Invasive Papillary Adenocarcinoma of Gallbladder: A Case Report.

Papillary gallbladder adenocarcinoma (PGA) represents 5.0% of all malignant tumor of gallbladder. An early diagnosis is essential as this malignancy progresses silently with a late diagnosis, often proving fatal. A 63 year old female presented with right upper quadrant pain, palpable gallbladder on clinical examination and hypoechoic shadow suggestive of gall stone inside on ultrasound. But during an attempt to open cholecystectomy surgeons found tiny papillary growth involving whole fundus and part of the body on June 2020 at an outside hospital, Khulna, Bangladesh. Radical cholecystectomy was done by the surgeon with enlarged portal lymph node dissection and a small portion of hepatic resection. Histopathology demonstrated a well-differentiated invasive papillary adenocarcinoma with muscle invasion. There was no metastasis in the liver and lymph nodes show reactive hyperplasia.

One-Step Colloidal Synthesis of Non-Toxic Electroactive Carbon Dots with a Better Threshold Cytotoxicity and Cytocompatibility.

Carbon dots (CDs), because of their characteristic size (<10 nm) and highly fluorescent nature, can be internalized in biological cells or can be tagged to the key components of a living system. While these attributes can be potentially exploited for biomedical applications, the toxicity of CDs remains an important issue to be addressed. Both the synthesis approach and morphological attributes critically determine the dose-dependent toxicity and cytocompatibility of CDs. Against this perspective, we report herein a one-step colloidal synthesis of CDs using different reaction solvents that lead to the formation of three types of CDs (type I, type II, and type III CDs). The cytocompatibility and cellular uptake of CDs in human mesenchymal stem cells (hMSCs) are dependent on the nature of functionalization and concomitantly on the type of precursors. In particular, type I CDs are synthesized using citric acid, hexadecylamine, and octadecene that are immiscible in culture media. The type II CDs synthesized using citric acid and octadecene emit green fluorescence at a 488 nm excitation and were found to be agglomerated when internalized in hMSCs, whereas the type III CDs, synthesized using citric acid and deionized water, exhibit an agglomeration-free behavior. Further, type III CDs show a wide particle distribution, wide emission bandwidth range of 280-700 nm, threshold toxicity of 1 mg/mL, and good cytocompatibility with hMSCs, much better than those in the published reports. When benchmarked against commercial graphene quantum dots, the as-synthesized type III CDs have better electrical conductivity and cytocompatibility at a given dosage. Thus, the electroactive nature of synthesized type III CDs along with their inherent fluorescent property and less cytotoxicity would enable their potential applications in bio-imaging, directional lineage commitment, and cell-based therapy.

Early derangement of INR predicts liver failure after liver resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection, where appropriate, remains one of the best treatment options for hepatocellular carcinoma (HCC), however outcomes can be compromised by the development of liver failure. We reviewed our experience of liver resection for HCC patients to identify factors that may predict the development of post-hepatectomy liver failure (PHLF) and survival. METHODS: A single centre retrospective cohort study. Data was collected between 1999 and 2017 from all patients undergoing HCC resection in a tertiary university hospital from electronic medical records. PHLF was defined as per the International Study Group for Liver Surgery criteria. Variables with p < 0.15 on univariate analysis were included in a multivariate binary logistic regression model. Kaplan-Meier analyses were used to determine correlations with overall survival (OS) and disease-free survival (DFS), and variables with p < 0.15 on univariate analysis selected for a step-down Cox proportional hazard regression model. RESULTS: Overall, 120 patients underwent liver resection within the study period, of which 22 (18%) developed PHLF. Patients with normal INR ≤1.20 at day 2 did not develop PHLF whereas patients with INR >1.60 were at significant risk. Resection of multiple tumours (odds ratio 21.63, p = 0.002) and deranged postoperative day 2 INR>1.6 (odds ratio 21.05, p < 0.0001) were identified as independent prognostic markers of PHLF. CONCLUSION: The use of INR measurement at day 2 predicts PHLF and may enable us to objectively identify and stratify patients who may be eligible for enhanced recovery programs from those who will merit close monitoring in high dependency areas.

Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. METHODS: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. RESULTS: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70). CONCLUSIONS: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.

Early Phase Clinical Trial Designs - State of Play and Adapting for the Future.

