Impact of COVID-19 on cancer services and patients' outcomes: a retrospective single-center study.

Background: Our main objective was to assess the impact of the coronavirus disease 2019 (COVID-19) on cancer services and cancer patients in terms of disease severity, morbidity and mortality. Secondary objectives were to characterize cancer type, affected age groups, gender, comorbidities, infectivity, and to identify cancer treatment delay and its complications after COVID-19 infection. Methods: A retrospective analysis of electronic health records of polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected cancer patients from April 2020 to March 2021 was done. The following parameters were investigated upon-new and follow-up cases during the pandemic and its preceding years (2018-2019, 2019-2020), age, sex, type of cancer, comorbidities, presentation, symptomatology and treatment for COVID-19, time to recovery, complications, delay in treatment and survival outcome. Statistical analysis using chi-square testing was done on the above variables. Results: There was a 50.49% reduction in the number of new and follow-up cases as compared to that of the previous years. Seventy-four out of 310 (23.87%) COVID-19 positive cancer patients were aged in their sixth decade with the commonest type being hematological malignancies. A proportion of 84.8% (n=263) patients were asymptomatic. Univariate analysis was statistically significant for mortality with regard to age ≥60 years (P=0.034), type of malignancy (P=0.000178), hypertension (P=0.0028), symptomatology of COVID-19 infection (P=0.0016), site of treatment and oxygen/intervention (P<0.0001). There was an average delay in treatment time of 5 to 6 weeks. Multivariate analysis showed that gastrointestinal (GI) and hepato-pancreato-biliary (HPB) malignancies and oxygen requirement (>2 L/min) were responsible for the 20.65% mortality rate. Conclusions: The pandemic significantly affected the care of cancer patients with decreased cases, late presentation, delayed treatment with potentially worse mortality outcome. Although they have decreased immunity, majority were asymptomatic. Most of the fatalities were in the GI and HPB malignancies.

Clinico-Pathological Factors Determining Recurrence of Phyllodes Tumors of the Breast: The 25-Year Experience at a Tertiary Cancer Centre.

BACKGROUND: Phyllodes tumors (PTs) of the breast are rare fibroepithelial tumors that are generally more prone to recurrence. AIMS AND OBJECTIVES: This study aimed to assess the clinicopathological features, diagnostic modalities, and therapeutic interventions, along with their respective outcomes, to identify the factors associated with a recurrence of PTs of the breast. METHODOLOGY: A retrospective cohort and observational study was conducted, which entailed analyzing the clinicopathological data of patients who were previously diagnosed or presented with PTs of the breast between 1996 and 2021. Data included the total number of patients diagnosed with PTs of the breast and their ages, tumor grade on initial biopsy, tumor location (left or right breast), tumor size, therapeutic interventions carried out (including surgery-either mastectomy or lumpectomy-and adjuvant radiotherapy), final tumor grade, recurrence status, type of recurrence, and time to recurrence. RESULTS: We analyzed data on a total of 87 patients who were pathologically proven to have PTs, and 46 patients (52.87%) were found to have recurrences. All patients were female, with a mean age at diagnosis of 39 years (range 15-70). Patients aged <40 years had the highest incidence of recurrence, with a rate of 54.35% (n = 25/46), followed by patients aged >40 years, with a rate of recurrence of 45.65% (n = 21/46). A total of 55.4% of patients presented with primary PTs and 44.6% had recurrent PTs at presentation. The average time to local recurrence (LR) from the completion of treatment was 13.8 months, whereas for systemic recurrence (SR), it was 15.29 months. Surgery (mastectomy/lumpectomy) was the major determinant for local recurrence (p < 0.05). CONCLUSION: Patients who received adjuvant radiotherapy (RT) had a minimal recurrence of PTs. Patients who were found to have a malignant biopsy on initial diagnosis (triple assessment) had a higher incidence of PTs and were more prone to SR than LR. Surgery was a determining factor in the increased rate of LR, with lumpectomy associated with a higher incidence of LR than mastectomy.

