A prospective analysis of the management practices for patients with Stage-III-N2Non-Small-Cell lung cancer (OBSERVE IIIA-B GFPC 04-2020Study).

Background: Management of stage-III-N2 non-small-cell lung cancer (NSCLC) based on a multimodal strategy (surgery or radiotherapycombined with systemic drugs) remains controversial. Patients are treated with a curative intent, and available data suggestprolonged survival after complete resection. However, no consensual definition of "tumor resectability" exists.

The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies.

Background: Clinical development paradigms for cell and gene therapies appear to be different to those of more conventional treatments: therefore, it is informative to explore this from the perspective of investments required to bring a new cell and/or gene therapy to the market. While there are a number of studies in the literature analyzing clinical-stage R&D costs for novel therapeutics, these are 'modality-agnostic' and thus do not elucidate costs specifically for the emerging class of cell and gene therapies.

Objectives: The objective of this study was to understand the research and development (R&D) costs associated with the clinical development of new cell and gene therapy assets METHODS: As part of our analysis of clinical-stage R&D costs for cell and gene therapies, we focused our efforts on cell and gene therapy assets recently approved by the US Food and Drug Administration (FDA) or expected to receive FDA approval by the end of 2024.

The UBC9/SUMO pathway affects E-cadherin cleavage in HPV-positive head and neck cancer.

Functional loss of E-cadherin is frequent during tumor progression and occurs through a variety of mechanisms, including proteolytic cleavage. E-cadherin downregulation leads to the conversion of a more malignant phenotype promoting Epithelial to Mesenchymal Transition (EMT). The UBC9/SUMO pathway has been also shown to be involved in the regulation of EMT in different cancers.

Pricing and Market Access Challenges in the Era of One-Time Administration Cell and Gene Therapies.

With a large number of one-time administration cell and gene therapies expected to come to the market in the coming years, there is a renewed need to understand the existing and future challenges that such modalities bring about, especially as it relates to their assessment of value, pricing and access. Payer, health technology assessment (HTA) bodies and manufacturers alike are faced with a number of unprecedented challenges stemming from the fact that such therapies are 'one-time' and/or have curative intent, but often lack sufficient evidence to support such claims at the time of launch (i.e.

Immune-Checkpoint Inhibitors for Malignant Pleural Mesothelioma: A French, Multicenter, Retrospective Real-World Study.

Backgrounds: Malignant pleural mesothelioma (MPM) is a cancer with poor prognosis. Second-line and onward therapy has many options, including immune-checkpoint inhibitors with demonstrated efficacy: 10−25% objective response rate (ORR) and 40−70% disease-control rate (DCR) in clinical trials on selected patients. This study evaluated real-life 2L+ nivolumab efficacy in MPM patients and looked for factors predictive of response.

Escherichia coli coculture for de novo production of esters derived of methyl-branched alcohols and multi-methyl branched fatty acids.

Background: A broad diversity of natural and non-natural esters have now been made in bacteria, and in other microorganisms, as a result of original metabolic engineering approaches. However, the fact that the properties of these molecules, and therefore their applications, are largely defined by the structural features of the fatty acid and alcohol moieties, has driven a persistent interest in generating novel structures of these chemicals.

Results: In this research, we engineered Escherichia coli to synthesize de novo esters composed of multi-methyl-branched-chain fatty acids and short branched-chain alcohols (BCA), from glucose and propionate.

Myeloprotective Effects of Trilaciclib Among Patients with Small Cell Lung Cancer at Increased Risk of Chemotherapy-Induced Myelosuppression: Pooled Results from Three Phase 2, Randomized, Double-Blind, Placebo-Controlled Studies.

Purpose: Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression (CIM) by protecting hematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myeloprotection). Here, we investigated the myeloprotective effects of trilaciclib among patients at increased risk of CIM.

Patients And Methods: Data were pooled from three randomized, double-blind, placebo-controlled, phase 2 clinical studies of trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC).

Adipocyte-induced transdifferentiation of osteoblasts and its potential role in age-related bone loss.

