p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis.

Mechanisms underlying p53-mediated protection of the replicating genome remain elusive, despite the quintessential role of p53 in maintaining genomic stability. Here, we uncover an unexpected function of p53 in curbing replication stress by limiting PARP1 activity and preventing the unscheduled degradation of deprotected stalled forks. We searched for p53-dependent factors and elucidated RRM2B as a prime factor. Deficiency in p53/RRM2B results in the activation of an NRF2 antioxidant transcriptional program, with a concomitant elevation in basal PARylation in cells. Dissecting the consequences of p53/RRM2B loss revealed a crosstalk between redox metabolism and genome integrity that is negotiated through a hitherto undescribed NRF2-PARP1 axis, and pinpoint G6PD as a primary oxidative stress-induced NRF2 target and activator of basal PARylation. This study elucidates how loss of p53 could be destabilizing for the replicating genome and, importantly, describes an unanticipated crosstalk between redox metabolism, PARP1 and p53 tumor suppressor pathway that is broadly relevant in cancers and can be leveraged therapeutically.

Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. METHODS: In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. FINDINGS: Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. INTERPRETATION: Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. FUNDING: This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.

PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression.

BACKGROUND: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. METHODS: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. RESULTS: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. CONCLUSIONS: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

The mayo adhesive probability score predicts postoperative fever and sepsis in retrograde intrarenal surgery.

Infectious complications are among the most common and potentially life-threatening morbidities of retrograde intrarenal surgery (RIRS). Few predictive tools on these complications include radiological signs. The Mayo adhesive probability (MAP) score is an image-based scoring system that incorporates two radiological signs: perinephric fat stranding and perinephric fat thickness. Previous studies have suggested an association between these signs and febrile urinary tract infection (UTI) following lithotripsy. This study aimed to evaluate the predictive factors, including the MAP score, for post-RIRS fever and sepsis. A total of 260 patients who underwent 306 RIRS between October 2019 to December 2023 due to renal or upper ureteral stones were included in this retrospective study. Patient demographics, perioperative characteristics, stone factors, radiological signs, and MAP scores were recorded. Multivariate logistic regression analysis was used to evaluate the risk factors associated with postoperative fever and sepsis. Postoperative fever and sepsis occurred in 20.8% and 8.5% of the patients, respectively. On multivariate analysis, female gender, history of recurrent UTI, larger maximal stone diameter, and higher MAP score were independent risk factors for postoperative fever and sepsis. Identifying the risk factors for post-RIRS infectious complications is imperative to providing the proper perioperative management. The MAP score is a promising, easily calculated, image-based scoring system that predicts post-RIRS fever and sepsis.

Copper affects virulence and diverse phenotypes of uropathogenic Proteus mirabilis.

BACKGROUND: Copper plays a role in urinary tract infection (UTI) and urinary copper content is increased during Proteus mirabilis UTI. We therefore investigated the effect of copper on uropathogenic P. mirabilis and the underlying mechanisms, focusing on the virulence associated aspects. METHODS: Mouse colonization, swarming/swimming assays, measurement of cell length, flagellin level and urease activity, adhesion/invasion assay, biofilm formation, killing by macrophages, oxidative stress susceptibility, OMPs analysis, determination of MICs and persister cell formation, RT-PCR and transcriptional reporter assay were performed. RESULTS: We found that copper-supplemented mice were more resistant to be colonized in the urinary tract, together with decreased swarming/swimming, ureases activity, expression of type VI secretion system and adhesion/invasion to urothelial cells and increased killing by macrophages of P. mirabilis at a sublethal copper level. However, bacterial biofilm formation and resistance to oxidative stress were enhanced under the same copper level. Of note, the presence of copper led to increased ciprofloxacin MIC and more persister cell formation against ampicillin. In addition, the presence of copper altered the outer membrane protein profile and triggered expression of RcsB response regulator. For the first time, we unveiled the pleiotropic effects of copper on uropathogenic P. mirabilis, especially for induction of bacterial two-component signaling system regulating fitness and virulence. CONCLUSION: The finding of copper-mediated virulence and fitness reinforced the importance of copper for prevention and therapeutic interventions against P. mirabilis infections. As such, this study could facilitate the copper-based strategies against UTI by P. mirabilis.

