tbuckley/cabot-search huggingface dataset:
Sexuality Challenges, Intimacy, and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG)
Authors: Holly Lynn Geyer, Amylou C. Dueck, Robyn M. Emanuel, Keith Cannon, Jean-Jacques Kiladjian, Stephanie Slot, Sonja Zweegman, Peter Boekhorst, Suzan Commandeur, Harry C. Schouten, Federico Sackmann, Ana Kerguelen Fuentes, Dolores Hernandez, Heike L. Pahl, Martin Griesshammer, Frank Stegelmann, Konstanze Döhner, Thomas Lehmann, Dana Ranta, Andreas Reiter, Françoise Boyer, Gabriel Etienne, Jean-Christophe Ianotto, Lydia Roy, Jean-Yves Cahn, Claire N Harrison, Deepti H Radia, Pablo J. Muxi, Norman I Maldonado, Carlos Besses, Francisco Cervantes, Peter Johansson, Tiziano Barbui, Giovanni Barosi, Alessandro M Vannucchi, Francesco Passamonti, Bjorn Andreasson, Maria Ferrari, Alessandro Rambaldi, Jan Samuelsson, Gunnar Birgegard, Zhijian Xiao, Zefeng Xu, Xiujuan Sun, Junqing Xu, Peihong Zhang, Robert Peter Gale, Ruben A Mesa
Journal: Blood (2013)
A phase I study of nab-paclitaxel (A), gemcitabine (GEM), and capecitabine (X) in patients with metastatic pancreatic adenocarcinoma (MPA).
Authors: Thach-Giao Truong, Margaret A. Tempero, Emily Kantoff, Kimberly Jones, Elizabeth Dito, Anna Ong, Andrew H. Ko
Journal: Journal of Clinical Oncology (2012)

4048 Background: GEM-based doublets, such as GEM + capecitabine (X), may be beneficial in select pts with MPA. Given preclinical evidence of synergy when a taxane is added to GEM + X, as well as recent phase I/II study results showing substantial activity with GEM + nab-paclitaxel (A) (ORR of 48%, median OS &gt; 12 mos at MTD), we conducted a phase I study evaluating the 3-drug combination of A, GEM, and X (AGX) given biweekly in pts with MPA. Methods: Pts with previously untreated MPA and ECOG PS 0-1 were eligible. A (100-150 mg/m 2 ) and GEM (750-1000 mg/m 2 at 10 mg/m 2 /min) were both administered on day 4, and X (500-1000 mg/m 2 bid) on days 1-7, of each 14-day cycle. A 3+3 dose escalation design was used, with expanded cohort at MTD. Primary objective was to establish MTD of this regimen; secondary objectives include safety and preliminary assessment of efficacy. DLT definitions: gr 3-4 ANC or neutropenic fever; gr 4 plts; gr 2-4 hand-foot syndrome (HFS), neuropathy or diarrhea; or other gr 3-4 non-heme toxicity. Results: Fifteen patients were enrolled across two dose levels (age range, 45-74 y). Final MTD was established at dose level 0, consisting of A 100 mg/m2, GEM 750 mg/m2, and X 750 mg/m2 bid. At dose level 1, two of 4 pts experienced DLTs (gr 3 LFT elevation, gr 3 ANC). For the entire study cohort, 10 pts (67%) experienced at least one gr 3-4 AE, including LFTs (20%), N/V (13%), and fatigue (7%). Gr 3-4 heme toxicity was uncommon. Other notable AEs (any grade): fatigue (87%), rash/HFS (67%), N/V (53%), diarrhea (40%), neuropathy (33%). Median # cycles received = 4 (range, 2-16). 73% of pts d/c’ed study treatment due to disease progression. Best response for the entire cohort (n=14 evaluable pts): 2 PR, 8 SD, 4 PD (disease control rate = 71%). Of 12 pts with elevated CA19-9 at baseline, 5 (42%) had &gt;50% biomarker decline. Conclusions: Recognizing the limits of cross-study comparisons and small sample size, these results do not match those reported at MTD in the phase I/II trial of GEM (1000 mg/m2) + A (125 mg/m 2 ). The modest activity seen with this AGX regimen may have resulted from suboptimal dosing, and suggests that dose intensity may be an important factor when trying to incorporate nab-paclitaxel into multidrug regimens.
Right Ventricular Contractile Reserve and Pulmonary Circulation Uncoupling During Exercise Challenge in Heart Failure
Authors: Marco Guazzi, Simona Villani, Greta Generati, Ottavia Eleonora Ferraro, Marta Pellegrino, Eleonora Alfonzetti, Valentina Labate, Maddalena Gaeta, Tadafumi Sugimoto, Francesco Bandera
Journal: JACC Heart Failure (2016)
Health-Related Quality of Life (Hrqol) and Disease Symptoms in Patients (Pts) with Locally Advanced or Metastatic Breast Cancer (Mbc) Treated with Eribulin (Eri) or Capecitabine (Cap) in a Post Anthracycline and Taxane Setting
Authors: G. Velikova, S. Hudgens, A. Forsythe, S. McCutcheon, J. Cortes
Journal: Annals of Oncology (2014)
O<scp>pening the</scp> D<scp>ebate on the</scp> N<scp>ew</scp> S<scp>epsis</scp> D<scp>efinition</scp>. Medicare’s Sepsis Reporting Program: Two Steps Forward, One Step Back
Authors: Ian J. Barbash, Jeremy M. Kahn, B. Taylor Thompson
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans
Authors: Masaki Yasukawa, Hideki Ohminami, Junko Arai, Yoshihito Kasahara, Yasushi Ishida, Shigeru Fujita
Journal: Blood (2000)
Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD
Authors: Jadwiga Wedzicha, Donald Banerji, Kenneth Chapman, Jorgen Vestbo, Nicolas Roche, R Timothy Ayers, Chau Thach, Robert Fogel, Francesco Patalano, Claus Vogelmeier, Arnaud Bourdin
Journal: New England Journal of Medicine (2016)

Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear.We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02).Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).
The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer Cells
Authors: Samantha S.W. Ho, Wendy Y.L. Zhang, Nikki Yi Jie Tan, Muznah Khatoo, Manuel A. Suter, Shubhita Tripathi, Florence S.G. Cheung, Weng Khong Lim, Puay Hoon Tan, Joanne Ngeow, Stephan Gasser
Journal: Immunity (2016)
Sarcoma in a Hamster Inoculated With BK Virus, a Human Papovavirus&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: K V Shah, R W Daniel, J D Strandberg
Journal: JNCI Journal of the National Cancer Institute (1975)

An undifferentiated sarcoma occurred in 1 of 52 hamsters inoculated when newborn with BK virus (BKV), A SIMIAN VIRUS 40 (SV40)-related human papovavirus. It was transplantable and grew in tissue culture. Sera of tumor-bearing hamsters were without antibodies reactive to BKV virion antigens in hemagglutination-inhibition and neutralizationtexts, but contained antibodies reactive in immunofluorescence (IF) tests to SV40 T antigen in SV40-TRANSFORMED CELLS AND TO ANTIGENS IN CELLS ACUTELY INFECTED WITH BKV or SV40. The IF reaction between tumor cells and sera of tumor-bearing hamsters was minimal in texts of tumor cells of an early passage but satisfactory in tests of cells from a later passage. Fusion of tumor cells with permissive (monkey and human) cells, induced by inactivated Sendai virus, did not lead to recovery of infectious BKV. Immunization of hamster with BKV or SV40 failed to protect against challenge with tumor cells. There was considerable cross-reactivity between the T antigens of BKV and SV40 viruses
Huntington's chorea--a family problem
Authors: L F W Rowe
Journal: BMJ (1981)

Management of suspected cardiac infarction by British immediate care doctors SIR,-In the interesting study by Dr D C Rawlins of the management of suspected cardiac infarction by British immediate care doctors (23 May, p 1677) it is stated that some of the 23 lives lost might have been saved if every practitioner had had his own portable defibrillator; and, of course, this may well be true.We have, however, trained deputies in Sheffield and provided them with portable defibrillators and, although on several occasions electrocardiographic tracings were used to confirm the diagnosis, over two years defibrillation was never found relevant and never tried, and no lives were saved.The project was dismantled as cost ineffective.If this type of resuscitation is going to be used by the practitioner only about once in every seven years, we had much better pin our faith on preventive care.The difficulties in maintaining apparatus, enthusiasm, and skill are too daunting to merit support.
Case 29-1965
Authors: Alexander S. Nadas, Robert E. Scully
Journal: New England Journal of Medicine (1965)