The process of anti-cancer drug development is complex, with high attrition rates. Factors that may optimise this process include well-constructed and relevant pre-clinical testing and use of biomarkers for patient selection. However, the design of early phase clinical trials will probably play a vital role in both the robust clinical investigation of new targeted therapies and in streamlining drug development. In this overview, we assess current concepts in phase I clinical trials, highlighting issues and opportunities to improve their meaningfulness. The particular challenge of how to design combination trials is addressed, with focus on the potential of new adaptive and model-based designs.

Arsenic load in rice ecosystem and its mitigation through deficit irrigation.

Rice the staple food is a notable intake source of arsenic to the rural population of eastern India through food-chain. A field survey was carried out to study the variation of arsenic load in different parts of rice genotype Shatabdi (most popular genotype of the region) exposed to varying level of arsenic present in the irrigation water and soil. As irrigation is the primary source of arsenic contamination, a study was conducted to assess arsenic load in rice ecosystem under deficit irrigation practices like intermittent ponding (IP), saturation (SAT) and aerobic (AER) imposed during stress allowable stage (16-40 days after transplanting) of the crop (genotype Shatabdi). Present survey showed that arsenic content in water and soil influenced the arsenic load of rice grain. Variation in arsenic among different water and soil samples influenced grain arsenic load to the maximum extent followed by straw. Deviation in root arsenic load due to variation in water and soil arsenic content was lowest. Arsenic concentration of grain is strongly related to the arsenic content of both irrigation water and soil. However, water has 10% higher impact on grain arsenic load over soil. Translocation of arsenic from root to shoot decreased with the increase in arsenic content of water. Imposition of saturated and aerobic environment reduced both yield and grain arsenic load. In contrast under IP a marked decrease in grain arsenic content recorded with insignificant reduction in yield. Deficit irrigation resulted in significant reduction (17.6-25%) in arsenic content of polished rice and the values were lower than that of the toxic level (<0.2 mg kg-1). In contrast the decrease in yield was to the tune of 0.9% under IP regime over CP.

Is neo-adjuvant chemotherapy a better option for management of cervical cancer patients of rural India?

OBJECTIVES: To explore alternate modality of treatment in patients of advanced cancer cervix by neo-adjuvant chemotherapy (NACT) followed by External Beam Radiotherapy (ERT) and Brachytherapy (BT). Short- (6 months) and long- (12 months) term follow-up data from these patients were compared with the retrospective data from an urban cancer centre, where standard protocol of concurrent chemo-radiotherapy is practiced. MATERIALS AND METHODS: Two hundred patients of advanced cervical cancer, treated at our rural cancer centre between January 2007 and December 2007, were included in the study arm (Group A). These patients received three cycles of neo-adjuvant chemotherapy with Cisplatin, Bleomycin, and Vincristine before External-Beam Radiotherapy (EBT) followed by brachytherapy. Patients in the control arm (Group B) of an urban cancer centre, received EBT with weekly concomitant Cisplatin, followed by brachytherapy. Short- (6 months) and long- (12 months) term follow-up data from our patients were compared with the retrospective data from the urban cancer centre. RESULTS AND ANALYSIS: Complete response rate was comparatively higher among patients of Group A, also correspondingly proportion of patients showing progressive disease and stable disease was lower among them. Local treatment failure was 87.5% among patients from Group A and 94.4% in Group B patients. Concomitant chemoradiation (CRT) was associated with more GI toxicities. CONCLUSION: Our result suggests NACT arm is as effective as CRT arm in respect of complete response with less pelvic failure and G.I toxicities. Further follow-up data are needed before arriving at a definite conclusion.

Mechanistic contribution of electroconductive hydroxyapatite-titanium disilicide composite on the alignment and proliferation of cells.

We elucidate here the mechanistic contribution of a novel electroconductive hydroxyapatite-20 wt.% titanium disilicide (HA-TiSi2) composite system in favorably modulating osteoblast functions in relation to the monolithic HA. The higher electrical conductivity of HA-TiSi2(σDC ∼ 67.117 ± 3.57 S/m) in comparison to glass sample effectively guided the electroactive myoblast, leading to their significant alignment and proliferation. This favorable behavior is attributed to the formation of small electrochemical cells between HA and TiSi2phase, which produce a small electric field, directing the electroactive myoblast to migrate and grow in a particular direction. In contrast, no impact of TiSi2on osteoblast function was observed because of their inability to respond to small electric field. However, thein vitrobioactivity in simulated body fluid indicated the nucleation and growth of apatite crystals. Moreover, in the context of load-bearing capability, the presence of 20 wt.% TiSi2in HA led to increase in the fracture toughness by ∼100%. This study underscores the effectiveness of HA-TiSi2in favorably modulating the cellular activity, myoblast in particular.

