The spatial distribution of intermediate fibroblasts and myeloid-derived cells dictate lymph node metastasis dynamics in oral cancer.

BACKGROUND: Oral cancer poses a significant health challenge due to limited treatment protocols and therapeutic targets. We aimed to investigate the invasive margins of gingivo-buccal oral squamous cell carcinoma (GB-OSCC) tumors in terms of the localization of genes and cell types within the margins at various distances that could lead to nodal metastasis. METHODS: We collected tumor tissues from 23 resected GB-OSCC samples for gene expression profiling using digital spatial transcriptomics. We monitored differential gene expression at varying distances between the tumor and its microenvironvent (TME), and performed a deconvulation study and immunohistochemistry to identify the cells and genes regulating the TME. RESULTS: We found that the tumor-stromal interface (a distance up to 200 µm between tumor and immune cells) is the most active region for disease progression in GB-OSCC. The most differentially expressed apex genes, such as FN1 and COL5A1, were located at the stromal ends of the margins, and together with enrichment of the extracellular matrix (ECM) and an immune-suppressed microenvironment, were associated with lymph node metastasis. Intermediate fibroblasts, myocytes, and neutrophils were enriched at the tumor ends, while cancer-associated fibroblasts (CAFs) were enriched at the stromal ends. The intermediate fibroblasts transformed into CAFs and relocated to the adjacent stromal ends where they participated in FN1-mediated ECM modulation. CONCLUSION: We have generated a functional organization of the tumor-stromal interface in GB-OSCC and identified spatially located genes that contribute to nodal metastasis and disease progression. Our dataset might now be mined to discover suitable molecular targets in oral cancer.

Translationally controlled tumor protein (TCTP) is required for TGF-ß1 induced epithelial to mesenchymal transition and influences cytoskeletal reorganization.

Epithelial-mesenchymal transition (EMT) is a programed course of developmental changes resulting in the acquisition of invasiveness and mobility in cells. In cancer, this course is used by epithelial cells to attain movability. Translationally controlled tumor protein (TCTP) has been extensively characterized following the observation on tumor reversion ensuing its depletion. However, the role of TCTP in cancer progression is still elusive. Here, we demonstrate for the first time that TCTP is a target of transforming growth factor-ß1 (TGF-ß1), a key regulator of EMT in A549 cells. We here present changes in expression patterns of intermediate filament markers (vimentin and cytokeratin 18a) of EMT following TCTP knockdown or over expression. The TCTP over-expression in cancer cells is associated with mesenchymal characters, while downregulation promotes the epithelial markers in the cells. Interaction of TCTP with ß-catenin seems to stabilize ß-catenin, preparative to its nuclear localization highlighting a role for ß-catenin signaling in EMT. Moreover, the induction of urokinase plasminogen activator (uPA) following ectopic expression of TCTP leads to destabilization of ECM. The cells knocked down for TCTP show diminished invasiveness and migration under TGF-ß1 treatment. The present results for the first time demonstrate that TGF-ß1 dependent TCTP expression is required for EMT in cells.

A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings.

Karyotyping along with a 3-probe fluorescence in situ hybridization (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia. Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

Isolated Supravalular Aortic Stenosis with Infective Endocarditis presenting as Pyrexia of Unknown Origin.

Supravalvular aortic stenosis is a less common form of left ventricular outflow tract obstruction (LVOTO); commonest being the valvular aortic stenosis followed by valvular and subvalvular forms respectively. Most of the supravalvular aortic stenosis is associated with Williams syndrome; isolated supravalvular aortic stenosis is further rarer. We present a case of isolated SVAS with infective endocarditis (1.6) as the cause of pyrexia of unknown origin (PUO).

Spontaneous Left Main Coronary Artery Dissection: An Enigmatic Cause of Acute Coronary Syndrome.

Coronary artery dissection is a rare cause of acute coronary syndrome with affection of Left Main Coronary artery in such case is rarest of rare in clinical practice.This rare diagnosis is rarely thought of as a cause of STEMI. Routine Thrombolysis in such cases can be a double edged sword by increasing the progression of dissection and can be catastrophic!

