HIF - 1α as a marker of risk assessment for malignant transformation in oral submucous fibrosis: An immunohistochemical study.

Background: Oral submucous fibrosis (OSMF) is a potentially malignant disorder associated with habit of chewing betel quid containing arecanut. Morphological features of OSMF especially fibrosis suggests a possibility of the hypoxic environment in diseased tissues. The adaptation of cells to hypoxia appears to be mediated via hypoxia inducible factor-1α (HIF-1α) which is also said to be associated with malignant transformation of epithelial cells in various other carcinomas like prostate and cervical carcinoma. Therefore, the main objective of this study was to investigate the role of HIF-1α in progression and malignant transformation of OSMF. Materials and Methods: The study group consisted of histo-pathologically diagnosed 30 cases of oral submucous fibrosis and 10 cases of OSCC were taken as control. The immunohistochemistry was carried out on neutral buffered formalin-fixed paraffin-embedded tissue sections by using the monoclonal antibody of HIF-1α. Statistical analysis was done using SPSS software version 2.0. Results: A gradual and significant rise in the expression of HIF-1α was observed in various grades of OSMF and OSCC cases. HIF 1α expression was increased in cases showing hylanization and constricted blood vessels. A cut off value of 39.6% of HIF-1α positive cells was determined statistically to categorize the cases into high risk and low risk group for malignant transformation. Conclusion: Overexpression of HIF-1α may contribute to the progression and malignant transformation of OSMF. Cases expressing more than 40% of HIF-1α positive cells are at a greater risk for malignant transformation.

Intracellular cytokine expression in invasive fungal sinusitis and its impact on patient outcome.

BACKGROUND: Cell-mediated immunity plays an important role in host defence against fungal pathogens, regulated by differentiation of lymphocytes towards T-helper 1 or 2 cells. This study reports intracellular cytokine variation in terms of invasive fungal sinusitis type and outcome. METHODS: The mononuclear leukocytes of 15 patients with invasive fungal sinusitis (mucormycosis in 8, aspergillus in 7) were stained with antibodies against intracellular cytokines, after fungal antigen stimulation and culture, and immunophenotyped. Patients were followed up for six months, with clinical course categorised as improvement, worsening or death. RESULTS: The mean percentages of mononuclear cells producing interleukins 4, 5, 10 and 12, and interferon-γ, in the mucormycosis group were 0.575, 0.284, 8.661, 4.460 and 1.134, respectively, while percentages in the aspergillosis group were 0.233, 0.492, 4.196, 4.466 and 1.533. Cells producing interleukin 4 and 10 were higher in the mucormycosis group, while those producing interleukin-12 and interferon-γ were lower. Cells producing interleukins 4 and 12 were higher in patients with a poor outcome (p-values of 0.0662 and 0.0373, respectively), while those producing interferon-γ were lower (p = 0.0864). CONCLUSION: Adaptive cell-mediated immunity is expressed differently in two categories of invasive fungal sinusitis, and the cytokine expression pattern is related to prognosis.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

A scoping review of artificial intelligence applications in thoracic surgery.

OBJECTIVES: Machine learning (ML) has great potential, but there are few examples of its implementation improving outcomes. The thoracic surgeon must be aware of pertinent ML literature and how to evaluate this field for the safe translation to patient care. This scoping review provides an introduction to ML applications specific to the thoracic surgeon. We review current applications, limitations and future directions. METHODS: A search of the PubMed database was conducted with inclusion requirements being the use of an ML algorithm to analyse patient information relevant to a thoracic surgeon and contain sufficient details on the data used, ML methods and results. Twenty-two papers met the criteria and were reviewed using a methodological quality rubric. RESULTS: ML demonstrated enhanced preoperative test accuracy, earlier pathological diagnosis, therapies to maximize survival and predictions of adverse events and survival after surgery. However, only 4 performed external validation. One demonstrated improved patient outcomes, nearly all failed to perform model calibration and one addressed fairness and bias with most not generalizable to different populations. There was a considerable variation to allow for reproducibility. CONCLUSIONS: There is promise but also challenges for ML in thoracic surgery. The transparency of data and algorithm design and the systemic bias on which models are dependent remain issues to be addressed. Although there has yet to be widespread use in thoracic surgery, it is essential thoracic surgeons be at the forefront of the eventual safe introduction of ML to the clinic and operating room.