Osteosarcoma of the maxilla presenting as a chronic pyogenic abscess: A case report.

INTRODUCTION: Osteosarcoma of the maxilla is recorded as the least common of all bone malignancies. It exhibits a clinical behavior and natural history distinct from their counterparts of the trunk and extremities. Transformation from a chronic pyogenic abscess of the maxilla is even more unusual. CASE SUMMARY: A 70 year old lady presented to our hospital with a hard, fixed and tender bony swelling in her left cheek. She had initially presented to a different hospital with a similar presentation which was excised after imaging and post excision was found to be a chronic pyogenic abscess. The swelling reappeared within one year and on re-excision was found to be a low grade paraosteal osteosarcoma of the hard palate. CECT and PET-CT work-up at our hospital showed a left maxillary sinus growth with prominent neck lymph nodes along with mediastinal lymphadenopathy and pulmonary metastasis. Final histopathology revealed ulcerated stratified squamous epithelium mucosa overlying a lesion suggestive of osteosarcoma. DISCUSSION: Complete surgical excision with negative margins continues to be the mainstay of treatment, but osteosarcomas of maxillofacial region pose difficulties in obtaining tumour free margins because of their complex anatomy around the cranium. Surgery may be complemented by radiotherapy with or without chemotherapy. Small size of the tumour and low-grade histology have been assumed to reflect a better prognosis. CONCLUSION: Osteosarcoma of maxillofacial region has variable appearance clinically as well as radiologically posing a diagnostic challenge for clinicians. Any chronic abscess or recurrent cheek swelling thus necessitates further suspicion and requires a full work-up to rule out this high risk malignancy.

Axillary Reverse Mapping in Patients Undergoing Axillary Lymph Node Dissection: A Single Institution Experience From India.

Introduction Axillary lymph node dissection (ALND) remains the gold standard for clinically node-positive and sentinel node biopsy (SLNB) positive breast cancer patients, but it is associated with the debilitating morbidity of lymphedema. Recently, a new technique of axillary reverse mapping (ARM) has been described which helps in differentiating arm lymphatics from breast lymphatics. Aim To evaluate the applicability of the ARM technique with blue dye and the incidence of metastases in ARM nodes in the Indian population. Method A total of 120 patients underwent ARM during ALND. Blue lymphatic channels and lymph nodes were noted. All axillary nodes along with ARM nodes were dissected and sent separately for pathological evaluation for metastases. Results ARM nodes or lymphatics were identified in 65 (54.17%) out of 120 patients. The mean ARM lymph node yield was 1.4. The patients in whom ARM lymph nodes or lymphatics were not identified had significantly higher T stage and N stage (p <0.00001) than in whom it was identified. There was no significant correlation between ARM identification with BMI, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2/neu), and neoadjuvant chemotherapy (NACT) status. ARM nodes were found metastatic in three patients (7.5%). All these patients had clinically N2 disease and all had pathologically more than ten nodes involved in the axilla. Conclusion The identification rate of ARM nodes and lymphatics with blue dye is lower in Indian patients who present with higher clinical T and N stage disease. Other clinicopathological parameters were not associated with the identification rate. The rate of metastasis in ARM nodes is high in patients with a high axillary tumor burden. Hence, preserving ARM nodes may not be oncologically safe in higher N stage disease.

Primary adenocarcinoma of the appendix presenting with fresh bleeding per rectum: A case report.