Experiences of Family Caregivers Providing Home Care to Older Patients With Cancer: A Qualitative Study.

BACKGROUND: Older patients with cancer receive anticancer therapy in outpatient settings, and care-related issues may occur after discharge, which often requires family caregivers (FCs) to play a significant role in providing cancer care at home. However, relatively few studies have been focused on exploring the care experiences of these FCs. PURPOSE: The aim of this study was to explore the care experiences of FCs caring for older family members with cancer at home. METHODS: A qualitative study design and in-depth individual interviews were used to explore the at-home care experiences of FCs of older patients with cancer. The research was conducted in chemotherapy outpatient settings of a medical center in northern Taiwan. Content analysis was used to analyze data. The analyses focused on first extracting meaningful units from the text and then inducting categories from these units and determining the major themes. RESULTS: Twenty FCs were interviewed. The three themes identified included (a) increased information needs and challenges in diet preparation and treatment decision making, (b) personal and patient-induced emotional stress, and (c) life rebalancing through the care experience. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings highlight the educational requirements, especially related to meeting personal dietary needs and obtaining psychological support, for FCs caring for older patients with cancer to help them rebalance their life.

Infected calcium oxalate stone leading to pyogenic spondylodiscitis and bilateral lower limb weakness: a case report.

Introduction and importance: It is rare for calcium oxalate renal stone, presented mainly in sterile urine, to result in urinary tract infection. The stone-related infection could develop spondylodiscitis, causing neurological deficits. To date, there are no reports about calcium oxalate partial staghorn stone and spondylodiscitis. Case presentation: A 62-year-old male suffered from haematuria, fever, and flank pain. He came to the urology outpatient department, where acute pyelonephritis was diagnosed, and a left partial staghorn stone was seen on computed tomography. Oral antibiotics were prescribed with improvement. Two weeks after antibiotics treatment, he developed bilateral lower limb weakness and numbness under the nipple level. He was brought to the emergency department, where the spine MRI revealed T2-T3 spondylodiscitis with epidural abscess and spinal cord compression. He underwent T2-T3 spine operation with improvement in muscle power and hypesthesia. The culture of the surgical lesion yielded Citrobacter koseri, the same as the urine culture obtained at his first visit. Left-side percutaneous nephrolithotomy was performed 1 month after with successful stone removal and resolution of pyuria. Stone analyses reported calcium oxalate. Follow-up MRI showed marked improvement with resolution of spondylodiscitis. Clinical discussion: Urinary tract infection resulting from partial staghorn stone, with additional hematogenous spread causing spondylodiscitis, is scarcely discussed. The authors illustrated a case with calcium oxalate stone, belonging to sterile Jensen's classification type 1. However, a urinary tract infection could be seen in urine stasis or obstruction. Conclusion: With accurate diagnosis and essential interventions, the patient had immediate neurological improvement and reached disease-free status.

Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities.

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles. In multiple tissues, EGFR is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively. TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering c-Myc and Cyclin D1 upregulation. Our findings suggest that p53 mutants carrying gain-of-function, mis-sense mutations affecting two different domains form new protein complexes that promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms, exposing clinically relevant therapeutic vulnerabilities.

New-onset diabetes mellitus risk associated with concurrent autonomous cortisol secretion in patients with primary aldosteronism.

Concurrent autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA patients) is not uncommon. This work aimed to determine the effect of cortisol levels on incident new-onset type 2 diabetes mellitus (NODM) in PA patients. Using the prospectively designed observational TAIPAI cohort, the PA patients were grouped by cortisol level after an overnight low-dose dexamethasone suppression test (1-mg DST). Of the 476 PA patients, 387 (43.7% men; mean age 52.8 years) did not have baseline DM. After a mean follow-up of 4.3 ± 2.9 years, 32 patients (8.3%) developed NODM. The cutoff value obtained via a generalized additive model showed that a serum cortisol level ≥ 2.65 µg/dL after 1-mg DST was a risk factor for developing NODM (HR, 3.5, p = 0.031) by Cox proportional- hazards model.. In PA patients with a higher body mass index (>25 kg/m2; HR, 3.16), lower estimated glomerular filtration rate (<90 ml/min/1.73 m2; HR, 3.18), longer hypertension duration (>7 years; HR, 3.34), and higher waist-to-hip ratio (>0.9; HR, 3.07), a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST were more likely to develop NODM. The high-cortisol group of patients with aldosterone-producing adenoma (APA) using mineralocorticoid receptor antagonist (MRA) was associated with an increased risk of NODM (HR, 5.72). Our results showed that PA patients with a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST, independent of the aldosterone level, had a higher incidence of NODM. Such PA patients should be carefully evaluated and managed to achieve better glucose control and prevent metabolic syndrome.

