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Objectives To construct a new scoring system utilizing biomarkers, vitals, and imaging data to predict 30-day mortality in acute pulmonary embolism (PE). Background Acute PE, a well-known manifestation of venous thromboembolic disease, is responsible for over 100,000 deaths worldwide yearly. Contemporary management algorithms rely on a multidisciplinary approach to care via PE response teams (PERT) in the identification of low, intermediate, and high-risk patients. The PESI and sPESI scores have been used as cornerstones of the triage process in assigning risk of 30-day mortality for patients presenting with acute PE; however, the specificity of these scoring systems has often come into question. Methods This study retrospectively analyzed 488 patients with acute PE who were managed at a tertiary care institution with either conservative therapy consisting of low molecular weight or unfractionated heparin, advanced therapies consisting of catheter directed therapies, aspiration thrombectomy, or a combination of these therapies, or surgical embolectomy. The CLOT-5 score was designed to include vital signs, biomarkers, and imaging data to predict 30-day mortality in patients presenting with acute PE. Results The CLOT-5 score had an area under the curve (AUC) of 0.901 with a standard error of 0.29, while the PESI and sPESI scores had an AUC and standard errors of 0.793 ±­ 0.43 and 0.728 ± 0.55, respectively. Conclusions When incorporated into the management algorithms of national PERT programs, the CLOT-5 score may allow for rapid and comprehensive assessment of patients with acute PE at high risk for clinical decompensation, leading to early escalation of care where appropriate.

Coronary calcified lesions are commonly encountered and coronary atherectomy is commonly used for lesion modification during percutaneous coronary interventions (PCI). The release of adenosine during atherectomy can result in bradyarrhythmias and aminophylline is commonly used to prevent this reaction. We identified 138 patients to evaluate the safety and efficacy of intravenous (IV) aminophylline administration prior to coronary atherectomy. A total of 159 calcified lesions were treated, and the atherectomy device was orbital atherectomy, rotational atherectomy, and both in 52 %, 42 %, and 6 %; respectively. After administration of aminophylline, 4.3 % of patients required intraprocedural insertion of a transvenous pacer (TVP), and 18.1 % of patients required administration of IV atropine. Technical success was achieved in 98.6 % of patients, and no adverse reactions to aminophylline were reported. All patients survived to discharge. In conclusion, aminophylline administration prior to coronary atherectomy was safe and effective. No adverse effects of aminophylline were seen, and the rate of bailout TVP placement was low.

Abstract Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Background Acute pulmonary embolism (PE) is a heterogeneous disease process with variable presentation and outcomes. The endogenous fibrinolytic system is a complex framework of regulatory pathways that maintains homeostasis by dissolving overabundant thrombi. We sought to investigate phenotypic profiles of the endogenous fibrinolytic system among patients presenting with acute PE and their impact on mortality. Methods We enrolled all consecutive patients with acute PE in our institutional Pulmonary Embolism Response Team registry. We collected blood samples at the time of PE diagnosis and analyzed concentrations of plasminogen activator inhibitor 1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and alpha-2-antiplasmin (A2A). We assessed the association of concentration of fibrinolytic inhibitors and 1-year all-cause mortality and various echocardiographic markers of right ventricular (RV) dysfunction. Results There is significant variability of PAI-1, A2A, and TAFI concentrations across the spectrum of PE risk profiles with high PAI-1, low TAFI, and low A2A (herein referred to as a high-risk biomarker profile) correlating with worse PE severity. High-risk biomarker profile correlated with high-risk echocardiographic features of RV dysfunction, including increased RV/left ventricular (LV) ratio, low tricuspid annular plane systolic excursion, and low right ventricular outflow tract velocity time integral. Higher-risk biomarker profile was able to discriminate and independently identify patients at high risk of all-cause mortality (Group 2 HR 6 95% CI 1.3-27.8, Group 3 HR 12, 95% CI 1.7-86). Conclusions Further studies are needed to assess the exact pathophysiological link between fibrinolytic status and poor outcome after acute PE and to ascertain the impact of anti-inhibitors of the fibrinolytic system on response to therapy and outcomes after acute PE.

Molecular subtypes of small cell lung cancer characterized by neuroendocrine differentiation have been described in cell lines and primary tumors. The clinical implications of neuroendocrine subtypes in metastatic and relapsed tumors, and the extent to which the subtype distribution is recapitulated in patient-derived models remains unclear. Here, the authors integrated genomics and transcriptomics on 100 small cell cancers from a range of metastatic sites finding complex intra- and intertumoral heterogeneity, notably not recapitulated in patient-derived model systems, and distinct therapeutic vulnerabilities associated with neuroendocrine subtypes.