Digital platforms and entrepreneurial support: a field experiment in online mentoring.

The benefits of entrepreneurial mentorship are well documented, but there is limited research on how entrepreneurs connect with mentors, especially in digital settings. We partnered with an online platform that connects entrepreneurs to potential mentors to conduct a field experiment in online mentoring. Drawing on literature on entrepreneurial mentorship and Social Cognitive Theory, we compared the effects of three interventions on the likelihood of reaching out and making a connection with a mentor in a digital setting. We find that showing entrepreneurs a video of a successful mentor-mentee relationship increases the chances that they will reach out to a potential mentor but does not improve their chances of making a connection. These findings are more pronounced for female entrepreneurs. While not all entrepreneurs adopt the offered interventions, those that make the effort to learn to navigate the online platform and craft a suitable introductory message are successful in establishing a mentoring connection. We discuss these implications for both theory and practice.

Loss of left ventricular component of biventricular pacing with low atrial rhythm, what is the mechanism?

Effective biventricular pacing is important to improve survival in patients with heart failure. We report a case of a patient with heart failure, who underwent cardiac resynchronization therapy, who had loss of biventricular pacing when in low atrial rhythm. We discuss the probable mechanism for the same.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

NCCN Guidelines Insights: Primary Cutaneous Lymphomas, Version 2.2020.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke.

Stroke is one of the commonest causes of death with limited treatment options. L-Carnosine has shown great promise as a neuroprotective agent in experimental stroke, but translation to the clinic is impeded by the large doses needed. We developed and evaluated the therapeutic potential of a novel delivery vehicle which encapsulated carnosine in lipoprotein receptor related protein-1 (LRP-1)-targeted functionalized polymersomes in experimental ischemic stroke. We found that following ischemic stroke, polymersomes encapsulating carnosine exhibited remarkable neuroprotective effects with a dose of carnosine 3 orders of magnitude lower than free carnosine. The LRP-1-targeted functionalization was essential for delivery of carnosine to the brain, as non-targeted carnosine polymersomes did not exhibit neuroprotection. Using Cy3 fluorescence in vivo imaging, we showed that unlike non-targeted carnosine polymersomes, LRP-1-targeted carriers accumulated in brain in a time dependent manner. Our findings suggest that these novel carriers have the ability to deliver neuroprotective cargo effectively to the brain.

Direct Detection of Akhiezer Damping in a Silicon MEMS Resonator.

Silicon Microelectromechanical Systems (MEMS) resonators have broad commercial applications for timing and inertial sensing. However, the performance of MEMS resonators is constrained by dissipation mechanisms, some of which are easily detected and well-understood, but some of which have never been directly observed. In this work, we present measurements of the quality factor, Q, for a family of single crystal silicon Lamé-mode resonators as a function of temperature, from 80-300 K. By comparing these Q measurements on resonators with variations in design, dimensions, and anchors, we have been able to show that gas damping, thermoelastic dissipation, and anchor damping are not significant dissipation mechanisms for these resonators. The measured f · Q product for these devices approaches 2 × 1013, which is consistent with the expected range for Akhiezer damping, and the dependence of Q on temperature and geometry is consistent with expectations for Akhiezer damping. These results thus provide the first clear, direct detection of Akhiezer dissipation in a MEMS resonator, which is widely considered to be the ultimate limit to Q in silicon MEMS devices.

Animal models of multiple sclerosis: From rodents to zebrafish.

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 2.2018.

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load.

