Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.

Structure elucidation and biological activity of antibacterial compound from Micromonospora auratinigra, a soil Actinomycetes.

AIMS: The aim of this study was to isolate and characterize the bioactive compound of Micromonospora auratinigra, HK-10 and its antibacterial inhibitory mechanism. METHODS AND RESULTS: An oily bioactive compound was extracted from HK-10 (GenBank accession no. JN381554) and found to have promising antibacterial activity. The compound was characterized as 2-methylheptylisonicotinate (1) by (1) H, (13) C NMR and mass spectroscopy. Minimum inhibitory concentration (MIC) of this molecule was tested by micro broth dilution method and was found to be 70, 40, 80, 60, 60 and 50 µg for Staphylococcus aureus, Bacillus subtilis, Proteus vulgaris, Echerichia coli, Pseudomonas aeruginosa and Mycobacterium abscessus respectively. The effects of compound 1 were studied on bacterial membrane structure using scanning electron microscopy. The results indicated a membrane-disrupting mechanism, resulting in the dysfunction of the cytoplasmic membrane structure and cell death of the pathogenic bacterial strains. Kinetics of growth of the test organisms was also analysed and indicated 2-methylheptylisonicotinate 1 as a bactericidal agent. Furthermore, we have studied the binding affinity of 1 towards different membrane proteins of pathogenic bacteria by in silico analysis. CONCLUSIONS: 2-methylheptylisonicotinate was isolated from M. auratinigra, a rare actinobacterial strain possessing antibacterial activity through a membrane-disrupting mechanism, and has MICs similar to standard antibiotic neomycin sulphate. It is the first report about a strain of M. auratinigra, isolated from Indo-Burma biodiversity hotspot of North-east India with new antimicrobial activities. In silico studies have also supported these results performed on various membrane targets of pathogenic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The antibacterial potential of M. auratinigra is reported for the first time. The results indicate the possible use of 2-methylheptylisonicotinate as a source of antibacterial agent against dreaded human pathogens.

Mutual response hypothesis between surface temperature and aerosol (BC and non-BC) mass concentration observed in an urban environment.

The mutual response between near surface aerosol concentration and surface temperature works in a complicated manner. A recent study has introduced a hypothesis of mutual response between surface temperature and near surface black carbon (BC) mass concentration which states that 'more fall in morning hour surface temperature (T) contribute to the enhancement of BC fumigation peak after the sunrise which positively impacts the extra rise in mid-day temperature over a region during the day time'. Morning hour surface temperature is proportionally linked with the strength of the night time near surface temperature inversion which contributes to the enhancement of the fumigation peak of BC aerosols after the sunrise and the enhanced fumigation peak can impact the degree of the mid-day surface temperature rise by influencing the instantaneous heating. However, it didn't mention the role of non-BC aerosols. Further, the hypothesis was drawn based on the co-located ground-based observations of surface temperature and BC concentration at a rural location of peninsular India. Though, it was mentioned that the hypothesis can be tested independently of locations, but was not thoroughly validated for an urban environment where the loading of both BC and non-BC aerosols are high. In this context, the first objective of the present work is to methodically test the BC -T hypothesis over an Indian metropolitan city, Kolkata, using the suite of measurements obtained from Kolkata Camp Observatory of NARL (KCON) along with other supporting data. In addition, the validity of the hypothesis for the non-BC fraction of PM2.5 aerosols over the same location is also tested. Besides ascertaining the above-mentioned hypothesis over an urban location, it is found that the enhancement of non-BC PM2.5 aerosols peak after the sunrise can negatively influences the mid-day temperature rise over a region during the day time.

Anterior pelvic exenteration with total vaginectomy for recurrent or persistent genitourinary malignancies: review of surgical technique, complications, and outcome.

