Correlation Clustering with Adaptive Similarity Queries

In correlation clustering, we are givennobjects together with a binary similarityscore between each pair of them. The goal is to partition the objects into clustersso to minimise the disagreements with the scores. In this work we investigatecorrelation clustering as an active learning problem: each similarity score can belearned by making a query, and the goal is to minimise both the disagreementsand the total number of queries. On the one hand, we describe simple activelearning algorithms, which provably achieve an almost optimal trade-off whilegiving cluster recovery guarantees, and we test them on different datasets. On theother hand, we prove information-theoretical bounds on the number of queriesnecessary to guarantee a prescribed disagreement bound. These results give a richcharacterization of the trade-off between queries and clustering error

Quantification of Women Who Could Benefit from Hormone Therapy after Endometrial Cancer Treatment: An Analysis of SEER Data

Our primary aim was to estimate the magnitude of stage I endometrial cancer (EC) survivors that could benefit from hormonal therapy (HT). Our secondary aims were to assess EC incidence in women below 50 and below 60 over the years, and analyze the overall survival and any influencing factors. We analyzed the endometrioid EC data from the Surveillance, Epidemiology, and End Results (SEER) program according to women’s age, tumor stage, and grade. We analyzed the proportions of EC survivors below 50 and below 60 years of age and stratified those age groups by race. For age distribution and survival analysis SEER, 18 registries’ research data (2000–2018) were analyzed. We analyzed the SEER 12 registries’ research data (1992–2019) for incidence time trends. Our investigation found a 14% and 40% cumulative prevalence of stage I EC that occurs in women below 50 or 60 years, respectively. EC’s prevalence has progressively risen in recent decades, but cancer-specific mortality remains low. The increasing number of women affected by EC in premenopause or early postmenopause face an 18 years-survival rate of 96.86% and 95.73%, respectively. A significant proportion of low-grade EC survivors can potentially benefit from HT treatment, and this requires awareness of other aspects of their health or quality of life, in addition to cancer treatments

Risk-Reducing Breast and Gynecological Surgery for BRCA Mutation Carriers: A Narrative Review

This narrative review aims to clarify the role of breast and gynecological risk-reduction surgery in BRCA mutation carriers. We examine the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options from the perspectives of a breast surgeon and a gynecologist. A comprehensive literature review was conducted using the PubMed/Medline, Scopus, and EMBASE databases. The databases were explored from their inceptions to August 2022. Three independent reviewers screened the items and selected those most relevant to this review’s scope. BRCA1/2 mutation carriers are significantly more likely to develop breast, ovarian, and serous endometrial cancer. Because of the Angelina effect, there has been a significant increase in bilateral risk-reducing mastectomy (BRRM) since 2013. BRRM and risk-reducing salpingo-oophorectomy (RRSO) significantly reduce the risk of developing breast and ovarian cancer. RRSO has significant side effects, including an impact on fertility and early menopause (i.e., vasomotor symptoms, cardiovascular disease, osteoporosis, cognitive impairment, and sexual dysfunction). Hormonal therapy can help with these symptoms. Because of the lower risk of developing breast cancer in the residual mammary gland tissue after BRRM, estrogen-only treatments have an advantage over an estrogen/progesterone combined treatment. Risk-reducing hysterectomy allows for estrogen-only treatments and lowers the risk of endometrial cancer. Although prophylactic surgery reduces the cancer risk, it has disadvantages associated with early menopause. A multidisciplinary team must carefully inform the woman who chooses this path of the broad spectrum of implications, from cancer risk reduction to hormonal therapies

Iperparatiroidismo ipercalcemico post-trapianto renale: un problema per il nefrologo