Bilateral Coronary Pulmonary Artery Fistulae.

Coronary cameral fistulae are rare and bicoronary pulmonary artery fistulae is even rarer. This is a case of a 70 year old male who presented to us with complaints of chest pain and dyspnoea. His ECG showed ST-T changes in inferior and anterior precordial leads suggestive of ischaemia in those territories. His coronary angiogram revealed bilateral coronary pulmonary arterial fistulae arising from left circumflex and right coronary artery and draining into pulmonary artery without any atherosclerotic narrowing of coronaries.

Device Closure of Ventricular Septal Defect by a Unique Technique.

In the current era where percutaneous coronary interventions are increasingly performed day by day can device closure of congenital heart defects be far behind. We describe one unusual case of ventricular septal defect (VSD) in a child with absent inferior vena cava which was tackled in a novel way using hemiazygous vein as the conduit (access) to the right side of heart.

Successful Balloon Pulmonary Valvotomy (BPV) of Severe Calcific Pulmonary Stenosis Presenting in an Octogenarian.

Severe pulmonary stenosis presents early in life; late presentation is rare. Very late presentation like in our case is rarest of rare. Likewise calcification of pulmonary valve is rare. We describe here, one such case in an eighty-one year old female who astonishingly not only tolerated severe form of pulmonary stenosis but had also gone through three full term pregnancy, successfully without any untoward effect!

Successful Sealing of Elli's Type 3 Coronary Artery Perforation with Cyanoacrylate Glue.

Coronary artery perforation (CAP) is a rare (0.43%) but scary complication of percutaneous coronary intervention with its associated morbidity and even mortality at times.It needs to be treated urgently either by percutaneous means or by open heart surgery, as the situation demands. In this report we are discussing a left anterior descending coronary (LAD) artery perforation sealed successfully using cyanoacrylate glue.

Mannosylated solid lipid nanoparticles for lung-targeted delivery of Paclitaxel.

OBJECTIVE: The present study discusses paclitaxel (PTX)-loaded mannosylated-DSPE (Distearoyl-phosphatidyl-ethanolamine) solid lipid nanoparticles (M-SLNs) using mannose as a lectin receptor ligand conjugate for lung cancer targeting and to increase the anticancer activity of PTX against A549 lung's epithelial cancer cells. MATERIALS AND METHODS: The PTX-SLNs were prepared by solvent injection method and mannose was conjugated to the free amine group of stearylamine. The M-SLNs obtained were characterized for their particle size, polydispersity index, zeta potential and morphology by transmission electron microscope. RESULTS: The M-SLNs were spherical in shape with 254 ± 2.3 nm average size, positive zeta potential (3.27 mV), 79.4 ± 1.6 drug entrapment efficiency and showed the lower extent of drug release 40% over 48 h in vitro. Cytotoxicity study on A549 cell lines and biodistrubtion study of drug revealed that M-SLNs deliver a higher concentration of PTX as compared to PTX-SLNs in an alveolar cell site. DISCUSSION AND CONCLUSION: These results suggested that mannosylated M-SLNs are safe and potential vector for lung cancer targeting.

Jumping translocation in a case of de novo infant acute myeloid leukemia.

An infant presented with fever and purulent discharge from the left ear, proptosis of the right eye, and hepatosplenomegaly. She was diagnosed with acute monoblastic leukemia on morphological and flowcytometric analysis of the bone marrow. Karyotyping showed a jumping translocation (JT) involving the long arm of chromosome 1 as the sole cytogenetic abnormality in 29 metaphases. The patient died within 2 months of diagnosis. The presence of JT in a de novo infant AML as a sole cytogenetic abnormality indicates its possible role in leukemogenesis unlike previous reports that have implicated its role in tumor progression only.

A Case Report of Complete Heart Block in an Uncommon Disease Entity: Kearns Sayre Syndrome.

Complete heart block has a varied aetiology; commoner being ischaemia and senile degeneration of AV node. In this article we report a case of complete heart block (AV nodal) in patient of Kearns Sayre Syndrome who has incidently SA node disease also which is further rarer in this disorder.