Visceral leishmaniasis (VL) is a disseminated and lethal disease of reticulo-endothelial system caused by protozoan parasites Leishmania donovani and L. infantum, which are known to induce host T cell suppression. To understand the impact of parasite load on T cell function, the present was focused on parasite load with T cell function in bone marrow of 26 VL patients. We observed significant enrichment of forkhead box protein 3 (FoxP3)+ (P = 0·0003) and interleukin (IL)-10+ FoxP3+ regulatory T cells (Treg ) (P = 0·004) in the bone marrow (BM) of patients with high parasite load (HPL) compared with low parasite load (LPL). Concordantly, T effector cells producing interferon (IFN)-γ (P = 0·005) and IL-17A (P = 0·002) were reduced in the BM of HPL. Blocking of Treg -cell derived suppressive cytokines [(IL-10 and transforming growth factor (TGF)-ß] rescued the effector T cells and their functions. However, it was observed that TGF-ß levels were dominant, favouring Treg cell differentiation. Furthermore, the low ratio of IL-6/TGF-ß favours the suppressive milieu in HPL patients. Here we show the change in levels of various cytokines with the parasitic load during active VL, which could be helpful in devising newer immunotherapeutic strategies against this disease.

Hypoxia Mimetic Agents for Ischemic Stroke.

Every year stroke claims more than 6 million lives worldwide. The majority of them are ischemic stroke. Small molecule-based therapeutics for ischemic stroke has attracted a lot of attention, but none has been shown to be clinically useful so far. Hypoxia-inducible factor-1 (HIF-1) plays a crucial role in the transcriptional adaptation of cells to hypoxia. Small molecule-based hypoxia-mimetic agents either stabilize HIF-1α via HIF-prolyl hydroxylases (PHDs) inhibition or through other mechanisms. In both the cases, these agents have been shown to confer ischemic neuroprotection in vitro and in vivo. The agents which act via PHD inhibition are mainly classified into iron chelators, iron competitors, and 2 oxoglutarate (2OG) analogs. This review discusses HIF structure and key players in the HIF-1 degradation pathway as well as the genes, proteins and chemical molecules that are connected to HIF-1 and how they affect cell survival following ischemic injury. Furthermore, this review gives a summary of studies that used PHD inhibitors and other HIF-1α stabilizers as hypoxia-mimetic agents for the treatment of ischemic injury.

Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma.

Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Nebivolol-Loaded Microsponge Gel for Healing of Diabetic Wound.

An attempt was made to formulate nebivolol-loaded microsponge gel to access drug at wound area, incorporated into gel that possess optimum moist wound management environment during later stages of wound closure. Nebivolol, antihypertensive drug, exhibits vasodilating effects via nitric oxide pathway, slows diabetic neuropathy, and restores endothelial function in diabetic wounds. Microsponges were prepared by optimizing independent variables; drug to polymer ratio and internal phase volume and their effects on production yield, entrapment efficiency, and particle size. Formulations of microsponges were evaluated for drug content. Differential scanning calorimetry indicated reduction in crystallinity of NB during the formation of microsponges. In vitro study (drug to polymer 1:4 and 10 ml internal phase volume acetone) showed 80% drug released within 8 h. Spherical and porous microsponges confirmed by scanning electron microscopy were incorporated in the carbopol 934 (2%) gel base. Gel was characterized for pH, viscosity, and drug content. Less spreadability determined by texture analyzer demonstrated viscous nature of gel. In vitro diffusion study revealed entrapped drug in porous microsponges with slow release to heal wound. In vivo study performed using streptozotocin-induced diabetic rats and excision wound model showed wound healing and closure activity within day 10. Histology revealed inflammatory cell infiltrations and neovascularization in granulation tissues, ultimately healing wound. Microsponge gel prolonged drug release due to entrapped form in porous structure of microsponges with significant and fast wound healing and closure in diabetic rats. Microsponges with loaded drug fulfilled accessibility at wound area, while gel provided optimum moist wound management environment during later stages of wound closure.

A unique CD4+ large granular lymphocytosis occurring in patients treated with tumor necrosis factor α inhibitors: report of 2 cases.

