Human gut microbiota analysis of cystic fibrosis infants using metaproteomics.

We report a metaproteomic analysis of the gut microbiota of eight infants with cystic fibrosis, during the first year of life. This is the first study in this disease that uses metaproteomics to analyze stool samples from patients at such a young age.

Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Exophthalmos and ocular pain as clinical debut of intracranial Hodgkin's lymphoma at diagnosis.

Intracranial involvement in Hodgkin's Lymphoma (HL) is extremely unusual, especially at the time of diagnosis. Because of its non-specific radiological behaviour, it can be confused with more common entities with a radically different prognosis. Pathologically, large and bi-nucleated cells, called Reed-Sternberg cells, embedded in an inflammatory network. In this report we describe the clinical case of a patient, with no medical history, with left ocular pain and exophthalmos as presetation of intracranial HL at diagnosis and review the most current literature. Intracranial involvement is often associated with extracranial disease. Therefore, a systemic study including body computed tomography, bone marrow biopsy and ophthalmological evaluation is necessary. Intracranial lesions respond favourably to treatment and the prognosis depends on the extracranial involvement. To date, there is no standardised management scheme for these patients. For us, the primary role of surgery in this context is to perform a biopsy to confirm the histological diagnosis.

Hepatocellular carcinoma in Peru: A molecular description of an unconventional clinical presentation.

INTRODUCTION AND AIM: Hepatocellular carcinoma (HCC) is the third most frequent cancer of digestive tract tumors in Peru, with a high mortality rate of 17.7 per 100,000 inhabitants. A significant number of HCC cases in Peru do not follow the classic clinical epidemiology of the disease described in other parts of the world. Those patients present with a distinct transcriptome profile and a singular tumor process, suggesting a particular type of hepatocarcinogenesis in a portion of the Peruvian population. Our aim was to understand the clinical and biologic involvement of the epigenetic profile (methylation) and gene expression (transcriptome) of HCC in Peruvian patients. METHODS: HCC and liver transcriptome and DNA methylation profiles were evaluated in 74 Peruvian patients. RESULTS: When grouped by age, there was greater DNA methylation in younger patients with HCC but no differences with respect to the transcriptomic profile. A high prevalence of the hepatitis B virus (HBV) (>90%) was also observed in the younger patients with HCC. Enrichment analyses in both molecular profiles pinpointed PRC2 as an important molecular effector of that liver tumor process in Peruvian patients. CONCLUSION: HCC in Peruvian patients has a unique molecular profile, associated with the presence of HBV, as well as overall DNA hypermethylation related to undifferentiated liver cells or cellular reprogramming.

An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment.

Protein phosphorylation is a major regulatory mechanism of cellular signalling. The c-JUN proto-oncoprotein is phosphorylated at four residues within its transactivation domain (TAD) by the JNK family kinases, but the functional significance of c-JUN multisite phosphorylation has remained elusive. Here we show that c-JUN phosphorylation by JNK exhibits defined temporal kinetics, with serine63 and serine73 being phosphorylated more rapidly than threonine91 and threonine93. We identify the positioning of the phosphorylation sites relative to the kinase docking motif, and their primary sequence, as the main factors controlling phosphorylation kinetics. Functional analysis reveals three c-JUN phosphorylation states: unphosphorylated c-JUN recruits the MBD3 repressor, serine63/73 doubly-phosphorylated c-JUN binds to the TCF4 co-activator, whereas the fully phosphorylated form disfavours TCF4 binding attenuating JNK signalling. Thus, c-JUN phosphorylation encodes multiple functional states that drive a complex signalling response from a single JNK input.

GREM1 is required to maintain cellular heterogeneity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1-4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3-5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1 inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1 overexpression caused an almost complete 'epithelialization' of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1 was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial-mesenchymal transition transcription factors Snai1 (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial-mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability.

