Female terminalia morphology and cladistic relations among Tok-Tok beetles (Tenebrionidae: Sepidiini).

Tok-tokkies are one of the most iconic lineages within Tenebrionidae. In addition to containing some of the largest darkling beetles, this tribe is recognized for its remarkable form of sexual communication known as substrate tapping. Nevertheless, the phylogenetic relationships within the group remain poorly understood. This study investigates the usefulness of female terminalia morphology for delimiting Sepidiini and reconstructing relationships among it. Data on the structure of the ovipositors, genital tubes and spicula ventrali have been generated for >200 species representing 28 Pimeliinae tribes. This dataset was used in a comparative analysis at the subfamilial level, which resulted in recognition of several unique features of tok-tokkie terminalia. Additionally, new features linking phenotypically challenging tribes also were recovered (Cryptochilini + Idisiini + Pimeliini). Secondly, 23 characters linked to the structure of female terminalia were defined for tok-tok beetles. Cladistic analysis demonstrates the nonmonophyletic nature of most of the recognized subtribes. The morphological dataset was analysed separately and in combination with available molecular data (CAD, Wg, cox1, cox2, 28S). All obtained topologies were largely congruent, supporting the following changes: Palpomodina Kaminski & Gearner subtr.n. is erected to accommodate the genera Namibomodes and Palpomodes; Argenticrinis and Bombocnodulus are transferred from Hypomelina to Molurina; 153 species and subspecies previously classified within Psammodes are distributed over three separate genera (Mariazofia Kaminski nom.n., Piesomera stat.r., Psammodes sens.n.). Psammodes sklodowskae Kaminski & Gearner sp.n. is described. Preliminary investigation of the ovipositor of Mariazofia basuto (Koch) comb.n. was carried out with the application of microcomputed tomography, illuminating the muscular system as a reliable reference point for recognizing homologous elements in highly modified ovipositors.

Developing and Validating Multi-Modal Models for Mortality Prediction in COVID-19 Patients: a Multi-center Retrospective Study.

The unprecedented global crisis brought about by the COVID-19 pandemic has sparked numerous efforts to create predictive models for the detection and prognostication of SARS-CoV-2 infections with the goal of helping health systems allocate resources. Machine learning models, in particular, hold promise for their ability to leverage patient clinical information and medical images for prediction. However, most of the published COVID-19 prediction models thus far have little clinical utility due to methodological flaws and lack of appropriate validation. In this paper, we describe our methodology to develop and validate multi-modal models for COVID-19 mortality prediction using multi-center patient data. The models for COVID-19 mortality prediction were developed using retrospective data from Madrid, Spain (N = 2547) and were externally validated in patient cohorts from a community hospital in New Jersey, USA (N = 242) and an academic center in Seoul, Republic of Korea (N = 336). The models we developed performed differently across various clinical settings, underscoring the need for a guided strategy when employing machine learning for clinical decision-making. We demonstrated that using features from both the structured electronic health records and chest X-ray imaging data resulted in better 30-day mortality prediction performance across all three datasets (areas under the receiver operating characteristic curves: 0.85 (95% confidence interval: 0.83-0.87), 0.76 (0.70-0.82), and 0.95 (0.92-0.98)). We discuss the rationale for the decisions made at every step in developing the models and have made our code available to the research community. We employed the best machine learning practices for clinical model development. Our goal is to create a toolkit that would assist investigators and organizations in building multi-modal models for prediction, classification, and/or optimization.

Multicenter analysis of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive breast cancer.

PURPOSE: In an era where neoadjuvant dual blockade is emerging as the standard of care for early and locally advanced HER2-positive breast cancer, we aimed to identify predictors of response to single-blockade chemotherapy. METHODS: This retrospective analysis reviewed all the incident stage I-III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in three institutions. pCR was defined as the absence of invasive tumor in breast and axillary nodes (ypT0/isypN0). RESULTS: From 2008 to 2015, 84 patients receiving neoadjuvant TCH were identified within our institutions. The mean age at diagnosis was 51.8 years. 59.5% of the patients were hormone receptor (HR) positive, lymph node involvement occurred in 67.9%, and clinical distribution was 2.4, 65.5, and 32.1% for stage I, II, and III, respectively. pCR rate was 47.6%; there was a significantly lower response in HR-positive patients compared to HR-negative ones (34 vs 67.6%, p = 0.005). pCR rate was associated with tumor size, whereas differences did not reach significance either for stage or for nodal status. Multivariate analysis found that only HR status was associated with response (p = 0.003). At a median follow-up of 31.7 months, disease-free survival, distant disease-free survival, and overall survival were 78.6, 85.7, and 94%, respectively. Breast-conserving surgery was performed in 44% of the patients. Overall, TCH was well tolerated, with low rates of grade 3-4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported. CONCLUSIONS: Neoadjuvant TCH, an anthracycline-free single-blockade regimen, achieved a pCR of 47.6%. Further molecular analyses are required in order to identify stronger predictive markers of pCR and thus for an accurate selection of patients who do not benefit from dual blockade.

