Carcinoma of the axillary tail of Spence: A rare case report.

INTRODUCTION: Carcinoma arising from the axillary tail of Spence (CATS) is a rare entity that requires a high level of clinical suspicion. The clinicopathologic, prognostic, and imaging features of CATS are poorly understood. CASE SUMMARY: A 46-year-old woman presented to our hospital with right axillary swelling associated with bleeding and foul-smelling discharge. She had initially presented to a different hospital with a similar presentation where she was diagnosed with metastatic carcinoma, favouring adenocarcinoma on the FNAC report, following which she received 3 cycles of chemotherapy. MRI and PET-CT scan workups at our hospital showed a soft tissue mass likely arising from the axillary tail of the right breast with a few enlarged axillary lymph nodes and an unremarkable right breast. She underwent excision of the mass with axillary lymph node dissection and reconstruction with a pedicled Latissimus dorsi flap. The final diagnosis was based on immunohistochemistry, with tumor cells positive for GATA3 and CK-7, negative for estrogen and progesterone receptors (ER, PR), positive for human epidermal growth factor receptor 2 (Her2 neu), and having a Ki-67 labelling index of 45 %. DISCUSSION: Carcinoma of the axillary tail of Spence (CATS) has a reported incidence of 0.3 %. There have been only few papers till date that have reported the clinicopathologic, prognostic, and imaging features of CATS. MRI is an important imaging modality to localize CATS. Histologic examination aids in the diagnosis by identifying the presence of a histologic pattern of primary breast carcinoma and immunohistochemical characteristics such as ER, PR, Her2neu, and gross cystic disease fluid protein (GCDFP). Due to the rarity of CATS, no specific guidelines concerning management currently exist. Surgical management involves wide local excision of the axillary mass with axillary lymph node dissection. CONCLUSION: CATS, even though rare, should be considered in the differential diagnosis of a patient presenting with an axillary mass. MRI is a valuable tool to distinguish CATS from other lesions. Immunohistochemistry is essential to confirm the diagnosis.

Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B.

The homologous P-type copper-ATPases (Cu-ATPases) ATP7A and ATP7B are the key regulators of copper homeostasis in mammalian cells. In polarized epithelia, upon copper treatment, ATP7A and ATP7B traffic from the trans-Golgi network (TGN) to basolateral and apical membranes, respectively. We characterized the sorting pathways of Cu-ATPases between TGN and the plasma membrane and identified the machinery involved. ATP7A and ATP7B reside on distinct domains of TGN in limiting copper conditions, and in high copper, ATP7A traffics to basolateral membrane, whereas ATP7B traverses common recycling, apical sorting and apical recycling endosomes en route to apical membrane. Mass spectrometry identified regulatory partners of ATP7A and ATP7B that include the adaptor protein-1 complex. Upon knocking out pan-AP-1, sorting of both Cu-ATPases is disrupted. ATP7A loses its trafficking polarity and localizes on both apical and basolateral surfaces in high copper. By contrast, ATP7B loses TGN retention but retained its trafficking polarity to the apical domain, which became copper independent. Using isoform-specific knockouts, we found that the AP-1A complex provides directionality and TGN retention for both Cu-ATPases, whereas the AP-1B complex governs copper-independent trafficking of ATP7B solely. Trafficking phenotypes of Wilson disease-causing ATP7B mutants that disrupts putative ATP7B-AP1 interaction further substantiates the role of AP-1 in apical sorting of ATP7B.

Copper-independent lysosomal localisation of the Wilson disease protein ATP7B.

In hepatocytes, the Wilson disease protein ATP7B resides on the trans-Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non-hepatic cells. These ATP7B-harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub-domain of the TGN with a lower pH and the TGN-proximal lysosomal compartments. The presence of ATP7B on TGN-lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper-replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN-proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper-independent lysosomal localisation of ATP7B and the importance of TGN-proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway.

Wilson disease-causing mutations in the carboxyl terminus of ATP7B regulates its localization and Golgi exit selectively in the unpolarized cells.