A post-trial follow-up study of pentosan polysulfate monotherapy on preventing recurrent urinary tract infection in women.

For women with recurrent urinary tract infection (UTI), previous U101 study has shown that pentosan polysulfate sodium (PPS) monotherapy for 16 weeks significantly reduced UTI episodes in the treatment group throughout the trial period. In this follow-up study, we aimed to assess whether the effects of PPS would last after completion of the trial to prevent recurrent UTIs. Conducted from 2018 to 2019, the U101 study was a multicenter, prospective, phase 2a, randomized trial, enrolling women with recurrent UTI to study the effects of a 16-week oral PPS monotherapy. After approximately two years, the follow-up was conducted by phone interview, obtaining data including self-reported UTI events, quality of life questionnaire, and adverse events. The primary endpoint of follow-up study was UTI recurrence-free survival and the secondary endpoints were quality of life and adverse events. Approximately two years after completion of the trial, the rate of recurrent UTI was 25% (3 of the 12 patients) in the PPS group and 85.7% (12 of the 14 patients) in the control group. Over the entire follow-up period, the UTI recurrence-free survival was significantly better in the PPS group than in the control group (log-rank test p < 0.001). The quality of life at two years was significantly improved in the PPS when compared to the control group (91.7 vs. 77.5, p < 0.001). No late adverse event was observed after cessation of the treatment. In this study, sixteen weeks of PPS monotherapy in women with recurrent UTI significantly reduced the numbers of recurrent UTI episodes during the 2-year follow-up.

[Emission Characteristics of Gas-and Particle-Phase Polycyclic Aromatic Hydrocarbons from Cooking].

Polycyclic aromatic hydrocarbons (PAHs) play a key role in the formation of secondary organic areole and ozone. This study sampled three commercial Chinese restaurants and a food plant in Shenzhen to analyze the emission characteristics of PAHs, especially the alkyl PAHs in both gas and particle phases. The results showed that the ρ(total PAHs)in the particle and gas phase were (1381.6±140.5) ng·m-3, (1030.2±116.4) ng·m-3, (908.3±111.9) ng·m-3, and (838.0±93.5) ng·m-3 in the food plant, Sichuan, Cantonese, and Zhejiang restaurants, respectively. More than 60% of the PAHs were distributed in the gas phase, especially the lower molecular weight PAHs (lower than Chrysene). The gas phase proportion of naphthalene was the highest, with over 75% of it distributed in the gas phase. However, the PAHs with a higher molecular weight than that of benzo(b)fluorescence were mainly distributed in the particle phase. The total concentration of alkyl PAHs emitted from cooking was much lower than that of the corresponding parent PAHs, and the distribution characteristics of alkyl PAHs were quite different from those of other emission sources. The linear fitting of lgKp and lgPL showed that the slopes of the three commercial restaurants ranged from -0.25 to -0.28, whereas for the food plant, the value was -0.18, which indicates that the gas-particle partitioning of PAHs were not in equilibrium.

Characterization of kiss2/kissr2 system in largemouth bass (Micropterus salmoides) and Kiss2-10 peptide regulation of the hypothalamic-pituitary-gonadal axis.

