Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations

Hereditary breast carcinomas constitute about 10% of all malignant mammary tumors, but the selection criteria to identify a high-risk population carrying BRCA1 mutations are not yet well-defined. We have collected 51 pedigrees of familial breast cancer, 16 pedigrees of familial breast and ovarian cancer, and 30 cases of early-onset breast cancer (<35 years of age) without any family history of breast cancer. The index cases of the 97 selected families were further subdivided into three groups based on histopathological parameters: group A (n = 19) was characterized by tumor grade III, negative estrogen and progesterone receptors, and high proliferative rate; group B (n = 20) was characterized by grade I-II tumors, positive hormonal receptors, and low proliferative rate; and group C (n = 58) was not homogeneous for the histopathological criteria. The aim of our study was to evaluate, in patients with a family history of breast cancer or with early diagnosis of breast cancer, the incidence of BRCA1 mutation on the basis of tumor phenotype. We found the highest rate of BRCA1 mutations in group A (53%), and low frequencies in groups B (5%) and C (0%). Our data strongly indicate that an aggressive tumor phenotype in patients with a positive family history or early diagnosis identifies a population with high probability of carrying BRCA1 mutations. Genes Chromosomes Cancer 27:130-135, 2000.     

Does Inflammation Mediate the Association Between Obesity and Insulin Resistance?

In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings.     

Case study of patents related to captopril,Squibb’s first blockbuster

Introduction: Arterial hypertension affects over one billion people around the world, making the prevention and treatment of this disease vital. Despite the efforts made to develop new antihypertensive drugs, few new therapies have become available. Angiotensin-converting enzyme (ACE) inhibitors have heralded major steps forward in the treatment of arterial hypertension and cardiovascular diseases since the first compound of this class, captopril, was approved for clinical use in 1981.

Areas covered: In this review, the authors investigated the patent documents that cite the priority patent for captopril, Squibb’s first blockbuster, or any other patent from its patent family. The documents were classified into the following: new compounds, new compositions, treatment, process (preparation of a compound), use of a compound, and process for the preparation of an intermediate. Therefore, the readers can identify potential innovations in the field.

Expert opinion: The pharmaceutical sector has attempted to provide significant technological developments on anti-hypertensive drugs based on the patenting of captopril, including the development of new compositions further comprising an ACE inhibitor and other antihypertensive agent, along with dual action compounds, novel molecules with dual activity. The target is to find a new agent with better blood pressure-lowering efficacy, improved safety and good tolerability pro?le.     

Tissue-selective inflammation in the oral cavity of the rat

In the current study, carrageenan (CG; 100–1000 μg/site) was injected intraorally in the cheeks of Holtzman or Wistar rats to evaluate the consequences of administration of a non-immunogenic stimulus in the orofacial region. Subsequent inflammation was measured as oedema (increased thickness of the cheek wall using digital calipers), relative to the other cheek injected with saline. Oedema formation and tissue collection for histopathological studies were assessed at 0.5, 1, 2, 3, 4, 6, 24, 48, 72, 96, 120 and 144 h after injection. In parallel, other groups of rats were injected with CG in the hind paw, to provide a reference response. The inhibitor of prostaglandin biosynthesis, indomethacin, and antagonists of histamine, serotonin and NK₁ receptors were injected s.c., 0.5 h before CG. CG induced a dose-related oedema more rapidly from 0 to 2 h which lasted for at least 72 h, showing a biphasic profile (peak at 2 and 24 h), compared with the monophasic oedema induced in rat paws (maximal duration of 24 h). Histopathological analysis of the CG-injected cheek revealed oedema formation with little leukocyte recruitment at 1–3 h, mast cell degranulation at 6 h, and a mixed polymorphonuclear and mononuclear cell infiltrate by 24 h. Histamine and serotonin antagonists and indomethacin, but not the NK₁ antagonist, decreased cheek oedema in the first 4 h following carrageenan. Taken together, our data indicated important differences in the pattern of inflammation between the oral cavity and the paw which will determine the therapeutic approach to the treatment of inflammatory conditions in the oral cavity.     

Lower Respiratory Tract Infection and Genus Enterovirus in Children Requiring Intensive Care: Clinical Manifestations and Impact of Viral Co-Infections

Infection by rhinovirus (RV) and enterovirus (EV) in children ranges from asymptomatic infection to severe lower respiratory tract infection (LRTI). This cohort study evaluates the clinical impact of RV/EV species, alone or in codetection with other viruses, in young children with severe LRTI. Seventy-one patients aged less than 5 years and admitted to the Paediatric Intensive Care Unit (PICU) of a reference children’s hospital with RV or EV (RV/EV) LRTI were prospectively included from 1/2018 to 3/2020. A commercial PCR assay for multiple respiratory pathogens was performed in respiratory specimens. In 22/71, RV/EV + respiratory syncytial virus (RSV) was found, and 18/71 had RV/EV + multiple viral detections. Patients with single RV/EV detection required invasive mechanical ventilation (IMV) as frequently as those with RSV codetection, whereas none of those with multiple viral codetections required IMV. Species were determined in 60 samples, 58 being RV. No EV-A, EV-C, or EV-D68 were detected. RV-B and EV-B were only found in patients with other respiratory virus codetections. There were not any associations between RV/EV species and severity outcomes. To conclude, RV/EV detection alone was observed in young children with severe disease, while multiple viral codetections may result in reduced clinical severity. Differences in pathogenicity between RV and EV species could not be drawn.     

Second-line therapy for metastatic urothelial carcinoma: Defining the best treatment option among immunotherapy,chemotherapy, and antiangiogenic targeted therapies. A systematic review and meta-analysis

There is no second-line standard of care universally accepted for platinum-refractory metastatic urothelial carcinoma. Immunotherapy and anti-VEGF(R) targeted therapies are 2 emerging strategies with promising though inconclusive results. We perform a systematic meta-analysis to assess the available options. We searched MEDLINE/PubMed, the Cochrane Library, and American society of clinical oncology (ASCO) Meeting abstracts to identify prospective studies. Data extraction was conduced according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The measured outcomes were overall survival (OS) and progression free survival (PFS). Seven randomized controlled trials were selected for final analysis, with a total of 2,451 evaluable patients. Chemotherapy with vinflunine did not reduce the risk of progression (HR?=?1.11; 95%CI 0.78–1.57; P = .56) or death (HR?=?0.97; 95%CI 0.70–1.34; P?=?.87) compared to taxanes. Immunotherapy with anti-PD-1/PD-L1 mAb improved OS over chemotherapy (HR?=?0.81; 95% CI 0.71–0.92; P<.0009). The OS benefit of immunotherapy was retained when compared to taxanes, but not compared to vinflunine, although without a significant difference between the 2 subgroups (P?=?.30). A lack of PFS (HR?=?0.73; P?=?.08) and OS (HR?=?1.0; P?=?.99) benefit was observed with an anti-VEGF(R) plus chemotherapy compared to chemotherapy alone. No PFS (P?=?.14) or OS (P?=?.13) differences were detected when comparing anti-VEGF(R) ± chemotherapy and immunotherapy. Immunotherapy significantly improved OS compared to chemotherapy in metastatic urothelial carcinoma unselected for PD-L1 status. The addition of anti-VEGF(R) to chemotherapy did not provide any statistically significant benefit in terms of PFS or OS. Single agent taxanes or vinflunine can be considered given their similar efficacy but different toxicity profiles.