Mutational inactivation of the P-type Cu-ATPase ATP7B interferes with its cellular functions to varying extent leading to varied cellular phenotypes. Wilson's disease (WD) primarily affects organs composed of polarized/differentiated epithelial cells. Therefore, phenotypic variability might differ depending on the polarization/differentiation of the cells. The present study investigates the intracellular stability and localization of ATP7B harboring WD mutations in both unpolarized/undifferentiated and polarized/differentiated cell-based models. Green fluorescent protein (GFP)-ATP7B harboring the WD causing mutations, N41S, S653Y, R778Q, G1061E, H1069Q, S1423N, S1426I, and T1434M, are included for investigation. The C-terminal WD mutations (S1423N, S1426I, and T1434M), exhibit distinct localization and Cu(I) responsive anterograde and retrograde trafficking in undifferentiated/unpolarized vs. differentiated/polarized cells. While basal localization of the S1423N mutant gets corrected in the differentiated glia, its Cu(I) responsive anterograde and retrograde trafficking behavior is not identical to the wild-type. But localization and trafficking properties are completely rescued for the S1426I and T1434M mutants in the differentiated cells. Comprehensive meta-analysis on the effect of the reported C-terminal mutations on patient phenotype and cultured cells demonstrate discrete regions having distinct effects. While mutations in the proximal C-terminus affect ATP7B stability, the present study shows that the distal region dictates cell-specific Trans Golgi Network (TGN) localization and exit. The localization and export properties are corrected in the differentiated cells, which is a plausible mechanism for the milder phenotype exhibited by these mutations. It highlights the critical role of the C-terminus in cell-specific TGN retention and exit of ATP7B.

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.

A comparative analysis of features and outcome of breast cancer in younger versus older women: A single center experience from Eastern Indian subcontinent.

Purpose: Globally, breast cancer is the leading malignancy in females. Indeed, Asian cohorts show prevalence of breast cancer among women with ages below 40 years. Moreover, these younger cases are globally characterized by poorer prognostic features as well as survival outcomes, than older sufferers with ages above 40 years. Despite this, comparative analyses between older and younger cohorts are sparse from India, where data from the country's eastern part falls shortest. This study attempted a comprehensive analysis of breast cancer between these two cohorts representing the Eastern Indian subcontinent. Methods: Documenting retrospective case-files registered between 2010 and 2015, 394 cases of younger (<40 years) and 1250 older (≥40 years) sufferers of primary breast cancer were noted. The relevant features and follow-up information were also retrieved. Kaplan-Meier analyses were performed to evaluate the survival outcome. Results: The data, in general, revealed a high percentage of younger sufferers from Eastern Indian regions. Moreover, this younger cohort showed poor survival. Among the younger cohort, cases with poor pathological features (triple negative, node-positive, grade III) were proportionately higher than the older cohort. Indeed, survival among these categories scored significantly low, compared to the older cohort. Conclusion: This Eastern Indian subcontinental data matched the analyses from other parts of India as well as Asian data and clearly showed the prevalence of younger sufferers of breast cancer with poor clinico-pathological features and survival outcomes. Impact: Analyzing age-based features and outcomes from Eastern India, this study provides data in supplementing Indian and Asian scenarios of breast cancer.

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.

Assembly and disassembly dynamics of nonmuscle myosin II control endosomal fission.

Endocytic vesicular trafficking requires merging of two lipid bilayers, but how the two lipid bilayers can come close together during fusion and fission in endocytic trafficking is not well explored. Here, we establish that knocking down nonmuscle myosin IIs (NM IIs) by small interfering RNA (siRNA) or inhibition of their activities by (-) blebbistatin causes the formation of a ring-like assembly of early endosomes (raEE). Inhibition of NM II assembly by an inhibitor of regulatory light-chain (RLC) kinase results in the formation of raEE, whereas inhibition of NM II disassembly by inhibitors of heavy chain kinases, protein kinase C (PKC) and casein kinase 2 (CK2), causes the dispersion of early endosomes. The raEEs retain EEA1, Rab7, and LAMP2 markers. Overexpression of an assembly incompetent form, RLC-AA, and disassembly incompetent form, NMHCIIB-S6A or NMHCIIA-1916A, induces such defects, respectively. Altogether, these data support that NM II assembly and disassembly dynamics participate in endocytic trafficking by regulating fission to maintain the size of early endosomes.

Dual stimuli-responsive cross-linked nanoassemblies from an amphiphilic mannose-6-phosphate based tri-block copolymer for lysosomal membrane permeabilization.