Fatal Autoimmune Storm After a Single Cycle of Anti-PD-1 Therapy: A Case of Lethal Toxicity but Pathological Complete Response in Metastatic Lung Adenocarcinoma.

As immunotherapy agents are incorporated into the routine oncological practice, the number of patients at the risk of immune-related adverse events has increased dramatically. However, the prompt identification and effective management of severe autoimmune complications remain a challenge. We report the case of a patient with metastatic lung adenocarcinoma who experienced a fatal autoimmune storm 3 weeks after the first dose of anti-programmed death receptor-1 (PD-1) agent pembrolizumab, which included thyroiditis, hepatitis, myositis, myocarditis, pneumonitis, and myasthenia gravis. Aggressive autoimmunity was supported by extensive T-cell and macrophage tissue infiltrates and autoantibody positivity. Remarkably, no residual tumor was found at autopsy. This case illustrates the potential harm caused by immunotherapy and our limited knowledge on its prevention, treatment, and association to antitumor efficacy.

Taxonomy of the North Moroccan and Iberian species of the subgenus Amblypteraca/ (Coleoptera: Tenebrionidae: Pimeliinae: Pimelia/).

The subgenus Amblypteraca Mas-Peinado, Buckley, Ruiz García-París, 2018 of Pimelia Fabricius, 1775, is restricted to the southern Iberian Peninsula and western Maghreb (northern and western Morocco). The distribution of Amblypteraca throughout the African-European edges overlaps largely with the geographic range of the subgenus Amblyptera, which is sister to the clade grouping subgenera Amblypteraca and Ecphoroma Solier, 1836. Delimiting species boundaries in the speciose genus Pimelia is often challenging, and the taxonomic status of some groups within the aforementioned subgenera is still a matter of debate. Here, we aim to stabilize some of the available names in Amblypteraca, and to correct some previous misidentifications. For that purpose, we discuss the composition and taxonomic structure within Amblypteraca by (i) assessing the phylogenetic congruence between mitochondrial and nuclear markers, and (ii) examining external morphological traits in 568 Amblypteraca specimens under the light of the phylogenetic hypotheses proposed here. Based on our results, Amblypteraca consists of three species: P. rotundipennis Kraatz, 1865, P. fairmairii Kraatz, 1865 and P. chrysomeloides Pallas, 1781. Both molecular and morphological data revealed four lineages within P. chrysomeloides: P. chrysomeloides chrysomeloides, distributed on both sides of the Strait of Gibraltar; P. chrysomeloides fornicata Herbst, 1799 from Portugal (Troia region); P. chrysomeloides bathyglypta Antoine, 1949, restricted to a narrow strip between Larache and Arbaoua (northern atlantic Moroccan coast), and P. chrysomeloides subris Koch, 1941 from Kenitra-La Mamora forest (Morocco). We designate a neotype of Tenebrio chrysomeloides Pallas, 1781 and propose the synonymy of P. chrysomeloides (Pallas, 1781) = P. obesa Solier, 1836 syn. n. Pimelia tristis Haag-Rutenberg, 1875, previously misidentified and included in Amblypteraca, is now transferred back to Amblyptera. Further studies with ad hoc sampling designs and analytical tools would be in need to delimit the exact geographic ranges of these taxa, and to analyse the patterns of diversity within and among species and subspecies.

Long-Lasting Response after Pembrolizumab in a Patient with Metastatic Triple-Negative Breast Cancer.