Objective: To comparatively evaluate ICU requirement, length of stay, and mortality between single-dose vaccinated and non-vaccinated hospitalized COVID-19 patients. Design: A retrospective observational study was carried out in a tertiary care hospital in western Indian, from April 1 to June 30, 2021. Results: Of the 569 patients who fulfilled the eligibility criteria and were enrolled in the study, 137 (24.08%) patients had received a single dose of ChAdOx1 nCoV-19 vaccine, while 432 (75.92%) patients had not received any form of vaccination. The overall length of stay in hospital was similar for both groups; however, a significant difference was seen in length of stay in the ward and in the ICU. Vaccinated patients were admitted to the ward for 6.21 ± 3.204 days, while non-vaccinated patients were admitted for 5.56 ± 4.55 days (p < 0.001). The mean length of ICU stay for the 21 vaccinated patients requiring intensive care was 4.47 ± 2.3 days, while that for the 145 non-vaccinated patients was 6.29 ± 2.19 days (p < 0.001). Mortality was observed in four patients in the vaccinated group and in 95 patients in the non-vaccinated group. Conclusion: A single dose of ChAdOx1 nCoV-19 vaccine was associated with a significantly lower severity of SARS-CoV-2 infection compared with no vaccination.

Missions into deep space will expose astronauts to the harsh space environment, and the degenerative tissue effects of space radiation are largely unknown. To assess the risks, in this study, male BALB/c mice were exposed to 500 mGy 5-ion simulated GCR (GCRsim) at the NASA Space Radiation Laboratory. In addition, male and female CD1 mice were exposed to GCRsim and administered a diet containing Transforming Growth Factor-beta (TGF-β)RI kinase (ALK5) inhibitor IPW-5371 as a potential countermeasure. An ultrasound was performed to investigate cardiac function. Cardiac tissue was collected to determine collagen deposition, the density of the capillary network, and the expression of the immune mediator toll-like receptor 4 (TLR4) and immune cell markers CD2, CD4, and CD45. In male BALB/c mice, the only significant effects of GCRsim were an increase in the CD2 and TLR4 markers. In male CD1 mice, GCRsim caused a significant increase in total collagens and a decrease in the expression of TLR4, both of which were mitigated by the TGF-β inhibitor diet. In female CD1 mice, GCRsim caused an increase in the number of capillaries per tissue area in the ventricles, which may be explained by the decrease in the left ventricular mass. However, this increase was not mitigated by TGF-β inhibition. In both male and female CD1 mice, the combination of GCRsim and TGF-β inhibition caused changes in left ventricular immune cell markers that were not seen with GCRsim alone. These data suggest that GCRsim results in minor changes to cardiac tissue in both an inbred and outbred mouse strain. While there were few GCRsim effects to be mitigated, results from the combination of GCRsim and the TGF-β inhibitor do point to a role for TGF-β in maintaining markers of immune cells in the heart after exposure to GCR.

Cancer is a multi-hit multi-step process that ultimately leads to malignant transformation. Genes encoding for extracellular matrix, proteins of epidermal development, and cell adhesion molecules are mostly altered in oral squamous cell carcinoma. Of late, the paradigm for diagnosis has shifted from clinical status to molecular one. This is because molecular changes occur immediately, whereas clinical changes take a long time to show up. Hence, by evaluating various markers of cancer, its progression, severity, resistance, and prognosis can be predicted way before the clinical signs occur. These markers are present either in the tumors or hosts and help to distinguish between normal and dysplastic tissue. They generally increase during the disease progression or relapse, and decrease when the disease goes into remission. They can also be detected in blood, plasma and saliva apart from tissues. Periostin is one such molecule that gets altered, and hence can be used as a marker. Studies on the expression of periostin in oral cancer are very few; therefore, an attempt is made to throw some light on this novel protein and its role in oral cancer. It can be used in target therapy solely or as an adjunct in treating oral squamous cell carcinoma.

The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.

The organization of eukaryotic genome in the nucleus, a double-membraned organelle separated from the cytoplasm, is highly complex and dynamic. The functional architecture of the nucleus is confined by the layers of internal and cytoplasmic elements, including chromatin organization, nuclear envelope associated proteome and transport, nuclear–cytoskeletal contacts, and the mechano-regulatory signaling cascades. The size and morphology of the nucleus could impose a significant impact on nuclear mechanics, chromatin organization, gene expression, cell functionality and disease development. The maintenance of nuclear organization during genetic or physical perturbation is crucial for the viability and lifespan of the cell. Abnormal nuclear envelope morphologies, such as invagination and blebbing, have functional implications in several human disorders, including cancer, accelerated aging, thyroid disorders, and different types of neuro-muscular diseases. Despite the evident interplay between nuclear structure and nuclear function, our knowledge about the underlying molecular mechanisms for regulation of nuclear morphology and cell functionality during health and illness is rather poor. This review highlights the essential nuclear, cellular, and extracellular components that govern the organization of nuclei and functional consequences associated with nuclear morphometric aberrations. Finally, we discuss the recent developments with diagnostic and therapeutic implications targeting nuclear morphology in health and disease.

