Cardiovascular diseases represent a significant public health issue, and the promotion of healthy lifestyles plays a major role in their prevention. Good adherence to the Mediterranean diet has a protective effect on cardiovascular health and may reduce the risk of developing cardiovascular disease. Our prospective study aimed to evaluate the impact of educational lifestyle interventions on cardiovascular risk parameters and the improvement in adherence to the Mediterranean diet of the involved population.Participants have been recruited by General Practitioners in Torresina neighborhood in Rome. From December 2018 to June 2020, 41 patients were involved in nutritional, psychological, and physical activity meetings by a multidisciplinary team of healthcare professionals. In particular, a nutritionist provided information to patients on balanced nutrition, considering the Mediterranean diet as a dietary model. Information on lifestyle, dietary habits and physical activity, anthropometric data and laboratory measurements were collected at baseline and after 12 months. The variations of the evaluated parameters were analyzed by paired t-test e Wilcoxon signed-rank test.The analysis showed statistically significant decreases in weight (p = 0.03) and BMI (p = 0.02), as well as in systolic (p < 0.001) and diastolic (p = 0.001) blood pressure and in total (p = 0.02) and LDL (p = 0.01) cholesterol level. Results also showed an improvement in the adherence to the Mediterranean diet (p = 0.001): the frequency of consumption of fruits and vegetables, legumes, cereals and fish has increased significantly, while the consumption of meat, milk and dairy products and alcohol decreased.This study highlights that a multidisciplinary educational program can be effective in improving healthy habits and in reducing cardiovascular risk factors, supporting its implementation in primary prevention at the community level.• Promoting healthy lifestyle through primary prevention and health promotion actions is critical to reduce the onset of cardiovascular diseases.• A population-based multidisciplinary educational intervention may be effective in improving adherence to a healthy, balanced diet and decreasing cardiovascular risk factors.


Thrombopoietin receptor agonists (TPO-RAs) are approved for immune thrombocytopenia (ITP), but their impact on health-related quality of life (HRQoL) remains poorly investigated in clinical practice. This observational study aimed to gain insight into real-world patient-reported experiences of the burden of ITP and TPO-RAs.An online questionnaire of closed questions was used to collect views of patients with primary ITP from Switzerland, Austria, and Belgium, between September 2018 and April 2020.Of 46 patients who completed the questionnaire , 41% were receiving TPO-RAs. A numerically higher proportion of patients reported being free from symptoms at the time of the questionnaire (54%) than at diagnosis (24%), irrespective of treatment type. Bleeding, the most frequently reported symptom at diagnosis (59%), was reduced at the time of the questionnaire (7%). Conversely, fatigue was reported by approximately 40% of patients at both diagnosis and the time of the questionnaire. Having a normal life and their disease under control was reported by 83% and 76%, respectively, but 41% were worried/anxious about their condition. Nearly 50% reported that ITP impaired their engagement in hobbies/sport or energy levels and 63% reported no impact on employment. When stratified by TPO-RA use, bleeding was better controlled in those receiving TPO-RAs than not (0% vs 11%). A numerically lower proportion receiving TPO-RAs than not reported worry/anxiety about their condition (16% vs 59%) and shifting from full-time to part-time employment (11% vs 22%). Similar proportions were satisfied with their therapy whether they were receiving TPO-RAs or not (89% vs 85%).Many factors affect HRQoL in patients with ITP. Of patients receiving TPO-RAs, none experienced bleeding at the time of the questionnaire; they also showed a more positive perspective for some outcomes than those not using TPO-RAs. However, fatigue was not reduced by any treatment. There were also some numerical differences between the cohorts for treatments currently received: a numerically lower proportion of patients using than those not using TPO-RAs were receiving steroids (37% [n = 7/19] vs 52% [n = 14/27]) and intravenous immunoglobulin (5% [n = 1/19] vs 19% [n = 5/27]), and a numerically higher proportion of patients using than those not using TPO-RAs were receiving rituximab (16% [n = 3/19] vs 7% [n = 2/27]). Furthermore, 26% (n = 7/27) of patients in the cohort not receiving TPO-RAs were not receiving any other therapy.A numerically higher proportion of patients in the total cohort reported being free from symptoms at the time of the questionnaire (54% [n = 25/46]) than at diagnosis , dizziness (0% [n = 0/19] vs 11% [n = 3/27]), and sleep deprivation  and that their disease was under control  and that their condition was under control (84% [n = 16/19] vs 70% [n = 19/27]). However, there was no marked difference between the cohorts regarding how informed they were about their disease (95% [n = 18/19] vs 89% [n = 24/27]), how well their doctor understood their situation (100% [n = 19/19] vs 92% [n = 25/27]), or the support they received from their doctor (100% [n = 19/19] vs 96% [n = 26/27]). For negative statements, a numerically lower proportion of patients receiving than those not receiving TPO-RAs felt worried/anxious about their condition (16% [n = 3/19] vs 59% [n = 16/27]). There was no marked difference for the other negative statements between patients using and those not using TPO-RAs.When asked about the impact of ITP on daily activities, engagement in hobbies/ability to play sport and energy levels were most reported to be affected equally in both cohorts, with almost half of patients  reporting that these activities were affected all of the time or often .When patients were stratified according to TPO-RA use, responses to questions about the impact of ITP on daily activities were generally aligned with the total cohort. There were some small numerical differences whether patients were receiving TPO-RAs or not for the proportion of patients for whom ITP had an impact all the time/often on sleeping (37% [n = 7/19] vs 26% [n = 7/27]), social life , or hobbies/ability to play sport (42% [n = 8/19] vs 52% [n = 14/27]).In the total cohort, 72% of patients reported that they were employed. Of the total cohort, the largest proportion of patients reported that their condition had not affected their employment (63% [n = 29/46]), while 24% (n = 11/46) had considered terminating their job (but had not), 17% (n = 8/46) had changed from full-time to part-time employment, 9% (n = 4/46) had been involuntarily terminated from their job, 4% (n = 2/46) had taken early retirement, and 2% (n = 1/46) had voluntarily terminated their job owing to ITP. When asked to describe their last working week, patients from the total cohort reported that their productivity had been affected to some degree .When stratified by TPO-RA use, the impact of ITP on employment and productivity was largely aligned with the total cohort. Almost equal proportions of patients who used TPO-RA and those who did not reported that ITP had not had an impact on their employment (68% [n = 13/19] vs 59% [n = 16/27]). Shifting to part-time employment was the outcome for which there was the clearest difference according to TPO-RA use, being numerically lower in those who used TPO-RA than those who did not (11% [n = 2/19] vs 22% [n = 6/27]). For productivity, there was no difference between responses according to whether patients were using TPO-RAs or not (mean productivity scores 66.3/100 vs 66.7/100).Similarly high proportions of patients were satisfied with their therapy over the previous 7 days whether they were receiving TPO-RAs (89% [n = 17/19]) or not (85% [n = 23/27]). Among patients receiving TPO-RAs, the majority were satisfied whether they were receiving TPO-RAs as a monotherapy (100% [n = 9/9]) or in combination with other therapies (80% [n = 8/10]).When asked about their level of agreement with negative statements that relate to treatment satisfaction, a numerically higher proportion of patients receiving than those not receiving TPO-RAs agreed with the statement regarding worry about the costs of treatment . HoweverThis real-world study, which was conducted across Switzerland, Austria, and Belgium, used an online questionnaire to assess the perspective of 46 patients with primary ITP on their symptomatic burden and the impact of the disease on their lives. Importantly, whilst other studies have explored these topics using patient-reported outcomes instruments, to the best of our knowledge, none has assessed all of these topics in a single questionnaire, or assessed patient views and opinions in a similar way to the present study. This study therefore adds to the growing body of real-world evidence by providing further insight into the multifactorial burden of this rare disease on patients’ HRQoL, which goes beyond bleeding, and in some patients includes fatigue, anxiety about their condition, and limitations on their ability to engage in daily life activities, relationships, and employment . To the In the present study, over 75% of patients in the total cohort experienced symptoms at diagnosis, of which the highest proportion reported bleeding. Following diagnosis, the proportion of patients experiencing symptoms was reduced to 46%, with the proportion reporting bleeding showing the greatest reduction (59% to 7%). This is encouraging and may reflect that patients received appropriate disease management following diagnosis to address their bleeding symptoms; in line with this, at the time of the questionnaire, 85% of patients were receiving treatment.In contrast to bleeding symptoms, non-bleeding symptoms persisted at the time of the questionnaire. Fatigue in particular was reported by approximately 40% of patients both at diagnosis and at the time of the questionnaire. Results for fatigue are aligned with those of the literature that report that chronic fatigue is a commonly reported symptom in patients with ITP , 39. TheAt the time of the questionnaire, approximately 40% of patients in the total cohort felt worry/anxiety about their condition and also reported some impact of ITP on their daily life activities or employment. However, the majority of patients felt that they had a normal life, that their condition was under control, and that they were being supported by their doctor. Furthermore, at least 60% rarely/never experienced impairments in their ability to engage in daily life