We report 2 cases of CD4(+) large granular lymphocyte (LGL) lymphocytosis occurring in patients being treated with a monoclonal antibody against tumor necrosis factor α for underlying autoimmune disorders. CD4(+) LGL lymphocytosis is a rare subset of LGL disease that has previously only been described in patients without underlying autoimmune disorders, and most demonstrate uniform coexpression of CD56 on the atypical T cells. The clinical features, with both cases occurring in patients with autoimmune disease, and immunophenotypic features, with both cases showing dim CD8 coexpression without CD56 in the CD4(+) LGLs, suggest that the reported cases are distinct from those previously described and may represent a novel T-cell LGL lymphocytosis emerging from iatrogenic immune modulation of patients with underlying autoimmune disorders.

Frequency of second mesiobuccal canal in permanent maxillary first molars using the operating microscope and selective dentin removal: A clinical study.

PURPOSE: The aim of this study was to investigate whether the combination of operating microscope and selective dentin removal increased the frequency of second mesiobuccal (MB2) canal detection in permanent maxillary first molar teeth. MATERIALS AND METHODS: One hundred fifty permanent maxillary first molars indicated for root canal treatment were randomly selected from patients belonging to the age group of 18-45 years irrespective of gender. After access cavity preparation and location of main canals, the MB2 canal orifice was sought in all teeth with an endodontic explorer under direct vision (Stage I), then under magnification with the aid of operating microscope (Stage II) and finally with the combined use of operating microscope and selective dentin removal (Stage III). RESULTS: MB2 canals were detected in 36%, 54% and 72% of the teeth in Stages I-III, respectively. CONCLUSION: This study demonstrated that dental operating microscope when used along with adjunctive aids such as selective dentin removal/troughing and good clinical knowledge will increase the ability of dental clinician to locate MB2 canals.

Quantum limit of quality factor in silicon micro and nano mechanical resonators.

Micromechanical resonators are promising replacements for quartz crystals for timing and frequency references owing to potential for compactness, integrability with CMOS fabrication processes, low cost, and low power consumption. To be used in high performance reference application, resonators should obtain a high quality factor. The limit of the quality factor achieved by a resonator is set by the material properties, geometry and operating condition. Some recent resonators properly designed for exploiting bulk-acoustic resonance have been demonstrated to operate close to the quantum mechanical limit for the quality factor and frequency product (Q-f). Here, we describe the physics that gives rise to the quantum limit to the Q-f product, explain design strategies for minimizing other dissipation sources, and present new results from several different resonators that approach the limit.

Immunohistochemical evaluation of MYC expression in mantle cell lymphoma.

AIM: To assess the validity and potential clinical utility of evaluating MYC expression by immunohistochemistry (IHC) in mantle cell lymphoma (MCL). METHODS AND RESULTS: MYC IHC was scored on a tissue microarray containing 62 MCLs and 29 controls by two pathologists. Inter-observer correlation was high (intra-class correlation of 0.98). MYC IHC scores correlated with MYC expression (Spearman's rank correlation 0.69, P < 0.0001) and weakly with Ki67 proliferation index (Spearman's rank correlation 0.30, P = 0.03). Six blastic MCLs did not have higher mean MYC IHC scores or MYC mRNA expression than non-blastic MCLs. None of 57 cases assessed, including all of the blastic cases, showed MYC rearrangement by fluorescence in-situ hybridization. Multivariate analysis with backward selection from potential predictors including age, lactate dehydrogenase, leukocyte count, MIPI score, ECOG performance status, blastic morphology and Ki67 index showed that MYC IHC score is an independent predictor of progression-free survival (hazard ratio 2.34, 95% CI 1.42-3.88, P = 0.0009) and overall survival (hazard ratio 1.90, 95% CI 1.05-3.43, P = 0.034). CONCLUSIONS: We show that a new monoclonal anti-MYC antibody can enable accurate and reproducible visual assessment of MYC expression that is independently predictive of clinical outcomes in MCL.