INTRODUCTION: Primary adenocarcinoma of appendix is a rarely diagnosed malignancy accounting for less than 6% of appendiceal neoplastic lesions and less than 0.5% of all gastrointestinal malignancies. It is mostly diagnosed as an incidental finding after appendicectomy. CASE SUMMARY: An 81 year old male patient presented with bleeding per rectum in a background of previous rectal polyp, hypertension, diabetes and hypothyroidism. CECT of whole abdomen findings revealed thickening at the appendix and base of the caecum. Colonoscopy showed a sessile polypoid growth at appendicular orifice, at the base of the caecum. Laparoscopy confirmed the clinical suspicion of appendicular carcinoma and laparoscopy assisted radical right hemicolectomy was performed. Final histopathology revealed well differentiated adenocarcinoma of the appendix with no lymph node involvement (pT3N0M0). DISCUSSION: Patients with primary adenocarcinoma of the appendix present with features similar to acute appendicitis whereas anaemia or fresh bleeding per rectum is a rare presentation. Surgery is the mainstay of treatment, the extent of which will depend upon the stage. Tumours staged as T1 may be managed by appendicectomy alone provided the base is free and there are no lymphadenopathies. T2 or above require right hemicolectomy as chances of lymph node metastasis are high. Nodal involvement warrants the need for adjuvant chemotherapy. Distant metastasis to the peritoneum or liver and lungs is very rare. CONCLUSION: While investigating unexplained anaemia or bleeding per rectum, full colonoscopic examination up to the appendicular orifice is important and if required, should be combined with CT scan of abdomen, to clinch the rare but possible and potentially curable diagnosis of appendicular carcinoma.

Increase in PPARγ inhibitory phosphorylation by Fetuin-A through the activation of Ras-MEK-ERK pathway causes insulin resistance.

Obesity induced insulin resistance is primarily regulated by the inhibitory phosphorylation of peroxisome proliferator-activated receptor γ at serine 273 (PPARγS273) which has been shown to be regulated by MEK and ERK. An upstream regulatory molecule of this pathway could be a therapeutic option. Here we analyzed the involvement of Fetuin-A (FetA), a key hepato-adipokine implicated in insulin resistance, as an upstream regulator molecule for the regulation of PPARγ inhibitory phosphorylation. Mice fed with standard diet (SD), high fat diet (HFD) and HFD with FetA knockdown (HFD-FetAKD) were used to examine the role of FetA on PPARγS273 phosphorylation in adipocytes. The mechanism of regulation and its effect on skeletal muscle were studied using primary adipocytes, 3T3-L1 (preadipocyte) and C2C12 (myotube) cell lines. Increased FetA in HFD mice strongly correlated with augmentation of PPARγS273 phosphorylation in inflamed adipocytes while knockdown of FetA suppressed it. This effect of FetA was mediated through the activation of Ras which in turn activated MEK and ERK. On addressing how FetA could stimulate activation of Ras, we found that FetA triggered TNFα in inflamed adipocytes which induced Ras activation. The ensuing sharp fall in adiponectin level attenuated AMPK activation in skeletal muscle cells affecting mitochondrial ATP production. Our data reveal the essential role of FetA induced activation of Ras in regulating PPARγ inhibitory phosphorylation through Ras-MEK-ERK pathway which downregulates adiponectin disrupting skeletal muscle mitochondrial bioenergetics. Thus, FetA mediated PPARγ inactivation has adverse consequences upon adipocyte-myocyte crosstalk leading to disruption of energy homeostasis and loss of insulin sensitivity.

Gustatory ultrastructures of an amphihaline migratory fish hilsa Tenualosa ilisha.

This study was conducted with the tongue samples of different life stages of hilsa, that is, adult Marine hilsa, adult Riverine hilsa, and Riverine juvenile hilsa, respectively. Three types of taste buds (Types I, II, and III based on their elevation from the epithelium at different levels) of the tongue, which may be to ensure full utilization of the gustatory ability of the fish were rocorded. Presence of specific taste buds indicate that the fish hilsa dwells in turbid waters with a possible preference toward diatom like planktonic food source. Enhanced expression of taste receptors (T1R1 and T1R3) and associated stimulatory G-proteins subunits on tongue also indicate occurrence of amino acid like substances that guided sensory cues for feeding by this fish. A firm regularity or stringency of the free surface of the epithelial cells may be attributed to compactly arranged microridges. These structures protect against physical abrasions potentially caused during food manoeuvring and swallowing. In our present observations, the surface architectures of the tongue of hilsa are discussed within the background of migratory adaptation of the species in the context of feeding and habitat preferences.