activities or employment. Results for impact of ITP on daily activities in the present study are largely aligned with those of the I-WISh , 39. HowWhen comparing disease and treatment burden between patients receiving and those not receiving TPO-RAs, several outcomes did not differ according to TPO-RA use. Because the study was not powered to detect statistically significant differences, it is important not to over-interpret numerical differences between groups. However, at the time of the questionnaire, a numerically lower proportion of patients using TPO-RAs reported bleeding as a symptom, feeling worried/anxious about their condition, or shifting to part-time employment than those not using TPO-RAs, and a numerically higher proportion agreed that they had a normal life and that their condition was under control. Furthermore, although overall treatment satisfaction was similar between those using and those not using TPO-RAs, a numerically lower proportion of patients receiving TPO-RAs were worried about getting infections or wanted to stop their treatment/take a different treatment. A lower proportion of patients receiving than those not receiving TPO-RAs were also worried about dietary restrictions. Dietary restrictions are a consideration only for patients receiving certain treatments, including eltrombopag. For eltrombopag, patients need to follow strict guidelines with regard to amounts and timings of calcium intake during meals. This may indicate that a majority of patients in the cohort that received TPO-RAs were receiving romiplostim, although it was not possible from the present data to identify the specific treatments that patients were receiving. Finally, as expected, owing to the price of TPO-RAs versus some other treatments , worry about cost of treatment was the only concern reported by a numerically higher proportion of patients using than those not using TPO-RAs. Further investigation is needed into the economic burden of ITP to patients from a broader perspective, including indirect costs to the patients as a result of ITP , and their reliance on social support or other financial dependencies.Overall, data stratified by TPO-RA use suggest that patients using TPO-RAs in the present study had a more positive perception of their clinical outcomes with regard to bleeding symptoms, and of their general psychosocial state, than those not using TPO-RAs. Results of the present study are aligned with those of clinical trials and extension studies, which have shown that TPO-RA treatment has a positive impact on patients’ HRQoL versus no TPO-RA treatment , 29, 41.The effectiveness and tolerability of TPO-RAs may account for their positive impact on HRQoL  comparedOne of the main limitations of this study is that patient recruitment was not monitored. During the invitation to participate, it was explicitly emphasized to the patient that there would be no way to identify whether they had participated or not to ensure that those who did respond could provide their opinions anonymously, so that they could respond honestly about sensitive topics such as medical care satisfaction and about their personal lives. It was therefore not possible to investigate how many patients were contacted for participation. Furthermore, barriers to completing the questionnaire, which may have resulted in non-participation, were also not investigated. Finally, there was no requirement or incentive for physicians to meet patient recruitment quotas; it was entirely up to physicians whether they wanted to hand out envelopes with unique access codes to the questionnaire to their patients. These factors, in combination with ITP being a rare disease, may account for the rather low number of participants (N = 46) recruited during the active periods of the study (3 periods over 3 months), over 2 years. Nevertheless, this study provides important insight into the views and feelings of a cohort of patients with ITP, and the impact of ITP on their lives, including in those receiving TPO-RAs.The questionnaire used closed questions and all responses were anonymous. It was therefore not possible to investigate outcomes further, or to correlate them with clinical characteristics that were not collected as part of the questionnaire . Because responses also relied on patients’ recollection of symptoms and treatment received at diagnosis, it is possible that they were not an accurate reflection of patients’ experiences at that time, particularly for those who were diagnosed several years before completing the questionnaire. The online nature of the questionnaire may have also precluded some patients from participating in the study, and may account for the numerically lower numbers of patients recruited who were over 60 years of age (24%) than who were in the younger age groups.Another limitation of the questionnaire is that it was not validated. However, the topics included in this questionnaire were selected by a panel of haematologists with extensive experience in, and dedication to, caring for patients with ITP. Therefore, the questionnaire is likely to reflect issues that impact patients in their daily lives and are of importance to them. Furthermore, questions were phrased in a way that was consistent with the language used by haematologists when discussing with patients about their physical and emotional condition and their HRQoL. Therefore, it was agreed by the panel of haematologists that the questionnaire was suitable for use in the present study.Finally, patients recruited into the study were being treated by haematologists. They may therefore have had more severe disease or required treatment, compared with patients managed by general practitioners or who were not receiving or in need of treatment or management by a healthcare professional, who would not have been represented in the study. Furthermore, physicians who sought to recruit patients to participate in the study may have also actively engaged in enquiring about their patients’ experiences and keeping patients informed of their condition; this would have had a positive impact on their patients’ lives and may have produced biased questionnaire results. Based on these limitations, the results of this study are not generalizable to the general population of patients with primary ITP, but they do provide valuable data from the patient’s perspective in a selected group of patients with primary ITP. To overcome some of these limitations, a future study could recruit patients with ITP from other sources, such as patient registries , that may include a broad population of patients, including those who are not under the care of haematologists or any healthcare professional.There is growing recognition of the importance of evaluating patients’ perspectives of the impact of their disease and treatment on their lives. The current study, which was conducted across Switzerland, Austria, and Belgium, provides further insight into the burden of ITP based on the feelings and opinions expressed by a cohort of patients in clinical practice. This is particularly relevant with regard to fatigue, the impact of which is often underestimated, and which is not generally responsive to available treatments. Importantly, to the best of our knowledge, this is also among the first studies assessing the patient-reported experience in those receiving versus those not receiving TPO-RAs: patients receiving TPO-RAs had better outcomes with regard to bleeding, but also for other aspects of the disease, such as anxiety.S1 File(DOCX)Click here for additional data file.


The p53 tumor suppressor is a central protein in the fight against cancer. Mutations that inactivate at least one p53 allele occur in more than half of all cancer cells. Finding p53 nuclear and cytoplasmic amyloid inclusions in many tumor cell lines and cancer biopsies suggests, but does not prove, that amyloid formation inactivates p53 and that conformationally-converted p53 can be transmitted in a prion-like fashion . We rWhile the initial prion hypothesis addressed the unusual features of the mammalian PrP protein, much of what we know about prions comes from studies in yeast, where prions control several endogenous traits ,5,6. PriConcerning p53 prion formation in yeast, Billant et al. , it takeA limited number of proteins can form prions in living cells. Even for these proteins, the de novo appearance of prion seeds in the absence of infection is rare. While certain mutations or the overexpression of the protein or its prion domain can enhance the de novo appearance of prion seeds, the frequency of new seed formation is low. However, once a protein forms a prion, it is fairly stable.We showed that either wild-type or p53-R175H mutant human p53 expressed in yeast can indeed propagate stably in either a bona fide prion or non-prion form . FurtherBillant et al.  showed tHowever, we emphasize that Billant et al.’s finding that mutant p53 does not inevitably take on a prion form or always exist as a prion does not lead to the interpretation that mutant or wild-type p53 cannot sometimes propagate as prions. Indeed, by definition, prion-forming proteins can take on and stably exist in either non-prion or prion forms.PSI+] prion in the presence of the [PIN+] prion at a rate of ~7 × 10−7 [PIN+]  .Although we have not quantified the frequency with which p53 forms a prion in yeast, we easily found p53 prions following transient p53-YFP overexpression in cells constitutively expressing untagged functional p53. We screened for cells that lost p53 activity using a color assay. When we turned p53-YFP synthesis back on in cells that retained their p53 activity, p53-YFP was diffused in the cell nuclei. This is what we see when we express p53-YFP in yeast lacking the p53 prion. However, in many of the isolates that lost p53 activity, when we turned the p53-YFP synthesis back on, p53-YFP was in nuclear and cytoplasmic aggregates, indicative of prion formation. Furthermore, cells with inactive p53 only appeared following p53-YFP overexpression, but not in the control samples expressing an empty vector. We characterized one such isolate extensively showing that the prion phenotypes of p53 inactivation and aggregation could be transferred to non-prion cells by infecting them with prion cells’ cytoplasm via either cytoduction or transfection.Importantly, we showed that the prion was maintained if just untagged p53 synthesis was retained. Indeed, p53 aggregates could be seen in prion cells lacking p53-YFP expression by staining them with the amyloid-binding dye thioflavin T , p53 inactivation is therapeutic . Thus, tIn conclusion, rather than being a victim of prion fashion, p53 is a sterling example of the likely relevance of prion formation to human health.