The kisspeptin system, which lies upstream of the hypothalamic-pituitary-gonadal (HPG) axis, is believed to function as a regulator of reproduction in teleosts. In this study, we isolated and characterized kiss2 and its receptor kissr2 in largemouth bass (Micropterus salmoides). The complete coding sequences of kiss2 and kissr2 were 375 and 1134 bp long and encoded precursor proteins 124 and 377 amino acid long, respectively. Real-time PCR showed that kiss2 and kissr2 were primarily expressed in the HPG axis. The expression profile of kiss2 and kissr2 varied with gonadal development, with the highest and lowest expression levels being detected during the immature and final maturation stages, respectively. Intraperitoneal injection of exogenous Kiss2-10 peptide increased the transcript levels of gnrh3, kissr2, fshß, lhß, ar, and er2 within 24 h (p < 0.05), as well as plasma levels of 17ß-estradiol and testosterone. Histological analysis indicated that chronic administration of exogenous Kiss2-10 peptide accelerated vitellogenesis in females and spermatogenesis in males. Further, in situ hybridization revealed that kiss2 is expressed in the ooplasm and vitelline envelope of oocytes and the spermatocytes of testes. In addition, experiments using gonad tissue primary cell cultures indicated that exogenous Kiss2-10 peptide stimulates the expression of reproduction-related genes. Collectively, our findings indicate that the kiss2/kissr2 system in largemouth bass is involved in regulating gonadal development through the HPG axis.

Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer.

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for ß-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

Effectiveness and Safety Evaluation of Chinese Medicine in Treatment of Metastatic Colorectal Cancer after Chemotherapy Failure: Protocol of a Prospective Multicenter Cohort Study.

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related deaths and has the third highest incidence in the world. Almost half of the patients with CRC have metastases at the time of diagnosis. However, the treatment for patients with metastatic CRC that progresses after approved conventional chemotherapy is still controversial. Chinese medicine (CM) has unique characteristics and advantages in treating metastatic CRC. OBJECTIVE: To assess the effectiveness and safety of CM in patients with metastatic CRC after failure of conventional chemotherapy. METHODS: The study is a multicenter prospective cohort study. A total of 384 patients with documented metastatic CRC after failure of conventional chemotherapy will be included from 9 hospitals among Beijing, Shanghai, Nanjing, and Guizhou, and assigned to three groups according to paitents' wishes: (1) integrated Chinese and Western medicine (ICM) group receiving CM herbal treatment combined with Western medicine (WM) anti-tumor therapy, (2) Chinese medicine (CM) group receiving only CM herbal treatment, and (3) WM group receiving only WM anti-tumor therapy. The primary endpoint is the overall survival (OS). Secondary endpoints include the progression free survival (PFS), quality of life (QOL) assessed by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, tumor control, and CM symptom score. DISCUSSION: This prospective study will assess the effectiveness and safety of CM in treating metastatic CRC after conventional chemotherapy failure. Patients in the ICM group will be compared with those in the WM group and CM group. If certified to be effective, national provision of CM treatment in metastatic CRC will probably be advised. (Registration No. NCT02923622 on ClinicalTrials.gov).

Preoperative %p2PSA and Prostate Health Index Predict Pathological Outcomes in Patients with Prostate Cancer Undergoing Radical Prostatectomy.

To evaluate the predictive accuracy of the %p2PSA and prostate health index (PHI) in predicting aggressive pathological outcomes in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), we enrolled 91 patients with organ-confined PCa who were treated with robot-assisted RP. p2PSA levels and the PHI were investigated for their ability to predict pathological results. The %p2PSA and PHI were both significantly higher in patients with ≥pT3 disease, high-risk disease, positive surgical margin, or seminal vesical invasion (SVI). In univariable analysis, p2PSA derivatives were significant predictors of the presence of ≥pT3 disease, high-risk disease, positive surgical margin, and SVI. To predict adverse pathological outcomes at a sensitivity of 90%, p2PSA derivatives had higher specificity than standard PSA derivatives. In multivariable analysis, additional increases in the area under the receiver operating characteristic curve (AUC) were observed with the %p2PSA and PHI for ≥pT3 disease, high-risk disease, and positive surgical margin (8.2% and 2.7%, 6.2% and 4.1%, and 8.6% and 5.4%, respectively). A PHI ≥61.26 enhanced the predictive accuracy of the model for SVI by increasing the AUC from 0.624 to 0.819 (p = 0.009). The preoperative %p2PSA and PHI accurately predict adverse pathological results and are useful for decision-making.