Presentation of Case First admission. A fourteen-year-old boy was admitted to the hospital because of pain in the abdomen.He had been well until five days previously, when vigorous bicycle riding was followed by the gradual development of dull, steady, nonradiating epigastric pain that disappeared promptly on recumbency. On the next day the pain began to recur after moderate exertion. On the day of admission the pain became persistent, and he vomited twice.There was no history of chest pain, dyspnea, orthopnea, edema, paroxysmal nocturnal dyspnea, sore throat or exposure to a communicable disease. He had had a nonproductive . . .
Tumour-specific delivery of siRNA-coupled superparamagnetic iron oxide nanoparticles, targeted against PLK1, stops progression of pancreatic cancer
Authors: Ujjwal M Mahajan, Steffen Teller, Matthias Sendler, Raghavendra Palankar, Cindy van den Brandt, Theresa Schwaiger, Jens-Peter Kühn, Silvia Ribback, Gunnar Glöckl, Matthias Evert, Werner Weitschies, Norbert Hosten, Frank Dombrowski, Mihaela Delcea, Frank-Ulrich Weiss, Markus M Lerch, Julia Mayerle
Journal: Gut (2016)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is projected to be the second leading cause of cancer-related death by 2030. Despite extensive knowledge and insights into biological properties and genetic aberrations of PDAC, therapeutic options remain temporary and ineffective. One plausible explanation for the futile response to therapy is an insufficient and non-specific delivery of anticancer drugs to the tumour site.Superparamagnetic iron oxide nanoparticles (SPIONs) coupled with siRNA directed against the cell cycle-specific serine-threonine-kinase, Polo-like kinase-1 (siPLK1-StAv-SPIONs), could serve a dual purpose for delivery of siPLK1 to the tumour and for non-invasive assessment of efficiency of delivery in vivo by imaging the tumour response. siPLK1-StAv-SPIONs were designed and synthesised as theranostics to function via a membrane translocation peptide with added advantage of driving endosomal escape for mediating transportation to the cytoplasm (myristoylated polyarginine peptides) as well as a tumour-selective peptide (EPPT1) to increase intracellular delivery and tumour specificity, respectively.A syngeneic orthotopic as well as an endogenous cancer model was treated biweekly with siPLK1-StAv-SPIONs and tumour growth was monitored by small animal MRI. In vitro and in vivo experiments using a syngeneic orthotopic PDAC model as well as the endogenous LSL-KrasG12D, LSL-Trp53R172H, Pdx-1-Cre model revealed significant accumulation of siPLK1-StAv-SPIONs in PDAC, resulting in efficient PLK1 silencing. Tumour-specific silencing of PLK1 halted tumour growth, marked by a decrease in tumour cell proliferation and an increase in apoptosis.Our data suggest siPLK1-StAv-SPIONs with dual specificity residues for tumour targeting and membrane translocation to represent an exciting opportunity for targeted therapy in patients with PDAC.
Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity
Authors: Z Estrov, R Kurzrock, M Wetzler, H Kantarjian, M Blake, D Harris, JU Gutterman, M Talpaz
Journal: Blood (1991)
Experimental infection of rabbits with genotype 3 hepatitis E virus produced both chronicity and kidney injury
Authors: Lin Wang, Junke Xia, Ling Wang, Youchun Wang
Journal: Gut (2016)

Dear Editor,

We read with great interest the elegant work of Sayed et al ,1 which established a mouse model for chronic hepatitis E virus (HEV) infections. The study showed that mice with humanised livers could be infected with both HEV-1 and HEV-3 and develop a chronic viral infection. The establishment of this model meets the urgent need for a research animal model to study chronic hepatitis E infection as increasing cases of such infections have been reported in immunocompromised patients.2 We have recently reported on a chronic hepatitis E case caused by HEV-4 in a woman with nephritic syndrome.3 HEV RNA and antigen were detected in the patient's urine and HEV RNA-positive urine successfully induced infection in Cynomolgus monkeys.3 We agree with the claim made by Sayed et al 1 that their model may allow the unravelling of the potential relationship between HEV infection and kidney disease. However, this will require …
Optical Coherence Tomography of Barrett’s Esophagus
Authors: A. Chak, M. B. Wallace, J. M. Poneros
Journal: Endoscopy (2005)