Background: Neurogenic lower urinary tract dysfunction requires lifelong surveillance and management for the perseveration of patients’ quality of life and the prevention of significant morbidity and mortality. Urine biomarkers are an attractive noninvasive method of surveillance for these patients. The aim of this systematic review is to search for and critically appraise studies that investigate the clinical usefulness of urine biomarkers in the management of neurogenic lower urinary tract dysfunction (NLUTD) in adults. Methods: This review was conducted according to PRISMA and MOOSE guidelines. Search strategy included PubMed, CENTRAL, and Scopus (until October 2022). Studies investigating potential urine biomarkers for the management of adults with NLUTD were included. Results: Fifteen studies fulfilled the criteria. To date, a variety of different urine molecules have been investigated for the diagnosis and management of neurogenic overactive bladder and detrusor overactivity , diagnosis of vesicoureteral reflux , urinary tract infection  and bladder cancer screening  in neurological patients. Conclusion: Further studies are needed to specify the utility of each molecule in the management algorithm of adult NLUTD. Aphorisms he associated the bubbles on the surface of fresh urine with chronic kidney disease and linked the sediment of urine with fever [A biomarker is traditionally defined as any biological parameter that can be measured objectively and evaluated as an indicator of a physiological or pathological process or a response to a therapeutic intervention . Biomarkth fever . In receth fever ,9,10,11.The lower urinary tract (LUT) consists of the urinary bladder and the bladder outlet  and serves the functions of storage of urine at low pressures and periodic urine expulsion . The actAdult neurogenic lower urinary tract dysfunction (NLUTD) according to the International Continence Society (ICS) refers to the abnormal or difficult function of the bladder and urethra (and/or prostate in men) in adults, in the context of a clinically confirmed relevant neurologic disorder . NLUTD iCurrently, the available studies on NLUTD and urine biomarkers have three main areas of research focus. The main research interest is the evaluation of the role of different molecules as potential biomarkers either in the diagnosis or in the assessment of the response to treatment and in the prediction of complications of neurogenic OAB ,25,26,27This systematic review aims to summarize and critically appraise the existing evidence on the use of urine biomarkers in the management of adult NLUTD.This systematic review followed the reporting recommendations of the PRISMA statement and the guidelines of the meta-analysis of observational studies in epidemiology (MOOSE) . We did We conducted a systematic literature search until October 2022 on three major electronic databases, including PubMed (Medline), CENTRAL (Cochrane Library) and Scopus looking for articles published in English without any publication date criteria. Additionally, so as to ensure literature saturation the reference lists from the included studies or reviews were hand-searched in order to retrieve additional studies that could have escaped the search. For the search strategy we used a combination of free text and medical subject headings (MeSH) of the terms “neurogenic bladder” or “neuropathic bladder” or “neurogenic lower urinary tract dysfunction” and “biomarkers” or “urine biomarkers” or “noninvasive biomarkers” or “cancer biomarkers”. After the Medline strategy was finalized, the search string was “translated” and used in other databases. The search was conducted independently by two authors  in a blinded manner. Any discrepancies were solved after consultation with a third investigator (AA). Retrospective or prospective studies or randomized controlled trials (RCTs) of adults who have been diagnosed with NLUTD, in whom urine biomarkers were assessed with the aim of identifying their potential use in the management of NLUTD, were eligible for this systematic review. Only English language studies were included. Case reports, animal studies and conference abstracts were excluded.All relevant studies were imported into the Mendeley reference manager . Eligibility assessment was performed independently by three investigators  who screened the studies based on the predefined criteria. Disagreements were solved based on discussion. In the end, studies that were found to be eligible were screened as full text. A risk of bias assessment was performed by two reviewers , as previously described in a blinded manner. As all the eligible studies were observational studies (prospective or retrospective cohort studies), they were evaluated using the Newcastle–Ottawa Scale (NOS) . Based oData from each study was extracted in an excel sheet that was designed a priori. The following details were collected: study design, biomarker evaluated, participants’ characteristics, and outcome analysis. Due to the great heterogeneity of the results, a meta-analysis was not possible. The systematic search yielded 160 results following the removal of duplicates . After screening titles and abstracts, 128 were excluded as irrelevant. From the remaining 32 full-text studies, one could not be retrieved and 16 were excluded due to eligibility criteria. In the end, 15 studies were included in the qualitative synthesis and are illustrated in p = 0.0001). No difference was found between patients with DO due to CVD and normal controls .Yokoyama et al. : a prospp = 0.000). Levels of uNGF/Cr were significantly higher in patients with high voiding detrusor pressure (>40 cm H2O) compared to patients with low voiding detrusor pressure . A significant decrease in uNGF/Cr levels was observed after therapy in responders (n = 14) to BoNT-A injections  but not in non-responders (n = 5) to BoNT-A injections (0.76 pg/mL vs. 1.64 pg/mL p = 0.129) at 3 months.Liu et al. : a prospn = 93) and controls (n = 40). The median uNGF/Cr level was significantly higher in all patients with CVA than in controls (0.13 pg/mL vs. not detectable), with wide variations in uNGF/Cr levels. No significant difference in uNGF/Cr levels was found between patients with different urological conditions (urgency urinary incontinence (UI), impaired awareness of UI, OAB or no OAB, p = 0.805) and with different urodynamic findings . The increasing level of the severity of neurological impairment according to the American Heart Association Stroke Outcome Classification was correlated with significantly higher uNGF/Cr levels .Liu et al. : a prosp2 (PGE2), prostaglandin F2α (PGF2a), NGF and substance p in patients with suprapontine brain diseases (n = 114) and controls (n = 27). The NLUTD cohort was classified into four groups: patients without LUT symptoms (n = 19); the increased bladder sensation group (IBS) (n = 37); the OAB-dry group (n = 22); and the OAB-wet group (n = 36). Urinary PGE2 levels were significantly higher in all four groups of patients compared with controls. Patients in the OAB-dry and OAB-wet groups had significantly increased levels of urinary PGE2 compared to the patient group without LUTS . In terms of urinary PGF2a levels, patients in the OAB-wet group had significantly higher levels compared to patients without LUTS (p < 0.001). Urinary levels of NGF and substance P were not significantly different between the four groups of patients and between NLUTD patients and controls. Yamauchi et al. : a prospn = 37) and controls (n = 10). The uNGF concentration was <10 pg/mL  in all investigated samples.Krebs et al. : a prosp2, transforming growth factor beta-1 (TGFβ-1) and the tissue inhibitor of metallopeptidase 2 (TIMP-2) between NLUTD patients of different neurogenic etiology . Patients suffering from multiple sclerosis had significantly higher levels of urinary NGF/Cr and BDNF/Cr compared to the other two groups . Patients suffering from SCI had significantly lower urinary levels of TGFβ-1 compared to spina bifida patients . Urodynamic parameters were not significantly associated with any of the urine biomarkers levels. Richard et al. : a singl2, BDNF, matrix metalloproteinase 2 (MMP-2), TIMP-2 and TGF-β1 for adverse urodynamic parameters and for upper urinary tract damage in NLUTD patients due to spina bifida (n = 40). In terms of urodynamic findings, the urinary levels of TIMP-2 and MMP-2 were significantly associated with poor bladder compliance (<20 mL/cmH2O) . TIMP-2 was significantly associated with upper urinary tract damage upon contrast-enhanced computed tomography scanning .Peyronnet et al. : a prospn = 60). The levels of the urinary exosomal vitronectin were significantly higher in VUR patients (n = 25) than in no-VUR patients (n = 35) (p < 0.0001), the sensitivity and the specificity of the biomarker was 80% and 82.9%, respectively. Li et al. : a prospn = 16), NLUTD (n = 12) and controls (n = 12). The levels of urinary microRNAs miR-10a-5p and miR-363-3p were significantly higher in the NLUTD group compared to BLUTD and controls . Urinary microRNA miR-301b-3p levels were significantly higher in BLUTD patients compared to NLUTD patients and controls (p = 0.0071).Von Siebenthal et al. : a prospn = 27) participating in a prospective clinical trial, assessing the correlation of urine neutrophil gelatinase-associated lipocalin levels (uNGAL) and likelihood of UTI. Patients of the likely-UTI group had significantly higher levels of uNGAL compared to the patients in the no-UTI group and the patients in the unlikely-UTI group . A difference in uNGAL levels was also found between the no-UTI and unlikely-UTI groups (p < 0.01).Forster et al. : A seconn = 12) and spinal lesions (n = 11). Urine levels of IL-6 were found to be significantly increased during UTI in pooled and intra-individual comparisons to ABU . A threshold value of 25 ng/L in the urinary levels of IL-6 had a specificity of 93% and sensitivity of 77% in the diagnosis of UTI episodes with high-scoring symptoms.Sunden et al. : a longin = 208) had undergone a bladder biopsy due to a long-term indwelling catheter, gross or persistent microscopic hematuria, bladder stone, progressive urethral stricture or suspicious cytology. The sensitivity and specificity of the suspicious cytology results for BCa diagnosis were 71% and 97%, respectively. Stonehill et al. : a retron = 16). Eight from the eleven available cytologies were positive for bladder cancer diagnosis.Hess et al. : a retron = 457). Three patients were diagnosed with non-invasive BCa during the study period, all three tests were negative before BCa diagnosis.Davies et al. : a prospn = 79). The sensitivity and specificity of cytology for BCa diagnosis were 83.3% and 43.7%, respectively.Pannek et al. : a retroQuality assessment was conducted using the NOS, as mentioned previously. Four of them were high-quality studies, seven medium- and four low-quality. Results of the quality evaluation are illustrated on This is the first systematic review to evaluate studies that investigate the use of urine biomarkers in patients diagnosed with NLUTD. The fact that urine biomarkers can be easily collected by non-invasive methods makes them attractive to be used not only as a tool for diagnosis but also for the surveillance of various conditions in this specific group of patients. 2, PGF2a, substance P and TGFβ-1) as potential biomarkers for the assessment of neurogenic DO.A common trait of most patients with NLUTD is neurogenic DO causing OAB symptoms, such as urinary frequency, urgency and incontinence, and carrying the risk of upper urinary tract deterioration . A plethNGF is undoubtedly the most studied urine biomarker in the NLUTD population. NGF is a small signaling protein that regulates the growth and survival of sensory and sympathetic fibers, which both have a vital role in the micturition pathways . In the 2, PGF2a and substance P) only PGE2 correlated with the severity of OAB symptoms [Concerning NLUTD due to suprapontine brain diseases, uNGF levels were not elevated in two studies ,22. In o2, TGFβ-1, MMP-2 and TIMP-2) and urodynamic findings. In the study by Richard et al., none of the biomarkers tested were associated with urodynamic parameters. The levels of urine NGF/Cr and BDNF/Cr were associated with the etiology of NLUTD, and were found to be elevated in multiple sclerosis patients when compared to SCI and spina bifida patients [Two studies examined the association between multiple urine biomarkers  in patients with NLUTD due to spina bifida. This was the only study which assessed the diagnostic performance of the biomarkers; the area under the ROC curve (AUC) for the diagnosis of poor bladder compliance was 0.70 for MMP-2 and 0.69 for TIMP-2. In the same study, TIMP-2 was associated with upper urinary tract damage diagnosed by CT scans with an AUC of 0.72; a threshold of 405.9 pg/mL had sensitivity of 72.7% and specificity of 72.6% for diagnosing upper urinary tract damage [2O [Peyronnet et al. described positive associations between elevated urinary TIMP-2 and MMP-2 and poor bladder compliance , HOXC6 and DLX1 miRNAs or TMPRSS2:ERG, which are used in the diagnosis or surveillance of men with prostate cancer ,56,57,58Another major issue for patients with NLUTD is the difficulty to accurately diagnose urinary tract infections (UTI) from asymptomatic bacteriuria (ABU). Impaired storage and voiding function results in elevated post-void residual urine that predisposes them to the risk of UTI . DiagnosAnother biomarker that has been investigated as a potential tool in diagnosing infection in this population is uNGAL. In the adult population it has been explored as a marker for identifying acute kidney injury, while in the paediatric population with NLUTD, it has been thoroughly studied as a tool that could aid in differentiating UTI from ABU ,69,70,71BCa in the NLUTD population is a major concern. Although its incidence is not as high as thought in previous years, the aggressiveness of the disease together with a younger age at diagnosis, higher percentage of squamous cell carcinoma and a higher mortality compared to the general population highlights the need for early diagnosis and treatment ,74,75,76Regarding urine cytology, three retrospective studies have reported a sensitivity ranging between 71 and 83.3% and two studies reported a specificity of 43.7–97% in SCI patients with long-term indwelling catheters or symptoms of BCa ,31,33. OIn our systematic review we tried to be as comprehensive as possible, adhering to the PRISMA and MOOSE guidelines. However, this study has some limitations. Most studies were of evidence level 2 or 3  and no randomized controlled trial compared the urine biomarkers to invasive methods of management. There was great heterogeneity regarding the biomarkers studied and the study designs, thus a meta-analysis was not possible. Furthermore, some of the studies were retrospective, which could possibly introduce confounding errors that could affect their results. Moreover, many of the included studies have a small sample size thus it is difficult to interpret their results with safety. Finally, our review did not include “grey literature”, thus some information related to our subject may have been missed.This systematic review summarized the available evidence for urine biomarkers in the management of adults diagnosed with NLUTD. During the last two decades, numerous urine molecules have gained interest, which are involved in the diagnosis and surveillance of neurogenic overactive bladder and detrusor overactivity, the diagnosis of vesicoureteral reflux and urinary tract infection, and bladder cancer screening in this specific population. However, the paucity of evidence and conflicting results do not allow the application of any of the urine biomarkers in every day clinical practice. Further studies providing a high level of evidence are needed to specify the utility of each molecule in the management algorithm of adult NLUTD.