The present investigation was carried out at Anand Agricultural University, Gujarat during the year 2016 to develop a micropropagation protocol for mass multiplication of medicinally rich stevia plants. Axenic culture was established by sequential application of 200 mg/l Kanamycin, 200 mg/l Carbendazim-50% and 1000 mg/l HgCl2. Out of two different basal media, viz. Gamborg (B5) and Murashige and Skoog (MS) used, full strength MS gave highest (98%) culture establishment. Out of three different basal media, viz. Gamborg’s (B5), Linsmair and Skoog (LS), Murashige and Skoog (MS) and four different cytokinins, viz. 6-benzylaminopurine (BAP), Kinetin (Kn), Thiadiazuron (TDZ), Zeatin (Zn) tested for multiple shoot induction, full strength MS medium and 2 mg/l BAP, respectively, promoted maximum shoot formation. In the experiment to study the effect of varying strength of MS media and various plant growth regulators, viz. Indole-3-acetic acid (IAA), Indole-3-butyric acid (IBA), Naphthalene acetic acid (NAA) on in vitro rooting, ½ strength MS and 1 mg/l NAA, respectively, gave superior response. Among the 26 different combinations of potting mixtures used for primary acclimatization of in vitro rooted plants, cocopeat based substrates yielded highest survival rate (75.06%). Secondary acclimatization was carried out in the soil bags in the poly house. Thus, a reproducible and reliable micropropagation protocol for mass multiplication of Stevia rebaudiana (Bertoni) Bertoni using nodal segments has been developed.

Tumor lysis syndrome (TLS) is a severe metabolic complication that usually occurs in patients with aggressive tumors who undergo treatment with chemotherapy. Traditionally, it was mainly associated with hematologic malignancies. However, over the past 4 decades, there have been increasing reports of TLS in solid tumors. We report a case of TLS in a patient with gastric cancer, as a complication of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy. Our patient was a 48-year-old man with metastatic gastric adenocarcinoma who presented with altered mental status and slurred speech. On examination, he was confused and disoriented, but the rest of his examination, including vitals, was unremarkable. Laboratory findings on admission were significant for an elevated uric acid of 14.5 mg/dL, creatinine of 4.1 mg/dL, and phosphorus of 6.9 mg/dL. He had received his first cycle of FOLFOX chemotherapy 4 days prior to admission. The constellation of electrolyte abnormalities and the temporal relationship to chemotherapy led to the diagnosis of chemotherapy-induced TLS. He was treated with aggressive fluid repletion and rasburicase, following which the electrolyte derangements resolved, and he improved clinically. This case highlights the importance of early recognition of TLS in patients with gastric cancer. Initiation of early treatment can reduce the high morbidity and mortality associated with this oncologic emergency.

Aim: To determine the influence of nanocomposites such as nanofilled, nanoceramic and fibre reinforced composite restorative systems on the fracture resistance of maxillary premolars with Class II mesio- occlusodistal (MOD) cavities. Materials and Method: Eighty sound maxillary human premolars were divided into four groups of 20 teeth each. Teeth in the first group were left intact (unprepared) and tested as positive controls. Teeth in the remaining three groups were prepared with MOD cavities and were restored with a nanofilled composite (Ice), a nanoceramic composite (CeramX mono) and a fibre reinforced composite (Tetric N Flow & CeramX mono). All groups were stored in water at 37΀C for 24 hours and thermocycled and then tested in universal testing machine. Statistical analysis was done by Kruskal-Wallis and Mann-Whitney U tests. The level of significance was set at 0.05. Results: Results between each group were statistically significant (P> 0.05) except between nanoceramic and fibre reinforced composite system. Conclusion: Under compressive load testing, all restored teeth had lower cuspal fracture resistance than unprepared control teeth. Nanoceramic showed the highest mean cuspal fracture resistance while nanofilled showed the least and fibre reinforced composite proved to be a true tooth reinforcing agent.

Filariasis is a prevalent parasitic infection of lymphatic frequently seen in tropical countries. It has been reported in cytological samples from various sites; however, presence of microfilaria in smears from the urine sample is an uncommon finding. We describe an interesting and unusual case of elderly female who presented with achylous hematuria and an exophytic mass lesion in urinary bladder on computed tomography scan suspected of neoplastic mass lesion; however diagnosed as urinary filariasis on urine cytology and bladder biopsy.

Leiomyosarcomas of soft tissue are the rare tumors and the retroperitoneum is the most common site involved. We report a case of primary leiomyosarcoma of the peritoneal cavity which clinically presented with suprapubic, freely mobile, nontender mass which measured 10×10 cm in size. Contrast enhanced computed tomography revealed well defined heterogenous hypodense solid cystic mass. The mass was surgically excised out in its entirety. The histopathological examination revealed spindle cells arranged in alternating fascicles having pleomorphic nuclei, indistinct margin and eosinophilic cytoplasm with foci of haemorrhage, necrosis and 5-6 mitosis/HPF. The spindle cells were immunoreactive for smooth muscle actin, desmin and negative for S-100, CD-34 and c-kit. Histopathology and immunohistochemistry were helpful in making the final confirmatory diagnosis. Leiomyosarcomas are aggressive tumors, with poor prognosis and often difficult to treat. The survival rates are lowest among all soft tissue sarcomas.