The endoscopic diagnosis of specialized intestinal metaplasia (Barrett’s esophagus) and dysplasia can be surprisingly difficult, especially when only short lengths of Barrett’s esophagus are suspected. Various imaging techniques have been used to aid the endoscopic diagnosis of Barrett’s esophagus and the staging of early neoplasia, including endoscopic ultrasound, magnification endoscopy, and the application of chemical stains and pigments to alter tissue appearances (i. e. chromoendoscopy). The ultimate goals of these advanced imaging methods are to: (i) detect intestinal metaplasia in the background of gastric metaplasia of the esophagus; (ii) detect foci of dysplasia and early neoplasia in the background of intestinal metaplasia; and (iii) distinguish early invasive carcinoma from mucosal dysplasia. Increasing amounts of data are available on the use of endoscopic optical coherence tomography (OCT) to aid in the diagnosis and classification of Barrett’s esophagus and associated dysplasia. OCT is a cross-sectional imaging technique that provides the highest endoscopic resolution currently available and produces images to a depth of a few millimeters. The in vivo resolution of OCT imaging (∼ 10 µm) is more than ten times greater than that of high-frequency ultrasound and has the potential to visualize subcellular structures including nuclei. OCT is analogous to ultrasound but uses light waves rather than acoustic waves.
Immune-related response evaluations during immune-checkpoint inhibitor therapy: establishing a “common language” for the new arena of cancer treatment
Authors: Mizuki Nishino
Journal: Journal for ImmunoTherapy of Cancer (2016)

The recent study by Hodi et al. published in the Journal of Clinical Oncology has evaluated unconventional response patterns during PD-1 inhibitor therapy using immune-related response criteria (irRC) in comparison with RECIST1.1, which constitutes an important step to further understand immune-related response phenomena. This commentary discusses the key observations in the study in terms of their implications and pitfalls, and describes unmet needs that remain to be addressed. The article also emphasizes the important role of tumor response criteria as a "common language" to describe the results of cancer treatment, and discusses future directions for further advances of the field of immuno-oncology.
Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: An AGEO multicenter study.
Authors: David Tougeron, Gaelle Sickersen, Thierry Lecomte, Guillaume Mouillet, Isabelle Trouilloud, Romain Coriat, Thomas Aparicio, Gaetan Des Guetz, Cedric Lecaille, Pascal Artru, Estelle Cauchin, David Sefrioui, Tarek Boussaha, Aurelie Ferru, Julien Taïeb, Pierre Michel, Lucie Karayan-Tapon, Dewi Vernerey, Franck Bonnetain, Aziz Zaanan
Journal: Journal of Clinical Oncology (2014)

3508 Background: Microsatellite instability (MSI) is found in 12% of colon cancers (CC) and associated with a low recurrence rate after curative surgery. Adjuvant chemotherapy with 5-FU seems ineffective, but small studies recently suggest that adjuvant chemotherapy with FOLFOX could be effective (Zaanan et al.). The aim of this study was to analyze efficacy of adjuvant chemotherapy with 5-FU or FOLFOX in relapse-free survival (RFS) of MSI CC. Methods: This multicenter retrospective study included patients with stage II or III MSI CC with curative surgery between 2000 and 2012. High-risk stage II CC were defined by one of these criteria: stage T4, bowel obstruction, tumoral perforation, vascular emboli, lymphatic invasion, perinervous invasion, or a number of lymph nodes examined inferior to 10. Prognostic factors of RFS were analyzed in univariate and multivariate analysis using Cox model. Results: A total of 433 MSI CC patients were analyzed, including 57% and 43% stage II and III, respectively. Median follow-up was 35 months. Mean age was 70 ± 17 years. Overall, 61%, 27%, 12% patients had a surgery alone (n=263), adjuvant FOLFOX (n=119) or 5-FU (n=51) respectively. Adjuvant chemotherapy was administered in 17% of stage II (n=41) and 70% of stage III (n=129). Recurrence rates were 6% (n=14) for stage II and 21% (n=39) for stage III. Adjuvant chemotherapy was associated with better RFS in univariate analysis, but only for FOLFOX (HR=0.46, 95%CI 0.23-0.79) and not for 5-FU (HR=1.02, 95%CI 0.60-1.73). Three-years RFS was 75% for surgery alone, 66% for 5-FU and 84% for FOLFOX (p=0.02). In multivariate analysis taking account the other prognosis factors, adjuvant chemotherapy with oxaliplatin remains significantly associated with better RFS (HR=0.29, 95%CI 0.13-0.65 ; p=0.003). In the subgroup analyses, benefit of FOLFOX, as compared to 5-FU and surgery alone, was significant in stage III (HR=0.38, 95%CI 0.21-0.69 ; p=0.0014) and a trend was observed for high-risk stage II (HR=0.141 95%CI 0.02-1.04 ; p=0.0549). Conclusions: This multicenter study confirms that adding oxaliplatin to 5-FU can restore the chemosensitivity of MSI CC.
Are the Results of the Extracranial–Intracranial Bypass Trial Generalizable?
Authors: H.J.M. Barnett, D. Sackett, D.W. Taylor, B. Haynes, S.J. Peerless, I. Meissner, V. Hachinski, A. Fox
Journal: New England Journal of Medicine (1987)