Cancer is largely caused by genetic alterations such as mutations in a group of genes known as cancer driver genes. Many of the key advances in cancer treatment in recent years have involved blocking these driver genes using a new generation of anti-cancer drugs. Although p53 is the most frequently mutated gene in human cancers, historically, it has proved difficult to develop drugs against it. However, recently, several new drugs have become available for neutralizing the cancer-promoting effects of mutant p53. The aim of this article is to discuss the most promising of these drugs, especially those that are being investigated in clinical trials.TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant  TP53 which encodes the p53 tumor suppressor protein.Molecularly targeted therapy has had a major beneficial impact on the outcome of patients with several different cancer types in recent years. Thus, the use of drugs targeting HER2 amplification/overexpression in breast cancer , mutant TP53 (p53) is the most widely studied gene in the human genome [TP53 mutations in most types of cancer. Indeed, across all human cancers, TP53 is the most frequently altered gene with mutations occurring in approximately 50% of cases [TP53 is the most frequently mutated gene in most types of solid tumors. Most of these mutations belong to the missense type (70–80%) and are located in the DNA-binding region. Functionally, these mutations may result in loss of function, exertion of a dominant-negative effect or acquisition of a new ability [n genome , with ovof cases ,7. Furth ability ,7. DespiAlthough there are currently no approved drugs for targeting mutant p53, several are currently undergoing clinical trials. Most of these investigational drugs mediate their action by either reactivating mutant p53 back to a form with at least some wild-type properties or by promoting degradation of the mutant protein ,9 Figur. The aimTP53 mutations are present in approximately 50% of all cancers. Importantly, however, mutations occur at a particularly high prevalence (>80%) in some of the currently most aggressive tumors such as high grade serous ovarian cancer [As mentioned above, n cancer , triple n cancer , esophagn cancer  and smaln cancer . Thus, iMutant p53 is believed to promote cancer development via two main mechanisms, i.e., cell intrinsic (direct effect on tumor cells) and cell extrinsic (direct effect on tumor microenvironment) ,15,16. CAvailable data suggest that several anti-cancer drugs act at least in part by promoting apoptosis mediated via wild-type p53 . ConsistClonal mutations, i.e., mutations that are present in all or most of the malignant cells within a tumor are believed to be superior targets for drug treatment than non-clonal mutations (mutations present in a subset of tumor cells). Based on available evidence, mutations in p53 appear to occur early and are clonal in many different cancer types .Mutant forms of p53 possessing missense mutations tend to accumulate in malignant cells. The accumulation may partly relate to the inability of the mutant protein to induce expression of the E3 ubiquitin ligase MDM2, which targets p53 for proteasomal-mediated catalyzed degradation ,26. In cWhile theoretically, mutant p53 is a highly attractive target for cancer therapy, there are several difficulties in designing drugs to block its functioning. Indeed, it is considerably more challenging to restore normal activity to a defective tumor suppressor protein such as mutant p53 than to block the actions of a driver oncoprotein . The difUnlike several oncogenes which are usually mutated at a small number of hot spot areas, p53 has been shown to undergo at least 2000 different mutations (giving rise to >2000 mutant/variant proteins) . Indeed,Further complicating the impact of the different mutations is that the same mutation might have different effects in different cell types, i.e., it is cell-context dependent. For example, p53 has been reported to induce the transcription of different sets of genes in different tissue types ,34. IndeAdding yet further diversity is that the mutant p53 protein can be post-translationally modified at multiple amino acid residue sites. These alterations, which include phosphorylation, acetylation, methylation, ubiquitylation and glycosylation , may alsDeveloping a specific inhibitor against all of the different forms of mutant p53 might be expected to be highly difficult, if not impossible.With the exceptions of Y220C, Y220S and Y220N, most mutant forms of p53 lack an obvious deep pocket into which low molecular compounds can bind with high affinity and specificity . DespiteMonoclonal antibodies are amongst the most specific drugs used to treat cancer, but their current use is largely confined to targeting transmembrane proteins. However, as mutant p53 is primarily located in the cell nucleus, it cannot be readily reached with the current generation of these antibodies. A possible strategy for overcoming this problem, however, is to target processed mutant p53 bound to MHC proteins on the cancer cell membranes with so-called bispecific T-cell receptor mimic antibodies ,43.By far, the most widely investigated mutant p53 reactivating drug is eprenetapopt (previously known as APR-246). As the mode of action of this compound has been previously discussed in detail ,45,46, iAs might be expected from a small molecule that binds to thiol groups, eprenetapopt/MQ can also attach to other intracellular molecules containing these structures. In particular, it can also attach to the tripeptide, glutathione (GSH) and the redox modulating enzymes, thioredoxin reductase thioredoxin and glutaredoxin ,48,49,50n = 7) or prostate cancer (n = 7). Overall, eprenetapopt was found to be well tolerated, the most frequent adverse effects were fatigue, dizziness, headache and confusion, all of which were reported to be reversible. Evidence for reactivation of mutant p53 was the finding of cell cycle arrest, induction of apoptosis and upregulation of p53 target genes in tumor cells from several treated patients.Based on several preclinical studies showing anti-cancer activity ,44, epreTP53 mutant myelodysplastic syndromes (MDS) (n = 40) or AML (n = 11) [TP53 mutations exhibited a significantly higher complete response rate than those lacking mutations . Furthermore, patients achieving a response had a reduction in both TP53 mutation levels  and p53 protein levels. The most frequent adverse events (grade ≥ 3) in this trial were febrile neutropenia (33%), leukopenia (29%) and neutropenia (29%). Essentially similar findings were reported with eprenetapopt plus azacytidine in a second phase II trial involving patients with MDS or AML [Subsequently, eprenetapopt in combination with azacytidine was investigated in a phase Ib/II trial in patients with (n = 11) . The oveS or AML .TP53 mutant MDS. Although results from this trial do not appear to have been published to date in the peer-reviewed literature, according to the Aprea website , it failed to meet the primary statistical endpoint of complete remission. Complete response rates however, tended to be higher in the combination arm, i.e., 33.3% of patients receiving eprenetapopt with azacytidine achieved a CR versus 22.4% in the azacitidine alone arm. However, the press release stated that with further follow-up, secondary endpoints such as overall response rate and duration of response might favor the combination arm.The above findings led to a phase III trial of eprenetapopt plus azacitidine versus azacitidine for the frontline treatment of patients with Despite this negative finding, eprenetapopt has received Breakthrough Therapy, Orphan Drug and Fast Track designations from the US FDA for MDS, and Orphan Drug designation from the European Commission for patients with MDS, AML and ovarian cancer.COTI-2 is described as a third generation thiosemicarbazone drug with broad anti-cancer activity ,57,58. COther actions of COTI-2 include activation of AMP-activated protein kinase (AMPK) and inhibition of mTOR signaling . These eClinicalTrial.gov website , this trial “is designed primarily to assess the safety and tolerability of COTI-2 monotherapy or combination therapy in patients with advanced and recurrent malignancies to establish a recommended phase II dose for future studies”. Preliminary data suggest that COTI-2 is well tolerated, the most frequent adverse effects being nausea, vomiting, fatigue and abdominal pain. Of the 24 patients treated, only 2 (8%) were reported to have to undergo a decrease in the dose of COTI2 administered [COTI-2 as a monotherapy or in combination with standard therapies has undergone evaluation for the treatment of several different types of recurrent cancers in a phase I clinical trial NCT02433626). According to the US National Library of Medicine, 6. AccordArsenic trioxide (ATO), a drug which has been used for several years to treat acute promyelocytic leukemia, was recently shown to reactivate mutant forms of p53 possessing structural mutations . This acIn addition, a reactivating p53, ATO, has also been reported to degrade the mutant protein . Thus, AClinicalTrials.gov Identifier: NCT04695223).A potential advantage of ATO over other mutant p53-reactivating drugs such as eprenetapopt and COTI-2 is that its pharmaceutical and toxicological properties are well established . It shouIn contrast to the mutant p53 reactivating drugs discussed above, PC14586 specifically reactivates mutant p53 proteins containing the Y220C mutation . As mentBAX, PUMA, MDM2 and CDKN1A (encodes p21) as well as induction of cell cycle arrest. Consistent with the ability of mutant p53 to induce immunosuppression (see above), administration of PC14586 was found to enhance immunity by increasing influx of immune cell such as CD4+ T cells, CD8+ T cells, T-regulatory cells and natural killer T cells into tumors [In mutant cell lines, PC14586 was found to