Descriviamo un caso di una paziente dializzata, sottoposta a paratiroidectomia pre-trapianto: la PTX non è stata risolutiva per mancato reperimento della IV ghiandola; a 6 mesi dall'intervento si è manifestata, infatti, una recidiva dell'iperparatiroidismo. Nel frattempo si è presentata la possibilità di eseguire un trapianto renale. Nonostante la "recidiva" dell'IPT, è stato deciso di optare per il trapianto renale che è stato effettuato con successo e con recupero precoce della funzione renale: si è manifestato, però, nel post-trapianto, un iperparatiroidismo residuale ipercalcemico. Di fronte al rischio di rendere aparatiroidea la paziente con una nuova PTX, si è optato per una terapia farmacologica. Per 6 anni la paziente trattata con calcitriolo (0,5–0,25 mcg a giorni alterni, con periodiche interruzioni dovute all'ipercalcemia) e difosfonati a cicli, ha mantenuto livelli di calcemia e di paratormone al di sopra dei valori di normalità senza raggiungere livelli di rischio, mentre il VFG si è mantenuto stabilmente nella norma. Nel dicembre 2008 a seguito di una frattura della branca ischio-pubica e per un progressivo incremento nell'ultimo anno dei livelli di calcemia e del PTH viene deciso di iniziare la somministrazione "off label" di Cinacalcet, di sospendere gradualmente lo steroide e di sostituire la ciclosporina con il Tacrolimus. Nei 3 anni di trattamento abbiamo notato, mantenendo costante la dose somministrata di Cinacalcet (30 mg/die), una riduzione significativa e persistente nel tempo dei livelli di calcemia e del PTH e un incremento della fosforemia. La funzione renale è persistita stabile senza episodi di rigetto. Indagini tomodensitometriche ripetute hanno rilevato un quadro di osteopenia sostanzialmente invariato. La nostra singola ma prolungata esperienza conferma in accordo con dati recenti della letteratura e in attesa dei risultati di uno studio RCT attualmente in corso, che questo farmaco può rappresentare una reale alternativa alla PTX mostrando grande efficacia e mancanza di effetti collaterali

Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections

BACKGROUND & AIMS: Chronic microial infections aare frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. METHODS: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls, B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand+IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide+IL-2, as innate immunity signal. Proliferation was examined by cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. RESULTS: A significantly higher proportion of B cells from both HCV-and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3(+) B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustin marker. CONCLUSIONS: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation

The fading guardian: clinical relevance of TP53 null mutation in high-grade serous ovarian cancers

Backgroundwe evaluated the concordance between immunohistochemical p53 staining and TP53 mutations in a series of HGSOC. Moreover, we searched for prognostic differences between p53 overexpression and null expression groups.Methodspatients affected by HGSOC were included. For each case p53 immunohistochemical staining and molecular assay (Sanger sequencing) were performed. Kaplan-Meier survival analyses were undertaken to determine whether the type of TP53 mutation, or p53 staining pattern influenced overall survival (OS) and progression free survival (PFS).Results34 HGSOC were considered. All cases with a null immunohistochemical p53 expression (n=16) showed TP53 mutations (n=9 nonsense, n=4 in-frame deletion, n=2 splice, n=1 in-frame insertion). 16 out of 18 cases with p53 overexpression showed TP53 missense mutation. Follow up data were available for 33 out of 34 cases (median follow up time 15 month). We observed a significant reduction of OS in p53 null group [HR = 3.64, 95% CI 1.01-13.16].Conclusionimmunohistochemical assay is a reliable surrogate for TP53 mutations in most cases. Despite the small cohort and the limited median follow up, we can infer that HGSOC harboring p53 null mutations are a more aggressive subgroup

Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections

Background & Aims: The phenotypic and functional characteristics of natural killer (NK) cells in chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are incompletely defined and largely controversial. Methods: We studied NK cell receptor expression, cytotoxic activity, and cytokine production in peripheral blood mononuclear cells from 35 patients with chronic hepatitis C, 22 with chronic hepatitis B, and 30 healthy controls. Results: Patients with chronic HBV infection had an increased proportion of NKG2C+ NK cells with normal inhibitory receptor expression and a lower proportion of activated NK cells compared with HCV+ patients, which was associated with normal or reduced cytolytic activity and markedly dysfunctional tumor necrosis factor-\u3b1 and interferon-\u3b3 production. Patients with chronic HCV infection showed a predominantly activating phenotype, featuring a decreased percentage of cells expressing the inhibitory receptor KIR3DL1 and a concomitant increase in the proportion of NKG2D+ NK cells. Expression of the CD69 early activation antigen on NK cells positively correlated with serum alanine aminotransferase and HCV RNA values, suggesting participation of virus-induced effector NK cells in liver necroinflammation. Phenotypic changes in HCV+ patients were associated with enhanced cytokine-induced cytolytic activity and increased usage of natural cytotoxicity and NKG2D receptor pathways, accompanied by defective cytokine production, although to a lesser extent than patients with chronic HBV infection. Conclusions: These findings provide evidence for a functional dichotomy in patients with chronic HBV and HCV infections, featuring conserved or enhanced cytolytic activity and dysfunctional cytokine production, which may contribute to virus persistence