INTRODUCTION: Breast cancer is the first cause of cancer death in women. The triple-negative subtype is associated with aggressive behavior and poor prognosis. Chemotherapy is the main therapeutic option available for these patients, but it is usually associated with short overall survival. CASE PRESENTATION: We report the case of a patient diagnosed with metastatic triple-negative breast cancer with an impressive long-lasting tumor response and long-term survival after pembrolizumab monotherapy. CONCLUSION: Immunotherapy is emerging as a promising treatment for some breast cancer patients. Nevertheless, monotherapy studies have shown a very limited activity. Nowadays, there is no good predictor biomarker. Further investigations are needed to identify the subgroup of patients who can benefit from checkpoint inhibitor treatment.

Catalogue, distribution, taxonomic notes, and conservation of the Western Palearctic endemic hunchback beetles (Tenebrionidae, Misolampus).

Hunchback darkling beetles of the Ibero-Maghrebian genus Misolampus Latreille, 1807 (Tenebrionidae, Stenochiinae) encompass six species: M. gibbulus (Herbst, 1799), M. goudotii Guérin-Méneville, 1834, M. lusitanicus Brême, 1842, M. ramburii Brême, 1842, M. scabricollis Graells, 1849, and M. subglaber Rosenhauer, 1856. Previously known distribution ranges of the species were delineated using many old records, the persistence of such populations being questionable under the current situation of global biodiversity loss. Additionally, the status of geographically isolated populations of the genus have been the subject of taxonomic controversy. An exhaustive bibliographical revision and field search was undertaken, and the Misolampus collection of the Museo Nacional de Ciencias Naturales (MNCN-CSIC) was revised. The aims are to (i) provide an updated geographic distribution range for the species of Misolampus; (ii) to determine the taxonomic status of controversial populations; (iii) to provide a catalogue for Misolampus; and (iv) to discuss the conservation status of these saproxylic beetles. As a result, a catalogue including synonymies and type localities, geographical records, diagnoses, and information on natural history for all species of Misolampus is presented. The results reveal that the distribution ranges of the species of Misolampus have not undergone a reduction in the last century, and indicate the presence of the genus in areas where it had never been recorded before. The morphological variability of M. goudotii drove the proposal of different taxa that are here formally synonymised as follows: M. goudotii Guérin-Méneville, 1834 = M. erichsoni Vauloger de Beaupré, 1900, syn. nov. = M. peyerimhoffi Antoine, 1926, syn. nov.

Prognostic Value of Lymphocyte-Activation Gene 3 (LAG3) in Cancer: A Meta-Analysis.

Introduction: Therapeutic targeting of inhibitors of the immune response has reached the clinical setting. Inhibitors of the novel receptor LAG3, which negatively regulates T-cell activation, are under investigation. Here we explore the presence and prognostic role of LAG3 in cancer. Methods: A systematic search of electronic databases identified publications exploring the effect of LAG3 on overall survival (OS) and (for early-stage cancers) disease-free survival (DFS). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and random effect modeling. Subgroup analyses were conducted based on disease site and tumor type. Results: Fifteen studies met the inclusion criteria. LAG3 was associated with better overall survival [HR 0.81, 95% confidence interval (CI) 0.66-0.99; P = 0.04], with subgroup analysis showing no significant differences between disease-site subgroups. The beneficial effect of LAG3 on OS was of greater magnitude in early-stage malignancies (HR 0.73, 95% CI 0.60-0.88) than in the metastatic setting (HR 1.20, 95% CI 0.70-2.05), but this difference was not statistically significant (subgroup difference p = 0.18). LAG3 did not have a significant association with DFS [HR 1.02, 95% confidence interval (CI) 0.77-1.37; P = 0.87], with subgroup analysis showing worse DFS in patients with lymphoma and improved DFS in those with breast cancer. Conclusions: High expression of LAG3 is associated with favorable overall survival in several solid tumors. A trend toward an association in early-stage disease suggests the importance of immune surveillance in this setting.

Prognostic value of receptor tyrosine kinase-like orphan receptor (ROR) family in cancer: A meta-analysis.