OBJECTIVE: To describe the surgical technique, complications, and outcomes after anterior pelvic exenteration with total vaginectomy (AETV) for recurrent or persistent genitourinary malignancies. METHODS: We reviewed the medical records of all patients who underwent AETV between 12/2002 and 07/2011. Relevant demographic, clinical, and pathological information was collected. Postoperative complications and rates of readmission and reoperation (up to 180 days after surgery) were examined, and preliminary survival data were obtained. RESULTS: We identified 11 patients who underwent AETV. The median age at the time of the surgery was 55 years (range, 36-71). The median tumor size was 0.9 cm (range, microscopic - 4). Primary tumor sites included: cervix, 6; uterus, 3; vagina, 1; and urethra, 1. Complete surgical resection with negative pathologic margins was achieved in all 11 patients. Major postoperative complications occurred in 4 patients (36%). Six patients (55%) required readmission to the hospital. No operative mortalities were observed, and none of the patients required a re-operation. With a median follow-up after the procedure of 25 months (range, 6-95), none of the patients developed a pelvic recurrence. Ten patients (91%) were alive without evidence of disease and one patient (9%) developed a pancreatic recurrence. CONCLUSION: AETV sparing the rectosigmoid and anus is feasible in highly selected patients with central pelvic recurrences. Compared to previously reported studies on total pelvic exenteration, data from this case series suggest that AETV may be associated with a lower rate of complications without compromising the oncologic outcome, while also preserving rectal function.

Relationship of obstructive sleep apnea with major depressive disorder and development of metabolic syndrome.

Objective: Major depressive disorder (MDD) is often linked with a number of coexisting disorders with a relation that is poorly understood. The aim of this study was to find out the role of obstructive sleep apnea (OSA) in metabolic syndrome (MS) in subjects with MDD and to develop a model for factors leading to MS. Methods: It was a cross-sectional study conducted on 119 subjects. They were evaluated on sociodemographic and clinical parameters, Berlin questionnaire, and Quick Inventory of Depressive Symptomatology. Comparisons were made using appropriate statistics. Binary logistic regression was used to find out the role of clinical parameters in the development of MS. Results: A total of 34% with MDD had a high risk of developing OSA while 19% had metabolic syndrome. Among all clinical variables, antidepressant exposure in terms of total fluoxetine units, duration of treatment, and risk of developing OSA was found to be significantly more in patients with MS. A higher risk of OSA was found to have a higher likelihood to cause MS in patients with MDD. Conclusion: There is a high risk of MS and OSA in subjects with MDD. The increased risk of MS is contributed by an increased risk of developing OSA among patients with MDD. Cross-sectional design and limited generalizability are the major limitations of this study.

A mutual response between surface temperature and black carbon mass concentration during the daytime.

The mutual response between surface temperature and the mass concentration of regional black carbon (BC) aerosols has still remained far from understanding due to its complex nature. A detailed analysis presented in this study using long-term data indicates a significant pattern of mutual response between surface temperature and BC in restricted background weather conditions (water vapor, cloud cover and wind speeds). The analysis shows that a fall in surface temperature which naturally occurs daily after the sunrise, leads to the development of a stronger inversion in the near-surface level and this, in turn, contributes to the enhancement of BC fumigation peak. Further, the enhanced fumigation peak (especially during pre-monsoon) is found positively influencing the mid-day temperature rise possibly due to the immediate impact of the direct radiative forcing of BC aerosols. These observations lead us to consider a hypothesis that 'an extra fall in the morning hour surface temperature contributes to the enhancement of BC fumigation peak and can degrade the morning hour air quality which gives positive feedback to the mid-day temperature rise over a region'. A substantial in situ data [over Gadanki (13.5°N, 79.2°E)] along with MERRA-2 and ERA-5 data are used in this methodical analysis. Moreover, the validity of the hypothesis has been tested over other locations. Regional weather and seasonal cycle are found to have apparent interference with the feature of the observed mutual response pattern. The results from this study clearly indicate that the approach used, can be executed location independently.

Histopathology based cancer pattern in Mymensingh region of Bangladesh.

To our knowledge, population-based published data regarding the cancer profile in Mymensingh region of Bangladesh is not available. This study was designed to provide information regarding the frequencies of cancers through sample data retrieved from histopathology (surgical pathology) laboratory based cancer registry from two laboratories in Mymensingh. All malignant tumours recorded in 2006 in the register of pathology laboratory of Mymensingh Medical College and one private pathology laboratory in Mymensingh town were taken as sample data for analysis in terms of age groups, gender and types of cancer with relation to site. A total of 470 cases diagnosed as cancer were found in the register, of which males were 249(53%) and females were 221(47%) with male to female ratio 1.2: 1. Highest numbers of cases were found in the age group of 51-60 years. In male group frequency of malignant tumours was found in the age group of 51-60 years and the female group it is 41-50 years. Top five sites of cancer, irrespective of sex, were of stomach, uterine cervix, colo-rectum, lymph nodes and breast. According to decreasing order of frequency, in the males, the top five cancers were of stomach, lymph node, oesophagus, urinary bladder and colo-rectum. In the female groups these were of uterine cervix, breast, ovary, colo-rectum and stomach. Cancer cases in the age group of 51-60 years were significantly higher in males than in females (p<0.001). The commonest cancers in males and females were of stomach and cervix, respectively. As the analysis was based only on surgical specimens, the exact incidence of cancer of lung and liver could not be evaluated. Because, majorities of the malignancies in these organs are diagnosed mainly on cytological examination. Population-based cancer registry should be maintained to explore the exact patterns of cancer in the study region. Cervical cancer screening program and eradication of H. pylori infection program may be helpful for the reduction of incidence of cancer in this region.

