Comets, historical records and vedic literature

A verse in book I of Rigveda mentions a cosmic tree with rope-like aerial roots held up in the sky. Such an imagery might have ensued from the appearance of a comet having `tree stem' like tail, with branched out portions resembling aerial roots. Interestingly enough, a comet referred to as `heavenly tree' was seen in 162 BC, as reported by old Chinese records. Because of weak surface gravity, cometary appendages may possibly assume strange shapes depending on factors like rotation, structure and composition of the comet as well as solar wind pattern. Varahamihira and Ballala Sena listed several comets having strange forms as reported originally by ancient seers such as Parashara, Vriddha Garga, Narada and Garga. Mahabharata speaks of a mortal king Nahusha who ruled the heavens when Indra, king of gods, went into hiding. Nahusha became luminous and egoistic after absorbing radiance from gods and seers. When he kicked Agastya (southern star Canopus), the latter cursed him to become a serpent and fall from the sky. We posit arguments to surmise that this Mahabharata lore is a mythical recounting of a cometary event wherein a comet crossed Ursa Major, moved southwards with an elongated tail in the direction of Canopus and eventually went out of sight. In order to check whether such a conjecture is feasible, a preliminary list of comets (that could have or did come close to Canopus) drawn from various historical records is presented and discussed.Comment: This work was presented in the International Conference on Oriental Astronomy held at IISER, Pune (India) during November, 201

Induced autotetraploidy in chickpea (Cicer arietinum L.)

In chickpea, out of three colchicine concentrations and two treatment durations used (combinations of 0.25, 0.05, 0.025% colchicine and 4 and 6 h duration), seed treatment with 0.25% for 4 h proved to be the most effective in producing autotetraploids. Colchicine treatment on seedlings failed. The induced tetraploidy was accompanied by larger leaves, flowers, stomata, pollen grains and seeds. Mean percentage stainable pollen and podset were reduced, but some plants had relatively normal meiosis and produced as many pods as the diploid parent, indicating the potential of induced autotetraploids in chickpea improvement

Chemokine Coreceptor Signaling in HIV-1 Infection and Pathogenesis

Binding of the HIV-1 envelope to its chemokine coreceptors mediates two major biological events: membrane fusion and signaling transduction. The fusion process has been well studied, yet the role of chemokine coreceptor signaling in viral infection has remained elusive through the past decade. With the recent demonstration of the signaling requirement for HIV latent infection of resting CD4 T cells, the issue of coreceptor signaling needs to be thoroughly revisited. It is likely that virus-mediated signaling events may facilitate infection in various immunologic settings in vivo where cellular conditions need to be primed; in other words, HIV may exploit the chemokine signaling network shared among immune cells to gain access to downstream cellular components, which can then serve as effective tools to break cellular barriers. This virus-hijacked aberrant signaling process may in turn facilitate pathogenesis. In this review, we summarize past and present studies on HIV coreceptor signaling. We also discuss possible roles of coreceptor signaling in facilitating viral infection and pathogenesis

The genomic and clinical consequences of replacing procarbazine with dacarbazine in escalated BEACOPP for Hodgkin lymphoma: a retrospective, observational study

\ua9 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Procarbazine-containing chemotherapy regimens are associated with cytopenias and infertility, suggesting stem-cell toxicity. When treating Hodgkin lymphoma, procarbazine in escalated-dose bleomycin–etoposide–doxorubicin–cyclophosphamide–vincristine–procarbazine–prednisolone (eBEACOPP) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity. We aimed to investigate the impact of this drug substitution on the mutation burden in stem cells, patient survival, and toxicity. Methods: In this two-part retrospective, observational study, we first compared mutational landscapes in haematopoietic stem and progenitor cells (HSPCs) from patients with advanced-stage Hodgkin lymphoma in remission for at least 6 months who had been treated with eBEACOPDac (eBEACOPDac cohort), eBEACOPP (real-world eBEACOPP cohort), or doxorubicin–bleomycin–vinblastine–dacarbazine (ABVD); in buccal DNA from five children of a female patient with classical Hodgkin lymphoma treated with eBEACOPP before conceiving the third child; in sperm DNA from a patient with mild oligospermia treated with eBEACOPP; and in caecal adenocarcinoma and healthy colon tissue from a survivor of Hodgkin lymphoma treated with chlorambucil–vinblastine–procarbazine–prednisolone. For the second part, we analysed efficacy and toxicity data from adult patients (aged >16 years) treated with first-line eBEACOPDac (eBEACOPDac cohort) at 25 centres across UK, Ireland, and France; efficacy was compared with the German HD18 eBEACOPP trial data and toxicity with a UK real-world dataset. Participants in the German HD18 and UK real-world datasets were adults (aged >16 years) with previously untreated Hodgkin lymphoma, treated with first-line eBEACOPP. We had two co-primary objectives: to define the comparative stem-cell mutation burden and mutational signatures after treatment with or without procarbazine-containing chemotherapy (first study part); and to determine progression-free survival of patients with Hodgkin lymphoma treated with eBEACOPP or eBEACOPDac (second study part). Secondary objectives included overall survival and explored differences in specific toxicity outcomes, including transfusion requirements and measures of reproductive health (second study part). Findings: In the first part of the study (mutational analysis), patients treated with eBEACOPP (n=5) exhibited a higher burden of point mutations in HSPCs compared with those treated with eBEACOPDac (n=4) or ABVD (n=3; excess mutations 1150 [95% CI 934–1366] vs 290 [241–339] vs 186 [116–254]). Two novel mutational signatures, SBSA (SBS25-like) and SBSB, were identified in HSPCs and in a single neoplastic and healthy colon sample from patients who received procarbazine-containing chemotherapy. SBSB was also identified in germline DNA of three children conceived after eBEACOPP and in sperm of a male patient treated with eBEACOPP. SBSC was detected in patients treated with either ABVD or eBEACOPDac. In the second part of the study (efficacy and toxicity analysis), dacarbazine substitution did not appear to compromise efficacy or safety. 312 patients treated with eBEACOPDac (eBEACOPDac cohort; treated 2017–22, 186 [60%] male, median follow-up 36\ub70 months [IQR 25\ub72–50\ub71]) had a 3-year progression-free survival of 93\ub73% (95% CI 90\ub73–96\ub74), which was similar to the 93\ub73% [95% CI 92\ub71–94\ub74]) progression-free survival seen in 1945 patients in the German HD18 eBEACOPP trial (treated 2008–14, 1183 [61%] male, median follow-up 57\ub70 months [35\ub74–64\ub77]). Patients treated with eBEACOPDac required fewer blood transfusions (mean 1\ub770 units [SD 2\ub777] vs 3\ub769 units [3\ub789]; p<0\ub70001), demonstrated higher post-chemotherapy sperm concentrations (median 23\ub74 million per mL [IQR 11\ub70–632\ub73] vs 0\ub70 million per mL [0\ub70–0\ub7001]; p=0\ub70040), and had earlier resumption of menstrual periods (mean 5\ub704 months [SD 3\ub707] vs 8\ub777 months [5\ub757]; p=0\ub70036) compared with 73 patients treated with eBEACOPP in the UK real-world dataset. Interpretation: Procarbazine induces a higher mutation burden and novel mutational signatures in patients with Hodgkin lymphoma treated with eBEACOPP and their germline DNA, raising concerns for the genomic health of survivors of Hodgkin lymphoma and hereditary consequences for their offspring. However, replacing procarbazine with dacarbazine appears to mitigate gonadal and stem-cell toxicity while maintaining similar clinical efficacy. Funding: Addenbrooke\u27s Charitable Trust and Wellcome Trust