Oxaliplatin is the first-line regime for advanced gastric cancer treatment, while its resistance is a major problem that leads to the failure of clinical treatments. Tumor cell heterogeneity has been considered as one of the main causes for drug resistance in cancer. In this study, the mechanism of oxaliplatin resistance was investigated through in vitro human gastric cancer organoids and gastric cancer oxaliplatin-resistant cell lines and in vivo subcutaneous tumorigenicity experiments. The in vitro and in vivo results indicated that CD133+ stem cell-like cells are the main subpopulation and PARP1 is the central gene mediating oxaliplatin resistance in gastric cancer. It was found that PARP1 can effectively repair DNA damage caused by oxaliplatin by means of mediating the opening of base excision repair pathway, leading to the occurrence of drug resistance. The CD133+ stem cells also exhibited upregulated expression of N6-methyladenosine (m6A) mRNA and its writer METTL3 as showed by immunoprecipitation followed by sequencing and transcriptome analysis. METTTL3 enhances the stability of PARP1 by recruiting YTHDF1 to target the 3'-untranslated Region (3'-UTR) of PARP1 mRNA. The CD133+ tumor stem cells can regulate the stability and expression of m6A to PARP1 through METTL3, and thus exerting the PARP1-mediated DNA damage repair ability. Therefore, our study demonstrated that m6A Methyltransferase METTL3 facilitates oxaliplatin resistance in CD133+ gastric cancer stem cells by Promoting PARP1 mRNA stability which increases base excision repair pathway activity.

[Prevalence of diabesity in the Spanish working population: influence of sociodemographic variables and tobacco consumption].

BACKGROUND: Obesity predisposes to type 2 diabetes so often that the combination is called diabesity. The aim of this study was to determine the prevalence of diabesity in the working population and to analyze the variables associated with it. METHOD: Cross-sectional study between January 2019 and June 2020 by 418,343 workers from 18 to 67 year-old, from different professions and Spanish geographic areas. The prevalence of diabesity was determined with six different for-mulae for obesity: BMI (body mass index), CUN BAE (Clínica Universidad de Navarra Body Adiposity Estimator), ECORE-BF (Equation Córdoba for Estimation of Body Fat), Formula Palafolls, FMI (fat mass index) of Deuremberg and RFM (relative fat mass). The association between diabetes and age, sex, social class and tobacco was analyzed. RESULTS: The global prevalence of diabetes ranged from 2.6% for BMI to 5.8% for the Palafolls formula. The variable most related to diabesity was age over 50 years (OR?=?5.9; 95%CI: 5.7-6.2 for BMI, and OR?=?8.1; 95%CI: 7.9-8.4 for FMI of Deuremberg). Male sex and social class III related with diabesity estimated by all formulas, while being a smoker was only related with the Palafolls formula. CONCLUSION: Diabesity prevalence varies depending on the formula used, with much lower prevalence among women and increased with age independent of the formula used. Its prevalence is higher in the lower social classes.

Pustular lesions in patients with Crohn disease and treatment with tumour necrosis factor-α inhibitors.

We present seven new cases of patients with Crohn disease who developed lesions clinically compatible with amicrobial pustulosis of the flexures during their treatment with anti-tumour necrosis factor therapy.

USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma.

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

PARP1 Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway.

Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients' follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited in vivo and in vitro OXA resistant organoid growth and viability.

Properties of the avocado oil extracted using centrifugation and ultrasound-assisted methods.

The aim of this work was to evaluate the technologies effect of cold extraction by centrifugation (CE) and ultrasound-assisted (US-CE) methods without adding water, on the avocado oil yield, nutritional composition, physicochemical characteristics, oxidative stability (oxidation temperature and time, besides activation energy) and accelerated shelf life regarding hexane extraction (control). The US-CE improved the physicochemical properties such as acidity, peroxides, and iodine indexes regarding CE and Control. US-CE improved the yield, nutritional quality of fatty acids, oxidative stability, shelf life, and ω-6/ω-3 ratio regarding CE. Furthermore, US-CE improved the ratio yield/time extraction of the oil and increased the oxidation temperature regarding control. The main advantage of oils extracted using CE and US-CE concerning control was higher oxidative stability. The most representative polyunsaturated fatty acids identified in all treatments were γ-linolenic and conjugated α-linolenic acids. α-linolenic acid was only detected in US-CE and control. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-021-00940-w.