reactivate and stabilize the p53 Y220C mutant protein . In turno tumors . In miceo tumors .PC14586 monotherapy is currently being investigated in a phase I/II clinical trial in patients with advanced cancers harboring the p53 Y220C mutation (NCT study identifier NCT04585750). The aim of this multicenter dose escalation study is to evaluate PC14586 safety, pharmacokinetics, pharmacodynamics and possibly efficacy in patients with advanced solid tumors possessing a p53 Y220C mutation. Preliminary findings presented at the 2022 American Society of Clinical Oncology conference suggest that PC14586 is generally well-tolerated with only grade I/II adverse events which were found in 79% of the treated patients . The mosTP53 Y220C mutation.Recently, the US FDA granted Fast Track designation to PC14586 for the treatment of cancer patients with locally advanced or metastatic solid tumors possessing a The advantage of mutant-specific drugs such as PC14586 over other mutant p53 reactivators such as eprenetapopt is that they are unlikely to bind to wild-type p53 or indeed to other intracellular proteins. The main disadvantage, however, is that the p53 Y220C mutation is relatively rare in cancer, being only the 9th most frequent mutation. Despite this low frequency, the Y220C is estimated to be responsible for in excess of 100,000 cases of cancer per year, worldwide .Another strategy for targeting “difficult to drug” driver oncoproteins such as mutant p53 is to treat with compounds that promote their degradation and thus their elimination from tumor cells. Such drugs in everyday clinical use include fulvestrant which acts by degrading the estrogen receptor and is used for the treatment of patients with estrogen receptor-positive metastatic breast cancer  and lenaProof of principle that the presence of mutant p53 was necessary for the maintenance of malignancy emerged from knockdown studies which showed that depletion of the mutant protein reduced oncogenicity . AmongstThese observations led to the testing of low molecular weight HSP inhibitors as potential drugs for cancer treatment. Early work using preclinical models confirmed that treatment with low molecular weight HSP90 inhibitors such as ganetespib, 17-allylamino-17-demethoxygeldanamycin or geldanamycin did indeed result in the degradation of specific forms of mutant p53 and inhibition of tumor cell growth . In contMore recently, treatment with a group of widely used drugs known as statins, was also shown to result in degradation of mutant p53 ,81,82,83Several studies have recently shown that decreased production of MVP leads to the degradation of mutant p53 ,81,82,83p53 with conformational mutations [Consistent with their ability to degrade mutant p53, several different statins when used alone have been shown to inhibit the in vitro and in vivo growth of cancer cells in model systems ,82,83,85utations , other sClinical evidence supporting an anti-cancer role for statins are multiple epidemiological studies showing that patients with a range of different cancer types undergoing treatment with statins have a superior outcome compared with those not receiving these drugs ,86,87,88TP53 mutation and are at risk of developing large intestinal cancer . A third trial  is investigation the benefit of neoadjuvant atorvastatin plus zoledronate in patients with triple negative breast cancer . In this study, response is being related to the level of cellular p53. In addition to these trials, several studies are investigating if statins have anti-cancer activity irrespective of p53 status  (accessed on 1 June 2022).One of these is a window-of-opportunity trial to determine if administration of atorvastatin decreases levels of p53 with conformational mutations in patients with different solid tumor or AML (NCT03560882). Another is a phase II trial investigating the effect of atorvastatin for treating patients with ulcerative colitis who have a dominant-negative missense Should any of these trials produce positive findings, statins might be expected to rapidly enter clinical use for the treatment of cancer. As with ATO (see above), statins have been in clinical use for several years. Thus, their pharmaceutical and toxicological properties are also well established. Since they are relatively safe, inexpensive and off-patent, they would be ideally suitable for repurposing for the treatment of cancer.Before concluding this section, it is also important to add that in addition to degrading mutant p53 via downregulation of the mevalonate pathway, there are several other mechanisms by which statins could exert anti-cancer activity . IndeedTP53 is mutated in a large proportion of human cancers, it would be expected to act as a neoantigen and promote an immune response, thereby opening up the potential of exploiting it as an anti-cancer vaccine. Evidence from mice models and patients with cancer showed that administration of certain p53 neo-epitopes containing hot-spot mutations did indeed provoke the generation of specific T cell (CD8+ and CD4+ cells) responses against p53 peptides containing the hot-spot mutations [25–35, p53110–124, p53149–157 and p53264–272 have been observed in experimental systems [A further strategy for targeting mutant p53 that has progressed to clinical trial investigations is vaccination against the mutant protein. The aim of therapeutic cancer vaccination is to stimulate a patient’s adaptive immune system against tumor (neo)antigens and thus block tumor growth. As utations ,94. Thus systems ,94. Thes systems ,94. Sinc systems . Althoug systems .Before concluding this section, it should be stated that these negative clinical findings are not unique to mutant p53 as a cancer vaccine . DespiteFuture research on anti-cancer vaccines including p53 vaccines should therefore focus on optimizing delivery of the vaccine to the appropriate cellular location, selecting the optimum adjuvant to be co-administered with the vaccine, identifying the optimum dose and treating patients with early cancer (where immunosuppression would be expected to be limited) rather that patients with advanced cancer (where immunosuppression would be expected to be strong).Several other strategies for targeting mutant p53 are currently undergoing investigations, most of which are still at a preclinical level . Gene thGoing forward, one of the most promising approaches for targeting mutant proteins such as mutant p53 is likely to be the use of bispecific T-cell receptor mimic antibodies, i.e., antibodies in which one end binds to a mutant epitope on a tumor cell and the other end to a T-cell. It was mentioned above that the present generation of monoclonal antibodies cannot readily access nuclear proteins such as mutant p53. However, peptides derived from such mutant proteins can be processed by the proteasome system and converted into small peptides. These peptides can attach to HLA proteins located on the cell membrane and hence be recognized by T-cell via their T-cell receptors.TP53 gene, i.e., the R175H mutation. The bispecific single chain antibody, named H2scD, bound to both the specific mutant p53 peptide attached to an HLA allele (A*02:01) and the T-cell receptor. By binding to both sites, the bispecific antibody was able to activate T cells and consequently eliminate cancer cells possessing the specific mutant peptide. Theoretically, this strategy could be used to target other mutant forms of p53 as well as other mutant proteins such as KRAS [To target such peptides, Hsiue et al.  develope as KRAS . AlthougTP53 mutation, R273H. Evidence of gene correction was the induction of several canonical p53 target proteins such as p21, MDM4, PUMA and GADD45A. Further work by Sayed et al. [TP53 R175H mutation in a cell line derived from a colorectal cancer organoid. The challenge will be to translate this technology to patients with cancer.Another potential strategy for targeting cancer-specific mutations is the use of CRISPR/Cas9 gene editing. This technology uses genetic engineering to alter the cells’ genome . In one d et al.  showed tTP53 mutations [Other potential strategies for targeting muting mutant p53 include the use of PROTACs/molecular glues which can lead to degradation of specific mutant proteins , inductiutations  and explutations . AlthougWith the multiplicity of ongoing clinical trials, we should soon know whether targeting mutant p53 has clinical efficacy in cancer. The recent demonstration of response to PC14586 provides some optimism that mutant p53 may eventually be targeted for cancer treatment. However, irrespective of the outcome of the ongoing trials, mutant p53 remains a highly attractive target for cancer treatment (see above). We, therefore, encourage academic researchers and pharma companies to intensify their research into exploiting the most frequently mutated gene in cancer for therapeutic potential. The ultimate reward could be a drug with wide application across a broad range of cancer types.


The purpose of this study is to explore cohort differences in the trajectories of cognition and functional limitations among oldest-old adults. Using 1992-2018 data from the Health and Retirement Study, participants included those who survived to at least 98 years (N=494). The study included three cohorts  predicting intercept and slope of cognition and functional limitations. Two separate latent growth curve models were computed, and models of cognition, χ2(5)=6.935, p=.226 and functional limitation, χ2(7)=7.743, p=.35 fit the data well. There was a significant decline in cognition levels and a significant increase in functional limitation over time. When adding cohort, results indicated that older cohorts were more likely to have a decrease in cognition and increase in functional limitations compared with the younger cohort. Future research should investigate trajectories of other health variables for a better understanding of health changes of centenarians.