A comprehensive study of the delay vector variance method for quantification of nonlinearity in dynamical systems.

Although vibration monitoring is a popular method to monitor and assess dynamic structures, quantification of linearity or nonlinearity of the dynamic responses remains a challenging problem. We investigate the delay vector variance (DVV) method in this regard in a comprehensive manner to establish the degree to which a change in signal nonlinearity can be related to system nonlinearity and how a change in system parameters affects the nonlinearity in the dynamic response of the system. A wide range of theoretical situations are considered in this regard using a single degree of freedom (SDOF) system to obtain numerical benchmarks. A number of experiments are then carried out using a physical SDOF model in the laboratory. Finally, a composite wind turbine blade is tested for different excitations and the dynamic responses are measured at a number of points to extend the investigation to continuum structures. The dynamic responses were measured using accelerometers, strain gauges and a Laser Doppler vibrometer. This comprehensive study creates a numerical and experimental benchmark for structurally dynamical systems where output-only information is typically available, especially in the context of DVV. The study also allows for comparative analysis between different systems driven by the similar input.

Environment-friendly route for stable aqueous dispersion of reduced graphene oxide for heat transfer application.

A simultaneous functionalization and reduction route to prepare stable dispersion of reduced graphene oxide from graphene oxide has been described. Diethanol amine has been introduced for the first time as an environment friendly reducing agent in a simple reflux reaction. Diethanol amine acts as a reducing agent and helps to enhance the stability of dispersion, making hydrogen bonding by virtue of two functional groups. The prepared dispersion of 0.025 mg/mL concentration is stable for months together and has a zeta potential value -45 V at room temperature. UV-Vis study shows peak at 264 nm that is signatory for reduced graphene oxide. TEM images confirm spread thin sheets of graphene of few hundred nanometer lateral dimension. Thermal diffusivity studies suggest nearly 60% enhancement for the dispersion in comparison to base fluid, water. This suggests graphene dispersion is promising for heat transfer applications.

Investigation of the protein alkylation sites of the STAT3:STAT3 inhibitor Stattic by mass spectrometry.

STAT3 (Signal Transducer and Activator of Transcription factor 3) is constitutively active in a wide range of human tumours. Stattic is one of the first non-peptidic small molecules reported to inhibit formation of the STAT3:STAT3 protein dimer complex. A mass spectrometry method has been developed to investigate the binding of Stattic to the un-phosphorylated STAT3ßtc (U-STAT3) protein. Alkylation of four cysteine residues has been observed with possible reaction at a fifth which could account for the mechanism of action.

GC-targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models.

DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-κB with its cognate DNA binding sequence.

Retting of jute grown in arsenic contaminated area and consequent arsenic pollution in surface water bodies.

Arsenic (As) toxicity of ground water in Bengal delta is a major environmental catastrophe. Cultivation of jute, a non edible crop after summer rice usually reduces arsenic load of the soil. However, during retting of jute As is present in the crop and thus increase its amount in surface water bodies. To test this hypothesis, a study was carried out in ten farmers' field located in As affected areas of West Bengal, India. As content of soil and variou the jute plant were recorded on 35 and 70 days after sowing (DAS) as well as on harvest date (110 DAS). During the study period, due to the influence of rainfall, As content of surface (0-150 mm) soil fluctuates in a narrow range. As content of jute root was in the range of 1.13 to 9.36 mg kg(-1). As content of both root and leaf attained highest concentration on 35 DAS and continuously decreased with the increase in crop age. However, in case of shoot, the As content initially decreased by 16 to 50% during 35 to 70 DAS and on 110 DAS the value slightly increased over 70 DAS. Retting of jute in pond water increased the water As content by 0.2 to 2.0 mg L(-1). The increment was 1.1 to 4 times higher over the WHO safe limit (0.05 mg L(-1)) for India and Bangladesh. Microbiological assessment in this study reveals the total bacterial population of pre and post retting pond water. Bacterial strains capable in transforming more toxic As-III to less toxic AS-V were screened and six of them were selected based on their As tolerance capacity. Importantly, identified bacterial strain Bacterium C-TJ19 (HQ834294) has As transforming ability as well as pectinolytic activity, which improves fibre quality of jute.