Chronic dietary administration of lower levels of diethyl phthalate induces murine testicular germ cell inflammation and sperm pathologies: Involvement of oxidative stress.

The wide occurrence of male infertility is a matter of grave concern. One of the major causes being exposure to endocrine disrupting chemicals (EDCs) many of which are known reproductive toxicants but the molecular mechanisms of action remain much unexplored. Diethyl phthalate (DEP) is ubiquitous in the environment due to its extensive use as plasticizer in myriad consumer products. In the present study, we sought to find out whether chronic DEP exposure affects reproductive function in sexually mature adult male mice. For this, 8-week old Swiss albino mice were treated with DEP (1 mg and 10 mg kg-1 body weight day-1) in diet for three months, mirroring the relevant doses of human exposure, and various analyses were carried out in the testicular germ cells and epididymal spermatozoa. We found that altered testicular histoarchitecture was accompanied with disturbed prooxidant: antioxidant balance in the germ cells. Involvement of Nrf2-HO-1 pathway was crucial in this altered cellular redox state. Besides, NFκB mediated inflammatory response was triggered in the germ cells leading to enhanced levels of proinflammatory cytokines. DEP adversely affected sperm count, motility, viability and morphology. Numerous structural anomalies were found in DEP treated mice spermatozoa reflecting decline in sperm function. Our results revealed overactivation of PARP-1 and subsequent cleavage in spermatozoa with induction of apoptosis as a key mechanism in DEP mediated sperm pathology. Given the indiscriminate use of plasticizers and long term low level human exposure, the present study highlights the undesirable male reproductive outcomes following chronic DEP exposure.

Transcriptome analysis reveals novel insights in air-breathing magur catfish (Clarias magur) in response to high environmental ammonia.

The facultative air-breathing magur catfish (Clarias magur) frequently face different environmental challenges, such as hyper-ammonia, and desiccation stresses in their natural habitats. All these stresses lead to higher accumulation of body ammonia, thereby causing various harmful effects to the fish due to its toxicity. Nonetheless, the mechanisms underlying ammonia-induced toxicity is yet not clear. In the present study, we used RNA sequencing and utilized a modified method for de novo assembly of the transcriptome to provide an exhaustive study on the transcriptomic alterations of magur catfish in response to high environmental ammonia (HEA; 25 mM NH4Cl). The final contig assembly produced a total of 311,076 unique transcripts (termed as unigenes) with a GC content of 48.3% and the average length of 599 bp. A considerable number of SSR marker associated with these unigenes were also detected. A total of 279,156 transcripts were successfully annotated by using various databases. Comparative transcriptomic analysis revealed a total of 3453 and 19,455 genes were differentially expressed in the liver and brain tissues, respectively, in ammonia-treated fish compared to the control. Enrichment analysis of the differentially expressed genes (DEGs) showed that several GO and KEGG pathway terms were significantly over-represented. Functional analysis of significantly elevated DEGs demonstrated that ammonia stress tolerance of the magur catfish was associated with quite a few pathways related to immune response, oxidative stress, and apoptosis, as well as few transporter proteins involved with ammonia and urea transport. Both liver and brain tissues showed HEA-mediated oxidative damage with consequent activation of antioxidant machinery. However, elevated ROS levels led to an activation of inflammatory cytokines and thus innate immune response in the liver. Conversely, in the brain ROS-mediated irreversible cell damages activated apoptosis via both p53-Bax-Bcl2 and caspase-mediated pathways. The present study provides a novel understanding of the molecular responses of this air-breathing catfish against the ammonia-induced stressors, which could elucidate the underlying mechanisms of adaptation of this facultative air-breather living under various environmental constraints.

Ectopic expression of olfactory receptors and associated G-protein subunits in the head integument of the amphihaline migratory fish hilsa Tenualosa ilisha.