Our preliminary findings have lead us to propose bone marrow adipocyte secretions as new contributors to bone loss. Indeed, using a coculture model based on human bone marrow stromal cells, we previously showed that soluble factors secreted by adipocytes induced the conversion of osteoblasts towards an adipocyte-like phenotype. In this study, microarray gene expression profiling showed profound transcriptomic changes in osteoblasts following coculture and confirmed the enrichment of the adipocyte gene signature.

The determinants of dyspnoea evaluated by the mMRC scale: The French Palomb cohort.

Introduction And Objective: Dyspnoea is a major symptom in COPD patients, but the determinants that could be associated with a higher dyspnoea mMRC score in COPD patients remain unclear. Our research aimed to study the determinants of dyspnoea at the threshold of 1, 2, 3 and 4 mMRC.

Patients And Methods: Diagnosis of COPD was made using spirometry with post-bronchodilator FEVFVC<70%.

Patent Cliffs in the Era of Complex Therapies and Biologics.

Introduction: The rise of new product classes such as biologics and complex molecules over the past two decades have brought to light some of the unique market dynamics that such products face. While we have seen and experienced the inception, growth and expansion phase of such products, the ongoing incumbent decline due to loss of exclusivity (LoE) is yet to be fully experienced. This raises the question of how one may go about modelling such a scenario given that forecasting the expected erosion curves accurately can ensure full brand value is retained for pharmaceutical companies.

Electrocardiogram for the Diagnosis of Acute Myocardial Infarction in Patients with Right Ventricular Paced Rhythm: Old but Gold.

Ventricular pacing may interfere with the interpretation of ECG among patients with suspected acute myocardial infarction (AMI), with possible delay of reperfusion therapy. Since left bundle branch block has a similar ECG morphology to right ventricular paced rhythm, Sgarbossa and modified Sgarbossa criteria could be useful in this setting. We present four clinical cases in which a recently proposed clinical-instrumental algorithm has been adopted to manage patients with right ventricular paced rhythm and suspected AMI.

Susceptibility to frequent exacerbation in COPD patients: Impact of the exacerbations history, vaccinations and comorbidities?

Introduction: Exacerbations are key events in the natural history of COPD, but our understanding of their longitudinal determinants remains unclear. We used data from a large observational study to test the hypothesis that vaccination status and comorbidities could be associated with the occurrence of exacerbations profile.

Methods: Diagnosed COPD patients have been included by their pulmonologists, with up to 3 years of follow-up.

Effect on splanchnic oxygenation of breast milk, fortified breast milk, and formula milk in preterm infants.

Background: Enteral feeding induces mesenteric hemodynamic changes in preterm infants, which may vary according to the milk used. Our aim in this study was to evaluate changes of splanchnic regional oxygenation (rSOS) measured by near-infrared spectroscopy (NIRS) in infants fed with mother's own milk (MOM), fortified human milk (FHM), or preterm formula (PTF).

Methods: Infants born at 25-31 weeks of gestational age (n = 54) received a bolus of MOM, FHM, or PTF.

Sodium butyrate induces genotoxic stress in function of photoperiod variations and differentially modulates the expression of genes involved in chromatin modification and DNA repair in Petunia hybrida seedlings.

Sodium butyrate applied to Petunia hybrida seeds under a long-day photoperiod has a negative impact (reduced seedling length, decreased production of photosynthetic pigments, and accumulation of DNA damage) on early seedling development, whereas its administration under dark/light conditions (complete dark conditions for 5 days followed by exposure to long-day photoperiod for 5 days) bypasses some of the adverse effects. Genotoxic stress impairs plant development. To circumvent DNA damage, plants activate DNA repair pathways in concert with chromatin dynamics.

Human Papilloma Virus Increases ΔNp63α Expression in Head and Neck Squamous Cell Carcinoma.

P63, and in particular the most expressed ΔNp63α isoform, seems to have a critical role in the outcome of head and neck cancer. Many studies have been conducted to assess the possible use of p63 as a prognostic marker in squamous cell carcinoma cancers, but the results are still not well-defined. Moreover, a clear relationship between the expression of ΔNp63α and the presence of high-risk HPV E6 and E7 oncoproteins has been delineated.

Analysis of Toll-Like Receptors in Human Milk: Detection of Membrane-Bound and Soluble Forms.