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Optimization of flow forming process parameters through design of experiments for thrust chambers for aerospace applications

In this paper design of experiments carried out to establish material and process parameters to achieve two important practical features identified for the intended use, i.e., excellent surface finish (<= 1.6 mu m) and very low out of roundness values (<= 160 mu m) are presented. This is done for a thin wall high strength thrust chamber flow formed from HSLA steel with high L/D leading to successful manufacture. A 2(5) factorial design involving 5 factors each one examined at two levels using the Yates method and the method of steepest ascent are employed to arrive at the optimum parameters. The optimized parameters are presented in this paper

Abstract PD5-05: Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index

Abstract Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer, which may be partly attributable to an inflammation-aromatase axis. Most individuals with elevated BMI harbor white adipose tissue inflammation (WATi), defined by the presence of crown-like structures in the breast (CLS-B). CLS-B are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. This inflammation is associated with activation of NF-κB and elevated expression of aromatase, which could contribute to tumor development. Additionally, WATi correlates with several circulating changes, including hyperinsulinemia, which increase breast cancer risk. Although breast WATi correlates with rising BMI, it is also present in some normal BMI individuals. Beyond inherited germline syndromes, the etiology of breast cancer in individuals with normal BMI is not well understood. Here we examined the impact of breast WATi on breast aromatase expression and circulating factors in women with normal BMI. Methods: Non-tumorous breast tissue and fasting blood were collected from 72 women with BMI &amp;lt; 25 kg/m2 undergoing mastectomy at MSKCC. Breast inflammation was detected by the presence of CLS-B using CD68 immunohistochemistry. The primary objective was to determine if breast WATi in normal BMI individuals correlates with elevated aromatase levels in the breast, measured by qPCR, western blotting, immunofluorescence and enzyme activity. Secondary objectives included assessment of breast adipocyte size and circulating metabolic and inflammatory factors. Results: Breast inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WATi versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=0.04). Aromatase mRNA expression was positively correlated with WATi (CLS-B/cm2; P=0.002). Those with severe WATi had highest aromatase mRNA levels, compared to those with no or mild WATi (P=0.005). Aromatase protein, assessed by measuring adipose stromal cell-specific immunofluorescence or western blotting, and activity were also higher in CLS-B+ cases compared to CLS-B- (P&amp;lt;0.001). Breast WATi correlated with larger adipocytes (P=0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P&amp;lt;0.05). Insulin resistance, characterized by the homeostasis model (HOMA2-IR), correlated with breast WATi (P=0.004). Finally, leptin, a known inducer of aromatase and driver of cancer growth, correlated with higher breast aromatase levels (P=0.02) and larger adipocytes (P&amp;lt;0.01). Conclusions: A metabolically unhealthy state occurs in women with inflamed breast adipose despite having a normal BMI. This subclinical inflammatory state is characterized by elevated aromatase in the breast, insulin resistance, and dysplipidemia. The presence of enlarged adipocytes in the breasts of normal BMI women with inflammation suggests a state of hyperadiposity which could not be predicted based on BMI alone. These findings indicate that normal BMI metabolic obesity may be associated with increased cancer risk. Our results suggest that objective measurements of adiposity rather than BMI may help to identify individuals at increased risk for disease. Citation Format: Iyengar NM, Brown KA, Zhou XK, Subbaramaiah K, Giri DD, Gucalp A, Howe LR, Zahid H, Bhardwaj P, Wendel NK, Falcone DJ, Morrow M, Wang H, Williams S, Pollak M, Hudis CA, Dannenberg AJ. Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-05.</jats:p