The chemosensory nature of the tissue from the dorsal surface of the head (also termed sensory pad; SP) of the amphihaline diadromous fish hilsa Tenualosa ilisha was investigated for odorant receptor (OR), olfactory marker protein (OMP) and G-protein subunits (Gαs-olf, Gαq, Gαo, Gαi3) through immunolocalization and immunoblotting techniques. The immunolocalization of OR, OMP and G-protein subunits showed clear expression of these proteins in the tissues of the SP. Robust expressions of these proteins in the SP were detected with immunoblot analysis. The strong expression of these proteins in the SP indicates that the tissues from this area in riverine T. ilisha may play significant role in chemosensing and signalling through ectopic expression of olfactory receptor proteins which are otherwise reported in olfactory organs in vertebrates. Being migratory in nature, ectopic expression of these receptors in T. ilisha probably helps them to prevent damage to epidermal tissues of the SP, or they may also utilize them as a chemo and mechanosensory tool to optimize chemo-communications during migration.

Structural organization of the olfactory organ in an amphihaline migratory fish Hilsa, Tenualosa ilisha.

The histological as well as ultramicroscopic structures of olfactory system of an amphihaline migratory fish hilsa Tenualosa ilisha, were studied. The sexually matured riverine fish were collected from a common breeding habitat-the Hooghly, a tributary of river Ganga, West Bengal, India. This study revealed that the riverine hilsa has larger olfactory bulb compared to marine hilsa with the olfactory lobes well exposed through nostrils. The olfactory lamellae (OL) are 40-45 in number and posses three distinct layers of sensory cells across each lamellae, namely, outer receptor cells (RC), middle sensory cells, and inner basal cells (BC). Besides the above arrangement, the sensory part of olfactory epithelium (OE) also bears rich microvillous cells exposed to the surface of the OE. The sensory and non-sensory surfaces on OL are distinguishable, with clear dendritic cells on sensory epithelium and solitary chemosensory cells on non sensory OE. Abundance of both types of cells in the OE is an indication of its chemoattraction ability towards molecules of amino acid origin. The feature of having abundant, dense, and large dendritic knobs on the surface of OE describes resemblance to the typical morphology of the chemosensory septal organs neuron. The expression of four G protein subunits, like Gαs/olf, Gαq, Gαo, and Gαi-3 in OE indicate that its olfaction is a functional attributes of two olfactory systems, namely main olfactory system and Vomaronasal Olfactory System. Expression of ACIII and PLCß2 in OE further confirms two signaling pathways involved in odorant reception in hilsa. RESEARCH HIGHLIGHTS: The olfactory bulb in the amphihaline migratory fish hilsa is big in size, with 40-45 lamellae. Its sensory areas showed multilayered cellular features with prominent sensory as well as microvillous cells, whereas non-sensory area possesses solitary chemosensory cells. The expression of four G protein subunits, Gαs/olf, Gαq, Gαo, and Gαi-3 in olfactory epithelium indicates that its olfaction is a functional attributes of two olfactory systems, namely main olfactory system and vomaronasal olfactory system.

Attenuation of macrophage accumulation and polarisation in obese diabetic mice by a small molecule significantly improved insulin sensitivity.

Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O2)2 (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFNγ. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFNγ promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFNγ levels, we found that it was due to the inactivation of NFκB because of its deacetylation by SIRT1. Since NFκB is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes.

Palmitate induced Fetuin-A secretion from pancreatic ß-cells adversely affects its function and elicits inflammation.

Islets of type 2 diabetes patients display inflammation, elevated levels of cytokines and macrophages. The master regulator of inflammation in the islets is free fatty acids (FFA). It has already been reported that FFA and TLR4 stimulation induces pro-inflammatory factors in the islets. In this report we demonstrate that excess lipid triggers Fetuin-A (FetA) secretion from the pancreatic ß-cells. Palmitate treatment to MIN6 cells showed significantly elevated FetA levels in respect to their controls. Fatty acid induces the FetA gene and protein expression in the pancreatic ß-cells via TLR4 and over-expression of NF-κB. In the NF-κB knocked down MIN6 cells palmitate could not trigger FetA release into the incubation medium. These results suggest that NF-κB mediates palmitate stimulated FetA secretion from the pancreatic ß-cells. Blocking the activity of TLR4 by CLI-095 incubation or TLR4 siRNA restored insulin secretion which confirmed the role of TLR4 in FFA-FetA mediated pancreatic ß-cell dysfunction. Palmitate mediated expression of NF-κB enahnced inflammatory response through expression of cytokines such as IL-1ß and IL-6. These results suggest that FFA mediated FetA secretion from pancreatic ß-cells lead to their dysfunction via FFA-TLR4 pathway. FetA thus creates an inflammatory environment in the pancreatic islets that can become a possible cause behind pancreatic ß-cell dysfunction in chronic hyperlipidemic condition.