Association of creatine kinase and skin toxicity in phase I trials of anticancer agents.

BACKGROUND: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. METHODS: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. RESULTS: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. CONCLUSION: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.

Creatinine clearance is associated with toxicity from molecularly targeted agents in phase I trials.

OBJECTIVES: This study aimed to evaluate any correlations between baseline creatinine clearance and the development of grade 3/4 toxicities during treatment within oncology phase I trials of molecularly targeted agents where entry criteria mandate a serum creatinine of ≤ 1.5 × the upper limit of normal. METHODS: Documented toxicity and creatinine clearance (calculated by the Cockcroft-Gault formula) from all patients treated with molecularly targeted agents in the context of phase I trials within our centre over a 5-year period were analyzed. RESULTS: Data from 722 patients were analyzed; 116 (16%) developed at least one episode of grade 3/4 toxicity. Patients who developed a late-onset (>1 cycle) grade 3/4 toxicity had a lower creatinine clearance than those who did not (82.69 ml/min vs. 98.97 ml/min; p = < 0.001). CONCLUSION: Creatinine clearance (even when within normal limits) should be studied as a potential factor influencing late toxicities in the clinical trials of molecularly targeted anti-cancer drugs.

STAT3 Regulates Proliferation and Immunogenicity of the Ewing Family of Tumors In Vitro.

The Ewing sarcoma family of tumors (ESFT) represents an aggressive spectrum of malignant tumour types with common defining histological and cytogenetic features. To evaluate the functional activation of signal transducer and activator of transcription 3 (STAT3) in ESFT, we evaluated its activation in primary tissue sections and observed the functional consequences of its inhibition in ESFT cell lines. STAT3 was activated (tyrosine 705-phosphorylated) in 18 out of 31 primary tumours (58%), either diffusely (35%) or focally (23%). STAT3 was constitutively activated in 3 out of 3 ESFT cell lines tested, and its specific chemical inhibition resulted in complete loss of cell viability. STAT3 inhibition in ESFT cell lines was associated with several consistent changes in chemokine profile suggesting a role of STAT3 in ESFT in both cell survival and modification of the cellular immune environment. Together these data support the investigation of STAT3 inhibitors for the Ewing family of tumors.

Inhibition of MT1-MMP activity using functional antibody fragments selected against its hemopexin domain.

The membrane associated MMP, MT1-MMP, is a critical pericellular protease involved in tumour cell invasion and angiogenesis and is highly up-regulated in numerous human cancers. It therefore represents an exciting new therapeutic cancer-specific target. We have generated recombinant human scFv antibodies against the non-catalytic, hemopexin domain of MT1-MMP that modulate its interactions with collagen. One of these is an effective inhibitor of the invasive capacity of cancer cells and of angiogenesis in model systems. This demonstrates that targeting sites outside the catalytic domain presents a potential novel approach to proteinase inhibition that could have applications in cancer therapeutics.

Cells with dendritic cell morphology and immunophenotype, binuclear morphology, and immunosuppressive function in dendritic cell cultures.

Culturing of human peripheral blood CD14 positive monocytes is a method for generation of dendritic cells (DCs) for experimental purposes or for use in clinical grade vaccines. When culturing human DCs in this manner for clinical vaccine production, we noticed that 5-10% of cells within the bulk culture were binuclear or multiple nuclear, but had typical dendritic cell morphology and immunophenotype. We refer to the cells as binuclear cells in dendritic cell cultures (BNiDCs). By using single cell PCR analysis of mitochondrial DNA polymorphisms we demonstrated that approximately 20-25% of cells in DC culture undergo a fusion event. Flow sorted BNiDC express low HLA-DR and IL-12p70, but high levels of IL-10. In mixed lymphocyte reactions, purified BNiDC suppressed lymphocyte proliferation. Blockade of dendritic cell-specific transmembrane protein (DC-STAMP) decreased the number of binuclear cells in DC cultures. BNiDC represent a potentially tolerogenic population within DC preparations for clinical use.