Our understanding of Alzheimer’s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses. More recently, the p53 protein, well-known as a genome guardian, has gained attention for its potential role in the early evolution of AD. This is due to the central involvement of p53’s in the control of oxidative stress and potential involvement in the Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can affect brain processes, thus contributing to AD development. The following review will explore the impact of p53 PTMs on its function and consequential involvement in AD pathogenesis. The greater understanding of the role of p53 in the pathogenesis of AD could result in more targeted therapies benefiting the many patients of this debilitating disease. Alzheimer’s disease (AD) is a pernicious condition of the aging population that leads to progressive degeneration of brain function, whose characteristic anatomopathological hallmarks, firstly described by Alois Alzheimer, remain the senile plaques and neurofibrillary tangles which consist of beta-amyloid peptides and hyperphosphorylated Tau proteins . The forThe amyloid hypothesis of AD pathology suggests that the increased presence of amyloid-beta (Aβ) is the triggering factor, which then links directly to Tau protein hyper-phosphorylation, synapse loss, and cell death .However, the classical amyloid hypothesis has been questioned  and otheGSK-3β is a critical cell cycle regulation factor and has an important function in neurons for Tau regulation. Increased GSK-3β activity has been shown to be one of the first events in AD pathology, leading to increased Aβ production and Tau hyper-phosphorylation . MoreoveMitochondrial dysfunction has also been implicated in AD pathology, Oxidative stress, damage by free radicals in parallel with changes in the expression of superoxide dismutase (SOD) and catalase, both important anti-oxidant enzymes, have been shown in tissue from AD patients .Interestingly, In the AD brain, fatty acid oxidation has been linked to Tau pathology, and p38 MAPK has been linked as a potential candidate gene within the relevant MAP Kinase pathway . FurtherThe development of clinical symptoms of AD requires many decades for pathological changes to develop . HoweverAs seen in cancer, cellular response mechanisms involve multiple pathways. The role of one of these genes, TP53, is now being revealed as central to the cellular response to cancer and other diseases, including obesity and aging-associated neurodegenerative disorders . Given tEver since the discovery of p53  it has bTumorigenesis of p53 has been shown in numerous mouse experiments where p53 loss-of-function predisposes cells to permanent damage and tumor transformation . Tumorigp53 has been shown to have further roles including the control of cell metabolism, pluripotency, epigenetic control, and aging . As p53 The role of p53 is now realized to be much greater than simply dealing with DNA damage. Thus, p53 should now be regarded not only as a “genome guardian” but as a “stress guardian.”There are several cellular mechanisms that control p53 function, and post-translational modifications (PTMs) are the most common and effective type of regulation .O-GlcNAcylation, ADP-ribosylation, and β-hydroxybutyrylation  are induced by cytotoxic stimuli, which results in p53 activation and stabilization . p53 aceMethylation of lysine and arginine residues is an important control mechanism of p53 function as it’s a reversible process . InteresMDM2 ubiquitination is critical for maintaining p53 levels in the cell. This has been postulated to occur by polyubiquitination of p53 leading to proteasome pathway mediated protein degradation, which then inhibits p53-mediated transactivation . The majDifferent types of p53 ubiquitination are known to cause changes in p53 function as well as stabilization, by regulating its cytosolic location and nuclear export. p53 ubiquitination is also implicated in the disruption of its binding to promoters of target genes, similar to the action of transcription factors in the nucleus. This results in halting the cell cycle and triggering apoptosis . In unstThese include neddylation and SUMOylation .These modifications all have several common features: (i) Multiple sites: on many different amino acids. (ii) Multiple functions: that are site-specific. (iii) Reversibility: such that there are functionally modifying and de-modifying mechanisms. (iv) Cross talk: modifications at certain sites can affect modifications at other sites .Aerobic metabolism has several by products including ROS and reactive nitrogen species (RNS). RNS can initiate signaling that is transduced through redox-based PTMs of proteins. It is known that redox signaling is a critical process in cell physiology and is an important regulator of redox-sensitive proteins . The brain vitro model of amyloid precursor protein (APP) overexpression-induced Aβ load. Concomitantly, they observed an associated increase in the expression of unfolded p53, and neuronal dysfunction. Restoring the native conformational state of p53 with Zinc chloride prevented neuronal dysfunction, supporting the role of p53 in maintaining neuronal functionality  and the TP53 induced glycolysis and apoptosis regulator (TIGAR) . An impaIn vitro experiments on BACE, the rate-limiting enzyme in the generation of Aβ, showed its transcription is repressed by p53, thus affecting potential Aβ accumulation. During oxidative damage exposure, p53 expression is upregulated. This leads to a decrease in the level of BACE1 expression and potentially contributes to AD pathogenesis , is known to regulate cellular metabolic activity through the process of deacetylation/acetylation. Sirtuins are NAD+-reliant deacetylases. Sirtuin deficiency disrupts mitophagy in numerous diseases, including AD .A recent publication has shown another potential p53 regulated pathway involved in AD development involving sirtuin 6 (SIRT6). The SIRT6 pathway promotes cell longevity by controlling several different processes including energy metabolism, genome integrity and inflammation, along with DNA repair. Interestingly a reduction in the level of the SIRT6 protein has been observed in human AD brain samples . The conUpregulation of p53 protein by Nutlin-3 avoids SIRT6 decline, and DNA impairment induced by Aβ .Sirtuin family is both a stimulatory and inhibitory factor linked to p53 and, in postnatal cortical neurons, the p53 related apoptosis required PUMA transcriptional activation. PUMA, along with the Bax-mediated permeabilization of the mitochondrial outer membrane, induces cytochrome C release, caspase activation, triggering cell death. SIRT1 inhibits the apoptosis pathway by deacetylation of p53 in several senescence models .Interestingly, a recent study showed the exposure of neurons to fragments 25–35 of Aβ peptide activates Cdk5, which promotes p53 phosphorylation and stabilization . Mitocho2O2), there is no activation of p53 dependent cell cycle regulators p21, GADD45, and BAX1 genes   . The con(GAP-43) . As a co(GAP-43) . Using i(GAP-43) . StudiesThe main AD signaling pathways implicated with p53 conformational change are summarized in The relationship between Tau, Aβ, and p53 has been explored in many studies and has been considered as a potential therapeutic target for AD . The rec2+-chelating activity, metal ions are sequestered from the p53 DNA binding domain, inducing conformational changes in p53, inhibiting its activity. This directly links to When Aβ is present at nanomolar levels, through the HIPK2 inhibition, it induces metallothionein 2A expression and, with Znin vitro study  from AD patients . InteresAs previously discussed, the expression of the unfolded conformational variant of p53 was investigated in other dementias, and other brain disorders such as Parkinson’s disease, where the data indicated that p53 is differentially expressed when compared to AD patients, thus suggesting specificity for AD .To further investigate the relationship of unfolded p53 isoforms in AD, The recent study by AZ), was further validated as a potential prognostic biomarker in AD in a set of plasma samples from the longitudinal and retrospective biobank, AIBL .The conformational variant of p53, detected by 2D3A8 and then quantified by mass spectroscopy (identified as U-p53nk, AIBL . In detaThe exact pathology of AD is controversial and remains to be fully elucidated. The validity of the amyloid hypothesis is still being challenged due to the failure of several high-profile drug trials. A significant amount of evidence supports the potential role of p53 in AD pathogenesis, particularly due to the protein’s functional dysregulation and involvement in many AD pathways. PTMs are an important part of the normal regulation of p53 cellular function, and the presence of a conformational change in p53 induced by redox dysfunction in AD, leading to a loss of function in many cellular response pathways, is an indication of a central role in AD. Further studies on the conformational unfolding of p53 showed that the conformational change of the protein impacts on its role, directly increasing or decreasing the activation of specific pathways involved in AD. A recent study has also shown that p53 is expressed in the AD brain in a phosphorylated isoform in correlation with p-Tau . This stFurther studies will be necessary to further elucidate the mechanism of actions for the specific PTMs of p53 and their involvement in AD pathways.JC, SP, and PK defined the review focus. JC and SP wrote the manuscript. GA, PK, DU, and RK provided approval for publication of the content. All authors contributed to manuscript revision, read, and approved the submitted version.JC, PK, and SP were employed by Diadem srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Keratins are a group of proteins that can constitute intermediate fibers. It is a component of the cytoskeleton and plays an important role in cell protection and structural support. Keratin 17, a Type I keratin, is a multifunctional protein that regulates a variety of biological processes, including cell growth, proliferation, migration, apoptosis and signal transduction. Abnormal expression of KRT17 is associated with a variety of diseases, such as skin diseases. In recent years, studies have shown that KRT17 is abnormally expressed in a variety of malignant tumours, such as lung cancer, cervical cancer, oral squamous cell carcinoma and sarcoma. These abnormal expressions are related to the occurrence, development and prognosis of malignant tumors. In this review, we summarized the expression patterns of KRT17 in a variety of malignant tumours, the role of KRT17 in the development and prognosis of different malignant tumors and its molecular mechanisms. We also discuss the potential clinical application of KRT17 as a valuable therapeutic target. Malignant tumours are considered a serious threat and one of the leading causes of death worldwide. In addition, with