The dramatic results of the extracranial–intracranial (EC–IC) bypass trial have stimulated the vigorous discussion and debate that are essential to the pursuit of truth and the advancement of useful clinical knowledge.1 2 3 We therefore thank Dr. Sundt for his spirited critique.4 We also thank the editors of the Journal for the opportunity to respond to Dr. Sundt and to emphasize again the usefulness of randomized clinical trials in determining whether an innovative therapy is of value.We begin by observing that Dr. Sundt has no quarrel with the evaluation, randomization, 100 percent follow-up, analysis, and interpretation of results among the 1377 . . .
Targeting Sphingosine Kinase Induces Apoptosis and Regression Of Virus-Associated Lymphoma In Vivo
Authors: Zhiqiang Qin, Lu Dai, Karlie Plaisance-Bonstaff, Can Senkal, Wenxue Wang, Thomas M. Reske, Luis Del Valle, Christina Voelkel-Johnson, Erik Flemington, Besim Ogretmen, Charles D Smith, Chris Parsons
Journal: Blood (2013)
Allogeneic Marrow Grafting for Hematologic Malignancy Using HL-A Matched Donor-Recipient Sibling Pairs
Authors: E. D. THOMAS, C. D. BUCKNER, R. H. RUDOLPH, A. FEFER, R. STORB, P. E. NEIMAN, J. I. BRYANT, R. L. CHARD, R. A. CLIFT, R. B. EPSTEIN, P. J. FIALKOW, D. D. FUNK, E. R. GIBLETT, K. G. LERNER, F. A. REYNOLDS, S. SLICHTER
Journal: Blood (1971)
Species-Specific Differences in Toxicity of Antimitotic Agents Toward Cultured Mammalian Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R S Gupta
Journal: JNCI Journal of the National Cancer Institute (1985)

Toxicities of various microtubule inhibitors, namely, colchicine, podophyllotoxin, maytansine, vinblastine, nocodazole, griseofulvin, and steganacine, toward numerous independently established cell lines from three different species, namely, human, mouse, and Chinese hamster, were examined. Some of these inhibitors (namely, colchicine, vinblastine, taxol, and maytansine) were found to exhibit large (between tenfold and fiftyfold) differences in their toxic and antimitotic concentrations toward various cell lines and these differences appeared to be species related inasmuch as all cell lines from a particular species showed similar sensitivities toward these inhibitors. Of the three species examined, cells of human origin exhibited maximum sensitivity toward these inhibitors while Chinese hamster cells were found to be most resistant. The reduced cellular transport of [3H]colchicine and [3H]vinblastine in Chinese hamster cells as compared to the cellular transport in human cells and the equivalent binding of [3H]colchicine and [3H]vinblastine to microtubule proteins in cell extracts from both these lines provided strong evidence that the observed differences in toxicity to these inhibitors were most likely caused by differences in the cellular transport of these drugs. In contrast to the toxicities of the above compounds, the toxicities of other microtubule inhibitors such as podophyllotoxin, steganacine, griseofulvin, and nocodazole were found to be very similar for cells from all three species, indicating that the cellular transport of these 2 groups of microtubule inhibitors differed in some important respect. Some implications of the observed species-specific differences in drug toxicity to clinical studies are discussed.
Looking Beyond the Hospital to Reduce Acute Myocardial Infarction
Authors: Karen E. Joynt, Thomas M. Maddox
Journal: JAMA Cardiology (2016)

Erica S. Spatz, MD, MHS; Adam L. Beckman; Yun Wang, PhD; Nihar R. Desai, MD, MS; Harlan M. Krumholz, MD, SM