The bioactive and anti-inflammatory role of human milk components has been recognized; active milk components include soluble forms of Toll-like receptors (TLRs). Preterm babies are more susceptible to infections and may succumb to necrotizing enterocolitis (NEC), a gastrointestinal disease which is exacerbated by an excessive inflammatory response after TLR activation. Here, we investigated the presence of Toll-like receptors TLR1/2/4/6 in colostrum and mature milk of women who delivered before (preterm) or after (term) 37 weeks of gestational age, integrating classical immune-related techniques with proteomic LC-MS/MS analysis.

Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from β-Amyloid Toxicity.

A novel form of thyroid hormone (TH) signaling is represented by 3-iodothyronamine (TAM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine-associated receptor 1 (TAAR), and induces pro-learning and anti-amnestic effects in mice. Dysregulation of TH signaling has long been hypothesized to play a role in Alzheimer's disease (AD). In the present investigation, we explored the neuroprotective role of TAM in beta amyloid (Aβ)-induced synaptic and behavioral impairment, focusing on the entorhinal cortex (EC), an area that is affected early by AD pathology.

Human papillomavirus as a driver of head and neck cancers.

The human papillomavirus (HPV) family includes more than 170 different types of virus that infect stratified epithelium. High-risk HPV is well established as the primary cause of cervical cancer, but in recent years, a clear role for this virus in other malignancies is also emerging. Indeed, HPV plays a pathogenic role in a subset of head and neck cancers-mostly cancers of the oropharynx-with distinct epidemiological, clinical and molecular characteristics compared with head and neck cancers not caused by HPV.

Lipolytic Effects of 3-Iodothyronamine (T1AM) and a Novel Thyronamine-Like Analog SG-2 through the AMPK Pathway.

3-Iodothyronamine (T1AM) and its synthetic analog SG-2 are rapidly emerging as promising drivers of cellular metabolic reprogramming. Our recent research indicates that in obese mice a sub-chronic low dose T1AM treatment increased lipolysis, associated with significant weight loss independent of food consumption. The specific cellular mechanism of T1AM's lipolytic effect and its site of action remains unknown.

Women's health providers' perspectives on preimplantation genetic testing.

Research Question: What are the perspectives of women's health providers on the use of preimplantation genetic testing (PGT) for common medical disorders?

Design: A cross-sectional 15-question online anonymous survey was conducted of women's health providers specializing in general obstetrics/gynaecology, gynaecologic oncology and infertility at a tertiary care academic institution in Massachusetts, USA. Respondents could answer 'yes', 'no' or 'unsure' to each thematic question.

Results: The survey was sent to 1060 providers and 240 providers responded (response rate 22.

Müllerian inhibiting substance/anti-Müllerian hormone as a fertility preservation agent.

Purpose Of Review: The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Müllerian inhibiting substance (MIS) as an ovarian fertoprotectant.

Recent Findings: MIS is unique in its mechanisms of ovarian protection by virtue of acting directly on granulosa cells of primordial follicles and for being a benign reproductive hormone, with few side effects. We will explore in this review how it may be utilized to protect the ovary from chemotherapy, or to enhance ovarian tissue cryopreservation therapy.

Biochemical characterization of the minimal domains of an iterative eukaryotic polyketide synthase.

Iterative type I polyketide synthases (PKS) are megaenzymes essential to the biosynthesis of an enormously diverse array of bioactive natural products. Each PKS contains minimally three functional domains, β-ketosynthase (KS), acyltransferase (AT), and acyl carrier protein (ACP), and a subset of reducing domains such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER). The substrate selection, condensation reactions, and β-keto processing of the polyketide growing chain are highly controlled in a programmed manner.

Müllerian-Inhibiting Substance/Anti-Müllerian Hormone as a Predictor of Preterm Birth in Polycystic Ovary Syndrome.

Context: There is increasing evidence for Müllerian-inhibiting substance (MIS)/anti-Müllerian hormone (AMH) physiologic activity in the human uterus, so it is relevant to study how MIS/AMH levels impact pregnancy.

Objective: To investigate the association of MIS/AMH levels with the risk of adverse obstetric outcomes.

Design: Retrospective cohort study.