the increase of the global population and unhealthy lifestyles, the situation will become more serious . AlthougKeratin is an important part of the cytoskeleton and a member of the intermediate filament superfamily. The intermediate filament (IF) cytoskeleton of mammalian epithelia is generated from pairs of type I and type II keratins, which are encoded by two large gene families and consist of 54 genes in humans and the mice . AccordiKRT17 is a type I keratin that is commonly expressed in epithelial cells . KRT17 iKeratin 17 (KRT17) belongs to the family of Type I intermediate keratins. Intermediate filaments (IFs) are a new cytoskeletal filament assembly between actin microfilaments (∼6–8 nm) and microtubules (∼25 nm). The diameter is ∼10 nm . Like alin vitro and in vivo , degree of differentiation (p = 0.011), sex (p < 0.001), age (p = 0.024), and lymph node metastasis (p = 0.04). Subgroup analysis showed that the high expression of KRT17 was only associated with sex (p = 0.002) in lung squamous cell carcinoma, while the high expression of KRT17 was associated with degree of differentiation (p = 0.036), advanced TNM stage (p = 0.005), and lymph node metastasis (p = 0.011) in lung adenocarcinoma  is a disease that can be caused by many factors . It is tColorectal cancer (CRC) is one of the major causes of cancer-related morbidity and mortality in the world . MetastaGallbladder cancer (GBC) is the sixth most common gastrointestinal malignancy and the most common bile duct cancer in the world, with a 5-years survival rate of 5–10% in most cases . TherefoPancreatic cancer is a highly fatal disease. The 5-years survival rate is only 9%, and the global incidence has increased significantly over the past few decades . SurgicaKidney cancer makes up a small percentage of all cancer types; only 2.2% . Renal cUrothelial carcinoma (UC) is a common urinary tract tumor , and aboCervical cancer ranks fourth in the incidence of malignancies and cancer-related deaths among women , accountEndometrial carcinoma (EC) is a common malignancy in women . The maiOvarian cancer is a common gynecological cancer and even the main cause of death of gynecological cancers. Although the prognosis is good at early diagnosis, the vast majority of patients are diagnosed with advanced stage, with a 5-years survival rate of about 30–40% . Therefop-mTOR, HIF1α and HIF1α glucose transporter 1 target gene expression also decreased. The re-expression of p-Akt, p-mTOR or HIF1α inhibited the inhibitory effect of KRT17 on cell proliferation and glycolysis. The results showed that KRT17 knockout inhibited the proliferation and glycolysis of osteosarcoma cells by inhibiting the Akt/mTOR/HIF1α pathway (Sarcoma is a mesenchymal malignancy with high heterogeneity. Although it accounts for only 1% of all malignancies, it is the second most common malignancy in children and adolescents . When th pathway . In Ewin pathway . AlthougSkin cancer is the most common cancer in humans. The most common types are keratinocyte derived basal cell carcinoma and SCC , but theKRT17 is highly expressed in a variety of human malignancies and may be considered a valuable gene for research. However, KRT17 is underexpressed in some tumors, and it is considered that KRT17 may play a role as a tumor suppressor gene in these tumors. The high expression of KRT17 is associated with poor clinicopathological parameters of various malignant tumours, such as tumour size, depth of invasion, lymph node metastasis, tumour differentiation, distant metastasis and survival rate. Hence, KRT17 can be used as a potential prognostic biomarker for malignant tumours. However, the prognostic significance of KRT17 in malignant tumours needs to be confirmed by a large number of clinical case studies. Similarly, KRT17 also shows the high expression levels in malignant tumour cell lines. Knockout or silenced KRT17 can inhibit the proliferation, migration, adhesion and invasion of tumour cells, and promote the apoptosis of tumour cells. It may regulate a wide variety of tumour-related molecules or pathways that play a role in tumour formation. Hence, the upstream and downstream regulatory pathways of KRT17 are of significance, but further validation is needed, especially in unreported tumours or more precise mechanism studies. In addition, KRT17 knockout can increase the chemotherapeutic sensitivity for paclitaxel and cisplatin, suggesting that KRT17 is also a feasible and valuable therapeutic target, but the exact mechanism of action remains unclear and needs further elucidation. However, whether KRT17 can improve the sensitivity of radiotherapy and the efficacy of immunotherapy and biotherapy may be a new research direction of KRT17 in the future . In addiIn conclusion, KRT17 is an important, but really understudied gene. It plays a key role in promoting the growth and metastasis of tumour cells, highlighting its role in the pathogenesis of tumour. However, KRT17 as a biomarker and therapeutic target for tumour prognosis remain a major challenge, as the exact molecular mechanisms of KRT17 action remain unclear. At present, there is no unified and standardized detection method for clinical screening of KRT17 expression.


TP73 gene belongs to the p53 family comprised by p53, p63, and p73. In response to physiological and pathological signals these transcription factors regulate multiple molecular pathways which merge in an ensemble of interconnected networks, in which the control of cell proliferation and cell death occupies a prominent position. However, the complex phenotype of the Trp73 deficient mice has revealed that the biological relevance of this gene does not exclusively rely on its growth suppression effects, but it is also intertwined with other fundamental roles governing different aspects of tissue physiology. p73 function is essential for the organization and homeostasis of different complex microenvironments, like the neurogenic niche, which supports the neural progenitor cells and the ependyma, the male and female reproductive organs, the respiratory epithelium or the vascular network. We propose that all these, apparently unrelated, developmental roles, have a common denominator: p73 function as a tissue architect. Tissue architecture is defined by the nature and the integrity of its cellular and extracellular compartments, and it is based on proper adhesive cell-cell and cell-extracellular matrix interactions as well as the establishment of cellular polarity. In this work, we will review the current understanding of p73 role as a neurogenic niche architect through the regulation of cell adhesion, cytoskeleton dynamics and Planar Cell Polarity, and give a general overview of TAp73 as a hub modulator of these functions, whose alteration could impinge in many of the Trp73–/– phenotypes.The  TP73 gene belongs to an evolutionary conserved family of transcription factors, the p53 family, with key functions to vertebrate’s biology. The genes that constitute this family, TP53, TP63, and TP73, have evolved from a common ancestor and, consequently, share a similar modular structure which consists of an amino-terminal transactivation domain (TAD), a central DNA binding domain (DBD) and a carboxy-terminal oligomerization domain (OD)  domain. This C-terminal region, involved in protein–protein interaction, might give p63 and p73 their unique signaling network of regulators and transcriptional targets  . Althougscovered , TP63 anhomologs  and diff targets . In addiM domain .Trp73–/–  and in the dentate gyrus, and loss of Cajal-Retzius (CR) neurons , has shed new light on the role of p73 isoforms in the development of the murine brain   and has in vitro . In accoin vitro . On the in vitro . This lene brain . These mhenotype . The authenotype . Intereshenotype . In the henotype . HoweverNeurogenesis in the mammalian brain is complex and requires specialized microenvironments called “niches” . In the Trp73–/– mice is the complete lack of cytoarchitecture in the SVZ neurogenic niche  10 and 12, when the tight junctions that couple neuroepithelial cells convert into adherens junctions, and the cells acquire features associated with glial cells . It is nto E16.5 . This isto E16.5 . By E16 to E16.5 . Moreoveto E16.5 . Neverthto E16.5 . Thus, cto E16.5 , should Trp73 is necessary for the efficient establishment of both types of PCP , even ahead of p73 role in controlling cell death/cell proliferation . Also coZonula occludens protein ZO2, a scaffold protein that physically links transmembrane tight junction proteins to the apical cytoskeleton of actomyosin  or Scd4 (DEG in Saos-TetOn and E14TG2α). FSCN1 is an actin binding-protein involved in the formation of essential cell structures for migration, cell-to-cell interactions and cell-matrix adhesion (A similar situation occurred for genes related to actin cytoskeleton regulation. In this case, we draw our attention to the functional annotation terms “GO:0030029∼actin filament-based process,” “GO:0032970∼regulation of actin filament-based process” and “GO:0007015∼actin filament organization.” Among the DEGs shared within cell models, we could find some genes playing relevant roles for cytoskeleton dynamics, like adhesion ; therefoadhesion . Syndecaadhesion . Loss ofadhesion . FindingTrp73 knockout scenario are further supported by the recent study of Trp73 gene isoforms. Altogether, the analyzed studies indicate that the integration of -omics data could be a very valuable strategy to provide a more comprehensive dissection of p73 regulated molecular networks and, overall, they place p73 as a central hub in the regulation of cell adhesion and cytoskeleton dynamics, two cornerstones for tissue architecture.The DEG analysis of cell adhesion and cytoskeleton dynamics clusters for the individual models led as to ask whether we could define a more global transcriptional profile by comparing the whole list of DEGs assigned to these clusters in Saos2-TetOn, MGCs, and mESCs . For botTP73 belongs to one of the most intensively studied gene families in molecular oncology. The considerable interest stems from the fact that most human tumors have subverted the function of the founding member of this family, the p53 protein. Thus, since its serendipitous discovery (TP73 gene is a very rare event in cancers involving chromosome 1p (iscovery , p73 tumiscovery . Howeverosome 1p . Moreoveosome 1p .Trp73 deficient mice have revealed that p73 function is essential for the organization and homeostasis of different complex microenvironments governing various aspects of tissue physiology. Altogether, this has raised the idea that TAp73 was not evolved for tumor suppression, but rather to perform unique functions in regulating developmental processes through p53-independent mechanisms (Trp73–/– mice are the reflection of the p73 requirement for the establishment and/or maintenance of tissue organization (The discovery of the TA- and DN-p73 isoforms with antagonist anti- and pro-oncogenic functions, and the TAp73KO mice predisposition to spontaneous tumorigenesis, demonstrated TAp73 role as a tumor suppressor gene . Howeverchanisms . We propnization . This funization . Thus, iIn this model, p73 regulates distinct transcriptional nodes in a hierarchical manner that would functionally interact with each other in a cell context and time dependent manner. Cell adhesion mechanisms are responsible for assembling cells together and, along with their connections to the internal cytoskeleton, determine the overall architecture of the tissue . In thisMCM and MMM conceived the review and took the lead in writing. LM-A performed data analysis and crafted the figures. LL-F performed a critical revision of the article. All authors provided critical feedback and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