Clinical effectiveness of Lactobacillus reuteri in the treatment of peri-implant diseases: a systematic review and meta-analysis.

In the last decades, the presence of peri-implant diseases (PD) has increased. One of the therapies currently used is probiotics with Lactobacillus reuteri (LR). The aim of this article is to determinate, through a systematic review and meta-analysis, the clinical effectiveness of LR in the treatment of PD. We searched the literature until January 2021, in the biomedical databases: Pubmed, Embase, Scielo, Science Direct, Scopus, SIGLE, LILACS, Google Scholar and Cochrane Central Registry of Clinical Trials. The selection criteria of the studies were: randomized controlled clinical trials, without language and time restriction, reporting the clinical effects (depth to probing, plaque index and bleeding index) of the LR in the PD treatment. The risk of study bias was analyzed through the Cochrane tool for randomized studies using Review Manager software. The search strategy resulted in 6 articles of which four investigated peri-implantitis and three peri-implant mucositis. All studies reported that there was a difference in the depth of the probing in the treatment of PD, in favor of the group using LR, though not always achieving significance. The use of LR can be clinically effective in terms of pocket depth reduction in the treatment of PD.

JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer.

The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.

SEOM clinical guideline for the management of cutaneous melanoma (2020).

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.

[Outcomes of comanagement with Internal Medicine in Otolaryngology]. / Resultados de la asistencia compartida con Medicina Interna en Otorrinolaringología.

BACKGROUND AND OBJECTIVE: The age and comorbidity of patients admitted to Otolaryngology are increasing, leading to increased consultations/referrals to Internal Medicine, but do not reach the required effectiveness. An alternative is comanagement. A study is conducted on the effect of comanagement on Otolaryngology. METHODS: A retrospective observational study was conducted on patients ≥16 years old admitted in Otolaryngology between 03 December 2017 and 03 December 2019, since 03/12/2018 with comanagement with Internal Medicine since 03 December 2018. An analysis was performed on age, gender, type of admission, and whether the patient had surgery, administrative weight associated with (diagnosis-related group) DRG, total number of diagnoses at discharge, Charlson comorbidity index, deaths, urgent readmissions, and length of stay. RESULTS: Comanaged patients were younger (3.1 years, 95% confidence interval [95% CI] 1.4 to 4.8), but with higher Charlson comorbidity index (0.2; 95% CI; 0.1 to 0.3), number of diagnoses (0.9; 95% CI; 0.6 to 1.2), and administrative weight (0.04; 95% CI; 0 to 0.09). On adjustment, comanagement reduced Otolaryngology length of stay by 26.7%, 0.8 days (95% CI; 0.3 to 1.3), 50% of urgent readmissions, and 60% mortality, both non-significant. The decrease in length of stay implies an Otolaryngology savings of at least € 320,476.5. CONCLUSIONS: Patients admitted to Otolaryngology are increasing in age and comorbidity. Comanagement is associated with reduced length of stay and costs similar to those observed in other surgical services.

Which surgical patients require shared care? / ¿Qué pacientes quirúrgicos necesitan asistencia compartida?

Most hospitalized surgical patients have significant medical comorbidity and are treated with a considerable number of drugs and/or experience significant complications. Shared care (SC) is the shared responsibility and authority in managing hospitalized patients. In this article, we discuss whether patients should be selected for SC or not. The various selection criteria are not an exact science nor are they easy to apply. Furthermore, they may leave out many patients who may be good candidates for SC. Perioperative management is essential for preventing postoperative mortality. Failure to rescue (in-hospital mortality secondary to postoperative complications) is the main factor linked to in-hospital surgical mortality and can affect any patient regardless of age, comorbidity, or type of surgery. The component that most reduces failure to rescue is the presence of internists in surgical wards. We believe that all patients hospitalized in surgery departments should receive SC.