Evolving Strategies for Therapeutically Targeting Cancer Stem Cells.

Cancer is a multifactor and multistep process that is affected intrinsically by the genetic and epigenetic makeup of tumor cells and extrinsically by the host microenvironment and immune system. A key component of cancer involves a unique subpopulation of highly malignant cancerous cells referred to as cancer stem cells (CSCs). CSCs are positioned at the apex of the tumor hierarchy with an ability to both self-renew and also generate non-CSC/differentiated progeny, which contribute to the majority of the tumor mass. CSCs undergo functional changes and show plasticity that is stimulated by specific microenvironmental cues and interactions in the tumor niche, which contribute to the complexity and heterogeneity of the CSC population. The prognostic value of CSCs in the clinic is evident since there are many examples in which CSCs serve as markers for poor patient prognosis. CSCs are innately resistant to many standard therapies and they display anoikis resistance, immune evasion, tumor dormancy, and field cancerization, which may result in metastasis and relapse. Many academic laboratories and biotechnology companies are currently focusing on strategies that target CSCs. Combination therapies, epigenetic modifiers, stemness inhibitors, CSC surface marker-based therapies, and immunotherapy-based CSC-targeting drugs are currently undergoing clinical trials. Potential new targets/strategies in CSC-targeted therapy include MDA-9/Syntenin (SDCBP), Patched (PTCH), epigenetic targets, noncoding RNAs, and differentiation induction. Defining ways of targeting and destroying CSCs holds potential to impact significantly on cancer therapy, including prevention of metastasis and cancer recurrence.

A stereoselective route to polysubstituted tetrahydroquinolines by benzotriazole-promoted condensation of aliphatic aldehydes and aromatic amines

By the promotion of benzotriazole (20 mol %), two molecules of anilines (or other arylamines) and two molecules of phenylacetaldehyde (or o-bromophenylacetaldehyde) condensed to give a series of 1,2,3,4-tetrahydroquinolines in a stereoselective manner. By the catalysis of SmI(2) or SmI(3), the N-(alpha-aminoalkyl)benzotriazoles derived from anilines and (R)-glyceraldehyde acetonide dissociated to the corresponding iminium and enamine species, which underwent asymmetric [4 + 2] cycloadditions to give optically active tetrahydroquinolines.

Eighth nerve involvement in meningo-encephalitis.

Seventy-two patients suffering from meningo-encephalitis were studied, clinically, biochemically, microbiologically and virologically. Evidence of rising titre in serum and CSF of antibodies to Japanese encephalitis were present in 50% of cases, and recent past infection in 20% of cases. Cranial nerve involvement particularly the "8th" was present in 70% of cases though there was a 2.5% involvement of the 2nd, 3rd and 6th nerves. All the patients belonged to plain Tribal population and all had a history of eating pork 7-10 days prior to development of the infection.

Patterns of fertility and mortality in four caste groups in West Bengal.

PIP: The problem of fertility and its variations have been examined in the present paper through 2 sets of variables, biological and social. For biological variables, bio-events, such as age at menarche, marriage, first and last birth and total reproductive span have been taken into consideration. The other set of social variables are caste status, economic status, occupation, education, and awareness and extent of the use of family planning measures. The biological and social variables and their relative roles in determining the fertility and mortality patterns are examined in 4 populations: Varendra Brahmin, Varendra Kayastha, Tili and Jele of Nabadwip town in Nadia district, West Bengal. The Varendra Kayastha are characterized by 2nd position in caste hierarchy, highest educational status, a better average economic status, low fertility and mortality, lowest number of mean surviving children and especially low reproductive wastage. The awareness of family planning measures is also highest in this caste group. On the other hand the Jele is characterized by low position in the caste hierarchy, lowest economic and educational status, high fertility and mortality and especially high reproductive wastage. The awareness of family planning measures is almost nil in this group. The Varendra Brahman and the Tili do not vary much in economic status. But in caste hierarchy the former is placed highest. The mean number of surviving children per mother is higher among the Tili than among the Varendra Brahman. In mortality and reproductive wastage the 2 castes do not vary much. Tables and charts illustrate results.^ieng

The emergency room at the Rotunda Hospital: evidence of an improving service over the past 3 years.

