patient characteristics. RESULTS: A total of 661 patients were identified who underwent DIEP free flap breast reconstruction across multiple institutions. Using logistic regression modeling, we found that body mass index (BMI) was an independent risk factor for umbilical complications (odds ratio [OR] 1.11, confidence interval [CI] 1.04-1.18, p = 0.001), seroma (OR 1.07, CI 1.01-1.13, p = 0.003), wound dehiscence (OR 1.10, CI 1.06-1.15, p = 0.001), and surgical site infection (OR 1.10, CI 1.05-1.15, p = 0.001) following DIEP free flap breast reconstruction. Further, immediate reconstruction decreases the risk of abdominal bulge formation (OR 0.22, CI 0.108-0.429, p = 0.001). Perforator selection was not associated with abdominal morbidity in our study population. CONCLUSIONS: Higher BMI is associated with increased abdominal donor-site complications following DIEP free flap breast reconstruction. Efforts to lower preoperative BMI may help decrease donor-site complications.

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.

Pencil beam kernel-based dose calculations on CT data for a mixed neutron-gamma fission field applying tissue correction factors.

Objective.For fast neutron therapy with mixed neutron and gamma radiation at the fission neutron therapy facility MEDAPP at the research reactor FRM II in Garching, no clinical dose calculation software was available in the past. Here, we present a customized solution for research purposes to overcome this lack of three-dimensional dose calculation.Approach.The applied dose calculation method is based on two sets of decomposed pencil beam kernels for neutron and gamma radiation. The decomposition was performed using measured output factors and simulated depth dose curves and beam profiles in water as reference medium. While measurements were performed by applying the two-chamber dosimetry method, simulated data was generated using the Monte Carlo code MCNP. For the calculation of neutron dose deposition on CT data, tissue-specific correction factors were generated for soft tissue, bone, and lung tissue for the MEDAPP neutron spectrum. The pencil beam calculations were evaluated with reference to Monte Carlo calculations regarding accuracy and time efficiency.Main results.In water, dose distributions calculated using the pencil beam approach reproduced the input from Monte Carlo simulations. For heterogeneous media, an assessment of the tissue-specific correction factors with reference to Monte Carlo simulations for different tissue configurations showed promising results. Especially for scenarios where no lung tissue is present, the dose calculation could be highly improved by the applied correction method.Significance.With the presented approach, time-efficient dose calculations on CT data and treatment plan evaluations for research purposes are now available for MEDAPP.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Novel non-MRI imaging techniques for primary diagnosis of prostate cancer: micro-ultrasound, contrast-enhanced ultrasound, elastography, multiparametric ultrasound, and PSMA PET/CT.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) provides enhanced diagnostic accuracy in the detection of prostate cancer, but is not devoid of limitations. Given the recent evolution of non-MRI imaging techniques, this critical review of the literature aimed at summarizing the available evidence on ultrasound-based and nuclear medicine imaging technologies in the initial diagnosis of PCa. METHODS: Three databases (PubMed®, Web of Science™, and Scopus®) were queried for studies examining their diagnostic performance in the primary diagnosis of PCa, weighted against a histological confirmation of PCa diagnosis, using a free-text protocol. Retrospective and prospective studies, both comparative and non-comparative, systematic reviews (SR) and meta-analysis (MA) were included. Based on authors' expert opinion, studies were selected, data extracted, and results qualitatively described. RESULTS: Micro-ultrasound (micro-US) appears as an appealing diagnostic strategy given its high accuracy in detection of PCa, apparently non-inferior to mpMRI. The use of multiparametric US (mpUS) likely gives an advantage in terms of effectiveness coming from the combination of different modalities, especially when certain modalities are combined. Prostate-specific membrane antigen (PSMA) PET/CT may represent a whole-body, one-step approach for appropriate diagnosis and staging of PCa. The direct relationship between lesions avidity of radiotracers and histopathologic and prognostic features, and its valid diagnostic performance represents appealing characteristics. However, intrinsic limits of each of these techniques exist and further research is needed before definitively considering them reliable tools for accurate PCa diagnosis. Other novel technologies, such as elastography and multiparametric US, currently relies on a limited number of studies, and therefore evidence about them remains preliminary. CONCLUSION: Evidence on the role of non-MRI imaging options in the primary diagnosis of PCa is steadily building up. This testifies a growing interest towards novel technologies that might allow overcoming some of the limitations of current gold standard MRI imaging.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Potassium levels in women with polycystic ovary syndrome using spironolactone for long-term.

OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.

Formaldehyde regulates S-adenosylmethionine biosynthesis and one-carbon metabolism.

One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.

Hospital admission from the emergency department for selected emergent diagnoses during the first year of the COVID-19 pandemic in Ontario: a retrospective population-based study.

BACKGROUND: Avoidance of care during the pandemic may have contributed to delays in care, and as a result, worse patient outcomes. We evaluated markers of illness acuity on presentation to the emergency department among patients with non-COVID-19-related emergent diagnoses and associated outcomes. METHODS: We conducted a retrospective study using linked administrative data from Ontario. We selected 4 emergent diagnoses, namely appendicitis, ectopic pregnancy, renal failure and diabetic ketoacidosis. We used the nonemergent diagnosis of cellulitis as a control. Our primary outcome of interest was hospital admission. Secondary outcomes were ambulance arrival, surgical intervention, subsequent hospital admission within 30 days of discharge from the emergency department or hospital and 30-day mortality. We compared outcomes during the first year of the COVID-19 pandemic (Mar. 15-Dec. 31, 2020) with a control period (Mar. 15-Dec. 31, 2018, and Mar. 15-Dec. 31, 2019). RESULTS: Emergency department visits for all conditions initially decreased during the pandemic. During this period, patients across all study diagnoses were more likely to arrive to the emergency department via ambulance. Patients with an ectopic pregnancy had higher odds of surgery in the pandemic period (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.04-1.55) but this was not observed among patients with appendicitis. Patients with renal failure had increased odds of hospital admission (OR 1.14, 95% CI 1.04-1.24) and 30-day mortality (OR 1.17, 95% CI 1.04-1.31) during the pandemic period. INTERPRETATION: The pandemic period was associated with increased arrival to the emergency department via ambulance across all study diagnoses. Although patients with renal failure had increased hospital admission and death, and patients with ectopic pregnancy had an increased risk of surgery, there were no differences in outcomes for other populations, suggesting the health care system was able to care for these patients effectively.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

UHPLC-HRMS-Based Analysis of S-Hydroxymethyl-Glutathione, GSH, and GSSG in Human Cells.

Glutathione (GSH) is one of the main antioxidant molecules present in cells. It harbors a thiol group responsible for sustaining cellular redox homeostasis. This moiety can react with cellular electrophiles such as formaldehyde yielding the compound S-hydroxymethyl-GSH (HSMGSH). HSMGSH is the substrate of the enzyme alcohol dehydrogenase 5 (ADH5) and thus a key intermediate in formaldehyde metabolism. In this work, we describe a method for the chemical synthesis of HSMGSH and a pipeline to identify this compound in complex cell extracts by means of ultra-high-performance liquid chromatography coupled to high-resolution spectrometry (UHPLC-HRMS). This method also allows determining GSH and oxidized disulfide (GSSG) in the same samples, thus providing broad information about formaldehyde-GSH metabolism.

Single-Port Robot-Assisted Radical Prostatectomy: Where Do We Stand?

In 2018, the da Vinci Single Port (SP) robotic system was approved by the US Food and Drug Administration for urologic procedures. Available studies for the application of SP to prostate cancer surgery are limited. The aim of our study is to summarize the current evidence on the techniques and outcomes of SP robot-assisted radical prostatectomy (SP-RARLP) procedures. A narrative review of the literature was performed in January 2023. Preliminary results suggest that SP-RALP is safe and feasible, and it can offer comparable outcomes to the standard multiport RALP. Extraperitoneal and transvesical SP-RALP appear to be the two most promising approaches, as they offer decreased invasiveness, potentially shorter length of stay, and better pain control. Long-term, high-quality data are missing and further validation with prospective studies across different sites is required.