Stimuli-responsive cross-linked nanocarriers that can induce lysosomal cell death (LCD) via lysosomal membrane permeabilization (LMP) represent a new class of delivery platforms and have attracted the attention of researchers in the biomedical field. The advantages of such cross-linked nanocarriers are as follows (i) they remain intact during blood circulation; and (ii) they reach the target site via specific receptor-mediated endocytosis leading to the enhancement of therapeutic efficacy and reduction of side effects. Herein, we have synthesized a mannose-6-phosphate (M6P) based amphiphilic ABC type tri-block copolymer having two chains of FDA-approved poly(ε-caprolactone) (PCL) as the hydrophobic block, and poly(S-(o-nitrobenzyl)-L-cysteine) (NBC) acts as the photoresponsive crosslinker block. Two different tri-block copolymers, [(PCL35)2-b-NBC20-b-M6PGP20] and [(PCL35)2-b-NBC15-b-M6PGP20], were synthesized which upon successful self-assembly initially formed spherical uncross-linked "micellar-type" aggregates (UCL-M) and vesicles (UCL-V), respectively. The uncross-linked nanocarriers upon UV treatment for thirty minutes were covalently crosslinked in the middle PNBC block giving rise to the di-sulfide bonds and forming interface cross-linked "micellar-type" aggregates (ICL-M) and vesicles (ICL-V). DLS, TEM, and AFM techniques were used to successfully characterize the morphology of these nanocarriers. The dual stimuli (redox and enzyme) responsiveness of the cross-linked nanocarriers and their trafficking to the lysosome in mammalian cells via receptor-mediated endocytosis was probed using confocal microscopy images. Furthermore, the addition of a chloroquine (CQ, a known lysosomotropic agent) encapsulated cross-linked nanocarrier (CQ@ICL-V) to non-cancerous (HEK-293T) cells and liver (HepG2), and breast cancer cells (MDA-MB-231) was found to initiate lysosomal membrane permeabilization (LMP) followed by lysosomal destabilization which eventually led to lysosomal cell death (LCD). Due to the targeted delivery of CQ to the lysosomes of cancerous cells, almost a 90% smaller amount of CQ was able to achieve similar cell death to CQ alone.

Polarized trafficking and copper transport activity of ATP7B: A mutational approach to establish genotype-phenotype correlation in Wilson disease.

Mutation in ATP7B gene causes Wilson disease (WD) that is characterized by severe hepatic and neurological symptoms. ATP7B localizes at the trans-Golgi Network (TGN) transporting copper to copper-dependent enzymes and traffics in apically targeted vesicles upon intracellular copper elevation. To decode the cellular underpinnings of WD manifestation we investigated copper-responsive polarized trafficking and copper transport activity of 15 WD causing point mutations in ATP7B. Amino-terminal mutations Gly85Val, Leu168Pro, and Gly591Asp displayed TGN and subapical localization whereas, Leu492Ser mislocalized at the basolateral region. The actuator domain mutation Gly875Arg shows retention in the endoplasmic reticulum (ER), Ala874Val and Leu795Phe show partial targeting to TGN and post-Golgi vesicles. The nucleotide-binding domain mutations His1069Gln and Leu1083Phe also display impaired targeting. The C-terminal mutations Leu1373Pro/Arg is arrested at ER but Ser1423Asn shows TGN localization. Transmembrane mutant Arg778Leu resides in ER and TGN while Arg969Gln is exclusively ER localized. Cellular Cu level does not alter the targeting of any of the studied mutations. Mutants that traffic to TGN exhibits biosynthetic function. Finally, we correlated cellular phenotypes with the clinical manifestation of the two most prevalent mutations; the early onset and more aggressive WD caused by Arg778Leu and the milder form of WD caused by mutation His1069Gln.

Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer.

Development of endocrine resistance in hormone-receptor-positive (HR+ve) subtype and lack of definitive target in triple-negative subtype challenge breast cancer management. Contributing to such endocrine resistance is a protein called CUEDC2. It degrades hormone receptors, estrogen receptor-α (ERα) and progesterone receptor. Higher level of CUEDC2 in ERα+ve breast cancer corresponded to poorer disease prognosis. It additionally influences mitotic progression. However, the crosstalk of these two CUEDC2-driven functions in the outcome of breast cancer remained elusive. We showed that CUEDC2 degrades ERα during mitosis, utilising the mitotic-ubiquitination-machinery. We elucidated the importance of mitosis-specific phosphorylation of CUEDC2 in this process. Furthermore, upregulated CUEDC2 overrode mitotic arrest, increasing aneuploidy. Finally, recruiting a prospective cohort of breast cancer, we found significantly upregulated CUEDC2 in HR-ve cases. Moreover, individuals with higher CUEDC2 levels showed a poorer progression-free-survival. Together, our data confirmed that CUEDC2 up-regulation renders ERα+ve malignancies to behave essentially as HR-ve tumors with the prevalence of aneuploidy. This study finds CUEDC2 as a potential prognostic marker and a therapeutic target in the clinical management of breast cancer.