INTRODUCTION: Identification of membrane proteins expressed exclusively on tumor cells is a goal for cancer drug development. The receptor tyrosine kinase-like orphan receptor type 1 and 2 (ROR1/2), are type-I transmembrane proteins expressed in cancer but not in adult normal tissue. Here, we explore the prognostic role ROR1/2 expression on patient outcome. METHODS: A systematic search of electronic databases identified publications exploring the effect of ROR1/2 on overall survival (OS). Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on disease site or tumor type. RESULTS: Twenty five studies met the inclusion criteria. ROR1 was associated with worse overall survival (HR 2.13, 95% confidence interval (CI) 1.62-2.80; P < 0.001) with subgroup analysis showing the strongest association between ROR1 and OS was in lung cancer. There was no significant difference between solid tumors and hematological malignancies (HR 2.15, 95% CI 1.52-3.06 vs. HR 2.02, 95% CI 1.46-2.84; subgroup difference P = 0.80). ROR2 was also associated with worse OS (HR 1.84, 95% CI 1.43-2.38; P < 0.001). There was no significant difference between disease sites although the highest association seen was in head and neck cancers (HR 3.19, 95% CI 1.13-8.97) and the lowest in gynecological cancers (HR 1.19, 95% CI 0.71-2.00; subgroup difference P = 0.10). CONCLUSIONS: ROR1 and ROR2 expression is associated with adverse outcome in several tumors. ROR1/2 warrants study as a target for developmental therapeutics.

Neuroendocrine Neoplasms in Rare Locations: Clinicopathological Features and Review of the Literature.

INTRODUCTION: Neuroendocrine tumors (NETs) occur more often in lungs, gastrointestinal tract, or pancreas. Data about terminology and grading of NETs in rare locations are scarce and variable, and they have been reported mainly as case reports. MATERIALS AND METHODS: We here describe our experience with NETs in unusual locations. We have reviewed all NETs diagnosed in our institution and summarized their clinicopathological features. We have also reviewed the literature and discussed the main characteristics of NETs in each site. RESULTS: Two hundred and forty-three primary NETs were diagnosed. About 55.2% of patients were men and the mean age was 62 years. About 90.7% of NETs were located in lungs, gastrointestinal tract, or pancreas, and 50.8% of them were low-grade tumors. We identified 13 NETs in rare locations: breast, ovary, endometrium, vulva, uterine cervix, extrahepatic biliary tract, kidney, sinonasal tract, and thymus. Three additional tumors were diagnosed by the senior author in other institution. Patients were asymptomatic or presented with nonspecific symptoms. All NETs were treated with surgery and 31% of patients received adjuvant therapy. There were 10 Grade 3 (62.5%), 2 Grade 2 (12.5%), and 4 Grade 1 (25%) tumors. Mean follow-up was 72 months. About 60% of G3 tumors recurred or progressed. G2 tumors were located in breast, and both patients are stable. About 50% of G1 tumors recurred or progressed (both renal NETs). CONCLUSIONS: NETs in rare locations are heterogeneous, and their behavior does not seem to correlate absolutely with tumor grade. More studies are needed to clarify the role of proliferation rate in these tumors.

A preliminary report on the distribution of lizards in Qatar.

We have updated the list of the lizard species present in Qatar and produced the first distribution maps based on two field surveys in 2012 and 2013. We used the QND95/Qatar National Grid with a grid of 10 × 10 km squares for mapping. Our results show the occurrence of 21 lizard species in Qatar, from the 15 species indicated in the last biodiversity report conducted in 2004. The most abundant family found in Qatar is Gekkonidae with nine species (Bunopus tuberculatus, Cyrtopodion scabrum, Hemidactylus robustus, H. flaviviridis, H. persicus, Stenodactylus arabicus, S. slevini, S. doriae, Pseudoceramodactylus khobarensis), followed by Lacertidae with four species (Acanthodactylus schmidti, A. opheodurus, Mesalina brevirostris, M. adramitana), Agamidae with three species (Trapelus flavimaculatus, Uromastyx aegyptia, Phrynocephalus arabicus), Scincidae with two species (Scincus mitranus, Trachylepis septemtaeniata), and Varanidae (Varanus griseus), Sphaerodactylidae (Pristurus rupestris) and Trogonophiidae (Diplometopon zarudnyi) with one species each. The species richness fluctuated largely across Qatar between one and eleven species per grid square. We believe that the lizard fauna records in Qatar are still incomplete and that additional studies are required. However, our study here fills a gap concerning lizard biodiversity knowledge in the Gulf Region.