INTRODUCTION: This is a retrospective review of the Rotunda Hospital Emergency Room (ER) documentation with respect to attendances for a 4-month period (August-November) in both 2009 and 2012. The aim was to quantify the workload and assess the quality of care offered to patients attending the ER over the two time periods and to highlight any improvements in care after changes were implemented following the initial 2009 review. MATERIALS AND METHODS: This study was done comparing the ER patient attendances over two time periods (1st August 2009 to 30th November 2009 and same period in 2012). SPSS version 20 was used to make statistical analysis along with simple percentage calculation. Comparing the two time frames, a decrease in the number of antenatal patients attending ER was seen (p < 0.001) [7,128 (91.0 %) in 2009 and 6,890 (89.4 %) in 2012], waiting times fell (p < 0.001) [4,351 (55.5 %) in 2009 seen within 2 h and 5,855 (76.2 %) in 2012], less women left ER without being seen (p < 0.001) [151 (1.9 %) in 2009 and 119 (1.5 %) in 2012] and record keeping regarding outcome of attendances improved (p < 0.001) [465 cases (5.9 %) in 2009 not recorded and 259 (3.3 %) in 2012]. CONCLUSION: The improvements noted may be due to establishment of an early pregnancy assessment unit facility and changes in ER staffing. Two registrars being on-call rather than one registrar. Increased numbers of gynaecology patients (p < 0.001) [334 (4.3 %) in 2009 and 463 (6 %) in 2012] were seen, most likely due to changes in benign gynaecology services in north Dublin. All the comparisons were statistically significant.

Serological diagnosis of dengue in laboratory practice in Kolkata.

PURPOSE: To find out the most suitable serological investigative procedures to diagnose dengue cases effectively in the laboratory practice identifying primary and secondary cases as well as period of suffering. MATERIALS AND METHODS: Dengue suspected cases sent to the laboratory in 2012 in central Kolkata by the local physicians were categorised into seven panels according to the investigations asked for such as (1) only dengue-specific NS1 antigen (2) only IgM antibodies, (3) NS1+IgM+IgG antibodies, (4) only IgM and IgG, (5) NS1+IgM, (6) NS1+IgG and (7) only IgG. RESULTS: Out of 1892 suspected cases, dengue was diagnosed in 725 (38.3%). Through panels I, II, III, IV, V, VI and VII, it was possible to diagnose dengue in (I) 35.98% (435/1209), (II) 37.5% (24/60), (III) 49% (173/354), (IV) 30.8% (68/221), (V) 60.5% (23/38), (VI) 40% (2/5) and (VII) 0 of cases respectively. Detail information such as confirmed diagnosis, duration of the disease (whether early or prolonged) and classification of primary and secondary dengue in such early or prolonged stages would only be possible in panel III, which information would be helpful for effective monitoring and treatment of dengue patients. In all other panels, merely fragmentary information would be obtained. CONCLUSIONS: Serodiagnostic tests dengue-specific NS1 antigen and IgM and IgG antibodies when conducted simultaneously would be able to diagnose confirmed dengue cases categorising primary and secondary dengue along with the duration of the disease, whether early or prolonged.

Generation of reactive low-valent titanium species using metal--arenes as efficient organic reductants for TiCl(3): applications to organic synthesis.

A comprehensive study on the use of metal-arene systems as organic reductants for TiCl(3) has resulted in an efficient method for the generation of highly reactive low-valent titanium (LVT) reagents. The activated titanium species could be prepared by refluxing a mixture of substoichiometric amounts of arenes, TiCl(3), and Li/Mg in THF or DME. Among the LVT reagents screened, TiCl(3)--Li--naphthalene--THF (reagent I) was the best for coupling of carbonyls to olefins. The reagent could carry out the McMurry olefination of both aromatic and aliphatic substrates at a lower temperature and in a much reduced time as compared to the conventional procedures. Subtle changes in the method of preparation of the LVT reagents influenced the stereoisomeric ratio of the olefins. The reagent was also useful for the synthesis of O- and N- heterocycles and vicinal diamines via intramolecular carbonyl coupling and reductive duplication of imines, respectively.