Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.     

New optimized piperamide analogues with potent in vivo hypotensive properties

We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. ¹H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4′-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates.     

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non‐endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low‐grade, non‐ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE‐positive endometrioid endometrial carcinomas (EECs). We performed exome‐sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling‐related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA‐repair‐related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co‐occurrence (RAD50‐KMT2D and RAD50‐SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.     

A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults’ trials

BackgroundDose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).MethodsPhase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials.ResultsFifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population.ConclusionsThese data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.     

Intranasal Exposure to Rift Valley Fever Virus Live-Attenuated Strains Leads to High Mortality Rate in Immunocompetent Mice

Rift Valley fever virus (RVFV) is a pathogenic arthropod-borne virus that can cause serious illness in both ruminants and humans. The virus can be transmitted by an arthropod bite or contact with contaminated fluids or tissues. Two live-attenuated veterinary vaccines—the Smithburn (SB) and Clone 13 (Cl.13)—are currently used during epizootic events in Africa. However, their residual pathogenicity (i.e., SB) or potential of reversion (i.e., Cl.13) causes important adverse effects, strongly limiting their use in the field. In this study, we infected immunocompetent mice with SB or Cl.13 by a subcutaneous or an intranasal inoculation. Interestingly, we found that, unlike the subcutaneous infection, the intranasal inoculation led to a high mortality rate. In addition, we detected high titers and viral N antigen levels in the brain of both the SB- and Cl.13-infected mice. Overall, we unveil a clear correlation between the pathogenicity and the route of administration of both SB and Cl.13, with the intranasal inoculation leading to a stronger neurovirulence and higher mortality rate than the subcutaneous infection.     

The clinical course of interstitial lung disease in an adult patient with an ABCA3 homozygous complex allele under hydroxychloroquine and a review of the literature

Objective: The gene mutations responsible for ABCA3 protein deficiency are involved in respiratory distress of the newborn and much more rarely in adult interstitial lung diseases (ILD). An adult patient homozygous for a complex allele encompassing the p.Ala1027Pro likely pathogenic mutation and the p.Gly974Asp variation was followed for a late-onset and fibrotic ILD. The evolution was marked by progressive clinical and functional degradation despite corticosteroid pulses. The patient, who was first registered on the list for lung transplantation, was improved quickly and persistently for at least 6.5 years with hydroxychloroquine treatment, allowing removal from the transplant list.     

Analysis of risk factors for amputation in patients with diabetic foot ulcers: a cohort study from a tertiary center

Objective: This study aimed to analyze risk factors for amputation (overall, minor and major) in patients with diabetic foot ulcers (DFUs).Methods: 407 patients with DFUs (286 male, 121 female; mean age = 60, age range = 32-92) who were managed in a tertiary care centre from 2009 to 2019 were retrospectively identified and included in the study. DFUs were categorized based on the Meggit-Wagner, PEDIS, S(AD)SAD, and University of Texas (UT) classification systems. To identify amputation risk-related factors, results of patients with DFUs who underwent amputations (minor or major) were compared to those who received other adjunctive treatments using Chi-Square, one-way analysis of variance (ANOVA) and Spearman correlation analysis.Results: The mean C-reactive protein (CRP) and White Blood Cell (WBC) values were significantly higher in patients with major or minor amputation than in those without amputation. The mean Neutrophil (PNL), Platelets (PLT), wound width, creatinine and sedimentation (ESR) values were significantly higher in patients with major amputation compared to other groups of patients. Elevated levels of High-density lipoprotein (HDL), Hemoglobin (HGB) and albumin were determined to be protective factors against the risk of amputation. Spearman correlation analysis revealed a positive-sided, strong-levelled, significant relation between Wagner grades and amputation status of patients.Conclusion: This study has identified specific factors for major and minor amputation risk of patients with DFUs. Especially infection markers such as CRP, WBC, ESR and PNL were higher in the amputation group. Most importantly, Meggit Wagner, one of the four different classification systems used in the DFUs, was determined to be highly associated with patients’ amputation risk.Level of Evidence: Level IV, Prognostic Study     

Exploring Reticular Pseudodrusen Extent and Impact on Mesopic Visual Sensitivity in Intermediate Age-Related Macular Degeneration

PurposeTo explore the impact of the extent of reticular pseudodrusen (RPD) on mesopic visual sensitivity in individuals with intermediate age-related macular degeneration (AMD).MethodsIn total, 570 eyes from 285 participants with bilateral large drusen underwent microperimetry testing to assess the visual sensitivity of the central 3.6-mm region and multimodal imaging to determine the extent of RPD in the central 20° × 20° region (at the eye level). Mean visual sensitivity within five sectors in the central 3.6-mm region sampled on microperimetry and the extent of RPD in these sectors were derived. Linear mixed models were used to examine the association between the extent of RPD on overall mean visual sensitivity and sector-based mean sensitivity.ResultsAn increasing extent of RPD at the eye level and within sectors was associated with a significant reduction in overall and sector-based mean sensitivity, respectively (P < 0.001 for both). However, when both RPD parameters were considered together in a multivariable model, only an increasing extent of RPD at the eye level (P < 0.001) and not within each sector (P = 0.178) was independently associated with reduced sector-based mean sensitivity.ConclusionsMesopic visual sensitivity is generally reduced in eyes with large drusen and coexistent RPD compared to eyes without RPD, with greater reductions with an increasing extent of RPD. However, reduced sector-based visual sensitivities are explained by the overall extent of RPD present, rather than their extent within the sector itself. These findings suggest that there are generalized pathogenic changes in eyes with RPD accounting for the observed mesopic visual dysfunction.     

Evolution of preclinical characterization and insights into clinical pharmacology of checkpoint inhibitors approved for cancer immunotherapy

Cancer immunotherapy has significantly advanced the treatment paradigm in oncology, with approvals of immuno‐oncology agents for over 16 indications, many of them first line. Checkpoint inhibitors (CPIs) are recognized as an essential backbone for a successful anticancer therapy regimen. This review focuses on the US Food and Drug Administration (FDA) regulatory approvals of major CPIs and the evolution of translational advances since their first approval close to a decade ago. In addition, critical preclinical and clinical pharmacology considerations, an overview of the pharmacokinetic and dose/regimen aspects, and a discussion of the future of CPI translational and clinical pharmacology as combination therapy becomes a mainstay of industrial immunotherapy development and in clinical practice are also discussed.