Percutaneous Interstitial Nd:YAG Laser Therapy for Axillary Osmidrosis.

BACKGROUND AND OBJECTIVES: To investigate the effects of percutaneous interstitial Nd:YAG laser irradiation on the apocrine glands and molecules involved in odor production (apolipoprotein [ApoD], androgen receptor [AR]) in the subcutaneous tissue of a pig. STUDY DESIGN/MATERIALS AND METHODS: Skin on the back of healthy adult miniature pigs was exposed to pulsed Nd:YAG laser irradiation at 5 or 10 W, or continuous Nd:YAG laser irradiation at 10 W. Samples were taken 1 hour, 1 week, and 1 month after treatment for histology, western blot, and real-time quantitative polymerase chain reaction (qRT-PCR) analysis. RESULTS: One week and 1 month after irradiation, the apocrine glands in pigskin became rounded, glandular cells were shorter, and the glandular cavities were larger compared with controls, but there were no obvious changes in fat cell distribution of collagen around the apocrine glands. One month after irradiation at 10 W in continuous mode, there was a significant decrease in ApoD expression in apocrine cells and ApoD and AR protein and expression levels in pigskin compared with controls. There were also significant differences in ApoD and AR protein and expression levels between treatments. CONCLUSIONS: Percutaneous interstitial Nd:YAG laser irradiation has potential as a safe and efficacious treatment for axillary osmidrosis as it may decrease the production of volatile unsaturated fatty acids, steroids, and associated unpleasant odors in the axilla. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

The efficacy of pentosan polysulfate monotherapy for preventing recurrent urinary tract infections in women: A multicenter open-label randomized controlled trial.

BACKGROUND/PURPOSE: Pentosan polysulfate sodium (PPS), a semi-synthetic polysaccharide that adheres to bladder mucosa, is effective in treating interstitial cystitis. We evaluated the clinical benefit of PPS for the prevention of recurrent urinary tract infection (UTI) in women. METHODS: We conducted a multicenter, open-label, prospective, phase II, randomized controlled trial enrolling women with recurrent UTI ≥ 2 times in the past 6 months or ≥ 3 times in the past 12 months. Patients received oral PPS monotherapy for 16 weeks in treatment group. All patients were followed every 28 days until UTI recurrence or up to 112 days. The primary endpoint was the UTI recurrence-free survival. Adverse events were recorded as secondary endpoint. RESULTS: A total of 26 women were eligible for analysis. In the PPS group, none (0%) of the 12 patients had UTI recurrence during the study period. However, 9 (64%) of 14 patients had UTI recurrence in the control group. The UTI recurrence-free survival was significantly higher in the PPS group than in the control group (log-rank test p = 0.0004). One adverse event which led to discontinuation of the trial regimen was regarded as irrelevance of PPS treatment. The limitation was the small number of cases. CONCLUSION: Among women with recurrent UTI, 16-week PPS monotherapy significantly reduced UTI recurrence when compared with the control group.

The Wnt/Ca2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes.

Tunneling nanotubes (TNTs) are actin-based transient tubular connections that allow direct communication between distant cells. TNTs play an important role in several physiological (development, immunity, and tissue regeneration) and pathological (cancer, neurodegeneration, and pathogens transmission) processes. Here, we report that the Wnt/Ca2+ pathway, an intracellular cascade that is involved in actin cytoskeleton remodeling, has a role in TNT formation and TNT-mediated transfer of cargoes. Specifically, we found that Ca2+ /calmodulin-dependent protein kinase II (CaMKII), a transducer of the Wnt/Ca2+ pathway, regulates TNTs in a neuronal cell line and in primary neurons. We identified the ß isoform of CaMKII as a key molecule in modulating TNT formation and transfer, showing that this depends on the actin-binding activity of the protein. Finally, we found that the transfer of vesicles and aggregated α-synuclein between primary neurons can be regulated by the activation of the Wnt/Ca2+ pathway. Our findings suggest that Wnt/Ca2+ pathway could be a novel promising target for therapies designed to impair TNT-mediated propagation of pathogens.

Methionine is a metabolic dependency of tumor-initiating cells.

Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.

Publisher Correction: Methionine is a metabolic dependency of tumor-initiating cells.

In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.