FANCM protein truncating variants (PTVs) are emerging as risk factors for ER-negative and triple negative breast cancer. Here, we discuss evidence that greatest risk associates with PTVs, such as p.Arg658*, that extensively truncate the 2048 amino acid FANCM protein. Moreover, risks associated with other less-truncating FANCM PTVs such as p.Gln1701* and p.Gly1906Alafs12* may be amplified by additional gene variants acting as modifiers. Further studies need to be conducted taking into considerations these aspects. BRCA1 and BRCA2 genes are associated with a high-risk of breast and ovarian cancers. These genes are now widely screened to assess the risk of developing these diseases in variant carriers and their relatives. Over the last 15 years, protein-truncating variants (PTVs) in several other genes have been described or proposed to cause moderate- to high-risk for breast cancer but insufficient data hamper a conclusive annotation. Early this year, two large case-control studies were published in the New England Journal of Medicine, which aimed to clarify which genes should be used clinically and to estimates the breast cancer risk magnitude associated with PTVs in each gene. These studies were based on the sequencing of 34 and 28 known or candidate breast cancer risk genes in 113,000 women from 25 countries, and 64,000 women from the US, respectively2. Both studies found that PTVs in the 8 genes BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were significantly associated with breast cancer risk. In particular, PTVs of ATM and CHEK2 were associated with risk of estrogen receptor (ER) positive breast cancer, and PTVs of BARD1, RAD51C, and RAD51D with a risk of ER-negative breast cancer. Moreover, among the genes previously proposed to be associated with an increased risk of breast cancer, the majority including NBN and RECQL, were found not associated. The unparalleled statistical power of such a large dataset appears to make this a definitive designation4. But for one of the candidate genes, FANCM, the role in breast cancer predisposition appears more nuanced. In the Dorling et al. study, FANCM PTVs were not found to be associated with overall breast cancer risk nor to have an effect on age at diagnosis, but were statistically associated with risk in ER-negative breast cancer cases  disease subtypes  change expected according to the genetic code. Instead, as we showed in cell-based experiments, the variant creates a consensus sequence for a splicing silencer triggering the skipping of exon 22. This causes a frameshift starting at aa position 1906 forming a stop codon 12 codons later6. Therefore, while the c.5791 C >T variant is universally known as p.Arg1931*, the correct protein annotation of this variant would be p.Gly1906Alafs12*. FANCM:c.5101 C >T (p.Gln1701*) is another PTV identified in a Finnish population study, by exome sequencing of 11 breast cancer families. Further genotyping of this allele found it to be significantly associated with breast cancer risk with higher ORs detected in ER-negative and TNBC cases8. In addition to single PTVs genotyping studies, two burden analyses of all FANCM PTVs discovered by gene sequencing were published10. Altogether, these data indicate that, while the association with risk for breast cancer was inconclusive, FANCM PTVs might be risk factors for familial breast cancer or for ER-negative and TNBC disease subtypes , which is the third most common FANCM PTV found in Europeans, in a large study including breast cancer cases and controls from 19 European countries. Surprisingly, we only found p.Arg658* to be associated with risk of ER-negative and TNBC subtypes11. We also functionally tested these three PTVs for their capacity to rescue survival and chromosome fragility in a FANCM−/− patient-derived cell line exposed to the DNA damaging agent diepoxy butane. We observed that p.Arg658* was unable to rescue the cell survival and chromosome fragility while p.Gln1701* and p.Gly1906Alafs12* showed an intermediate effect11. This is consistent with the fact that the p.Gln1701* and p.Gly1906Alafs12*, located in the C-terminus of the protein, are both expected to just disrupt the binding domain of the partner protein FAAP24; while p.Arg658*, located much upstream in the gene, is expected to cause the loss of greater protein portions. Based on these genetic and functional data, it is possible to speculate that the effects on breast cancer risk of the different FANCM PTVs might be due to the extent of protein truncation of the PTV. In support of this hypothesis, two women with early-onset breast cancer (at age 29 and 32); were genotyped as homozygotes for p.Arg658*. In addition, one developed several cancers, and the other demonstrated chromosomal fragility12. In the same study, two women genotyped as homozygotes for p.Gln1701*, and one homozygous for p.Gly1906Alafs12*, developed breast cancer at age 52 or later, and their cells did not demonstrate chromosome fragility.More recently, we tested 13 which are lost in the Arg658* variant protein. Previous in vitro work has shown that the ability to recruit Fanconi and Bloom syndrome complexes is more important to the function of FANCM protein than the association with FAAP2413. Furthermore, although yet to be experimentally validated, Arg658* can be predicted to act in a dominant-negative fashion. Because the Arg658* protein variant retains the N-terminal DNA binding and ATPase domain, it could potentially block the recruitment of DNA repair complexes by the full-length protein in heterozygotes and reduce DNA repair capacity. In most other breast cancer genes, including BRCA1 and BRCA2, it is the loss of DNA repair capacity that associates with variant severity.As FANCM protein is a large, multi-domain anchor that binds both DNA and other protein complexes at DNA damage sites, different effects may arise relating to breast cancer predisposition, depending upon the protein domains deleted. For example, p.Gln1701* and p.Gly1906Alafs12* delete the C-terminal DNA binding domain and FAAP24 interaction site but retain interaction with two complexes necessary for DNA repair (the Fanconi Anemia core complex and the Bloom syndrome complex). These protein complexes associate at distinct regions located between aa 960–1210BRCA1, BRCA2, and other genes associated with breast cancer, there is also an impact of population ancestry and potential modifier alleles. Could this explain the differences between studies investigating FANCM variants and their impact on breast cancer? First, the Finnish studies were based on the p.Gln1701* and p.Gly1906Alafs12* genotyping in geographically, ethnically, and genetically matched cases and controls. In addition, the p.Gln1701* and p.Gly1906Alafs12* carrier frequencies are high in Finns being 1.62% and 0.92%, vs. 0.21% and 0.21% in non-Finnish Europeans (https://gnomad.broadinstitute.org/), respectively. This has allowed the authors of these studies to derive robust associations with ER-negative and TNBC risk in a relatively small sample size. Second, the multicentric study was based on greater case-control numbers allowing to reach a statistical power sufficiently large to show that p.Arg658*, despite a low carrier frequency of 0.033% in non-Finnish Europeans (https://gnomad.broadinstitute.org/), was associated with ER-negative and TNBC risks11. It is hence puzzling that in this study no association was found for p.Gln1701* and for p.Gly1906Alafs12* and risk for breast cancer or the ER-negative and TNBC disease subtypes. One potential explanation is the relative genetic isolation of the Finnish population. Finns have recurrent BRCA1/2 founder PVs and at least 12 other PVs in the moderate risk genes ATM, CHEK2, FANCM, PALB2, RAD51C, and RAD51D have known that account for the majority of Finnish breast cancer cases with a genetic component14. In addition, an excess of double heterozygosity for variants in the moderate penetrance genes has also been documented in Finns14. It can therefore be speculated that some other modifier allele exists within this population which amplifies the p.Gln1701* and p.Gly1906Alafs12* risk effects, although the studies to locate such a modifier have yet to be conducted.For FANCM PTVs could be moderate risk factors for ER-negative and TNBC. It is possible that deletions that remove more of the FANCM protein, such as p.Arg658*, are likely to have a stronger effect on both the DNA repair defect and the risk for ER-negative or TNBC. Conversely, the risk effects of FANCM:p.Gln1701* and p.Gly1906Alafs12* on these breast cancer subtypes are probably lower but may be amplified by additional variants acting as modifiers. Importantly, the two new very large studies from Dorling et al. and Hu et al. have not analyzed each FANCM PTVs singularly nor grouped based on their location within the gene. More clear results about which of the FANCM PTVs are moderate risk factors for ER-negative or TNBC and which are not may arise if this were to be done.In conclusion, all these observations indicate that certain


As 87Sr/86Sr ratio, and furthermore, the 87Sr/86Sr ratio is far more influenced by the type of bedrock  than the age of bedrock.Generally, the geological age of the bedrock does not necessarily indicate a certain 87Sr/86Sr ratio does not seem to have been successful, as this isn’t even shown. Such an evaluation was done only in combination with further isotopic parameters analyzed.Based on the geological situation of Slovenia, as shown by Gregorcic et al. 2021) [ [1], a f87Sr/86Sr ratio of soil  or also enriched (acidic-magmatic and metamorphic rocks)   , (Fi, (Fi87Sr87Sr/86Sr ratio for determination and control of geographic origin can be a very potent tool, depending on the exact question intended to be answered. Areas with homogenous bedrock geology and variations in 87Sr/86Sr ratio are very well suited, whereas heterogeneous bedrock geological settings are a challenge for this method, as outliers and heterogeneous values within individual areas are to be expected. One must keep in mind that the highest 87Sr/86Sr ratio for Slovenian truffles [Application of truffles ,7 was re