A Novel Ligand of Toll-like Receptor 4 From the Sheath of Wuchereria bancrofti Microfilaria Induces Proinflammatory Response in Macrophages.

Background: Lymphatic filariasis, frequently caused from Wuchereria bancrofti infection, is endemic in several parts of the globe and responsible for human health problems and socioeconomic loss to a large extent. Inflammatory consequences originating from host-parasite interaction play a major role in the disease pathology and allied complications. The identity of the key mediator of this process is yet unknown in filarial research. Methods: Microfilarial protein (MfP) was isolated from the sheath of W. bancrofti microfilariae through ultrafiltration, followed by chromatographic separation. Expression of signaling molecules was studied by enzyme-linked immunosorbent assay and immunoblotting. Binding of MfP to Toll-like receptor 4 (TLR4) was determined by co-immunoprecipitation, fluorescein isothiocyanate-probing, and surface plasmon resonance analysis. Results: We found that MfP (approximately 70 kDa) binds to macrophage-TLR4 and triggers nuclear factor kappa beta activation that upregulates secretion of proinflammatory cytokines. Microfilarial protein failed to induce inflammation in either TLRKO macrophage or macrophage treated with TLR4 inhibitor, indicating that MfP acts through TLR4. We have also detected phenotypic transformation of macrophages from anti-inflammatory (M2) to proinflammatory (M1) subtype after incubation with MfP. Conclusions: Microfilarial protein appears to be a new ligand of TLR4 from W. bancrofti. Determination of its functional attributions in the host-parasite relationship, especially immunopathogenesis of filarial infection, may improve our understanding.

A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice.

Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic ß-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17µM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.

Fetuin-A downregulates adiponectin through Wnt-PPARγ pathway in lipid induced inflamed adipocyte.

Adiponectin secreted from adipocytes is an anti-diabetic and anti-atherogenic adipokine. Adiponectin level is known to fall significantly in obesity induced type 2 diabetes which worsen insulin sensitivity because of aberrant lipid management. However, underlying mechanism of adiponectin decrease in obese diabetic condition is yet unclear. We report here that lowering of plasma adiponectin coincided with the higher Fetuin A (FetA) level in high fat diet (HFD) induced obese diabetic mice. Knock down of FetA gene (FetAKD) elevated adiponectin level markedly in HFD mice, while reinforcement of FetA into FetAKDHFD mice reduced its level again. These results indicate FetA's involvement in the lowering of adiponectin level in obesity induced diabetic mice. Our findings to understand how FetA could affect adiponectin decrease demonstrated that FetA could enhance Wnt3a expression in the adipocyte of HFD mice. FetA addition to 3T3L1 adipocyte incubation elevated Wnt3a expression in a dose dependent manner. Overexpression of Wnt3a by FetA inhibited PPARγ and adiponectin. FetA failed to reduce PPARγ and adiponectin in Wnt3a gene knocked down 3T3L1` adipocytes. All these suggest that FetA mediate its inhibitory effect on adiponectin through Wnt3a-PPARγ pathway. Inhibition of adiponectin expression through FetA and Wnt3a significantly compromised with the activation of AMPK and its downstream signalling molecules which adversely affected lipid management causing loss of insulin sensitivity. Downregulation of adiponectin in inflamed adipocyte by FetA through the mediation of Wnt3a and PPARγ is a new report.