Design and Analysis of a Low-Cost Electronically Controlled Mobile Ventilator, Incorporating Mechanized AMBU Bag, for Patients during COVID-19 Pandemic.

The outbreak of novel COVID-19 has severely and unprecedentedly affected millions of people across the globe. The painful respiratory distress caused during this disease calls for external assistance to the victims in the form of ventilation. The most common types of artificial ventilating units available at the healthcare facilities and hospitals are exorbitantly expensive to manufacture, and their number is fairly inadequate even in the so-called developed countries to cater to the burning needs of an ever-increasing number of ailing human subjects. According to available reports, without the provision of ventilation, the novel COVID-19 patients are succumbing to their ailments in a huge number of cases. This colossal problem of the availability of ventilator units can be addressed to a great extent by readily producible and cost-effective ventilating units that can be used on those suffering patients during an acute emergency and in the absence of conventional expensive ventilators at hospitals and medical care units. This paper has made an attempt to design and simulate a simple, yet effective, mechanized ventilator unit, which can be conveniently assembled without a profuse skillset and operated to resuscitate an ailing human patient. The stepper motor-controlled kinematic linkage is designed to deliver the patient with a necessitated discharge of air at optimum oxygen saturation through the AMBU bag connected in a ventilation circuit. With the associated code on MATLAB, the motor control parameters such as angular displacement and speed are deduced according to the input patient conditions (age group, tidal volume, breathing rate, etc.) and thereafter fed to the controller that drives the stepper motor. With a proposed feedback loop, the real-time static and dynamic compliance, airway resistance values can be approximately determined from the pressure variation cycle and fed to the controller unit to adjust the tidal volume as and when necessary. The simplistic yet robust design not only renders easy manufacturability by conventional and rapid prototyping techniques like 3D printing at different scales but also makes the product easily portable with minimal handling difficulty. Keeping the motto of Health for All as envisioned by the WHO, this low-cost indigenously engineered ventilator will definitely help the poor and afflicted towards their right to health and will help the medical professionals buy some time to manage the patient with acute respiratory distress syndrome (ARDS) towards recovery. Moreover, this instrument mostly includes readily available functional units having standard specifications and can be considered as standard bought-out items.

Copper dependent ERK1/2 phosphorylation is essential for the viability of neurons and not glia.

Intracellular copper [Cu(I)] has been hypothesized to play role in the differentiation of the neurons. This necessitates understanding the role of Cu(I) not only in the neurons but also in the glia considering their anatomical proximity, contribution towards ion homeostasis, and neurodegeneration. In this study, we did a systematic investigation of the changes in the cellular copper homeostasis during neuronal and glial differentiation and the pathways triggered by them. Our study demonstrates increased mRNA for the plasma membrane copper transporter CTR1 leading to increased Cu(I) during the neuronal (PC-12) differentiation. ATP7A is retained in the trans-Golgi network (TGN) despite high Cu(I) demonstrating its utilization towards the neuronal differentiation. Intracellular copper triggers pathways essential for neurite generation and ERK1/2 activation during the neuronal differentiation. ERK1/2 activation also accompanies the differentiation of the foetal brain derived neuronal progenitor cells. The study demonstrates that ERK1/2 phosphorylation is essential for the viability of the neurons. In contrast, differentiated C-6 (glia) cells contain low intracellular copper and significant downregulation of the ERK1/2 phosphorylation demonstrating that ERK1/2 activation does not regulate the viability of the glia. But ATP7A shows vesicular localization despite low copper in the glia. In addition to the TGN, ATP7A localizes into RAB11 positive recycling endosomes in the glial neurites. Our study demonstrates the role of copper dependent ERK1/2 phosphorylation in the neuronal viability. Whereas glial differentiation largely involves sequestration of Cu(I) into the endosomes potentially (i) for ready release and (ii) rendering cytosolic copper unavailable for pathways like the ERK1/2 activation.