Multiple giant coronary arterial aneurysms following sirolimus drug eluting stents implantation.

Coronary artery aneurysm after coronary interventions are rare but variable (0.2%-1.7%) clinicopathological entity depending on whether a incidental or a routine 6 monthly angiographic follow up finding and is seen more common with drug eluting stents (DES) rather than bare metal stents (BMS). It is of three types and depending on the type and patient clinical response further strategy (conservative, covered stents or coronary artery bypass surgery) is decided. We report a patient with large type 2 coronary artery aneurysms post percutaneous coronary intervention (PCI) to the right coronary artery (RCA) and the Left anterior descending (LAD) coronary artery and presenting four months later.

An unusual case of transverse myelitis in dengue fever: A case report from Nepal.

Key Clinical Message: Dengue fever can also have various neurological complications but involvement of the spinal cord is often unusual. This is a case where the patient had transverse myelitis as a complication of dengue fever. Abstract: Dengue fever can have various neurological complications but involvement of the spinal cord is often unusual. We report a case of a 49-year-old female, a known case of dengue fever, who presented with urine retention, inability to stand and walk with tingling sensation of bilateral lower limbs. Her vibration and joint position sensation was reduced below T2 level along with altered reflexes but MRI could not explain the examination findings. She was diagnosed clinically as transverse myelitis (TM) in the background of dengue fever. She showed drastic improvement with treatment of steroids. As TM as a complication in a patient with dengue fever is rare, and due to the paucity of similar case reports in Nepal, this case report is of value for the scientific community.

Melphalan-associated encephalopathy following autologous stem cell transplant: a transplanter's nightmare!

Melphalan-induced encephalopathy is a rare complication observed in patients undergoing autologous stem cell transplantation (ASCT) and is characterized by symptoms ranging from drowsiness to seizures. Previous reports have described similar cases, including a review of a large cohort of patients in whom melphalan-associated encephalopathy was identified in 2% of the patients undergoing ASCT. We describe the case of a 63-year-old male with Multiple Myeloma and underlying chronic kidney disease (CKD) who underwent ASCT with a reduced dose of melphalan due to renal dysfunction in complete remission following induction therapy and subsequent neurological deterioration, which necessitated an extensive evaluation of several neurological and infective etiologies. In this report, we highlight that melphalan-associated encephalopathy is a distinct entity complicating ASCT in patients with myeloma, especially in those with preexisting renal insufficiency, and consider its management.

Preclinical pediatric brain tumor models for immunotherapy: Hurdles and a way forward.

Brain tumors are the most common solid tumor in children and the leading cause of cancer-related deaths. Over the last few years, improvements have been made in the diagnosis and treatment of children with Central Nervous System tumors. Unfortunately, for many patients with high-grade tumors, the overall prognosis remains poor. Lower survival rates are partly attributed to the lack of efficacious therapies. The advent and success of immune checkpoint inhibitors (ICIs) in adults have sparked interest in investigating the utility of these therapies alone or in combination with other drug treatments in pediatric patients. However, to achieve improved clinical outcomes, the establishment and selection of relevant and robust preclinical pediatric high-grade brain tumor models is imperative. Here, we review the information that influenced our model selection as we embarked on an international collaborative study to test ICIs in combination with epigenetic modifying agents to enhance adaptive immunity to treat pediatric brain tumors. We also share challenges that we faced and potential solutions.

Uracil as a biomarker for spatial pyrimidine metabolism in the development of gingivobuccal oral squamous cell carcinoma.

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.

Takatsubo cardiomyopathy: a case series of seven patients.

Takatsubo cardiomyopathy is new emerging disease characterised by transient left ventricular systolic dysfunction followed by complete recovery of the same gradually over the course of few months. It represents 1-2% of all patients who present with acute ST elevation based on ECG finding and has a mortality of 1% and a recurrence of about 10%. The acute presentation greatly mimics acute coronary syndrome and needs differentiation from the same to avoid inadvertent thrombolysis and its consequences. We describe seven such patients at our institute over a period of 18 months.