A carbazole alkaloid deactivates mTOR through the suppression of rictor and that induces apoptosis in lung cancer cells.

Non-small cell lung cancer (NSCLC) is known to be a difficult cancer to treat because of its poor prognosis, limited option for surgery, and resistance to chemo or radiotherapy. In this study, we have demonstrated that suppression of rictor expression in A549 and H1299 NSCLC cells by mahanine, a carbazole alkaloid, disrupted constitutive activation of mTOR and Akt. Mahanine suppression of rictor gene expression and consequent attenuation of its protein expression affected the inhibition of mTOR (Ser-2481) and Akt (Ser-473) phosphorylation. Since mahanine treatment revealed this new insight of rictor-mTOR relationship, we examined an association between mTOR activation with rictor expression. Interestingly, in rictor knockdown (KD) NSCLC cells, mTOR activation was significantly impaired. Transfection of rictor over-expression vector into the NSCLC cells reversed this situation. In fact, both rictor KD and mahanine treated cells showed considerably depleted phospho-mTOR level. These results indicate that rictor is required to maintain constitutive activation of mTOR in lung cancer cells. When mTOR kinase activity in rictor KD cells was examined with Akt as substrate, a significant reduction of Akt phosphorylation indicated impairment of mTOR kinase potentiality. Disruption of mTOR and Akt activation caused drastic mortality of NSCLC cancer cells through apoptosis. Hence, our study reveals a new dimension in mTOR-rictor relationship, where rictor stands to be a suitable therapeutic target for lung cancer.

Association of MMP7 -181A→G Promoter Polymorphism with Gastric Cancer Risk: INFLUENCE OF NICOTINE IN DIFFERENTIAL ALLELE-SPECIFIC TRANSCRIPTION VIA INCREASED PHOSPHORYLATION OF cAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB).

Elevated expression of matrix metalloproteinase7 (MMP7) has been demonstrated to play a pivotal role in cancer invasion. The -181A→G (rs11568818) polymorphism in the MMP7 promoter modulates gene expression and possibly affects cancer progression. Here, we evaluated the impact of -181A→G polymorphism on MMP7 promoter activity and its association with gastric cancer risk in eastern Indian case-control cohorts (n = 520). The GG genotype as compared with the AA genotype was predisposed (p = 0.02; odds ratio = 1.9, 95% confidence interval = 1.1-3.3) to gastric cancer risk. Stratification analysis showed that tobacco addiction enhanced gastric cancer risk in GG subjects when compared with AA subjects (p = 0.03, odds ratio = 2.46, and 95% confidence interval = 1.07-5.68). Meta-analysis revealed that tobacco enhanced the risk for cancer more markedly in AG and GG carriers. Activity and expression of MMP7 were significantly higher in GG than in AA carriers. In support, MMP7 promoter-reporter assays showed greater transcriptional activity toward A to G transition under basal/nicotine-induced/cAMP-response element-binding protein (CREB) overexpressed conditions in gastric adenocarcinoma cells. Moreover, nicotine (a major component of tobacco) treatment significantly up-regulated MMP7 expression due to enhanced CREB phosphorylation followed by its nuclear translocation in gastric adenocarcinoma cells. Furthermore, chromatin immunoprecipitation experiments revealed higher binding of phosphorylated CREB with the -181G than the -181A allele. Altogether, specific binding of phosphorylated CREB to the G allele-carrying promoter enhances MMP7 gene expression that is further augmented by nicotine due to increased CREB phosphorylation and thereby increases the risk for gastric cancer.

Giant subcutaneous leiomyosarcoma of anterior abdominal wall.

Subcutaneous leiomyosarcomas are rare tumors accounting for 1% to 2% of all superficial soft tissue malignancies. Although they may arise anywhere in the body, they most frequently occur in the lower extremities. The incidence of subcutaneous LMS affecting the anterior abdominal wall is very rare. We herein report the case of a patient with a giant subcutaneous leiomyosarcoma arising in the anterior abdominal wall. It was diagnosed by histopathology and immunohistochemistry and treated accordingly.