Copper(II) import and reduction are dependent on His-Met clusters in the extracellular amino terminus of human copper transporter-1.

Copper(I) is an essential metal for all life forms. Though Cu(II) is the most abundant and stable state, its reduction to Cu(I) via an unclear mechanism is prerequisite for its bioutilization. In eukaryotes, the copper transporter-1 (CTR1) is the primary high-affinity copper importer, although its mechanism and role in Cu(II) reduction remain uncharacterized. Here we show that extracellular amino-terminus of human CTR1 contains two methionine-histidine clusters and neighboring aspartates that distinctly bind Cu(I) and Cu(II) preceding its import. We determined that hCTR1 localizes at the basolateral membrane of polarized MDCK-II cells and that its endocytosis to Common-Recycling-Endosomes is regulated by reduction of Cu(II) to Cu(I) and subsequent Cu(I) coordination by the methionine cluster. We demonstrate the transient binding of both Cu(II) and Cu(I) during the reduction process is facilitated by aspartates that also act as another crucial determinant of hCTR1 endocytosis. Mutating the first Methionine cluster (7Met-Gly-Met9) and Asp13 abrogated copper uptake and endocytosis upon copper treatment. This phenotype could be reverted by treating the cells with reduced and nonreoxidizable Cu(I). We show that histidine clusters, on other hand, bind Cu(II) and are crucial for hCTR1 functioning at limiting copper. Finally, we show that two N-terminal His-Met-Asp clusters exhibit functional complementarity, as the second cluster is sufficient to preserve copper-induced CTR1 endocytosis upon complete deletion of the first cluster. We propose a novel and detailed mechanism by which the two His-Met-Asp residues of hCTR1 amino-terminus not only bind copper, but also maintain its reduced state, crucial for intracellular uptake.

A novel leishmanial copper P-type ATPase plays a vital role in parasite infection and intracellular survival.

Copper (Cu) is essential for all life forms; however, in excess, it becomes toxic. Toxic properties of Cu are known to be utilized by host species against various pathogenic invasions. Leishmania, in both free-living and intracellular forms, exhibits appreciable tolerance toward Cu stress. While determining the mechanism of Cu-stress evasion employed by Leishmania, we identified and characterized a hitherto unknown Cu-ATPase in Leishmania major and established its role in parasite survival in host macrophages. This novel L. major Cu-ATPase, LmATP7, exhibits homology with its orthologs at multiple motifs. In promastigotes, LmATP7 primarily localized at the plasma membrane. We also show that LmATP7 exhibits Cu-dependent expression patterns and complements Cu transport in a Cu-ATPase-deficient yeast strain. Promastigotes overexpressing LmATP7 exhibited higher survival upon Cu stress, indicating efficacious Cu export compared with Wt and heterozygous LmATP7 knockout parasites. We further explored macrophage-Leishmania interactions with respect to Cu stress. We found that Leishmania infection triggers upregulation of major mammalian Cu exporter, ATP7A, in macrophages, and trafficking of ATP7A from the trans-Golgi network to endolysosomes in macrophages harboring amastigotes. Simultaneously, in Leishmania, we observed a multifold increase in LmATP7 transcripts as the promastigote becomes established in macrophages and morphs to the amastigote form. Finally, overexpressing LmATP7 in parasites increases amastigote survivability within macrophages, whereas knocking it down reduces survivability drastically. Mice injected in their footpads with an LmATP7-overexpressing strain showed significantly larger lesions and higher amastigote loads as compared with controls and knockouts. These data establish the role of LmATP7 in parasite infectivity and intramacrophagic survivability.

Cancer Care-Post-Independence Evolution in West Bengal and Eastern India.

The Cancer Care in Eastern India, especially West Bengal, started evolving a long time back along with a few other centres in India. Some of them were government institutes and the others were NGOs and private hospitals. The last decade however saw a huge boom of many cancer centres-either a part of government hospitals/multispecialty private hospitals or some as standalone comprehensive cancer centres. This article briefly covers the evolution, referring to the Official Websites of the Institutes. References were taken from the Official Websites of the cancer hospitals and also Google search for Cancer Care facilities in Eastern and North East India.

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.

Synthesis, Characterization, and Cytotoxicity of Morpholine-Containing Ruthenium(II) p-Cymene Complexes.

Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1-6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2-4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1̅ space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1-14 µM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.

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.